Table of Contents
Partial table of contents: Carbon Compounds and Chemical Bonds. Representative Carbon Compounds. An Introduction to Organic Reactions: Acids and Bases. Alkanes and Cycloalkanes: Conformations of Molecules. Stereochemistry: Chiral Molecules. Alkenes and Alkynes I: Properties and Synthesis. Alkenes and Alkynes II: Addition Reactions. Radical Reactions. Alcohols and Ethers. Conjugated Unsaturated Systems. Aromatic Compounds. Reactions of Aromatic Compounds. Aldehydes and Ketones I: Nucleophilic Additions to the Carbonyl Group. Aldehydes and Ketones II: Aldol Reactions. Carboxylic Acids and Their Derivatives: Nucleophilic Substitution at the Acyl Carbon. Amines. Carbohydrates. Lipids. Answers to Selected Problems. Glossary. Index.

Solomons/Advices

ADVICES FOR STUDYING ORGANIC CHEMISTRY
1. Keep up with your studying day to day –– never let yourself get behind, or better yet, be a little ahead of your instructor. Organic chemistry is a course in

which one idea almost always builds on another that has gone before. 2. Study materials in small units, and be sure that you understand each new section before you go on to the next. Because of the cumulative nature of organic

chemistry, your studying will be much more effective if you take each new idea as it comes and try to understand it completely before you move onto the nest concept. 3. Work all of the in-chapter and assigned problems. 4. Write when you study. over and over again. Write the reactions, mechanisms, structures, and so on,

You need to know the material so thoroughly that you can This level of understanding comes to most of us Only by writing the

explain it to someone else.

(those of us without photographic memories) through writing.

reaction mechanisms do we pay sufficient attention to their details: 1) which atoms are connected to which atoms. 2) which bonds break in a reaction and which bonds form. 3) the three-dimensional aspects of the structure. 5. Learning by teaching and explaining (教學相長). Study with your student peers

and practice explaining concepts and mechanisms to each other. 6. Use the answers to the problems in the Study Guide in the proper way: 1) Use the Study Guide to check your answer after you have finished a problem. 2) Use the Study Guide for a clue when you are completely stuck. The value of a problem is in solving it!

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7. Use the introductory material in the Study Guide entitled “Solving the puzzle –– or –– Structure is everything (Almost)” as a bridge from general chemistry to your beginning study of organic chemistry. Once you have a firm understanding of

structure, the puzzle of organic chemistry can become one of very manageable size and comprehensible pieces. 8. Use molecular models when you study.

ADVICES FROM STUDENTS TAKING ORGANIC CHEMISTRY COURSE CHEM 220A AT YALE UNIVERSITY
The students listed below from the 2000 fall term have agreed to serve as mentors for Chem 220a during the 2001 fall term. Chem 220a last year. They are a superb group of people who did exceptionally well in Some of

They know the material and how best to approach learning it.

them have provided their thoughts on attaining success in the course.

Partial List as of April 20, 2001 • Catherine Bradford My advice on Organic Chemistry: 1. Figure out what works for you and stick with it. 2. Tests: I think the key to doing well on the tests is as much about getting a lot of It's important to be sharp when you walk into a test, As far as studying

sleep as it is about studying.

so that you'll be able to think clearly about the tricky problems. goes, start studying for them a few nights early.
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My suggestion for a test on

Solomons/Advices

Friday is to go through the material on Monday, Tuesday, and Wednesday nights, then relax on Thursday night and review as needed. 3. Problem Sets: Don't save them for Sunday night. Work out the problem sets so

that YOU understand them.

Get people's help when needed, but the most important

thing is actually understanding how to get the right answer. 4. Don't look at Organic Chemistry as if it were a monster to be battled. about it as a challenge. Rather, think

When you come across a problem that looks long and You

complicated, just start writing down what you know and work from there. might not get it completely right, but at least you have something. • Claire Brickell

1. As far as I'm concerned, the only way to do well in orgo is to do your work all along. I wish there were a less obnoxious way to say it, but there it is. You probably already I like orgo.

think I'm a dork by now, so I'm going to go ahead and say this, too:

There is a really beautiful pattern to it, and once you get past the initial panic you'll realize that most of what you're learning is actually interesting. 2. The thing is, if you do your work regularly, you'll realize that there really isn't ALL that much of it, and that it really isn't as hard as you think. I can't really give you I hate I

advice on HOW to do your work, because everybody learns differently.

memorizing, and I am proud to say that I have never used a flash card in my life.

found the best way to learn the reactions was to do as many problems as possible. Once you've used your knowledge a couple of times, it sort of memorizes itself. 3. Last thing: there are a ton of people out there who know a lot about orgo, and a lot about explaining orgo to other people. really helpful, as are the tutors. • Caroline Drewes So I'm sure by now all of you have heard the “nightmares” that organic chemistry is universally associated with. But don't worry!! The rumored nights of endless Use them. The STARS help sessions are

memorization and the “impossible” tests that follow them are completely optional.
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By optional I mean that if you put the work in (some time before the night before a test) by reading the textbook before class, taking notes in Ziegler's (helpful) lectures, spending time working through the problem sets and going to your invaluable TA's at section, then you'll probably find orgo to be a challenging class but not unreasonably so. And don't let yourself be discouraged! Orgo can be frustrating at times (especially

at late hours) and you may find yourself swearing off the subject forever, but stick with it! Soon enough you'll be fluent in the whole “orgo language” and you'll be able to use the tools you have accumulated to solve virtually any problem –– not necessarily relying on memorization but rather step-by-step learning. I would swear by flashcards,

complete with mechanisms, because they're lighter to lug around than the textbook meaning you can keep them in your bag and review orgo when you get a free minute at the library or wherever. Going over the reactions a whole bunch of times well before

the test takes 5-10 minutes and will help to solidify the information in your head, saving you from any “day-before-anxiety”. One more hint would be to utilize the extensive

website –– you never know when one of those online ORGO problems will pop up on a test! So good luck and have fun!!

• Margo Fonder I came to the first orgo class of the year expecting the worst, having heard over and over that it would be impossible. chore had become my favorite. But by mid-semester, the class I'd expected to be a I think that the key to a positive experience is to stay And once you

on top of things –– with this class especially, it’s hard to play catch-up.

get the hang of it, solving problems can even be fun, because each one is like a little puzzle. True –– the problem sets are sometimes long and difficult, but it's worth it

to take the time to work through them because they really do get you to learn the stuff. Professor Ziegler makes a lot of resources available (especially the old exams, old

problem sets, and study aids he has on his website) that are really helpful while studying for exams. I also found copying over my (really messy) class notes to be a good way to

study, because I could make sure that I understood everything presented in class at my own pace. My number one piece of advice would probably be to use Professor Ziegler's
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office hours! him.

It helped me so much to go in there and work through my questions with

(Plus, there are often other students there asking really good questions, too.)

• Vivek Garg There's no doubt about it, organic chemistry deals with a LOT of material. you handle it and do well? How do

You've heard or will hear enough about going to every class,

reading the chapters on time, doing all of the practice problems, making flashcards, and every other possible study technique. Common sense tells you to do all of that anyway, So, my advice is a bit broader.

but let's face it, it's almost impossible to do all the time.

You've got to know the material AND be able to apply it to situations that aren't cookie-cutter from the textbook or lecture. all of the facts/theories. We'll assume that you can manage learning

That's not enough: the difference between getting the average

on an orgo test and doing better is applying all of those facts and theories at 9:30 Friday morning. When you study, don't just memorize reactions (A becomes B when you

add some acid, Y reacts with water to give Z), THINK about what those reactions let you do. Can you plot a path from A to Z now? Also, it's easy to panic in a test. You better, because you'll have to do it DON'T leave anything blank, even if

on the test.

it seems totally foreign to you. it.

Use the fundamentals you know, and take a stab at For me, doing the problem sets on my

Partial credit will make the difference.

own helped enormously.

Sure, it's faster to work with a group, but forcing yourself to The problem sets aren't

work problems out alone really solidifies your knowledge.

worth a lot, and it's more important to think about the concepts behind each question than to get them right. Also, the Wade textbook is the best science text I've ever had.

Tests are based on material beyond just lecture, so make the text your primary source for the basics. Lastly, you're almost certainly reading this in September, wondering what

we mean by writing out mechanisms and memorizing reactions...come back and re-read all of this advice after the first test or two, and it will make much more sense. luck! • Lauren Gold
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Good

Solomons/Advices

Everyone hears about elusive organic chemistry years before arriving at college, primarily as the bane of existence of premeds and science majors. The actual experience

however, as my classmates and I quickly learned, is not painful or impossible but rather challenging, rewarding, and at times, even fun. All that's required, moreover, is an open No one will deny

mind and a willingness to study the material until it makes sense.

that orgo is a LOT of work, but by coming to class, reading the chapters, starting problem sets early and most of all, working in study groups it all becomes pretty manageable. By forming a good base in the subject it becomes easier and more Moreover, the relationships you'll make with other orgo'ers

interesting as you go along.

walking up science hill at 9 am are definitely worth it. • Tomas Hooven When you take the exams, you'll have to be very comfortable WRITING answers to organic problems quickly. This may be self-evident, but I think many students spend a

lot of time LOOKING at their notes or the book while they study without writing anything. I don't think reading about chemical reactions is anywhere near as useful as I structured my study regime so that I wrote constantly. Then I made

drawing them out by hand.

First, I recopied my lecture notes to make them as clear as possible. flash cards to cover almost every detail of the lectures.

After memorizing these cards,

I made a chart of the reactions and mechanisms that had been covered and memorized it. Also, throughout this process I worked on relevant problems from the

book to reinforce the notes and reactions I was recopying and memorizing. • Michael Kornberg Most of the statements you've read so far on this page have probably started out by saying that Organic Chemistry really isn't that bad and can, in fact, be pretty interesting. I think it's important to understand from the start that this is completely true…I can almost assure you that you will enjoy Orgo much more than General Chemistry, and the work & endash; although there may be a lot of it & endash; is certainly not overwhelming. Just stay on top of it and you'll be fine. Always read the chapter before starting the
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Solomons/Advices

problem set, and make sure that you read it pretty carefully, doing some of the practice problems that are placed throughout the chapter to make sure that you really understand the material. Also, spend a lot of time on the problem sets & endash; this will really

help you to solidify your understanding and will pay off on the exams. As for the exams, everyone knows how they study best. Just be sure to leave

yourself enough time to study and always go over the previous years' exams that Dr. Ziegler posts on the website & endash; they're a really good indicator of what's going to be on your exam. • Kristin Lucy The most important concept to understand about organic chemistry is that it is a “do-able” subject. Orgo's impossible reputation is not deserved; however, it is a subject As far as tips go, read the chapters Set time aside to do the Make use of the That's all I have to say, so good luck.

that takes a lot of hard work along the way.

before the lectures; concepts will make a lot more sense.

problem sets; they do tend to take a while the first time around.

problems in the book (I did them while I read through the chapter) and the study guide and set aside several days prior to exams for review. weapon –– they have all the answers! continuing into 2nd semester. • Sean McBride Organic chemistry can, without a doubt, be an intimidating subject. You've heard Your TA can be a secret

Also, everything builds on everything else

Good luck and have fun with the chairs and boats!

the horror stories from the now ex-premeds about how orgo single handedly dashed their hopes of medical stardom (centering around some sort of ER based fantasy). fret! Orgo is manageable. Be confident in yourself. But do not With

You can handle this.

that said, the practical advise I can offer is twofold: 1. When studying for the tests, look over the old problem sets, do the problems from the back of the book, and utilize the website!! down the studying. Do not cram. Time management is crucial. Break

Orgo tests are on Fridays.

It helps if you

divide the material and study it over the course of the week.
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Solomons/Advices

2. Work in a group when doing the problem sets.

Try to work out the problems on I worked with the same

your own first, then meet together and go over the answers.

group of 4 guys for the entire year and it definitely expedited the problem set process. Not only that, but it also allows you to realize your mistakes and to help explain concepts to others; the best way to learn material is to attempt to teach it. It may

feel overwhelming at times and on occasion you may sit in lecture and realize you have no idea what is going on. • Timothy Mosca So you're about to undertake one of the greatest challenges of academia. young squire, welcome to Organic Chemistry. IMPOSSIBLE! Yes, That is completely and totally normal.

Let's dispel a myth first: IT'S NOT

I won't lie & it is a challenge and it's gonna take some heavy work, but Orgo should be taken a little at a

in the end, contrary to the naysayers, it's worth it. time and if you remember that, you're fine. small amounts of time.

Never try to do large amounts of Orgo in The single most important

Do it gradually, a little every day.

piece of advice I can give is to not fall behind. get behind in the material.

You are your own worst enemy if you

If you read BEFORE the lectures, they're going to make

a whole lot more sense and it'll save you time, come exams, so you're not struggling to learn things anew two days before the test, rather, you're reviewing them. you time and worry on the problem sets. It'll also save

Though they can be long and difficult, and you

may wonder where in Sam Hill some of the questions came from, they are a GREAT way to practice what you've learned and reinforce what you know. And (hint hint!), Also, use

the problem sets are fodder for exams; similar problems MAY appear!

your references: if there's something you don't get, don't let it fester, talk to the mentors, talk to your TA, visit Professor Ziegler and don't stop until you get it! attitude that a certain concept is needed for 1 exam. Never adopt the

See, Orgo has this dastardly way You'll save

of building on itself and stuff from early on reappears EVERYWHERE! yourself time if, every now and again, you review.

Make a big ol' list of reactions Guaranteed, it will help!

and mechanisms somewhere and keep going back to it.

And finally, don't get discouraged by minor setbacks & even Wade (the author of the text)
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Solomons/Advices

got a D on his second exam and so did this mentor!! Yes, really, it can be; I'm not just saying that.

Never forget & Orgo can be fun!

Like any good thing, it requires practice But by the end, it actually gets

in problems, reactions, thinking, and, oh yeah, problems. easy! So, BEST OF LUCK!!!!

• Raju Patel If you are reading these statements of advise, you already have the most valuable thing you'll need to do well in organic chemistry: a desire to succeed. I felt intimidated

by the mystique that seems to surround this course, about how painful and difficult it is, but realized it doesn't need to be so. If you put in the time, and I hesitate to say hard It's in the approach: think of

work because it can really be enjoyable, you will do well.

it as a puzzle that you need to solve and to do so you acquire the tools from examples you see in the book and the reasoning Prof. Ziegler provides in lecture. all resources to train yourself like your TA and the website. Take advantage of

Most importantly, do mad

amounts of practice problems (make the money you invested in the solutions manual and model kit worth it). When the time comes to take the test, you won't come up Once patterns start emerging for you and you realize

against anything you can't handle.

that all the information that you need is right there in the problem, that it is just a matter of finding it, it will start feeling like a game. • Sohil Patel Chemistry 220 is a very interesting and manageable course. The course load is So play hard.

certainly substantial but can be handled by keeping up with the readings and using the available online resources consistently through the semester. It always seemed most

helpful to have read the chapters covered in lecture before the lecture was given so that the lecture provided clarification and reinforcement of the material you have once read. Problem sets provided a valuable opportunity to practice and apply material you have learned in the readings and in lecture. In studying for tests, a certain degree of

memorization is definitely involved, but by studying mechanisms and understanding the chemistry behind the various reactions, a lot of unnecessary memorization is
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avoided.

Available problem sets and tests from the past two years were the most

important studying tools for preparing for tests because they ingrain the material in your head, but more importantly, they help you think about the chemistry in ways that are very useful when taking the midterms and final exam. And more than anything, organic

chemistry certainly has wide applications that keep the material very interesting. • Eric Schneider I didn't know what to expect when I walked into my first ORGO test last year. To

put it plainly, I didn't know how to prepare for an ORGO test –– my results showed. The first ORGO test was a wake-up call for me, but it doesn't need to be for you. My

advice about ORGO is to make goals for yourself and set a time-frame for studying. Lay out clear objectives for yourself and use all of the resources available (if you don't you're putting yourself at a disadvantage). and problem sets on the Internet. Professor Ziegler posts all of the old exams Reading the textbook is

They are extremely helpful.

only of finite help –– I found that actually doing the problems is as important or even more important than reading the book because it solidifies your understanding. That

having been said, don't expect ORGO to come easily –– it is almost like another language. It takes time to learn, so make sure that you give yourself enough time. While knowing the mechanisms is

But once you have the vocabulary, it's not that bad.

obviously important, you need to understand the concepts behind the mechanisms to be able to apply them to exam situation. Remember –– ORGO is like any other class in the It is manageable. Just one more

sense that the more you put in, the more you get out. tip –– go to class! • Stanley Sedore 1. Welcome to Organic Chemistry.

The first and most important thing for success in

this class is to forget everything you have ever heard about the “dreaded” orgo class. It is a different experience for everyone, and it is essential that you start the It is not like the chemistry you have had in

class with a positive and open mind.

the past and you need to give it a chance as its own class before you judge it and your
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own abilities. 2. Second, organic chemistry is about organization. You'll hear the teachers say it as There are

well as the texts: organic chemistry is NOT about memorization.

hundreds of reactions which have already been organized by different functional groups. If you learn the chemistry behind the reactions and when and why they

take place, you'll soon see yourself being able to apply these reactions without memorization. 3. Third, practice. This is something new, and like all things, it takes a lot of practice Do the problems as you read the chapters, do the

to become proficient at it.

problems at the end of the chapters, and if you still feel a bit uneasy, ask the professor for more. 4. Remember, many people have gone through what you are about to embark upon and done fine. You can and will do fine, and there are many people who are there to

help you along the way • Hsien-yeang Seow Organic Chemistry at Yale has an aura of being impossible and “the most difficult class at Yale”. It is certainly a challenging class but is in no way impossible. Do not

be intimidated by what others say about the class.

Make sure that you do the textbook The

readings well before the tests –– I even made my own notes on the chapters. textbook summarizes the mechanisms and reactions very well. the textbook. of the course. beginning.

Class helps to re-enforce

Moreover, the textbook problems are especially helpful at the beginning DO NOT fall behind...make sure you stay on top of things right at the Organic Chemistry keeps building on the material that you have I assure you, that if you keep up, the course will seem easier and I

already learned. easier.

I personally feel that the mechanisms and reactions are the crux of the course.

used a combination of flashcards and in-text problems to help memorize reactions. However, as the course went on, I quickly found that instead of memorizing, I was actually learning and understanding the mechanisms and from there it was much easier to grasp the concepts and apply them to any problem.
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There are lots of

Solomons/Advices

resources that are designed to HELP you...The TA's are amazing, the old problems sets and tests were very helpful for practicing before test, and the solutions manual is a good idea. Good luck.

• Scott Thompson The best way to do well in Organic Chemistry is to really try to understand the underlying concepts of how and why things react the way that they do. It is much

easier to remember a reaction or mechanism if you have a good understanding of why it is happening. Having a good grasp of the concepts becomes increasingly So, I recommend working hard to understand It will pay off in the exams, including

beneficial as the course progresses.

everything at the BEGINNING of the semester. those in the second semester.

If you understand the concepts well, you will be able to

predict how something reacts even if you have never seen it before. Organic Chemistry is just like any other course; the more time you spend studying, the better you will do. 1. Read the assigned chapters thoroughly and review the example problems. 2. Work hard on the problem sets, they will be very good preparation. 3. Do not skip lectures. Most importantly, begin your study of “Orgo” with an open mind. Once you get

past all the hype, you'll see that it's a cool class and you'll learn some really interesting stuff. Good Luck!

1. Keep up with your studying day to day. 2. Focus your study. 3. Keep good lecture notes. 4. Carefully read the topics covered in class. 5. Work the problems.

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C OMPOUNDS
1.1 INTRODUCTION

AND

C HEMICAL B ONDS

1. Organic chemistry is the study of the compounds of carbon. 2. The compounds of carbon are the central substances of which all living things on this planet are made. 1) DNA: 2) proteins: 3) enzymes: the giant molecules that contain all the genetic information for a given species. blood, muscle, and skin. catalyze the reactions that occur in our bodies.

4) furnish the energy that sustains life. 3. Billion years ago most of the carbon atoms on the earth existed as CH4: 1) CH4, H2O, NH3, H2 were the main components of the primordial atmosphere. 2) Electrical discharges and other forms of highly energetic radiation caused these simple compounds to fragment into highly reactive pieces which combine into more complex compounds such as amino acids, formaldehyde, hydrogen cyanide, purines, and pyrimidines. 3) Amino acids reacted with each other to form the first protein. 4) Formaldehyde reacted with each other to become sugars, and some of these sugars, together with inorganic phosphates, combined with purines and pyrimidines to become simple molecules of ribonucleic acids (RNAs) and DNA. 4. We live in an Age of Organic Chemistry: 1) clothing: natural or synthetic substance.

2) household items: 3) automobiles: 4) medicines: 5) pesticides: 5. Pollutions: 1) insecticides: 2) PCBs:
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natural or synthetic substance.

Solomons/SoloCh01

3) dioxins: 4) CFCs:

1.2

THE DEVELOPMENT OF ORGANIC CHEMISTRY AS A SCIENCE

1. The ancient Egyptians used indigo (藍靛) and alizarin (茜素) to dye cloth. 2. The Phoenicians (腓尼基人) used the famous “royal purple (深藍紫色)”, obtained from mollusks (墨魚、章魚、貝殼等軟體動物), as a dyestuff. 3. As a science, organic chemistry is less than 200 years old.

1.2A Vitalism
“Organic” ––– derived from living organism chemist) ⇒ ⇒ the study of compounds extracted from living organisms such compounds needed “vital force” to create them (In 1770, Torbern Bergman, Swedish

1. In 1828, Friedrich Wöhler Discovered:

NH4

+ −

OCN

heat

O H2N C NH2 Urea (organic)

Ammonium cyanate (inorganic)

1.2B Empirical and Molecular Formulas
1. In 1784 Antoine Lavoisier ( 法國化學家拉瓦錫 ) first showed that organic compounds were composed primarily of carbon, hydrogen, and oxygen. 2. Between 1811 and 1831, quantitative methods for determining the composition of

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organic compounds were developed by Justus Liebig (德國化學家), J. J. Berzelius, J. B. A. Dumas (法國化學家). 3. In 1860 Stanislao Cannizzaro (義大利化學家坎尼薩羅) showed that the earlier hypothesis of Amedeo Avogadro (1811, 義大利化學家及物理學家亞佛加厥) could be used to distinguish between empirical and molecular formulas. molecular formulas C2H4 (ethylene), C5H10 (cyclopentane), and C6H12

(cyclohexane) all have the same empirical formula CH2.

1.3

THE STRUCTURAL THEORY OF ORGANIC CHEMISTRY

1.3A. The Structural Theory: (1858 ~ 1861)
August Kekulé (German), Archibald Scott Couper (Briton), and Alexander M. Butlerov 1. The atoms can form a fixed number of bonds (valence):

H H C H Carbon atoms are tetravalent Oxygen atoms are divalent Hydrogen and halogen atoms are monovalent H H O H H Cl

2. A carbon atom can use one or more of its valence to form bonds to other atoms:
Carbon-carbon bonds

H H C H

H C H Double bond Triple bond H C C H C C H

Single bond 3. Organic chemistry:

A study of the compounds of carbon (Kekulé, 1861).
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1.3B. Isomers:
1. Isomers:

The Importance of Structural Formulas

different compounds that have the same molecular formula

2. There are two isomeric compounds with molecular formula C2H6O: 1) dimethyl ether: 2) ethyl alcohol: a gas at room temperature, does not react with sodium. a liquid at room temperature, does react with sodium.

Table 1.1 Properties of ethyl alcohol and dimethyl ether

Ethyl Alcohol C2H6O Boiling point, °Ca Melting point, °C Reaction with sodium a Dimethyl Ether C2H6O –24.9 –138 No reaction

78.5 –117.3 Displaces hydrogen

Unless otherwise stated all temperatures in this text are given in degree Celsius.

3. The two compounds differ in their connectivity: Ethyl alcohol H H C H H C H O H

C–O–C and C–C–O Dimethyl ether H H C H O H C H H

Figure 1.1 Ball-and-stick models and structural formulas for ethyl alcohol and dimethyl ether

1) O–H:

accounts for the fact that ethyl alcohol is a liquid at room temperature.

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H 2 H C H

H C H O H + 2 Na 2 H

H C H

H C H O− Na+ + H2

2 H 2) C–H:

O

H + 2 Na

2 H

O− Na+ +

H2

normally unreactive

4. Constitutional isomers:* different compounds that have the same molecular formula, but differ in their connectivity (the sequence in which their atoms are bounded together). *
An older term, structural isomers, is recommended by the International Union of Pure and Applied Chemistry (IUPAC) to be abandoned.

1.3C. THE TETRAHEDRAL SHAPE OF METHANE
1. In 1874, Jacobus H. van't Hoff (Netherlander) & Joseph A. Le Bel (French): The four bonds of the carbon atom in methane point toward the corners of a regular tetrahedron, the carbon atom being placed at its center.

Figure 1.2 The tetrahedral structure of methane. Bonding electrons in methane principally occupy the space within the wire mesh.

1.4

CHEMICAL BONDS:
Why do atoms bond together?

THE OCTET RULE more stable (has less energy)
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How to describe bonding? 1. G. N. Lewis (of the University of California, Berkeley; 1875~1946) and Walter Kössel (of the University of Munich; 1888~1956) proposed in 1916: 1) The ionic (or electrovalent) bond: formed by the transfer of one or more

electrons from one atom to another to create ions. 2) The covalent bond: results when atoms share electrons.

2. Atoms without the electronic configuration of a noble gas generally react to produce such a configuration.

1.4A Ionic Bonds
1. Electronegativity measures the ability of an atom to attract electrons.

Table 1.2 Electronegativities of Some of Elements H 2.1 Li 1.0 Na 0.9 K 0.8 Be 1.5 Mg 1.2 B 2.0 Al 1.5 C 2.5 Si 1.8 N 3.0 P 2.1 O 3.5 S 2.5 F 4.0 Cl 3.0 Br 2.8

1) The electronegativity increases across a horizontal row of the periodic table from left to right: 2) The electronegativity decreases go down a vertical column:
F Cl Br I
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Li Be B C N O F Increasing electronegativity

Decreasing electronegativity

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3) 1916, Walter Kössel (of the University of Munich; 1888~1956)

Li

+

F

Li+

+

F−

•• Li + F •• electron transfer

Li+ He configuration

•• − F •• Ne configuration

Li+ F− •• ionic bond

4) Ionic substances, because of their strong internal electrostatic forces, are usually very high melting solids, often having melting points above 1,000 °C. 5) In polar solvents, such as water, the ions are solvated, and such solutions usually conduct an electric current..

1.4B Covalent Bonds
1. Atoms achieve noble gas configurations by sharing electrons. 1) Lewis structures:

••

•• ••

H2

H

+ H

H

H

or

H

H

each H shares two electrons (He configuration) or Cl Cl

Cl2

Cl +

Cl

Cl Cl

H H C H H
H H C N

H or H C H
H H C •• H C•• O H H
⇒

H

N

N

or N2

N

N

methane

lone pair H

lone pair H

H C H chloromethane Cl •• lone pair ••

H H methyl amime

H

ethanol

nonbonding electrons

affect the reactivity of the compound

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C carbon (4)

•• N nitrogen (3)

•• O •• oxygen (2)

H hydrogen

•• Cl •• halogens (1)

H C H or H C H C C

H H H H

H C H or H C H formaldehyde O O

H C H or H C H N H N H double bond

ethylene

formaldimine

1.5

WRITING LEWIS STRUCTURES

1.5A. Lewis structure of CH3F
1. The number of valence electrons of an atom is equal to the group number of the atom. 2. For an ion, add or subtract electrons to give it the proper charge. 3. Use multiple bonds to give atoms the noble gas configuration.

1.5B. Lewis structure of ClO3– and CO32–
O O Cl O O
−

O C O

2−

1.6

EXCEPTIONS TO THE OCTET RULE

1.6A. PCl5

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1.6B. SF6 1.6C. BF3 1.6D. HNO3 (HONO2)
Cl Cl Cl P Cl Cl F F F F S F F F F B F H O O
+

N O
−

1.7

FORMAL CHARGE

1.7A In normal covalent bond:
1. Bonding electrons are shared by both atoms. electron. 2. “Formal charge” is calculated by subtracting the number of valence electrons assigned to an atom in its bonded state from the number of valence electrons it has as a neutral free atom. Each atom still “owns” one

1.7B For methane:
1. Carbon atom has four valence electrons. 2. Carbon atom in methane still owns four electrons. 3. Carbon atom in methane is electrically neutral.

1.7C For ammonia:
1. Atomic nitrogen has five valence electrons. 2. Ammonia nitrogen still owns five electrons. 3. Nitrogen atom in ammonia is electrically neutral.

1.7D For nitromethane:
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Solomons/SoloCh01

1. Nitrogen atom: 1) Atomic nitrogen has five valence electrons. 2) Nitromethane nitrogen has only four electrons. 3) Nitrogen has lost an electron and must have a positive charge. 2. Singly bound oxygen atom: 1) Atomic oxygen has six valence electrons. 2) Singly bound oxygen has seven electrons. 3) Singly bound oxygen has gained an e– and must have a negative charge.

1.7E Summary of Formal Charges
See Table 1.3

1.8

RESONANCE

1.8A. General rules for drawing “realistic” resonance structures:
1. Must be valid Lewis structures. 2. Nuclei cannot be moved and bond angles must remain the same. may be shifted. 3. The number of unpaired electrons must remain the same. remain paired in all the resonance structures. 4. Good contributor has all octets satisfied, as many bonds as possible, as little charge separation as possible. Negative charge on the more EN atoms. All the electrons must Only electrons

5. Resonance stabilization is most important when it serves to delocalize a charge over two or more atoms. 6. Equilibrium: 7. Resonance:

1.8B. CO32–
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Solomons/SoloCh01

O C
−

O O−
−

−

O C O O 3

−

O 1

O

C 2
O
−

O

−

O
•• ••

O O becomes C O 3 O
−

−

C
−

O 1

O−
••

becomes

C
−

O 2

O−
−

O2/3−
2/3−

•• ••

O C
−

O C O O 3

C O

O2/3−

O 1

O−

C
−

O 2

O−

Figure 1.3 A calculated electrostatic potential map for carbonate dianion, showing the equal charge distribution at the three oxygen atoms. In electrostatic potential maps like this one, colors trending toward red mean increasing concentration of negative charge, while those trending toward blue mean less negative (or more positive) charge.

1.9

QUANTUM MECHANICS

1.9A Erwin Schrödinger, Werner Heisenberg, and Paul Dirac (1926)
1. Wave mechanics (Schrödinger) or quantum mechanics (Heisenberg) 1) Wave equation ⇒ wave function (solution of wave equation, denoted by Greek
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Solomons/SoloCh01

letter psi (Ψ) 2) Each wave function corresponds to a different state for the electron. 3) Corresponds to each state, and calculable from the wave equation for the state, is a particular energy. 4) The value of a wave function: phase sign

5) Reinforce: a crest meets a crest (waves of the same phase sign meet each other)
⇒ add together ⇒ resulting wave is larger than either individual wave.

6) Interfere: a crest meets a trough (waves of opposite phase sign meet each other)
⇒ subtract each other ⇒ resulting wave is smaller than either individual wave.

7) Node: the value of wave function is zero ⇒ the greater the number of nodes, the greater the energy.

Figure 1.4 A wave moving across a lake is viewed along a slice through the lake. For this wave the wave function, Ψ, is plus (+) in crests and minus (–) in troughs. At the average level of the lake it is zero; these places are called nodes.

1.10 ATOMIC ORBITALS
1.10A. ELECTRON PROBABILITY DENSITY:
1. Ψ2 for a particular location (x,y,z) expresses the probability of finding an electron at that particular location in space (Max Born). 1) Ψ2 is large: large electron probability density.
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Solomons/SoloCh01

2) Plots of Ψ2 in three dimensions generate the shapes of the familiar s, p, and d atomic orbitals. 3) An orbital is a region of space where the probability of finding an electron is large (the volumes would contain the electron 90-95% of the time).

Figure 1.5 The shapes of some s and p orbitals. Pure, unhybridized p orbitals are almost-touching spheres. The p orbitals in hybridized atoms are lobe-shaped (Section 1.14).

1.10B. Electron configuration:
1. The aufbau principle (German for “building up”): 2. The Pauli exclusion principle: 3. Hund’s rule: 1) Orbitals of equal energy are said to degenerate orbitals.

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Solomons/SoloCh01

2p 2s 1s Boron 2s 1s Carbon

2p 2s 1s Nitrogen

2p

2p 2s 1s Oxygen
Figure 1.6

2p 2s 1s Fluorine 2s 1s Neon

2p

The electron configurations of some second-row elements.

1.11 MOLECULAR ORBITALS
1.11A. Potential energy:

Figure 1.7 The potential energy of the hydrogen molecule as a function of internuclear distance.
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Solomons/SoloCh01

1. Region I: 2. Region II:

the atoms are far apart ⇒ No attraction each nucleus increasingly attracts the other’s electron ⇒ the

attraction more than compensates for the repulsive force between the two nuclei (or the two electrons) ⇒ the attraction lowers the energy of the total system 3. Region III: the two nuclei are 0.74 Å apart ⇒ bond length ⇒ the most stable
(lowest energy) state is obtained

4. Region IV: the repulsion of the two nuclei predominates ⇒ the energy of the system rises

1.11B. Heisenberg Uncertainty Principle
1. We can not know simultaneously the position and momentum of an electron. 2. We describe the electron in terms of probabilities (Ψ2) of finding it at particular place. 1) electron probability density ⇒ atomic orbitals (AOs)

1.11C. Molecular Orbitals
1. AOs combine (overlap) to become molecular orbitals (MOs). 1) The MOs that are formed encompass both nuclei, and, in them, the electrons can move about both nuclei. 2) The MOs may contain a maximum of two spin-paired electrons.
3) The number of MOs that result always equals the number of AOs that combine. 2. Bonding molecular orbital (Ψmolec): 1) AOs of the same phase sign overlap ⇒ leads to reinforcement of the wave function ⇒ the value of is larger between the two nuclei ⇒ contains both electrons in the lowest energy state, ground state

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Solomons/SoloCh01

Figure 1.8 The overlapping of two hydrogen 1s atomic orbitals with the same phase sign (indicated by their identical color) to form a bonding molecular orbital.
* 3. Antibonding molecular orbital (ψ molec ):

1) AOs of opposite phase sign overlap ⇒ leads to interference of the wave function in the region between the two nuclei ⇒ a node is produced ⇒ the value of is smaller between the two nuclei ⇒ the highest energy state, excited state ⇒ contains no electrons

Figure 1.9 The overlapping of two hydrogen 1s atomic orbitals with opposite phase signs (indicated by their different colors) to form an antibonding molecular orbital.

4. LCAO (linear combination of atomic orbitals): 5. MO: 1) Relative energy of an electron in the bonding MO of the hydrogen molecule is substantially less than its energy in a Ψ1s AO. 2) Relative energy of an electron in the antibonding MO of the hydrogen molecule is substantially greater than its energy in a Ψ1s AO.

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1.11D. Energy Diagram for the Hydrogen Molecule

Figure 1.10 Energy diagram for the hydrogen molecule. Combination of two atomic orbitals, Ψ1s, gives two molecular orbitals, Ψmolec and Ψ*molec. The energy of Ψmolec is lower than that of the separate atomic orbitals, and in the lowest electronic state of molecular hydrogen it contains both electrons.

1.12 THE STRUCTURE OF METHANE AND ETHANE: sp3 HYBRIDZATION
1. Orbital hybridization: A mathematical approach that involves the combining

of individual wave functions for s and p orbitals to obtain wave functions for new orbitals ⇒ hybrid atomic orbitals

Ground state 2p 2s 1s 2p 2s 1s Promotion of electron

Excited state

sp2-Hybridized state 4sp3

1s Hybridization

1.12A. The Structure of Methane
1. Hybridization of AOs of a carbon atom:
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Solomons/SoloCh01

Figure 1.11 Hybridization of pure atomic orbitals of a carbon atom to produce sp3 hybrid orbitals.

2. The four sp3 orbitals should be oriented at angles of 109.5° with respect to each other ⇒ an sp3-hybridized carbon gives a tetrahedral structure for methane.

Figure 1.12 The hypothetical formation of methane from an sp3-hybridized carbon atom. In orbital hybridization we combine orbitals, not electrons. The electrons can then be placed in the hybrid orbitals as necessary for bond formation, but always in accordance with the Pauli principle of no more than two electrons (with opposite spin) in each orbital. In this illustration we have placed one electron
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Solomons/SoloCh01

in each of the hybrid carbon orbitals. In addition, we have shown only the bonding molecular orbital of each C–H bond because these are the orbitals that contain the electrons in the lowest energy state of the molecule.

3. Overlap of hybridized orbitals: 1) The positive lobe of the sp3 orbital is large and is extended quite far into space.

Figure 1.13

The shape of an sp3 orbital.

Figure 1.14

Formation of a C–H bond.

2) Overlap integral: a measure of the extent of overlap of orbitals on neighboring atoms. 3) The greater the overlap achieved (the larger integral), the stronger the bond formed. 4) The relative overlapping powers of atomic orbitals have been calculated as follows: s: 1.00; p: 1.72; sp: 1.93; sp2: 1.99; sp3: 2.00

4. Sigma (σ) bond: 1) A bond that is circularly symmetrical in cross section when viewed along the bond axis.

2) All purely single bonds are sigma bonds.

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Solomons/SoloCh01

Figure 1.15

A σ (sigma) bond.

Figure 1.16 (a) In this structure of methane, based on quantum mechanical calculations, the inner solid surface represents a region of high electron density. High electron density is found in each bonding region. The outer mesh surface represents approximately the furthest extent of overall electron density for the molecule. (b) This ball-and-stick model of methane is like the kind you might build with a molecular model kit. (c) This structure is how you would draw methane. Ordinary lines are used to show the two bonds that are in the plane of the paper, a solid wedge is used to show the bond that is in front of the paper, and a dashed wedge is used to show the bond that is behind the plane of the paper.

1.12B. The Structure of Ethane

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Solomons/SoloCh01

Figure 1.17 The hypothetical formation of the bonding molecular orbitals of ethane from two sp3-hybridized carbon atoms and six hydrogen atoms. All of the bonds are sigma bonds. (Antibonding sigma molecular orbitals –– are called σ* orbitals –– are formed in each instance as well, but for simplicity these are not shown.)

1. Free rotation about C–C: 1) A sigma bond has cylindrical symmetry along the bond axis ⇒ rotation of groups joined by a single bond does not usually require a large amount of energy ⇒ free rotation.

Figure 1.18 (a) In this structure of ethane, based on quantum mechanical calculations, the inner solid surface represents a region of high electron density. High electron density is found in each bonding region. The outer mesh surface represents approximately the furthest extent of overall electron density for the
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Solomons/SoloCh01

molecule. (b) A ball-and-stick model of ethane, like the kind you might build with a molecular model kit. (c) A structural formula for ethane as you would draw it using lines, wedges, and dashed wedges to show in three dimensions its tetrahedral geometry at each carbon.

2. Electron density surface: 1) An electron density surface shows points in space that happen to have the same electron density. 2) A “high” electron density surface (also called a “bond” electron density surface) shows the core of electron density around each atomic nucleus and regions where neighboring atoms share electrons (covalent bonding regions). 3) A “low” electron density surface roughly shows the outline of a molecule’s electron cloud. This surface gives information about molecular shape and

volume, and usually looks the same as a van der Waals or space-filling model of the molecule.

Dimethyl ether

1.13 THE STRUCTURE OF ETHENE (ETHYLENE): sp2 HYBRIDZATION

Figure 1.19 The structure and bond angles of ethene. The plane of the atoms is perpendicular to the paper. The dashed edge bonds project behind the plane of the paper, and the solid wedge bonds project in front of the paper.
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Solomons/SoloCh01

Figure 1.20

A process for obtaining sp2-hybridized carbon atoms.

1. One 2p orbital is left unhybridized. 2. The three sp2 orbitals that result from hybridization are directed toward the corners of a regular triangle.

Figure 1.21

An sp2-hybridized carbon atom.

Figure 1.22

A model for the bonding molecular orbitals of ethane formed from
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Solomons/SoloCh01

two sp2-hybridized carbon atoms and four hydrogen atoms.

3. The σ-bond framework: 4. Pi (π) bond: 1) The parallel p orbitals overlap above and below the plane of the σ framework. 2) The sideway overlap of p orbitals results in the formation of a π bond. 3) A π bond has a nodal plane passing through the two bonded nuclei and between the π molecular orbital lobes.

Figure 1.23 (a) A wedge-dashed wedge formula for the sigma bonds in ethane and a schematic depiction of the overlapping of adjacent p orbitals that form the π bond. (b) A calculated structure for enthene. The blue and red colors indicate opposite phase signs in each lobe of the π molecular orbital. A ball-and-stick model for the σ bonds in ethane can be seen through the mesh that indicates the π bond.

4. Bonding and antibonding π molecular orbitals:

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Solomons/SoloCh01

Figure 1.24 How two isolated carbon p orbitals combine to form two π (pi) molecular orbitals. The bonding MO is of lower energy. The higher energy antibonding MO contains an additional node. (Both orbitals have a node in the plane containing the C and H atoms.)

1) The bonding π orbital is the lower energy orbital and contains both π electrons (with opposite spins) in the ground state of the molecule. 2) The antibonding π∗ orbital is of higher energy, and it is not occupied by electrons when the molecule is in the ground state. π* MO Antibonding Energy σ* MO π MO Bonding σ MO

1.13A. Restricted Rotation and the Double Bond
1. There is a large energy barrier to rotation associated with groups joined by a double bond.

1) Maximum overlap between the p orbitals of a π bond occurs when the axes of the
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Solomons/SoloCh01

p orbitals are exactly parallel ⇒ Rotation one carbon of the double bond 90° breaks the π bond. 2) The strength of the π bond is 264 KJ mol–1 (63.1 Kcal mol–1)⇒ the rotation barrier of double bond. 3) The rotation barrier of a C–C single bond is 13-26 KJ mol–1 (3.1-6.2 Kcal mol–1).

Figure 1.25 A stylized depiction of how rotation of a carbon atom of a double bond through an angle of 90° results in breaking of the π bond.

1.13B. Cis-Trans Isomerism
Cl H Cl H

Cl

H

H

Cl

cis-1,2-Dichloroethene

trans-1,2-Dichloroethene

1. Stereoisomers

1) cis-1,2-Dichloroethene and trans-1,2-dichloroethene are non-superposable ⇒ Different compounds ⇒ not constitutional isomers 2) Latin: cis, on the same side; trans, across. 3) Stereoisomers ⇒ differ only in the arrangement of their atoms in space.
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Solomons/SoloCh01

4) If one carbon atom of the double bond bears two identical groups ⇒ cis-trans isomerism is not possible.

Cl Cl

H H

Cl Cl

Cl H

1,1-Dichloroethene (no cis-trans isomerism)

1,1,2-Trichloroethene (no cis-trans isomerism)

1.14 THE STRUCTURE OF ETHYNE (ACETYLENE): sp HYBRIDZATION
1. Alkynes H C C H Ethyne (acetylene) (C2H2) H3C C C Propyne (C2H2) H H C C H 180o 180o

2. sp Hybridization:

Figure 1.26

A process for obtaining sp-hybridized carbon atoms.
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Solomons/SoloCh01

3. The sp hybrid orbitals have their large positive lobes oriented at an angle of 180° with respect to each other.

Figure 1.27

An sp-hybridized carbon atom.

4. The carbon-carbon triple bond consists of two π bonds and one σ bond.

Figure 1.28 Formation of the bonding molecular orbitals of ethyne from two sp-hybridized carbon atoms and two hydrogen atoms. (Antibonding orbitals are formed as well but these have been omitted for simplicity.)
5. Circular symmetry exists along the length of a triple bond (Fig. 1.29b) ⇒ no

restriction of rotation for groups joined by a triple bond.

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Solomons/SoloCh01

Figure 1.29 (a) The structure of ethyne (acetylene) showing the sigma bond framework and a schematic depiction of the two pairs of p orbitals that overlap to form the two π bonds in ethyne. (b) A structure of ethyne showing calculated π molecular orbitals. Two pairs of π molecular orbital lobes are present, one pair for each π bond. The red and blue lobes in each π bond represent opposite phase signs. The hydrogenatoms of ethyne (white spheres) can be seen at each end of the structure (the carbon atoms are hidden by the molecular orbitals). (c) The mesh surface in this structure represents approximately the furthest extent of overall electron density in ethyne. Note that the overall electron density (but not the π bonding electrons) extends over both hydrogen atoms.

1.14A. Bond lengths of Ethyne, Ethene, and Ethane
1. The shortest C–H bonds are associated with those carbon orbitals with the

greatest s character.

Figure 1.30

Bond angles and bond lengths of ethyne, ethene, and ethane.

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1.15 A SUMMARY OF IMPORTANT CONCEPTS THAT COME FROM QUANTUM MECHANICS
1.15A. Atomic orbital (AO):
1. AO corresponds to a region of space with high probability of finding an electron. 2. Shape of orbitals:

s, p , d

3. Orbitals can hold a maximum of two electrons when their spins are paired. 4. Orbitals are described by a wave function, ψ. 5. Phase sign of an orbital: “+”, “–”

1.15B. Molecular orbital (MO):
1. MO corresponds to a region of space encompassing two (or more) nuclei where electrons are to be found. 1) Bonding molecular orbital: ψ

2) Antibonding molecular orbital:

ψ*

3) Node: 4) Energy of electrons:
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Solomons/SoloCh01

5) Number of molecular orbitals: 6) Sigma bond (σ): 7) Pi bond (π):

1.15C. Hybrid atomic orbitals:
1. sp3 orbitals ⇒ tetrahedral 2. sp2 orbitals ⇒ trigonal planar 3. sp orbitals ⇒ linear

1.16 MOLECULAR GEOMETRY: THE VALENCE SHELL ELECTRON-PAIR REPULSION (VSEPR) MODEL
1. Consider all valence electron pairs of the “central” atom ––– bonding pairs, nonbonding pairs (lone pairs, unshared pairs) 2. Electron pairs repel each other ⇒ The electron pairs of the valence tend to stay as far apart as possible.
1) The geometry of the molecule ––– considering “all” of the electron pairs. 2) The shape of the molecule ––– referring to the “positions” of the “nuclei (or

atoms)”.

1.16A Methane

Figure 1.31 A tetrahedral shape for methane allows the maximum separation of the four bonding electron pairs.
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Solomons/SoloCh01

Figure 1.32

The bond angles of methane are 109.5°.

1.16B Ammonia

Figure 1.33 The tetrahedral arrangement of the electron pairs of an ammonia molecule that results when the nonbonding electron pair is considered to occupy one corner. This arrangement of electron pairs explains the trigonal pyramidal shape of the NH3 molecule.

1.16C Water

Figure 1.34 An approximately tetrahedral arrangement of the electron pairs for a molecule of water that results when the pair of nonbonding electrons are considered to occupy corners. This arrangement accounts for the angular shape of the H2O molecule.
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1.16D Boron Trifluoride

Figure 1.35 The triangular (trigonal planar) shape of boron trifluoride maximally separates the three bonding pairs.

1.16E Beryllium Hydride
180o H Be H

H Be H

Linear geometry of BeH2

1.16F Carbon Dioxide
O C O O C O 180o
The four electrons of each double bond act as a single unit and are maximally separated from each other.

Table 1.4

Shapes of Molecules and Ions from VSEPR Theory
Hybridization Shape of Molecule State of Central Examples or Iona Atom

Number of Electron Pairs at Central Atom Bonding Nonbonding Total

2 3 4 3 2 a 0 0 0 1 2

2 3 4 4 4

sp sp2 sp3 ~sp3 ~sp3

Linear BeH2 Trigonal planar BF3, CH3+ Tetrahedral CH4, NH4+ Trigonal pyramidal NH3, CH3– Angular H2O

Referring to positions of atoms and excluding nonbonding pairs.

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1.17 REPRESENTATION OF STRUCTURAL FORMULAS

H H C H Ball-and-stick model CH3CH2CH2OH
Condensed formula Figure 1.36

H C H

H C H O H

Dash formula
OH Bond-line formula

Structural formulas for propyl alcohol. H H H C O C H H H Dot structure H = H C H O H C H Condensed formula H = CH3OCH3

Dash formula

1.17A Dash Structural Formulas
1. Atoms joined by single bonds can rotate relatively freely with respect to one another. H H C H H C H HH C O H H or H H C H HO C C H H or H H C H HH H C C H H O H

Equivalent dash formulas for propyl alcohol ⇒ same connectivity of the atoms 2. Constitutional isomers have different connectivity and, therefore, must have different structural formulas.

3. Isopropyl alcohol is a constitutional isomer of propyl alcohol.

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H H H C O C H C H or H

H C H

H C O

H C H H or H

H C

O C

H H

H C H H H H H H H Equivalent dash formulas for isopropyl alcohol ⇒ same connectivity of the atoms 4. Do not make the error of writing several equivalent formulas.

1.17B Condensed Structural Formulas
H H C H H C H C H C H H CH3CHCH2CH3 or Cl Condensed formulas CH3CHCH3 H OH CH3CHOHCH 3 or (CH3)2CHOH CH3CH(OH)CH 3 CH3CHClCH2CH3

Cl H

Dash formulas H H C H H C O H Dash formulas H C H

Condensed formulas

1.17C Cyclic Molecules
H H C H C C H H H or CH2 H 2C CH2 Formulas for cyclopropane

1.17D Bond-Line Formulas (shorthand structure)
1. Rules for shorthand structure: 1) Carbon atoms are not usually shown ⇒ intersections, end of each line
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Solomons/SoloCh01

2) Hydrogen atoms bonded to C are not shown. 3) All atoms other than C and H are indicated.
H3C CH3CHClCH2CH3 = H3C CH3CH(CH3)CH2CH3 = H3C (CH3)2NCH2CH3 = CH2

CH Cl CH

CH3

= Cl

CH2

CH3

=

CH3 N CH2 CH3 = N

CH3 Bond-line formulas
CH2 H 2C CH2 H 2C H 2C CH2 CH2

=

and

=

H3C

CH CH CH3

CH2

CH3 =

CH2=CHCH2OH =

OH

Table 1.5
Compound

Kekulé and shorthand structures for several compounds
Kekulé structure
H H H H

Shorthand structure

Butane, C4H10

H C C C C H H H H H C

C

C

C

Chloroethylene (vinyl chloride), C2H3Cl

H C C H

H Cl C C

Cl Cl

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H

2-Methyl-1,3-butadiene (isoprene), C5H8

H H C H H C C C C H H H

Cyclohexane, C6H12

H H H C H C C H H H C C H H H H H C

Vitamin A, C20H30O

H HH H H H H C H H H C H H C H C H H H H C C C C C C H C C C C C C O H H H H H H C C H C C H H H H H

OH

1.17E Three-Dimensional Formulas
H H H Br C C H H

H C H H H or H H

H C H Br

H C H H or H H

H C

Methane
H C H

Bromomethane
H C Br I or

H Ethane H

or H C Br H Br Cl Cl Bromo-chloromethane

I C Br Cl Cl Bromo-chloro-iodomethane

Figure 1.37 formulas.

Three-dimensional

formulas

using

wedge-dashed

wedge-line

~ 37 ~

REPRESENTATIVE CARBON COMPOUNDS: FUNCTIONAL GROUPS, INTERMOLECULAR FORCES, AND INFRARED (IR) SPECTROSCOPY
Structure Is Everything
1. The three-dimensional structure of an organic molecule and the functional groups it contains determine its biological function. 2. Crixivan, a drug produced by Merck and Co. (the world’s premier drug firm, $1 billion annual research spending), is widely used in the fight against AIDS (acquired immune deficiency syndrome).

N N H

H

OH H

C 6H 5 H N O H HO H

N O H Crixivan (an HIV protease inhibitor)

1) Crixivan inhibits an enzyme called HIV (human immunodeficiency virus) protease. 2) Using computers and a process of rational chemical design, chemists arrived at a basic structure that they used as a starting point (lead compound). 3) Many compounds based on this lead are synthesized then until a compound had optimal potency as a drug has been found. 4) Crixivan interacts in a highly specific way with the three-dimensional structure of HIV protease. 5) A critical requirement for this interaction is the hydroxyl (OH) group near the center of Crixivan. This hydroxyl group of Crixivan mimics the true chemical intermediate that forms when HIV protease performs its task in the AIDS virus. 6) By having a higher affinity for the enzyme than its natural reactant, Crixivan ties
~1~

up HIV protease by binding to it (suicide inhibitor). 7) Merck chemists modified the structures to increase their water solubility by introducing a side chain.

2.1

CARBON–CARBON COVALENT BONDS

1. Carbon forms strong covalent bonds to other carbons, hydrogen, oxygen, sulfur, and nitrogen. 1) Provides the necessary versatility of structure that makes possible the vast number of different molecules required for complex living organisms. 2. Functional groups:

2.2

HYDROCARBONS: REPRESENTATIVE ALKANES, ALKENES, ALKYNES, AND AROMATIC COMPOUNDS compounds contain the maximum number of H

1. Saturated compounds: atoms. 2. Unsaturated compounds:

2.2A ALKANES
1. The principal sources of alkanes are natural gas and petroleum. 2. Methane is a major component in the atmospheres of Jupiter (木星), Saturn (土
星), Uranus (天王星), and Neptune (海王星).

3. Methanogens, may be the Earth’s oldest organisms, produce methane from carbon dioxide and hydrogen. cow’s stomachs. They can survive only in an anaerobic (i.e., oxygen-free) environment and have been found in ocean trenches, in mud, in sewage, and in

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2.2B ALKENES
1. Ethene (ethylene): US produces 30 billion pounds (~1,364 萬噸) each year.

1) Ethene is produced naturally by fruits such as tomatoes and bananas as a plant hormone for the ripening process of these fruits. 2) Ethene is used as a starting material for the synthesis of many industrial compounds, including ethanol, ethylene oxide, ethanal (acetaldehyde), and polyethylene (PE). 2. Propene (propylene): US produces 15 billion pounds (~682 萬噸) each year.

1) Propene is used as a starting material for the synthesis of acetone, cumene (isopropylbenzene), and polypropylene (PP). 3. Naturally occurring alkenes:

¡Ý

β-Pinene (a component of turpentine)

An aphid (蚜蟲) alarm pheromone

2.2C ALKYNES
1. Ethyne (acetylene): 1) Ethyne was synthesized in 1862 by Friedrich Wöhler via the reaction of calcium carbide and water. 2) Ethyne was burned in carbide lamp (miners’ headlamp). 3) Ethyne is used in welding torches because it burns at a high temperature. 2. Naturally occurring alkynes: 1) Capilin, an antifungal agent. 2) Dactylyne, a marine natural product that is an inhibitor of pentobarbital metabolism.
~3~

Br
O

Cl

O Br
Capilin Dactylyne

3. Synthetic alkynes: 1) Ethinyl estradiol, its estrogenlike properties have found use in oral contraceptives.
OH CH3 H H HO
Ethinyl estradiol (17α-ethynyl-1,3,5(10)-estratriene-3,17β-diol)

H

2.2D BENZENE: A REPRESENTATIVE AROMATIC HYDROCARBON
1. Benzene can be written as a six-membered ring with alternating single and double bonds (Kekulé structure).
H H H or H H H

Kekulé structure

Bond-line representation

2. The C−C bonds of benzene are all the same length (1.39 Å). 3. Resonance (valence bond, VB) theory:

~4~

Two contributing Kekulé structures

A representation of the resonance hybrid

1) The bonds are not alternating single and double bonds, they are a resonance hybrid ⇒ all of the C−C bonds are the same. 4. Molecular orbital (MO) theory: 1) Delocalization:

H H H

H H H

2.3

POLAR COVALENT BONDS

1. Electronegativity (EN) is the ability of an element to attract electrons that it is sharing in a covalent bond. 1) When two atoms of different EN forms a covalent bond, the electrons are not shared equally between them. 2) The chlorine atom pulls the bonding electrons closer to it and becomes somewhat electron rich ⇒ bears a partial negative charge (δ–). 3) The hydrogen atom becomes somewhat electron deficient ⇒ bears a partial positive charge (δ+).

δ+ δ− H Cl 2. Dipole:

+
A dipole

−

Dipole moment = charge (in esu) x distance (in cm)

µ = e x d (debye, 1 x 10–18 esu cm)
~5~

1) The charges are typically on the order of 10–10 esu; the distance 10–8 cm.
Figure 2.1 a) A ball-and-stick model for hydrogen chloride. B) A calculated electrostatic potential map for hydrogen chloride showing regions of relatively more negative charge in red and more positive charge in blue. Negative charge is clearly localized near the chlorine, resulting in a strong dipole moment for the molecule.

2) The direction of polarity of a polar bond is symbolized by a vector quantity: (negative end) ⇒ H
Cl

(positive end)

3) The length of the arrow can be used to indicate the magnitude of the dipole moment.

2.4

POLAR AND NONPOLAR MOLECULES

1. The polarity (dipole moment) of a molecule is the vector sum of the dipole moment of each individual polar bond.

Table 2.1 Dipole Moments of Some Simple Molecules
Formula

µ (D)
0 0 1.91 1.08 0.80 0.42 0 0
~6~

Formula

µ (D)
0 1.87 1.55 1.02 0 1.47 0.24 1.85

H2 Cl2 HF HCl HBr HI BF3 CO2

CH4 CH3Cl CH2Cl2 CHCl3 CCl4 NH3 NF3 H2O

Figure 2.2

Charge distribution in carbon tetrachloride.

Figure 2.3 A tetrahedral orientation of equal bond moments causes their effects to cancel.

Figure 2.4 The dipole moment of chloromethane arises mainly from the highly polar carbon-chlorine bond.

2. Unshared pairs (lone pairs) of electrons make large contributions to the dipole moment. (The O–H and N–H moments are also appreciable.)

Figure 2.5

Bond moments and the resulting dipole moments of water and ammonia.
~7~

2.4A DIPOLE MOMENTS IN ALKENES
1. Cis-trans alkenes have different physical properties: m.p., b.p., solubility, and etc. 1) Cis-isomer usually has larger dipole moment and hence higher boiling point.

Table 2.2
Compound

Physical Properties of Some Cis-Trans Isomers
Melting Point (°C) Boiling Point (°C) Dipole Moment (D)

Cis-1,2-Dichloroethene Trans-1,2-Dichloroethene Cis-1,2-Dibromoethene Trans-1,2-Dibromoethene

-80 -50 -53 -6

60 48 112.5 108

1.90 0 1.35 0

2.5

FUNCTIONAL GROUPS

2.5A ALKYL GROUPS AND THE SYMBOL R

Alkane

Alkyl group

Abbreviation

CH4
Methane

CH3–
Methyl group

Me–

CH3CH3
Ethane

CH3CH2– or C2H5–
Ethyl group

Et–

CH3CH2CH3
Propane

CH3CH2CH2–
Propyl group

Pr–

CH3CH2CH3
Propane

CH3
CH3CHCH3 or CH3CH
Isopropyl group i-Pr– All of these alkyl groups can be designated by R.

~8~

2.5B PHENYL AND BENZYL GROUPS
1. Phenyl group: or or C6H5– or

φ– or Ph–

or 2. Benzyl group: CH2

Ar– (if ring substituents are present)

or

CH2

or

C6H5CH2–

or

Bn–

2.6

ALKYL HALIDES OR HALOALKANES

2.6A HALOALKANE
1. Primary (1°), secondary (2°), or tertiary (3°) alkyl halides:
1o Carbon 2o Carbon H H 3o Carbon

H H o H C H Cl H

H C H o CH3 H3C o C H

C

C

H

C CH3

Cl

Cl H

A 1 alkyl chloride

A 2 alkyl chloride

A 3 alkyl chloride

2. Primary (1°), secondary (2°), or tertiary (3°) carbon atoms:

2.7

ALCOHOLS

1. Hydroxyl group

~9~

C

O

H

This is the functional group of an alcohol 2. Alcohols can be viewed in two ways structurally: (1) as hydroxyl derivatives of alkanes and (2) as alkyl derivatives of water.

Ethyl group
H2CH3C CH3CH3 109o H O 105o H O H

Hydroxyl group

Ethane

Ethyl alcohol (ethanol)

Water

3. Primary (1°), secondary (2°), or tertiary (3°) alcohols:

1o Carbon
H H C H H C H O H

OH CH2OH

Ethyl alcohol (a 1o alcohol)

Geraniol (a 1 alcohol with the odor of roses) o Benzyl alcohol (a 1o alcohol)

H H C H

2o Carbon H H
C O C H H OH ¡Ý OH

H Isopropyl alcohol (a 2o alcohol)

Menthol (a 2 alcohol found in pepermint oil) o ~ 10 ~

OH CH3 3o Carbon CH3 H3C C O H O Norethindrone (an oral contraceptive that contains a 3o alcohol group, as well as a ketone group and carbon-carbon double and triple bonds) CH3 tert-Butyl alcohol (a 3o alcohol) H H H H

2.8

ETHERS

1. Ethers can be thought of as dialkyl derivatives of water. R O R or R R' O H3C 110o H3C Dimethyl ether (a typical ether) O

General formula for an ether

H2C C O C

CH2

O O Ethylene oxide Tetrahydrofuran (THF) Two cyclic ethers

The functional of an ether

2.9

AMINES

1. Amines can be thought of as alkyl derivatives of ammonia.

~ 11 ~

H

N

H

R

N

H

C6H5CH2CHCH3 NH2 Amphetamine (a dangerous stimulant)

H2NCH2CH2CH2CH2NH2 Putrescine (found in decaying meat)

H Ammonia

H An amine

2. Primary (1°), secondary (2°), or tertiary (3°) amines:

R

N

H

R

N

H

R

N

R"

H A primary (1o) amine
H H C H H C H C H

R' A secondary (2o) amine

R' A tertiary (3o) amine

H N H Piperidine (a cyclic 2o amine)

NH2 Isopropylamine (a 1o amine)

2.10 ALDEHYDES AND KETONES
2.10A CARBONYL GROUP

C

O

The carbonyl group

O
Aldehyde

R O Ketone R C

C

R may also be H H O O or R' R1 C R2

or R R

C

1. Examples of aldehydes and ketones:
~ 12 ~

O Aldehydes: C

O C

O C 6H 5 H Benzaldehyde C

O C 6H 5 H trans-Cinnamaldehyde (present in cinnamon) C

H H H 3C H Formaldehyde Acetaldehyde

O
Ketones:

O CH3 H3CH2C C CH3 O
Carvone (from spearmint)

H3C

C

Acetone

Ethyl methyl ketone

2. Aldehydes and ketones have a trigonal plannar arrangement of groups around the carbonyl carbon atom. The carbon atom is sp2 hybridized.
H 118o H C 121o O 121o

2.11 CARBOXYLIC ACIDS, AMIDES, AND ESTERS
2.11A CARBOXYLIC ACIDS
O R C O or RCO2H or RCOOH H C O O or H CO2H or COOH

A carboxylic acid
O Formic acid H C O H or

The carboxyl group

HCO2H

or

HCOOH

~ 13 ~

O Acetic acid H 3C C O H O Benzoic acid C O or H C6H5CO2H or C6H5COOH or CH3CO2H or CH3COOH

2.11B AMIDES
1. Amides have the formulas RCONH2, RCONHR’, or RCONR’R”: O H3C C NH2 Acetamide H3C C NHCH3 O H3C C NHCH3 CH3 N,N-Dimethylacetamide O

N-Methylacetamide

2.11C ESTERS
1. Esters have the general formula RCO2R’ (or RCOOR’): O R C O R' or RCO2R' or RCOOR'

General formula for an ester O H3C C O or CH3CO2CH2CH3 or CH3COOCH 2CH3 R' An specific ester called ethyl acetate

~ 14 ~

O H3C C O Acetic acid H Ethyl alcohol + HOCH2CH3 H3C C

O + H2O O CH2CH3

Ethyl acetate

2.12 NITRILES
1. The carbon and the nitrogen of a nitrile are sp hybridized. 1) In IUPAC systematic nonmenclature, acyclic nitriles are named by adding the suffix nitrile to the name of the corresponding hydrocarbon.

H3C C N Ethanenitrile (acetonitrile) H2C CH C N Propenenitrile (acrylonitrile)
3 2 1

2

1

H3CH2CH2C C N Butanenitrile (butyronitrile) H2C HCH2CH2C C 4-Pentenenitrile
5 4 3 2 1

4

3

2

1

N

2) Cyclic nitriles are named by adding the suffix carbonitrile to the name of the ring system to which the –CN group is attached.

C

N

C

N

Benzenecarbonitrile (benzonitrile)

Cyclohexanecarbonitrile

~ 15 ~

2.13 SUMMARY OF IMPORTANT FAMILIES OF ORGANIC COMPOUNDS
Table 2.3
Family Alkane Specific example CH3CH3

Important Families of Organic Compounds
IUPAC name Ethane Common name Ethane General formula RH RCH=CH2 RCH=CHR R2C=CHR R2C=CR2 HC≡CR RC≡CR Functional group C–H and C–C bond

Alkene

CH2=CH2

Ethane

Ethylene

C

C

Alkyne Aromatic

HC

CH

Ethyne Benzene

Acetylene Benzene

C

C

ArH

Aromatic ring

Haloalkane

CH3CH2Cl

Chloroethane

Ethyl chloride

RX

C

X

Alcohol

CH3CH2OH

Ethanol

Ethyl alcohol

ROH

C

OH

Ether

CH3OCH3

Methoxy-methane Dimethyl ether

ROR RNH2 R2NH R3N O RCH
O RCR'

C

O

C

Amine

CH3NH2 O CH3CH
O CH3CCH3 O CH3COH O CH3COCH3

Methanamine

Methylamine

C

N

Aldehyde

Ethanal

Acetaldehyde

O C O C C
O C OH

H C

Ketone

Propanone

Acetone

Carboxylic acid

Ethanoic acid

Acetic acid

O RCOH O RCOR' CH3CONH2 CH3CONHR’ CH3CONR’R” RCN
O C

Ester

Methyl ethanoate Methyl acetate

O

C

Amide Nitrile

O CH3CNH2 H3CC N

Ethanamide Ethanenitrile

Acetamide Acetonitrile
~ 16 ~

O C N

C

N

2.14 PHYSICAL PROPERTIES AND MOLECULAR STRUCTURE
1. Physical properties are important in the identification of known compounds. 2. Successful isolation of a new compound obtained in a synthesis depends on making reasonably accurate estimates of the physical properties of its melting point, boiling point, and solubilities.

Table 2.4
Compound Methane Ethane Ethene Ethyne Chloromethane Chloroethane Ethyl alcohol Acetaldehyde Acetic acid Sodium acetate Ethylamine Diethyl ether Ethyl acetate a Physical Properties of Representative Compounds
Structure CH4 CH3CH3 CH2=CH2 HC CH CH3Cl CH3CH2Cl CH3CH2OH CH3CHO CH3CO2H CH3CO2Na CH3CH2NH2 (CH3CH2)2O CH3CO2CH2CH3 mp (°C) -182.6 -183 -169 -82 -97 -138.7 -115 -121 16.6 324 -80 -116 -84 bp (°C) (1 atm) -162 -88.2 -102 -84 subla -23.7 13.1 78.5 20 118 deca 17 34.6 77

In this table dec = decomposes and subl = sublimes.

An instrument used to measure melting point.
~ 17 ~

A microscale distillation apparatus.

2.14A ION-ION FORCES
1. The strong electrostatic lattice forces in ionic compounds give them high melting points. 2. The boiling points of ionic compounds are higher still, so high that most ionic organic compounds decompose before they boil.

Figure 2.6

The melting of sodium acetate.

2.14B DIPOLE-DIPOLE FORCES
1. Dipole-dipole attractions between the molecules of a polar compound:

Figure 2.7

Electrostatic potential models for acetone molecules that show how acetone molecules might align according to attractions of their partially positive regions and partially negative regions (dipole-dipole interactions).
~ 18 ~

2.14C HYDROGEN BONDS
1. Hydrogen bond: the strong dipole-dipole attractions between hydrogen atoms bonded to small, strongly electronegative atoms (O, N, or F) and nonbonding electron pairs on other electronegative atoms. 1) Bond dissociation energy of about 4-38 KJ mol–1 (0.96-9.08 Kcal mol–1). 2) H-bond is weaker than an ordinary covalent bond; much stronger than the dipole-dipole interactions. δ− Z

H

δ+

δ−

Z

H

δ+

A hydrogen bond (shown by red dots)
Z is a strongly electronegative element, usually oxygen, nitrogen, or fluorine.

H3CH2C δ− δ+ O H

δ−

H δ+ CH2CH3

O

The dotted bond is a hydrogen bond. Strong hydrogen bond is limited to molecules having a hydrogen atom attached to an O, N, or F atom

2. Hydrogen bonding accounts for the much higher boiling point (78.5 °C) of ethanol than that of dimethyl ether (–24.9 °C). 3. A factor (in addition to polarity and hydrogen bonding) that affects the melting point of many organic compounds is the compactness and rigidity of their individual molecules.
CH3 H 3C C CH3 OH
CH3CH2CH2CH2OH CH3 CH3CHCH2OH CH3 CH3CH2CHOH

tert-Butyl alcohol (mp 25 °C)

Butyl alcohol (mp –90 °C)

Isobutyl alcohol (mp –108 °C)

sec-Butyl alcohol (mp –114 °C)

~ 19 ~

2.14D VAN DER WAALS FORCES
1. van der Waals Forces (or London forces or dispersion forces): 1) The attractive intermolecular forces between the molecules are responsible for the formation of a liquid and a solid of a nonionic, nonpolar substance. 2) The average distribution of charge in a nonpolar molecule over a period of time is uniform. 3) At any given instant, because electrons move, the electrons and therefore the

charge may not be uniformly distributed ⇒ a small temporary dipole will occur. 4) This temporary dipole in one molecule can induce opposite (attractive) dipoles in surrounding molecules.

Figure 2.8

Temporary dipoles and induced dipoles in nonpolar molecules resulting from a nonuniform distribution of electrons at a given instant.

5) These temporary dipoles change constantly, but the net result of their existence is to produce attractive forces between nonpolar molecules. 2. Polarizability: 1) The ability of the electrons to respond to a changing electric field. 2) It determines the magnitude of van der Waals forces. 3) Relative polarizability depends on how loosely or tightly the electrons are held. 4) Polarizability increases in the order F < Cl < Br < I. 5) Atoms with unshared pairs are generally more polarizable than those with only bonding pairs. 6) Except for the molecules where strong hydrogen bonds are possible, van der Waals forces are far more important than dipole-dipole interactions.
~ 20 ~

3. The boiling point of a liquid is the temperature at which the vapor pressure of the liquid equals the pressure of the atmosphere above it. 1) Boiling points of liquids are pressure dependent. 2) The normal bp given for a liquid is its bp at 1 atm (760 torr). 3) The intermolecular van der Waals attractions increase as the size of the molecule increases because the surface areas of heavier molecules are usually much greater. 4) For example: the bp of methane (–162 °C), ethane (–88.2 °C), and decane (174 °C) becomes higher as the molecules grows larger.

Table 2.5

Attractive Energies in Simple Covalent Compounds
Attractive energies (kJ mol–1)

Molecule
H2O NH3 HCl HBr HI a Dipole Dipole-Dipole moment (D)
1.85 1.47 1.08 0.80 0.42 36a 14 a 3a 0.8 0.03

van der Melting point Boiling point (°C) (°C) Waals
88 15 17 22 28 0 –78 –115 –88 –51 100 –33 –85 –67 –35

These dipole-dipole attractions are called hydrogen bonds. 4. Fluorocarbons have extraordinarily low boiling points when compared to hydrocarbons of the same molecular weight. 1) 1,1,1,2,2,3,3,4,4,5,5,5-Dodecafluoropentane (C5F12, m.w. 288.03, bp 28.85 °C) has a slightly lower bp than pentane (C5H12, m.w. 72.15, bp 36.07 °C). 2) Fluorine atom has very low polarizability resulting in very small van der Waals forces. 3) Teflon has self-lubricating properties which are utilized in making “nonstick” frying pans and lightweight bearings.
~ 21 ~

2.14E SOLUBILITIES
1. Solubility 1) The energy required to overcome lattice energies and intermolecular or interionic attractions for the dissolution of a solid in a liquid comes from the formation of new attractions between solute and solvent. 2) The dissolution of an ionic substance:

hydrating or solvating the ions.

3) Water molecules, by virtue of their great polarity and their very small, compact shape, can very effectively surround the individual ions as they freed from the crystal surface. 4) Because water is highly polar and is capable of forming strong H-bonds, the

dipole-ion attractive forces are also large. δ+ δ+

H O δ− H H δ− H O δ− δ+

H

− + − +

+ − + −

O H + − +

H δ+ H δ− δ− δ+

O H

δ−

+ δ− O H

O H H δ+ δ+

− + −

O

H H δ− H δ+ Dissolution

H δ+ O H

− δ+ O H

δ−

H O δ− H

Figure 2.9

The dissolution of an ionic solid in water, showing the hydration of positive and negative ions by the very polar water molecules. The ions become surrounded by water molecules in all three dimensions, not just the two shown here.

2. “Like dissolves like” 1) Polar and ionic compounds tend to dissolve in polar solvents. 2) Polar liquids are generally miscible with each other. 3) Nonpolar solids are usually soluble in nonpolar solvents.
~ 22 ~

4) Nonpolar solids are insoluble in polar solvents. 5) Nonpolar liquids are usually mutually miscible. 6) Nonpolar liquids and polar liquids do not mix. 3. Methanol (ethanol, and propanol) and water are miscible in all proportions. H3CH2C δ− Hδ+

O

Hydrogen bond δ+ δ−

H

δ+

H

O

1) Alcohol with long carbon chain is much less soluble in water. 2) The long carbon chain of decyl alcohol is hydrophobic (hydro, water; phobic, fearing or avoiding –– “water avoiding”. 3) The OH group is hydrophilic (philic, loving or seeking –– “water seeking”.
Hydrophobic portion

Hydrophilic group

CH3CH2CH2CH2CH2CH2CH2CH2CH2CH2OH
Decyl alcohol

2.14F GUIDELINES FOR WATER SOLUBILITIES
1. Water soluble: at least 3 g of the organic compound dissolves in 100 mL of water. 1) Compounds containing one hydrophilic group: 1-3 carbons are water soluble; 4-5 carbons are borderline; 6 carbons or more are insoluble.

2.14G INTERMOLECULAR FORCES IN BIOCHEMISTRY

~ 23 ~

Hydrogen bonding (red dotted lines) in the α-helix structure of proteins.

2.15 SUMMARY OF ATTRACTIVE ELECTRIC FORCES
Table 2.6
Electric Force Relative Strength

Attractive Electric Forces
Type Example

Cation-anion (in a crystal)

Very strong

Lithium fluoride crystal lattice H–H (435 kJ mol–1) Shared electron pairs δ+ δ−

Strong Covalent bonds (140-523 kJ mol–1)

CH3–CH3 (370 kJ mol–1) I–I (150 kJ mol–1)

Ion-dipole

Moderate

δ+ δ− δ− δ+

δ− δ+

Na＋ in water (see Fig. 2.9)

δ+ H

Dipole-dipole Moderate to (including weak (4-38 kJ hydrogen mol–1) bonds)

δ− O

δ+

H

δ− R

δ−

Z

H

δ+

R
H3C
δ+

O

and
Cl
δ−

H3C

δ+

Cl

δ−

van der Waals

Variable

Transient dipole

Interactions between methane molecules

2.16 INFRARED SPECTROSCOPY:
~ 24 ~

AN INSTRUMENTAL METHOD

FOR DETECTING FUNCTIONAL GROUPS

2.16A An Infrared spectrometer:

Figure 2.10

Diagram of a double-beam infrared spectrometer. [From Skoog D. A.; Holler, F. J.; Kieman, T. A. principles of instrumental analysis, 5th ed., Saunders: New York, 1998; p 398.].

1. RADIATION SOURCE: 2. SAMPLING AREA: 3. PHOTOMETER: 4. MONOCHROMATOR: 5. DETECTOR (THERMOCOUPLE):

~ 25 ~

The oscillating electric and magnetic fields of a beam of ordinary light in one plane. The waves depicted here occur in all possible planes in ordinary light.

2.16B Theory:
1. Wavenumber ( ν ):
–1 ν (cm ) =

1 λ (cm) 1 x 10,000

ν (Hz) = ν c (cm) =

c (cm/sec) λ (cm)

cm–1 =

(µ )

and

µ=

1 x 10,000 (cm -1 )

* the wavenumbers ( ν ) are often called "frequencies".

2. THE MODES OF VIBRATION AND BENDING:
Degrees of freedom: Nonlinear molecules: linear molecules: 3N–6 3N–5 vibrational degrees of (fundamental vibrations) freedom

* Fundamental vibrations involve no change in the center of gravity of the molecule.

3. “Bond vibration”:

A stretching vibration
~ 26 ~

4. “Stretching”:

Symmetric stretching 5. “Bending”:

Asymmetric stretching

Symmetric bending 6. H2O:
3 fundamental vibrational modes

Asymmetric bending
3N – 3 – 3 = 3

Symmetrical stretching (νs OH) 3652 cm–1 (2.74 µm) coupled stretching

Asymmetrical stretching (νas OH) 3756 cm–1 (2.66 µm)

Scissoring (νs HOH) 1596 cm–1 (6.27 µm)

7. CO2:

4 fundamental vibrational modes

3N – 3 – 2 = 4

Symmetrical stretching (νs CO) 1340 cm–1 (7.46 µm) coupled stretching
~ 27 ~

Asymmetrical stretching (νas CO) 2350 cm–1 (4.26 µm) normal C=O 1715 cm–1

Doubly degenerate

Scissoring (bending) (δs CO) 666 cm–1 (15.0 µm)

Scissoring (bending) (δs CO) 666 cm–1 (15.0 µm)

resolved components of bending motion and indicate movement perpendicular to the plane of the page

8. AX2:

Stretching Vibrations

Symmetrical stretching (νs CH2)

Asymmetrical stretching (νas CH2)

Bending Vibrations

In-plane bending or scissoring (δs CH2)

Out-of-plane bending or wagging (ω CH2)

In-plane bending or rocking (ρs CH2)
~ 28 ~

Out-of-plane bending or twisting (τ CH2)

9. Number of fundamental vibrations observed in IR will be influenced:
(1) Overtones (2) Combination tones (3) Fall outside 2.5-15 µm region Too weak to be observed Two peaks that are too close Degenerate band Lack of dipole change
⇒ reduce the number of bands ⇒ increase the number of bands

10. Calculation of approximate stretching frequencies:

ν =

1 2πc

K

µ

⇒

ν (cm–1) = 4.12

K

µ

–1 ν = frequency in cm

c = velocity of light = 3 x 1010 cm/sec

µ=

m1m2 masses of atoms in grams or m1 + m2 M 1M 2 masses of atoms ( M 1 + M 2 )(6.02 x 10 23 ) in amu

µ =

M 1M 2 where M1 and M2 are M1 + M 2 atomic weights

K = 5 x 105 dynes/cm (single) K = force constant in dynes/cm
= 10 x 105 dynes/cm (double) = 15 x 105 dynes/cm (triple)

(1) C=C bond:

ν = 4.12

K

µ

K = 10 x 105 dynes/cm

µ=

MCMC (12)(12) =6 = MC + MC 12 + 12

10 x 10 5 = 1682 cm–1 (calculated) ν = 4.12 6

–1 ν = 1650 cm (experimental)

~ 29 ~

(2) C–H bond ν = 4.12 C–D bond ν = 4.12

K

K

µ

µ

K= 5 x 105 dynes/cm µ= K= 5 x 105 dynes/cm µ= MCM H (12)(1) = 0.923 = MC + M H 12 + 1

MCM D (12)(2) = 1.71 = MC + M D 12 + 2

5 x 10 5 5 x 10 5 –1 = 3032 cm (calculated); ν = 4.12 = 2228 cm–1 (calculated); ν = 4.12 0.923 1.71 –1 –1 ν = 3000 cm (experimental) ν = 2206 cm (experimental)

(3)
C C C C increasing K C H C C C O C Cl C Br C I C C 2150 cm–1 1650 cm–1 1200 cm–1

3000 cm–1

1200 cm–1 increasing µ

1100 cm–1

800 cm–1

550 cm–1

~500 cm–1

(4) Hybridization affects the force constant K:

sp
C H 3300 cm–1

sp2
C H 3100 cm–1

sp3
C H 2900 cm–1

(5) K increases from left to the right across the periodic table: C–H: 3040 cm–1 F–H: 4138 cm–1

(6) Bending motions are easier than stretching motions: C–H stretching: ~ 3000 cm–1
~ 30 ~

C–H bending:

~ 1340 cm–1

2.16C COUPLED INTERACTIONS:
1. CO2: symmetrical 1340 cm–1 2. Symmetric Stretch H Methyl C H C Asymmetric Stretch H H asymmetrical 2350 cm–1 normal 1715 cm–1

H ~ 2872 cm–1

H ~ 2962 cm–1

O
Anhydride

O

O C

O

C O ~ 1760 cm–1 H N H ~ 3300 cm–1
O N O ~ 1350 cm–1

C

C O ~ 1800 cm–1 H C H ~3400 cm–1
O N O ~ 1550 cm–1

Amine

Nitro

Asymmetric stretching vibrations occur at higher frequency than symmetric ones. 3. H H3C CH2 CH2 OH : OH : νC νC
−1 O 1034 cm

O 1053 cm

−1

νC

C

O

~ 31 ~

2.16D HYDROCARBONS:
1. ALKANES:

Figure 2.11

The IR spectrum of octane.

2. AROMATIC COMPOUNDS:

Figure 2.12

The IR spectrum of methylbenzene (toluene).

~ 32 ~

3. ALKYNES:

Figure 2.13

The IR spectrum of 1-hexyne.

4. ALKENES:

Figure 2.14

The IR spectrum of 1-hexene.

~ 33 ~

2.16E OTHER FUNCTIONAL GROUPS
1. Shape and intensity of IR peaks:

Figure 2.15

The IR spectrum of cyclohexanol .

2. Acids:

Figure 2.16

The infrared spectrum of propanoic acid.
~ 34 ~

HOW TO APPROACH THE ANALYSIS OF A SPECTRUM
1. Is a carbonyl group present?
The C=O group gives rise to a strong absorption in the region 1820-1660 cm–1 (5.5-6.1 µ). The peak is often the strongest in the spectrum and of medium width. You can't miss it.

2. If C=O is present, check the following types (if absent, go to 3). ACIDS is OH also present?

– broad absorption near 3400-2400 cm–1 (usually overlaps C–H)

AMIDES is NH also present?
– medium absorption near 3500 cm–1 (2.85 µ) Sometimes a double peak, with equivalent halves.

ESTERS is C–O also present?
– strong intensity absorptions near 1300-1000 cm–1 (7.7-10 µ)

ANHYDRIDES have two C=O absorptions near 1810 and 1760 cm–1 (5.5 and 5.7 µ) ALDEHYDES is aldehyde CH present?
– two weak absorptions near 2850 and 2750 cm–1 (3.50 and 3.65 µ) on the right-hand side of CH absorptions

KETONES

The above 5 choices have been eliminated

3. If C=O is absent ALCOHOLS Check for OH PHENOLS
– broad absorption near 3400-2400 cm–1 (2.8-3.0 µ)

– confirm this by finding C–O near 1300-1000 cm–1 (7.7-10 µ)

AMINES Check for NH
~ 35 ~

– medium absorptions(s) near 3500 cm–1 (2.85 µ)

ETHERS Check for C–O (and absence of OH) near 1300-1000 cm–1 (7.7-10 µ) 4. Double Bonds and/or Aromatic Rings
– C=C is a weak absorption near 1650 cm–1 (6.1 µ) – medium to strong absorptions in the region 1650-1450 cm–1 (6-7 µ) often imply an aromatic ring – confirm the above by consulting the CH region; aromatic and vinyl CH occurs to the left of 3000 cm–1 (3.33 µ) (aliphatic CH occurs to the right of this value)

5. Triple Bonds
– C≡N is a medium, sharp absorption near 2250 cm–1 (4.5 µ) – C≡C is a weak but sharp absorption near 2150 cm–1 (4.65 µ) Check also for acetylenic CH near 3300 cm–1 (3.0 µ)

6. Nitro Groups
– two strong absorptions at 1600 - 1500 cm–1 (6.25-6.67 µ) and 1390-1300 cm–1 (7.2-7.7 µ)

7. Hydrocarbons
– none of the above are found – major absorptions are in CH region near 3000 cm–1 (3.33 µ) – very simple spectrum, only other absorptions near 1450 cm–1 (6.90 µ) and 1375 cm–1 (7.27 µ)
Note: In describing the shifts of absorption peaks or their relative positions, we have used the terms “to the left” and “to the right.” This was done to save space when using both microns and reciprocal centimeters. The meaning is clear since all spectra are conventionally presented left to right from 4000 cm–1 to 600 cm–1 or from 2.5 µ to 16 µ. “To the right” avoids saying each time “to lower frequency (cm–1) or to longer wavelength (µ)” which is confusing since cm–1 and µ have an inverse relationship; as one goes up, the other goes down.

~ 36 ~

AN INTRODUCTION TO ORGANIC REACTIONS: ACIDS AND BASES
SHUTTLING THE PROTONS
1. Carbonic anhydrase regulates the acidity of blood and the physiological conditions relating to blood pH.

HCO3 + H

−

+

H2CO3

Carbonic anhydrase

H2O + CO2

2. The breath rate is influenced by one’s relative blood acidity. 3. Diamox (acetazolamide) inhibits carbonic anhydrase, and this, in turn, increases the blood acidity. The increased blood acidity stimulates breathing and thereby decreases the likelihood of altitude sickness.
O N H N S O N S NH2 O Diamox (acetazolamide)

3.1

REACTIONS AND THEIR MECHANISMS

3.1A CATEGORIES OF REACTIONS
1. Substitution Reactions:

H3C

Cl + Na OH

+

−

H2O

H3C

OH

+ Na+ Cl−

A substitution reaction
~1~

2. Addition Reactions: H C H C H H + Br Br CCl4 H H C H C H

An addition reaction

Br Br

3. Elimination Reactions:
H H C H C H H C C H

KOH (−HBr)

H H H Br An elimination reaction (Dehydrohalogenation) 4. Rearrangement Reactions:

H C C

H

H+

H3C C C

CH3 CH3

H H3C C H3C H3C An rearrangement CH3

3.1B MECHANISMS OF REACTIONS
1. Mechanism explains, on a molecular level, how the reactants become products. 2. Intermediates are the chemical species generated between each step in a multistep reaction. 3. A proposed mechanism must be consistent with all the facts about the reaction and with the reactivity of organic compounds. 4. Mechanism helps us organize the seemingly an overwhelmingly complex body of knowledge into an understandable form.

3.1C HOMOLYSIS AND HETEROLYSIS OF COVALENT BONDS
1. Heterolytic bond dissociation (heterolysis):
~2~

electronically unsymmetrical bond

breaking ⇒ produces ions.

A B

A+ + Ions

B−

Hydrolytic bond cleavage

2. Homolytic bond dissociation (homolysis): electronically breaking ⇒ produces radicals. A B A + B

symmetrical

bond

Homolytic bond cleavage

Radicals 3. Heterolysis requires the bond to be polarized. of oppositely charged ions. δ+ Heterolysis requires separation

A B

δ−

A+ +

B−

4. Heterolysis is assisted by a molecule with an unshared pair: δ+ δ− +

Y Y

+ +

A B B

Y A + Y
+

B− B−

δ+

A

δ−

A +

Formation of the new bond furnishes some of the energy required for the heterolysis.

3.2

ACID-BASE REACTIONS

3.2A THE BRØNSTED-LOWRY DEFINITION OF ACIDS AND BASES
1. Acid is a substance that can donate (or lose) a proton; Base is a substance that can accept (or remove) a proton.

~3~

H

O

+

H

Cl

H

O

H

+

Cl− Conjugate base of HCl

H Base Acid (proton acceptor) (proton donor)

H Conjugate acid of H2O

1) Hydrogen chloride, a very strong acid, transfer its proton to water. 2) Water acts as a base and accepts the proton. 2. Conjugate acid: the molecule or ion that forms when a base accepts a proton. 3. Conjugate base: the molecule or ion that forms when an acid loses its proton. 4. Other strong acids: Hydrogen iodide Hydrogen bromide Sulfuric acid HI HBr HSO4− H2SO4 + H 2O + H 2O + H 2O + H 2O H 3O + + I−

H3O+ + Br−

H3O+ + HSO4−

H3O+ + SO42− (~10%)

5. Hydronium ions and hydroxide ions are the strongest acid and base that can exist in aqueous solution in significant amounts. 6. When sodium hydroxide dissolves in water, the result is a solution containing solvated sodium ions and solvated hydroxide ions. Na+ OH−(solid) H2O H2O H2O Na H2O Solvated sodium ion
+

Na+(aq) + HO(aq)− H H O H O H H

OH2 OH2

O H

H

−

O H

H

O

Solvated hydroxide ion

7. An aqueous sodium hydroxide solution is mixed with an aqueous hydrogen chloride (hydrochloric acid) solution:
~4~

1) Total Ionic Reaction

H

O+ H + Cl H

−

+ Na+

−

O

H

2 H Spectator inos

O + H

Na+ + Cl

−

2) Net Reaction H O+ H H +
−

O

H

2 H

O H

3) The Net Reaction of solutions of all aqueous strong acids and bases are mixed:
H 3O + + OH− 2 H 2O

3.2B THE LEWIS DEFINITION OF ACIDS AND BASES
1. Lewis acid-base theory: in 1923 proposed by G. N. Lewis (1875~1946; Ph. D. Harvard, 1899; professor, Massachusetts Institute of Technology, 1905-1912; professor, University of California, Berkeley, 1912-1946). 1) Acid: 2) Base:

electron-pair acceptor electron-pair donor
+

H+ NH3 + Lewis acid Lewis base (electron-pair acceptor) (electron-pair donor)

H

NH3

curved arrow shows the donation of the electron-pair of ammonia
Cl Cl Al Cl + NH3 Cl Cl Al NH3 Cl
−

+

Lewis acid Lewis base (electron-pair acceptor) (electron-pair donor)
~5~

3) The central aluminum atom in aluminum chloride is electron-deficient because it has only a sextet of electrons. Group 3A elements (B, Al, Ga, In, Tl) have only a sextet of electrons in their valence shell. 4) Compounds that have atoms with vacant orbitals also can act as Lewis acids.

R

O

H

+

ZnCl2

R

O H

+ −

ZnCl2

Lewis base Lewis acid (electron-pair donor) (electron-pair acceptor)
+ FeBr3

Br

Br

Br

Br FeBr3

+ −

Lewis base Lewis acid (electron-pair donor) (electron-pair acceptor)

3.2C OPPOSITE CHARGES ATTRACT
1. Reaction of boron trifluoride with ammonia:

Figure 3.1

Electrostatic potential maps for BF3, NH3, and the product that results from reaction between them. Attraction between the strongly positive region of BF3 and the negative region of NH3 causes them to react. The electrostatic potential map for the product for the product shows that the fluorine atoms draw in the electron density of the formal negative charge, and the nitrogen atom, with its hydrogens, carries the formal positive charge.
~6~

2. BF3 has substantial positive charge centered on the boron atom and negative charge located on the three fluorine atoms. 3. NH3 has substantial negative charge localized in the region of its nonbonding electron pair. 4. The nonbonding electron of ammonia attacks the boron atom of boron trifluoride, filling boron’s valence shell. 5. HOMOs and LUMOs in Reactions: 1) HOMO: 2) LUMO: highest occupied molecular orbital lowest unoccupied molecular orbital

HOMO of NH3

LUMO of BF3

3) The nonbonding electron pair occupies the HOMO of NH3. 4) Most of the volume represented by the LUMO corresponds to the empty p orbital in the sp2-hybridized state of BF3. 5) The HOMO of one molecule interacts with the LUMO of another in a reaction.

3.3

HETEROLYSIS OF BONDS TO CARBON: CARBOCATIONS AND CARBANIONS

3.3A CARBOCATIONS AND CARBANIONS

~7~

δ+

C Zδ−

Heterolysis

C+ Carbocation

+

Z

−

δ−

C Z

δ+

Heterolysis

C

−

+

Z+

Carbanion 1. Carbocations have six electrons in their valence shell, and are electron deficient. ⇒ Carbocations are Lewis acids. 1) Most carbocations are short-lived and highly reactive. 2) Carbonium ion (R+)
⇔

Ammonium ion (R4N+)

2. Carbocations react rapidly with Lewis bases (molecules or ions that can donate electron pair) to achieve a stable octet of electrons.
−

C+ Carbocation (a Lewis acid) C+ Carbocation (a Lewis acid) 3. Electrophile: electrons. +

+

B

C

B

Anion (a Lewis base) O H C O+ H H

H Water (a Lewis base)

“electron-loving” reagent

1) Electrophiles seek the extra electrons that will give them a stable valence shell of 2) A proton achieves the valence shell configuration of helium; carbocations achieve the valence shell configuration of neon. 4. Carbanions are Lewis bases. 1) Carbanions donate their electron pair to a proton or some other positive center to neutralize their negative charge.
~8~

5. Nucleophile:

“nucleus-loving” reagent

C

−

+

H

δ+

Aδ−

C

H +

A−

Carbanion
−

Lewis acid δ+ C

+

C

Lδ−

C

C

+

L−

Carbanion

Lewis acid

3.4

THE USE OF CURVED ARROWS IN ILLUSTRATING REACTIONS

3.4A A Mechanism for the Reaction
Reaction:

H2O Mechanism: H O +

+

HCl

H3O+ + Cl−

H

δ+

Cl

δ−

H

O+ H

+

Cl−

H A water molecule uses one of the electron pairs to form a bond to a proton of HCl. The bond between the hydrogen and chlorine breaks with the electron pair going to the chlorine atom

H This leads to the formation of a hydronium ion and a chloride ion.

Curved arrows point from electrons to the atom receiving the electrons.

1. Curved arrow: 1) The curved arrow begins with a covalent bond or unshared electron pair (a site of higher electron density) and points toward a site of electron deficiency.
~9~

2) The negatively charged electrons of the oxygen atom are attracted to the positively charged proton. 2. Other examples: H O+ H H Acid O H3C C Acid
O H 3C C O Acid H +
−

+

−

O

H

H

O H

+ H

O

H

Base O

O

H

+

O

H

H3C

C

O−

+

H

O+ H H

H Base
O O H H 3C C O− + H

O

H

Base

3.5

THE STRENGTH OF ACIDS AND BASES:

Ka AND pKa

1. In a 0.1 M solution of acetic acid at 25 °C only 1% of the acetic acid molecules ionize by transferring their protons to water.

O H3C C O H + H2O H3C

O C O− + H3O+

3.5A THE ACIDITY CONSTANT, Ka
1. An aqueous solution of acetic acid is an equilibrium:
[H 3O + ] [CH 3CO 2 − ] Keq = [CH 3CO 2 H] [H 2 O] 2. The acidity constant: 1) For dilute aqueous solution:
M)
~ 10 ~

water concentration is essentially constant (~ 55.5

[H 3O + ] [CH 3CO 2 − ] Ka = Keq [H2O] = [CH 3CO 2 H] 2) At 25 °C, the acidity constant for acetic aicd is 1.76 × 10−5. 3) General expression for any acid: HA + H2O H3O+ + A−

[H 3O + ] [A − ] Ka = [HA] 4) A large value of Ka means the acid is a strong acid, and a smaller value of Ka means the acid is a weak acid. 5) If the Ka is greater than 10, the acid will be completely dissociated in water.

3.5B ACIDITY AND pKa
1. pKa: 2. pH: pKa = −log Ka pH = −log [H3O+]

3. The pKa for acetic acid is 4.75: pKa = −log (1.76 × 10−5) = −(−4.75) = 4.75 4. The larger the value of the pKa, the weaker is the acid.

CH3CO2H pKa = 4.75

CF3CO2H pKa = 0.18

HCl pKa = −7

Acidity increases

1) For dilute aqueous solution: water concentration is essentially constant (~ 55.5
M)

~ 11 ~

Table 3.1 Relative Strength of Selected Acids and their Conjugate Bases
Acid
Strongest Acid HSbF6 (a super acid) HI H2SO4 HBr HCl C6H5SO3H (CH3)2O+H (CH3)2C=O+H CH3O+H2 H3O+ HNO3 CF3CO2H HF H2CO3 CH3CO2H CH3COCH2COCH3 NH4+ C6H5OH HCO3− CH3NH3+ H2O CH3CH2OH (CH3)3COH CH3COCH3 HC≡CH H2 NH3 CH2=CH2 Weakest Acid CH3CH3

Approximate pKa
< −12 −10 −9 −9 −7 −6.5 −3.8 −2.9 −2.5 −1.74 −1.4 0.18 3.2 3.7 4.75 9.0 9.2 9.9 10.2 10.6 15.74 16 18 19.2 25 35 38 44 50

Conjugate Base
SbF6− Weakest Base − I HSO4− Br− Cl− C6H5SO3− (CH3)2O (CH3)2C=O CH3OH H3O HNO3− CF3CO2− F− HCO3− CH3CO2− CH3COCH−COCH3 NH4+ C6H5O− HCO32− CH3NH3 HO− CH3CH2O− (CH3)3CO− − CH2COCH3 HC≡C− H− NH2− CH2=CH− CH3CH2− Strongest Base

3.5C PREDICTING THE STRENGTH OF BASES
1. The stronger the acid, the weaker will be its conjugate base. 2. The larger the pKa of the conjugate acid, the stronger is the base.
~ 12 ~

Increasing acid strength

Increasing base strength

Increasing base strength Cl− Very weak base pKa of conjugate acid (HCl) = −7 CH3CO2− pKa of conjugate acid (CH3CO2H) = −4.75 HO− Strong base pKa of conjugate acid (H2O) = −15.7

3. Amines are weak bases:

H NH3 + H Base O Acid H H N
+

H

+

−

O

H

H Conjugate acid pKa = 9.2 H
+

Conjugate base

CH3NH2 + H Base

O Acid

H

H3C

N

H

+

−

O

H

H Conjugate acid pKa = 10.6

Conjugate base

1) The conjugate acids of ammonia and methylamine are the ammonium ion, NH4+ (pKa = 9.2) and the methylammonium ion, CH3NH3+ (pKa = 10.6) respectively. Since methylammonium ion is a weaker acid than ammonium ion, methylamine is a stronger base than ammonia.

3.6

PREDICTING THE OUTCOME OF ACID-BASE REACTIONS

3.6A General order of acidity and basicity:
1. Acid-base reactions always favor the formation of the weaker acid and the weaker base. 1) Equilibrium control: the outcome of an acid-base reaction is determined by the position of an equilibrium.
~ 13 ~

O R C O H + Na+ −O H Stronger acid Stronger base pKa = 3-5

O R C O− + Weaker base H Weaker acid pKa = 15.7 H O

Large difference in pKa value ⇒ the position of equilibrium will greatly favor the formation of the products (one-way arrow is used) 2. Water-insoluble carboxylic acids dissolve in aqueous sodium hydroxide:
O C O H + Na+ −O H O C O− Na+ + H O H

Insoluble in water

Soluble in water (Due to its polarity as a salt)

1) Carboxylic acids containing fewer than five carbon atoms are soluble in water. 3. Amines react with hydrochloric acid: H R NH2 + H O+ H Cl− R N
+

H Cl−

+

H

O

H

H Stronger base Stronger acid pKa = -1.74

H Weaker acid pKa = 9-10

Weaker base

4. Water-insoluble amines dissolve readily in hydrochloric acid:

H C6H5 NH2 + H O+ H Cl− H C6H5 N
+

H Cl− + H

O

H

Water-insoluble

H Water-soluble salt

1) Amines of lower molecular weight are very soluble in water.

~ 14 ~

3.7

THE RELATIONSHIP BETWEEN STRUCTURE AND ACIDITY

1. The strength of an acid depends on the extent to which a proton can be separated from it and transferred to a base. 1) Breaking a bond to the proton ⇒ the strength of the bond to the proton is the dominating effect. 2) Making the conjugate base more electrically negative. 3) Acidity increases as we descend a vertical column: Acidity increases H–F pKa = 3.2 H–Cl pKa = −7 H–Br pKa = −9 H–I pKa = −10

The strength of H−X bond increases

4) The conjugate bases of strong acids are very weak bases: Basicity increases F− Cl− Br− I−

2. Same trend for H2O, H2S, and H2Se: Acidity increases H2O H2S H2Se

Basicity increases HO− HS−
~ 15 ~

HSe−

3. Acidity increases from left to right when we compare compounds in the same horizontal row of the periodic table. 1) Bond strengths are roughly the same, the dominant factor becomes the electronegativity of the atom bonded to the hydrogen. 2) The electronegativity of this atom affects the polarity of the bond to the proton, and it affects the relative stability of the anion (conjugate base). 4. If A is more electronegative than B for H—A and H—B: δ+ H

δ−

A

and

δ+

H

δ−

B

1) Atom A is more negative than atom B ⇒ the proton of H—A is more positive than that of H—B ⇒ the proton of H—A will be held less strongly ⇒ the proton of H—A will separate and be transferred to a base more readily. 2) A will acquire a negative charge more readily than B ⇒ A−.anion will be more stable than B−.anion 5. The acidity of CH4, NH3, H2O, and HF: Electronegativiity increases C N O F

Acidity increases δ− δ+ δ− δ+

H 3C

H

H 2N

H

HO

δ− δ+

H

δ− δ+

F

H

pKa = 48

pKa = 38

pKa = 15.74

pKa = 3.2

6. Electrostatic potential maps for CH4, NH3, H2O, and HF: 1) Almost no positive charge is evident at the hydrogens of methane (pKa = 48). 2) Very little positive charge is present at the hydrogens of ammonia (pKa = 38). 3) Significant positive charge at the hydrogens of water (pKa = 15.74).
~ 16 ~

4) Highest amount of positive charge at the hydrogen of hydrogen fluoride (pKa = 3.2).

Figure 3.2

The effect of increasing electronegativity among elements from left to right in the first row of the periodic table is evident in these electrostatic potential maps for methane, ammonia, water, and hydrogen fluoride.

Basicity increases CH3− H2N− HO− F−

3.7A THE EFFECT OF HYBRIDIZATION
1. The acidity of ethyne, ethane, and ethane:
H H C C H H C C H H H H H C C H H H

Ethyne pKa = 25

Ethene pKa = 44

Ethane pKa = 50

1) Electrons of 2s orbitals have lower energy than those of 2p orbitals because electrons in 2s orbitals tend, on the average, to be much closer to the nucleous than electrons in 2p orbitals.
~ 17 ~

2) Hybrid orbitals having more s character means that the electrons of the

anion will, on the average, be lower in energy, and the anion will be more stable.
2. Electrostatic potential maps for ethyne, ethene, and ethane:

Figure 3.3

Electrostatic potential maps for ethyne, ethene, and ethane.

1) Some positive charge is clearly evident on the hydrogens of ethyne. 2) Almost no positive charge is present on the hydrogens of ethene and ethane. 3) Negative charge resulting from electron density in the π bonds of ethyne and ethene is evident in Figure 3.3. 4) The π electron density in the triple bond of ethyne is cylindrically symmetric. 3. Relative Acidity of the Hydrocarbon: HC≡CH > H2C=CH2 > H3C−CH3

4. Relative Basicity of the Carbanions: H3C−CH2:− > H2C=CH:−
~ 18 ~

>

HC≡C:−

3.7B INDUCTIVE EFFECTS
1. The C—C bond of ethane is completely nonpolar: H3C−CH3

Ethane

The C−C bond is nonpolar.
2. The C—C bond of ethyl fluoride is polarized: δ+ δ− H3C→−CH2→−F 2 1 δ+ 1) C1 is more positive than C2 as a result of the electron-attracting ability of the fluorine. 3. Inductive effect: 1) Electron attracting (or electron withdrawing) inductive effect 2) Electron donating (or electron releasing) inductive effect 4. Electrostatic potential map: 1) The distribution of negative charge around the electronegative fluorine is

evident.

Figure 3.4

Ethyl fluoride (fluoroethane): structure, dipole moment, and charge distribution.

~ 19 ~

3.8

ENERGY CHANGES

1. Kinetic energy and potential energy: 1) Kinetic energy is the energy an object has because of its motion. mv 2 K.E. = 2 2) Potential energy is stored energy.

Figure 3.5

Potential energy (PE) exists between objects that either attract or repel each other. When the spring is either stretched or compressed, the PE of the two balls increases.

2. Chemical energy is a form of potential energy. 1) It exists because attractive and repulsive electrical forces exist between different pieces of the molecule. 2) Nuclei attract electrons, nuclei repel each other, and electrons repel each other. 3. Relative potential energy: 1) The relative stability of a system is inversely related to its relative potential energy. 2) The more potential energy an object has, the less stable it is.

~ 20 ~

3.8A POTENTIAL ENERGY AND COVALENT BONDS
1. Formation of covalent bonds: H• + H• H−H
∆H° = −435 kJ mol−1

1) The potential energy of the atoms decreases by 435 kJ mol−1 as the covalent bond forms.

Figure 3.6

The relative potential energies of hydrogen atoms and a hydrogen molecule.

2. Enthalpies (heat contents), H: (Enthalpy comes from en + Gk: thalpein to heat) 3. Enthalpy change, ∆H°: the difference in relative enthalpies of reactants and products in a chemical change. 1) Exothermic reactions have negative ∆H°. 2) Endothermic reactions have positive ∆H°.

3.9

THE RELATIONSHIP BETWEEN THE EQUILIBRIUM CONSTANT AND THE STANDARD FREE-ENERGY CHANGE, ∆G°

3.9A Gibbs Free-energy
1. Standard free-energy change (∆G°):
∆G° = −2.303 RT log Keq

1) The unit of energy in SI units is the joule, J, and 1 cal = 4.184 J. 2) A kcal is the amount of energy in the form of heat required to raise the
~ 21 ~

temperature of 1 Kg of water at 15 °C by 1 °C. 3) The reactants and products are in their standard states: and 1 M for a solution. 2. Negative value of ∆G°: reached. 1) The Keq is larger than 1. 2) Reactions with a ∆G° more negative than about 13 kJ mol−1 (3.11 kcal mol−1) are said to go to completion, meaning that almost all (>99%) of the reactants are converted into products when equilibrium is reached. 3. Positive value of ∆G°: is reached. 1) The Keq is less than 1. 4. ∆G° = ∆H° − T∆S° 1) ∆S°: i) changes in the relative order of a system. 1 atm pressure for a gas,

favor the formation of products when equilibrium is

unfavor the formation of products when equilibrium

A positive entropy change (+∆S°): a change from a more ordered system to a less ordered one.

ii) A negative entropy change (−∆S°): a change from a less ordered system to a more ordered one. iii) A positive entropy change (from order to disorder) makes a negative

contribution to ∆G° and is energetically favorable for the formation of products.
2) For many reactions in which the number of molecules of products equals the number of molecules of reactants ⇒ the entropy change is small ⇒ ∆G° will

be determined by ∆H° except at high temperatures.

3.10 THE ACIDITY OF CARBOXYLIC ACIDS
~ 22 ~

1. Carboxylic acids are much more acidic than the corresponding alcohols: 1) pKas for R–COOH are in the range of 3-5;.pKas for R–OH are in the range of 15-18. O H3C C OH

H3C

CH2

OH

Acetic acid pKa = 4.75 ∆G° = 27 kJ mol−1

Ethanol pKa = 16 ∆G° = 90.8 kJ mol−1

Figure 3.7

A diagram comparing the free-energy changes that accompany ionization of acetic acid and ethanol. Ethanol has a larger positive free-energy change and is a weaker acid because its ionization is more unfavorable.

~ 23 ~

3.10A AN EXPLANATION BASED ON RESONANCE EFFECTS
1. Resonance stabilized acetate anion:
Acetic Acid O H 3C C O H + H 2O H 3C C O− Aceate Ion O + H 3O +

O− H 3C C O
+

O− H 3C H C O Largeresonance stabilization (The structures are equivalent and there is no requirement for charge separation.)

Small resonance stabilization (The structures are not equivalent and the lower structure requires charge separation.) Figure 3.8

Two resonance structures that can be written for acetic acid and two that can be written for acetate ion. According to a resonance explanation of the greater acidity of acetic acid, the equivalent resonance structures for the acetate ion provide it greater resonance stabilization and reduce the positive free-energy change for the ionization.

1) The greater stabilization of the carboxylate anion (relative to the acid) lowers the free energy of the anion and thereby decreases the positive free-energy change required for the ionization. 2) Any factor that makes the free-energy change for the ionization of an acid less positive (or more negative) makes the acid stronger. 2. No resonance stabilization for an alcohol and its alkoxide anion:
H3C CH2 O H + H2O No resonance stabilization
− H3C CH2 O + H 3O + No resonance stabilization

~ 24 ~

3.10B AN EXPLANATION BASED ON INDUCTIVE EFFECTS
1. The inductive effect of the carbonyl group (C=O group) is responsible for the acidity of carboxylic acids. O

<
H3C C T2). The number of collisions with energies greater than the free energy of activation is indicated by the appropriately shaded area under each curve.

3) Because of the way energies are distributed at different temperature, increasing the temperature by only a small amount causes a large increase in the number of collisions with larger energies. 10. The relationship between the rate constant (k) and ∆G‡: k = k0 e − ∆G
‡

/ RT

1) k0 is the absolute rate constant, which equals the rate at which all transition states proceed to products. At 25 °C, k0 = 6.2 × 1012 s–1. 2) A reaction with a lower free energy of activation will occur very much faster

than a reaction with a higher one.
11. If a reaction has a ∆G‡ less than 84 kJ mol–1 (20 kcal mol–1), it will take place readily at room temperature or below. If ∆G‡ is greater than 84 kJ mol–1, heating

~ 17 ~

will be required to cause the reaction to occur at a reasonable rate. 12. A free-energy diagram for the reaction of methyl chloride with hydroxide ion:

Figure 6.5

A free-energy diagram for the reaction of methyl chloride with hydroxide ion at 60 °C.

1) At 60 °C, ∆G‡ = 103 kJ mol–1 (24.6 kcal mol–1) ⇒ the reaction reaches completion in a matter of a few hours at this temperature.

6.9

THE STEREOCHEMISTRY OF SN2 REACTIONS

1. In an SN2 reaction, the nucleophile attacks from the back side, that is, from the

side directly opposite the leaving group.
1) This attack causes a change in the configuration (inversion of configuration) of the carbon atom that is the target of nucleophilic attack.

~ 18 ~

H

O

−

H Hδ+ δ− C Cl H

δ−

HH C H

H

O

Cl

δ−

H H O C

H +

Cl −

H

An inversion of configuration 2. Inversion of configuration can be observed when hydroxide ion reacts with

cis-1-chloro-3-methylcyclopentane in an SN2 reaction:
An inversion of configuration H 3C H Cl + H OH H 3C S N2 H H + OH

−

Cl −

cis-1-Chloro-3-methylcyclopentane 1) The transition state is likely to be:

trans-3-methylcyclopentanol

H3C H

Leaving group departs from the top side. H − Nucleophile attacks δ OH from the bottom side. Cl

δ−

3. Inversion of configuration can be also observed when the SN2 reaction takes place at a stereocenter (with complete inversion of stereochemistry at the chiral carbon center): H C6H13 Br C CH3
(R)-(–)-2-Bromooctane [α ]25 = –34.25° D
~ 19 ~

Br

C6H13 H C CH3

(S)-(+)-2-Bromooctane [α ]25 = +34.25° D

H

C6H13 OH C CH3

HO

C6H13 H C CH3

(R)-(–)-2-Octanol [α ]25 = –9.90° D

(S)-(+)-2-Octanol [α ]25 = +9.90° D

1) The (R)-(–)-2-bromooctane reacts with sodium hydroxide to afford only (S)-(+)-2-octanol. 2) SN2 reactions always lead to inversion of configuration. The Stereochemistry of an SN2 Reaction SN2 Reaction takes place with complete inversion of configuration: An inversion of configuration H3C H δ− HO

−

C

δ+

Br

δ−

CH3 C

HO

Br

δ−

CH3 HO C H C6H13 +

Br−

C6H13

HC H 6 13

(R)-(–)-2-Bromooctane [α ]25 = –34.25° D Enantiomeric purity = 100%

(S)-(+)-2-Octanol [α ]25 = +9.90° D Enantiomeric purity = 100%

6.10 THE REACTION OF TERT-BUTYL CHLORIDE WITH HYDROXIDE ION: AN SN1 REACTION
1. When tert-butyl chloride with sodium hydroxide in a mixture of water and acetone, the rate of formation of tert-butyl alcohol is dependent on the concentration of

tert-butyl chloride, but is independent of the concentration of hydroxide ion.
~ 20 ~

1) tert-Butyl chloride reacts by substitution at virtually the same rate in pure water (where the hydroxide ion is 10–7 M) as it does in 0.05 M aqueous sodium hydroxide (where the hydroxide ion concentration is 500,000 times larger). 2) The rate equation for this substitution reaction is first order respect to

tert-butyl chloride and first order overall.
(CH3)3C Cl + OH− acetone H2O
⇒

(CH3)3C

OH

+

Cl−

Rate ∝ [(CH3)3CCl]

Rate = k [(CH3)3CCl]

2. Hydroxide ions do not participate in the transition state of the step that controls the rate of the reaction. 1) The reaction is unimolecular ⇒ SN1 reaction (Substitution, Nucleophilic, Unimolecular).

6.10A MULTISTEP REACTIONS AND THE RATE-DETERMINING STEP
1. The rate-determining step or the rate-limiting step of a multistep reaction:

Step 1 Step 2 Step 3

Reactant

slow

Intermediate 1

⇒

Rate = k1 [reactant] Rate = k2 [intermediate 1] Rate = k3 [intermediate 2]

Intermediate 1 Intermediate 2

fast fast

Intermediate 2 ⇒ Product
⇒

k1 R C+ R o 3 > (most stable)

R R C+ H o 2 > >

H R C+ H o 1 > >

H H C+ H Methyl (least stable)

1) A charged system is stabilized when the charge is dispersed or delocalized. 2) Alkyl groups, when compared to hydrogen atoms, are electron releasing.

Figure 6.9

How a methyl group helps stabilize the positive charge of a carbocation. Electron density from one of the carbon-hydrogen sigma bonds of the methyl group flows into the vacant p orbital of the carbocation because the orbitals can partly overlap. Shifting electron density in this way makes the sp2-hybridized carbon of the carbocation somewhat less positive, and the hydrogens of the methyl group assume some of the positive charge. Delocalization (dispersal) of the charge in this way leads to greater stability. This interaction of a bond orbital with a p orbital is called hyperconjugation.

2. The delocalization of charge and the order of stability of carbocations parallel the number of attached methyl groups.

H3C

δ+

is δ+ more H C C δ+ stable 3 δ+CH3 than

δ+CH3

δ+CH3

C δ+ H

is δ+ more H C 3 stable than

is C δ+ more H stable H than

H

H C δ+ H

tert-Butyl cation (3°) (most stable)

Isopropyl cation (2°)

Ethyl cation (1°)

Methyl cation (least stable)

3. The relative stabilities of carbocations is 3° > 2° > 1° > methyl.
~ 25 ~

4. The electrostatic potential maps for carbocations:

Figure 6.10 Electrostatic potential maps for (a) tert-butyl (3°), (b) isopropyl (2°), (c) ethyl (1°), and (d) methyl carbocations show the trend from greater to lesser delocalization (stabilization) of the positive charge. (The structures are mapped on the same scale of electrostatic potential to allow direct comparison.)

6.13 THE STEREOCHEMISTRY OF SN1 REACTIONS
1. The carbocation has a trigonal planar structure ⇒ It may react with a nucleophile from either the front side or the back side:
Same product
+

CH3 C CH3 CH3

H2O

back side attack

CH3 H2O C+ H3C CH
3

OH2

front side attack

H 3C H 3C H 3C C

OH2

+

1) With the tert-butyl cation it makes no difference. 2) With some cations, different products arise from the two reaction possibilities.

6.13A REACTIONS THAT INVOLVE RACEMIZATION
1. Racemization: a reaction that transforms an optically active compound into a racemic form.
~ 26 ~

1) Complete racemization and partial racemization: 2) Racemization takes place whenever the reaction causes chiral molecules to be converted to an achiral intermediate. 2. Heating optically active (S)-3-bromo-3-methylhexane with aqueous acetone results in the formation of racemic 3-methyl-3-hexanol.
H3CH2CH2C H 3C H3CH2C C H2O H3CH2CH2C C Br H 3C acetone H3CH2C O H + H O CH2CH2CH3 + HBr C CH3 CH2CH3

(S)-3-bromo-3-methylhexane (S)-3-methyl-3-hexanol (R)-3-methyl-3-hexanol (optically active) (optically inactive, a racemic form) i) The SN1 reaction proceeds through the formation of an achiral trigonal planar carbocation intemediate.

The stereochemistry of an SN1 Reaction CH2CH2CH3 C+ H3C CH CH 2 3

H3CH2CH2C H 3C H3CH2C

C

Br

− Br slow

−

The carbocation has a trigonal planar structure and is achiral.

H3CH2CH2C H H C Back side O Front side H3C attack Pr-n attack H3CH2C C+ fast Enantiomers

O

+

OH2 H H3CH2CH2C H fast H3C H3CH2C

C

O + H3O+ H

A racemic mixture C CH2CH2CH3 CH3 CH2CH3 + H3O+

H3C CH CH H CH2CH2CH3 2 3 + O O C Front side and back aside CH3 attack take place at equal H H CH2CH3 rates, and the product is OH2 formed as a racemic mixture.

The SN1 reaction of (S)-3-bromo-3-methylhexane proceeds with racemization because the intermediate carbocation is achiral and attacked by the nucleophile can occur from either side. 3. Few SN1 displacements occur with complete racemization.
~ 27 ~

Most give a minor

(0 ~ 20 %) amount of inversion. H3C C2H5 Cl H3C C2H5 OH + HO C2H5 CH3

H2O

C2H5OH (CH2)3CH(CH3)2 (R)-6-Chloro2,6-dimethyloctane
This side open to attack B D C Br H2O

(CH2)3CH(CH3)2 40% R (retention)
This side shielded from attack BD

+ HCl (CH2)3CH(CH3)2

60% S (inversion)

BD Br
−

Br

−

H2O

C

+

H2O

C

+

H2O

A

A Ion pair D HO C

A Free carbocation D HO C D C OH

B

B

+

B

A Inversion

A

A

Racemization

6.13B SOLVOLYSIS
1. Solvolysis is a nucleophilic substitution in which the nucleophile is a molecule of the solvent (solvent + lysis: cleavage by the solvent). 1) Hydrolysis: 2) Alcoholysis: when the solvent is water. when the solvent is an alcohol (e.g. methanolysis).

Examples of Solvolysis
(H3C)3C (H3C)3C Br Cl + H2O (H3C)3C (H3C)3C OH + HBr HCl

+ CH3OH

OCH3 +

O (H3C)3C Cl + HCOH (H3C)3C

O OCH + HCl

~ 28 ~

2. Solvolysis involves the initial formation of a carbocation and the subsequent reaction of that cation with a molecule of the solvent:
Step 1
(H3C)3C Cl slow (CH3)3C+ + Cl −

Step 2

O (CH3)3C+ + H
Step 3

O fast H O CH

+

C(CH3)3 H O
+

O CH

C(CH3)3

O

CH

O Cl − H O
+

CH

C(CH3)3 fast

O C(CH3)3 O O CH HC O C(CH3)3 + H Cl

6.14 FACTORS AFFECTING THE RATES OF SN1 AND SN2 REACTIONS
1. Factors Influencing the rates of SN1 and SN2 reactions: 1) The structure of the substrate. 2) The concentration and reactivity of the nucleophile (for bimolecular reactions). 3) The effect of the solvent. 4) The nature of the leaving group.

6.14A THE EFFECT OF THE STRUCTURE OF THE SUBSTRATE
1. SN2 Reactions:

1) Simple alkyl halides show the following general order of reactivity in SN2 reactions: methyl > 1° > 2° >> 3° (unreactive)

~ 29 ~

Table 6.4

Relative Rates of Reactions of Alkyl Halides in SN2 Reactions Compound CH3X CH3CH2X (CH3)2CHX (CH3)3CCH2X (CH3)3CX Relative Rate

Substituent Methyl 1° 2° Neopentyl 3°

30 1 0.02 0.00001 ~0

i)

Neopentyl halids are primary halides but are very unreactive. CH3 H 3C C CH2 CH3 X
A neopentyl halide

2) Steric effect: i) A steric effect is an effect on relative rates caused by the space-filling properties of those parts of a molecule attached at or near the reacting site.

ii) Steric hindrance: the spatial arrangement of the atoms or groups at or near the reacting site of a molecule hinders or retards a reaction. iii) Although most molecules are reasonably flexible, very large and bulky groups can often hinder the formation of the required transition state. 3) An SN2 reaction requires an approach by the nucleophile to a distance within bonding range of the carbon atom bearing the leaving group. i) Substituents on or near the reacting carbon have a dramatic inhibiting effect.

ii) Substituents cause the free energy of the required transition state to be increased and, consequently, they increase the free energy of activation for the reaction.

~ 30 ~

Figure 6.11

Steric effects in the SN2 reaction.

CH3–Br

CH3CH2–Br

(CH3)2CH–Br

(CH3)3CCH2–Br

(CH3)3C–Br

2. SN1 Reactions:

1) The primary factor that determines the reactivity of organic substrates in an SN1 reaction is the relative stability of the carbocation that is formed.

Table 6A
CH3Br

Relative rates of reaction of some alkyl halides with water:
Type Product Relative rate of reaction

Alkyl halide

Methyl 1° 2° 3°

CH3OH CH3CH2OH (CH3)2CHOH (CH3)3COH

1.0 1.0 12 1,200,000

CH3CH2Br (CH3)2CHBr (CH3)3CBr

2) Organic compounds that are capable of forming relatively stable carbocation can undergo SN1 reaction at a reasonable rate. i) Only tertiary halides react by an SN1 mechanism for simple alkyl halides.
~ 31 ~

ii) Allylic halides and benzylic halides: A primary allylic or benzylic carbocation is approximately as stable as a secondary alkyl carbocation (2° allylic or benzylic carbocation is about as stable as a 3° alkyl carbocation). iii) The stability of allylic and benzylic carbocations: delocalization. H H H2C CH CH2+ Allyl carbocation C H C C C+ H
+

H H H
+C

C

C H

H

H
+

C

C

C

C

C

H

C

+

H

H

C

H
+

H

C

H

H
+

C

H

CH2

+

+

Benzyl carbocation

+

H H

+

H H

Table 10B

Relative rates of reaction of some alkyl tosylates with ethanol at 25 °C
Alkyl tosylate Product Relative rate

CH3CH2OTos (CH3)2CHOTos H2C=CHCH2OTos C6H5CH2OTos (C6H5)2CHOTos (C6H5)3COTos

CH3CH2OCH2CH3 (CH3)2CHOCH2CH3 H2C=CHCH2OCH2CH3 C6H5CH2OCH2CH3 (C6H5)2CHOCH2CH3 (C6H5)3COCH2CH3
~ 32 ~

1 3 35 400 105 1010

4) The stability order of carbocations is exactly the order of SN1 reactivity for alkyl halides and tosylates. 5) The order of stability of carbocations: 3° > 2° ≈ Allyl ≈ Benzyl >> 1° > Methyl > CH3+

R3C+ >

R2CH+ ≈

H2C=CH–CH2+ ≈ C6H5–CH2

>> RCH2+

6) Formation of a relatively stable carbocation is important in an SN1 reaction
⇒

low free energy of activation (∆G‡) for the slow step of the reaction.

i)

The ∆G° for the first step is positive (uphill in terms of free energy) ⇒ the first step is endothermic (∆H° is positive; uphill in terms of enthalpy).

7) The Hammond-Leffler postulate: i)
The structure of a transition state resembles the stable species that is nearest it in free energy ⇒ Any factor that stabilize a high-energy intermediate should

also stabilize the transition state leading to that intermediate. ii) The transition state of a highly endergonic step lies close to the products in free energy ⇒ it resembles the products of that step in structure. iii) The transition state of a highly exergonic step lies close to the reactants in free energy ⇒ it resembles the reactants of that step in structure.

~ 33 ~

Figure 6.12 Energy diagrams for highly exergonic and highly endergonic steps of reactions. 7) The transition state of the first step in an SN1 reaction resembles to the product of that step:

CH3
Step 1 H3C

CH3 Cl H2O H3C C δ+ δ−

CH3 Cl H2O H3C C+ + Cl− CH3

C CH3

CH3

Reactant

Transition state Product of step Resembles product of step stabilized by three electronBecause ∆G° is positive releasing groups

i)

Any factor that stabilizes the carbocation ––– such as delocalization of the positive charge by electron-releasing groups ––– should also stabilize the transition state in which the positive charge is developing.

8) The activation energy for an SN1 reaction of a simple methyl, primary, or secondary halide is so large that, for all practical purposes, an SN1 reaction does not compete with the corresponding SN2 reaction.
~ 34 ~

6.14B THE EFFECT OF THE CONCENTRATION AND STRENGTH OF THE NUCLEOPHILE
1. Neither the concentration nor the structure of the nucleophile affects the rates of SN1 reactions since the nucleophile does not participate in the rate-determining step. 2. The rates of SN2 reactions depend on both the concentration and the structure of the nucleophile. 3. Nucleophilicity: the ability for a species for a C atom in the SN2 reaction.

1) It depends on the nature of the substrate and the identity of the solvent. 2) Relative nucleophilicity (on a single substrate in a single solvent system): 3) Methoxide ion is a good nucleophile (reacts rapidly with a given substrate): CH3O− + CH3I rapid CH3OCH3 + I−

4) Methanol is a poor nucleophile (reacts slowly with the same substrate under the same reaction conditions): CH3OH + CH3I very slow CH3OCH3 + I− H 5) The SN2 reactions of bromomethane with nucleophiles in aqueous ethanol:
Nu− Nu = HS– + CH3Br CN– I– CH3O– NuCH3 HO– 16,000 + Br− Cl– 1,000 NH3 700 H2O 1
+

Relative 125,000 125,000 100,000 25,000 reactivity 4. Trends in nucleophilicity:

1) Nucleophiles that have the same attacking atom: nucleophilicity roughly parallels basicity.
~ 35 ~

i)

A negatively charged nucleophile is always a more reactive nucleophile than its conjugate acid ⇒ HO– is a better nucleophile than H2O; RO– is a better nucleophile than ROH.

ii) In a group of nucleophiles in which the nucleophilic atom is the same, nucleophilicities parallel basicities: RO– > HO– >> RCO2– > ROH > H2O

2) Correlation between electrophilicity-nucleophilicity and Lewis acidity-basicity: i) “Nucleophilicity” measures the affinity (or how rapidly) of a Lewis base for a carbon atom in the SN2 reaction (relative rates of the reaction). ii) “Basicity”, as expressed by pKa, measures the affinity of a base for a proton (or the position of an acid-base equilibrium). Correlation between Basicity and Nucleophilicity Nucleophile Rates of SN2 reaction with CH3Br pKa of conjugate acid CH3O– 25 15.5 HO– 16 15.7 CH3CO2– 0.3 4.7 H2O 0.001 –1.7

iii) A HO– (pKa of H2O is 15.7) is a stronger base than a CN– (pKa of HCN is ~10) but CN– is a stronger nucleophile than HO–. 3) Nucleophilicity usually increases in going down a column of the periodic table. i) HS– is more nucleophilic than HO–. I– > Br– > Cl– ii) The halide reactivity order is:

iii) Larger atoms are more polarizable (their electrons are more easily distorted)

⇒ a larger nucleophilic atom can donate a greater degree of electron density to the substrate than a smaller nucleophile whose electrons are more tightly held.

6.14C SOLVENT EFFECTS ON SN2 REACTIONS: PROTIC AND APROTIC SOLVENTS
1. Protic Solvents:

hydroxylic solvents such as alcohols and water
~ 36 ~

1) The solvent molecule has a hydrogen atom attached to an atom of a strongly electronegative element. 2) In protic solvents, the nucleophile with larger nucleophilic atom is better. i) Thiols (R–SH) are stronger nucleophiles than alcohols (R–OH); RS– ions are more nucleophilic than RO– ions. ii) The order of reactivity of halide ions: I– > Br– > Cl– > F–

3) Molecules of protic solvents form hydrogen bonds nucleophiles:

H O H H O

H X
−

O H

H

H

O H

Molecules of the protic solvent, water, solvate a halide ion by forming hydrogen bonds to it.

i) A small nucleophile, such fluoride ion, because its charge is more concentrated, is strongly solvated than a larger one. 4) Relative Nucleophilicity in Protic Solvents:

SH– > CN– > I– > HO– > N3– > Br– CH3CO2– > Cl–> F– > H2O
2. Polar Aprotic Solvent: 1) Aprotic solvents are those solvents whose molecules do not have a hydrogen

atom attached to an atom of a strongly electronegative element.
i) Most aprotic solvents (benzene, the alkanes, etc.) are relatively nonpolar, and they do not dissolve most ionic compounds. ii) Polar aprotic solvents are especially useful in SN2 reactions:

O H C N

CH3 CH3 H3C

O S CH3

O CH3C N

CH3 CH3

O (H3C)2N P N(CH3)2

N(CH3)2
Hexamethylphosphoramide

N,N-Dimethylformamide Dimethyl sulfoxide

Dimethylacetamide ~ 37 ~

(DMF)

(DMSO)

(DMA)

(HMPA)

1) Polar aprotic solvents dissolve ionic compounds, and they solvate cations very well.
H3C OH2 Na H2O OH2
+

S O

CH3 O O

H2O

OH2 OH2

(H3C)2S (H3C)2S

O O

Na

+

S(CH3)2 S(CH3)2

O H3C S CH3

A sodium ion solvated by molecules of the protic solvent water

A sodium ion solvated by molecules of the aprotic solvent dimethyl sulfoxide

2) Polar aprotic solvents do not solvate anions to any appreciable extent because they cannot form hydrogen bonds and because their positive centers are well shielded from any interaction with anions.

i)

“Naked” anions are highly reactive both as bases and nucleophiles.

ii) The relative order of reactivity of halide ions is the same as their relative basicity in DMSO:
F–> Cl– > Br– > I–

iii) The relative order of reactivity of halide ions in alcohols or water:
I– > Br– > Cl– > F–

3) The rates of SN2 reactions generally are vastly increased when they are carried out in polar aprotic solvents.

4) Solvent effects on the SN2 reaction of azide ion with 1-bromobutane:

N3− + CH3CH2CH2CH2Br Solvent HMPA

Solvent

CH3CH2CH2CH2N3 + DMSO H2O

Br− CH3OH

CH3CN

DMF

~ 38 ~

Relative reactivity

200,000

5,000

2,800

1,300

6.6

1

6.14D SOLVENT EFFECTS ON SN1 REACTIONS: THE IONIZING ABILITY OF THE SOLVENTS
1. Polar protic solvent will greatly increase the rate of ionization of an alkyl halide in any SN1 reaction.

1) Polar protic solvents solvate cations and anions effecttively. 2) Solvation stabilizes the transition state leading to the intermediate carbocation and halide ion more it does the reactants ⇒ the free energy of activation is lower. 3) The transition state for the ionization of organohalide resembles the product carbocation.
(H3C)3C Cl (H3C)3C δ+ Cl

δ−

− (CH3)3C+ + Cl

Reactant

Transition state Separated charges are developing

Products

2. Dielectric constant: a measure of a solvent’s ability to insulate opposite charges from each other.

~ 39 ~

Table 6.5 Name

Dielectric Constants of Some Common Solvents Structure Dielectric constant, ε

APROTIC (NONHYDROXYLIC) SOLVENTS
Hexane Benzene Diethyl ether Chloroform Ethyl acetate Acetone Hexamethylphosphoramide (HMPA) Acetonitrile Dimethylformamide (DMF) Dimethyl sulfoxide (DMSO) CH3CH2CH2CH2CH2CH3 C6H6 CH3CH2–O–CH2CH3 CHCl3 CH3C(O)OC2H5 (CH3)2CO [(CH3)2N]3PO CH3CN (CH3)2NCHO (CH3)2SO 1.9 2.3 4.3 4.8 6.0 20.7 30 36 38 48

PROTIC (HYDROXYLIC) SOLVENTS
Acetic acid CH3C(O)OH (CH3)3COH CH3CH2OH CH3OH HC(O)OH H2O 6.2 10.9 24.3 33.6 58.0 80.4

tert-Butyl alcohol
Ethanol Methanol Formic acid Water

1) Water is the most effective solvent for promoting ionization, but most organic compounds do not dissolve appreciably in water. 2) Methanol-water and ethanol-water are commonmixed solvents for nucleophilic substitution reactions.

~ 40 ~

Table 6C Relative rates for the reaction of 2-chloro-2-methylpropane with different solvents Solvent
Ethanol Acetic acid Aqueous ethanol (40%) Aqueous ethanol (80%) Water

Relative rate
1 2 100 14,000 105

6.14E THE NATURE OF THE LEAVING GROUP
1. Good Leaving Group: 1) The best leaving groups are those that become the most stable ions after they depart. 2) Most leaving groups leave as a negative ion ⇒ the best leaving groups are those ions that stabilize a negative charge most effectively ⇒ the best leaving groups are weak bases. 2. The leaving group begins to acquire a negative charge as the transition state is reached in either an SN1 or SN2 reaction.

SN1 Reaction (rate-limiting step) δ+ δ−
− C+ + X

C

X

C

X

Transition state
SN2 Reaction
Nu − δ− δ−

C

X

Nu

C

X

Nu

C

+ X−

Transition state
1) Stabilization of the developing negative charge at the leaving group stabilizes
~ 41 ~

the transition state (lowers its free energy) ⇒ lowers the free energy of activation ⇒ increases the rate of the reaction. 3. Relative reactivity of some leaving groups:

Leaving group Relative reactivity

TosO– 60,000

I– 30,000

Br– 10,000

Cl– 200

F– 1

HO–, H2N–, RO– ~0

4. Other good leaving groups: O
−

O R
−

O O R
−

O

S O

O

S O

O

S O

CH3

An alkanesulfonate ion

An alkyl sulfate ion

p-Toluenesulfonate ion

1) These anions are all the conjugate bases of very strong acids. 2) The trifluoromethanesulfonate ion (CF3SO3–, triflate ion) is one of the best leaving group known to chemists. i) It is the anion of CF3SO3H, an exceedingly strong acid –– one that is much stronger than sulfuric acid. CF3SO3–, triflate ion (a “super” leaving group) 5. Strongly basic ions rarely act as leaving groups.

X−

R

OH

R

X

+

OH−

This reaction doesn't take place because the leaving group is a strongly basic hydroxide ion. 1) Very powerful bases such as hydride ions (H:–) and alkanide ions (R:–) virtually never act as leaving groups.

~ 42 ~

Nu − + Nu − +

CH3CH2 H 3C

H

CH3CH2 H 3C Nu

Nu + H − + CH3 −

CH3

These are not leaving groups

6. Protonation of an alcohol with a strong acid turns its poor OH– leaving group (strongly basic) into a good leaving group (neutral water molecule). X− R OH H
+

R X + H2O This reaction take place cause the leaving group is a weak base.

6.14F SUMMARY: SN1 VERSUS SN2
1. Reactions of alkyl halides by an SN1 mechanism are favored by the use of: 1) substrates that can form relatively stable carbocations. 2) weak nucleophiles. 3) highly ionizing solvent. 2. Reactions of alkyl halides by an SN2 mechanism are favored by the use of: 1) relatively unhindered alkyl halides. 2) strong nucleophiles. 3) polar aprotic solvents. 4) high concentration of nucleophiles. 3. The effect of the leaving group is the same in both SN1 and SN2: R–I > R–Br > R–Cl SN1 or SN2

~ 43 ~

Table 6.6
Factor

Factors Favoring SN1 versus SN2 Reactions
SN1 SN2

Substrate

3° (requires formation of a relatively stable carbocation) Weak Lewis base, neutral molecule, nucleophile may be the solvent (solvolysis) Polar protic (e.g. alcohols, water)

Methyl > 1° > 2° (requires unhindered substrate) Strong Lewis base, rate favored by high concentration of nucleophile Polar aprotic (e.g. DMF, DMSO)

Nucleophile
Solvent

Leaving group

I > Br > Cl > F for both SN1 and SN2 (the weaker the base after departs, the better the leaving group)

6.15 ORGANIC SYNTHESIS: FUNCTIONAL GROUP TRANSFORMATIONS USING SN2 REACTIONS
1. Functional group transformation (interconversion): (Figure 6.13)

2. Alkyl chlorides and bromides are easily converted to alkyl iodide by SN2 reaction

OH− R'O− SH− R'S− R X (R=Me, 1o, or 2o) (X=Cl, Br, or I) − X− R' CN− C O R'CO− NR'3 N3− C
−

R R R R R R R R R

OH OR' SH SR' C N

Alcohol Ether Thiol Thioether Nitrile R' Alkyne Ester Quaternary ammonium halide Alkyl azide

C C O OCR' NR'3X− N3

Figure 6.13 Functional group interconversions of methyl, primary, and secondary alkyl halides using SN2 reactions.
~ 44 ~

R R

Br Cl

I−

R

− − I (+ Cl or Br )

3. Inversion of configuration in SN2 reactions:
−

CH3 + CH2CH3 (R)-2-Bromobutane H C Br

N

C

S N2 (inversion)

CH3 N C C

H CH2CH3 (S)-2-Methylbutanenitrile

+ Br−

6.15A THE UNREACTIVITY OF VINYLIC AND PHENYL HALIDES
1. Vinylic halides and phenyl halides are generally unreactive in SN1 or SN1 reactions. 1) Vinylic and phenyl cations are highly unstable and do not form readily. 2) The C–X bond of a vinylic or phenyl halide is stronger than that of an alkyl halide and the electrons of the double bond or benzene ring repel the approach of a nucleophile from the back side.

C

C

X Phenyl halide

X A vinylic halide

The Chemistry of.…
Biological Methylation: A Biological Nucleophilic Substitution Reaction
−

O2CCHCH 2CH2SCH3 Methionine NH3+ HO CH3 CHCH2NHCH3 OH Adrenaline
~ 45 ~

N CH3 N Nicotine

HO

H3C N+ CH2CH2OH CH3 Choline

Triphosphate group O− Nucleophile
−

O− O P O

O− P OH Leaving group
NH2 N

O S

P O

O2C NH3+

+ CH2 H O H CH3 H OH ATP

O O Adenine Adenine =

N N

Methionine CH3
−

H OH

N

O2C NH3+

S+

CH2 Adenine O H H + H

O−
−

O− O P O O

O− P O OH

O

P O

H OH OH S-Adenosylmethionine CH3 2-(N,N-Dimethylamino)ethanol HOH2CH2C
−

Triphosphate ion

N

CH3 CH 3 S+ CH2 Adenine O H H H H OH

O2C NH3+

OH

CH3 HOH2CH2C N
+

−

O2C NH3+

S

CH3 +

CH2 Adenine O H H H H OH

CH3 Choline

OH

~ 46 ~

6.16 ELIMINATION REACTIONS OF ALKYL HALIDES
C Y C Z elimination (−YZ) C C

6.16A DEHYDROHALOGENATION
1. Heating an alkyl halide with a strong base causes elimination to happen: CH3CHCH3 Br CH3 H 3C C CH3 Br C2H5ONa H2C CH (79%) CH3 H 3C C CH2 + NaBr + C2H5OH (91%) CH3 + NaBr + C2H5OH

C2H5OH, 55oC

C2H5OH, 55oC

C2H5ONa

2. Dehydrohalogenation:
H C

β

C

α

+

X

B− Base

Dehydrohalogenation (−HX) X = Cl, Br, I

C

C

+ H B + X−

1) alpha (α) carbon atom: 2) beta (β) hydrogen atom: 3) β-elimination (1,2-elimination):

6.16B BASES USED IN DEHYDROHALOGENATION
1. Potassium hydroxide dissolved in ethanol and the sodium salts of alcohols (such as sodium ethoxide) are often used as the base for dehydrohalogenation. 1) The sodium salt of an alcohol (a sodium alkoxide) can be prepared by treating an alcohol with sodium metal:
~ 47 ~

2R

OH + 2 Na

2R

O− Na+ + H2

Alcohol

sodium alkoxide

i)

This is an oxidation-reduction reaction.

ii) Na is a very powerful reducing agent. iii) Na reacts vigorously (at times explosively) with water:

2H

OH + 2 Na

2H

O− Na+ + H2

sodium hydroxide 2) Sodium alkoxides can also be prepared by reacting an alcohol with sodium hydride (H:–):
R O H + Na+ :H− R O− Na+ + H H

2. Sodium (and potassium) alkoxides are usually prepared by using excess of alcohol, and the excess alcohol becomes the solvent for the reaction. 1) Sodium ethoxide:

2 CH3CH2

OH + 2 Na

2 CH3CH2

O− Na+ + H2

Ethanol (excess) 2) Potassium tert-butoxide: CH3 H3CC OH + 2 K CH3 tert-Butyl alcohol (excess)

sodium ethoxide

CH3 H3CC O − K+ + H2 CH3 Potassium tert-butoxide

6.16C MECHANISMS OF DEHYDROHALOGENATIONS
~ 48 ~

1. E2 reaction 2. E1 reaction

6.17 THE E2 REACTION
1. Rate equation Rate = k [CH3CHBrCH3] [C2H5O–]

A Mechanism for the E2 Reaction
Reaction: C2H5O– Mechanism: H

+ CH3CHBrCH3

CH2=CHCH3

+ C2H5OH

+

Br–

CH3CH2

O

−

H

C C H β α H Br

CH3

CH3CH2

O

δ−

H

H

+ +

C C δ− H β α H Br

CH3

Transition state The basic ethoxide ion begins to remove Partial bonds now exist between the a proton from the β -carbon using its oxygen and the β hydrogen and electron pair to form a bond to it. At the between the α carbonand the same tim, the electron pair of the β bromine. The carbon-carbon bond is C−H bond begins to move in to become developing double bond character. the π bond of a double bond, and the bromide begins to depart with the electrons that bonded it to the α carbon.

H C C

CH3 + CH3CH2
OH

+

Br −

H H Now the double bond of the alkene is fully formed and the alkene has a trigonal plannar geometry at each carbon atom. The other products are a molecule of ethanol and a bromide ion.

~ 49 ~

6.18 THE E1 REACTION
1. Treating tert-butyl chloride with 80% aqueous ethanol at 25°C gives substitution products in 83% yield and an elimination product in 17% yield.

CH3 H3CC CH3 H3CC CH3 Cl 80% C2H5OH 20% H2O 25 oC

CH3 OCH2CH3

OH + H3CC

CH3 CH3 tert-Butyl alcohol tert-Butyl ethyl ether (83%) CH3 H2C C CH3
2-Methylpropene (17%)

1) The initial step for reactions is the formation of a tert-butyl cation. CH3 H3CC CH3
Cl −

slow

CH3 H3CC + CH3 (solvated) +

Cl − (solvated)

2) Whether substitution or elimination takes place depends on the next step (the fast step). i) The SN1 reaction: CH3 H3CC + HO CH3
Sol

fast

CH3 H3CC CH3
+

Sol

CH3 H3CC
O Sol O Sol + H

H O Sol
+

O H
H

S N1 reaction

(Sol = H− or CH3CH2−) ii) The E1 reaction:

CH3

~ 50 ~

CH3
Sol O H H

CH2

C

+

fast

Sol

O

+

H + H 2C C

CH3
E1 reaction

CH3

H

CH3 2-Methylpropene

iii) The E1 reaction almost always accompany SN1 reactions.

A Mechanism for the E1 Reaction
Reaction:

(CH3)3CBr
Mechanism:

+ H2O

CH2=C(CH3)3

+ H2O+

+ Cl–

Step 1

CH3 H3C C CH3
Aided by the polar solvent a chlorine departs with the electron pair that bonded it to the carbon.

Cl

slow H2O

H3C

C

+

CH3 + CH3

Cl −

This slow step produces the relatively stable 3o carbocatoin and a chloride ion. The ions are solvated(and stabilized) by surrounding water molecules.

Step 2
H H O

+

H

C αC + β

CH3
H

O

+

H
H

+

C

C

CH3

CH3 H H A molecule of water removes one of the hydrogens from the β carbon of the carbocation. An electron pair moves in to form a double bond between the α and β carbon atoms.

CH3 H H This step produces the alkene and a hydronium ion

~ 51 ~

6.19 SUBSTITUTION VERSUS ELIMINATION
1. Because the reactive part of a nucleophile or a base is an unshared electron pair, all nucleophiles are potential bases and all bases are potential nucleophiles. 2. Nucleophileic substitution reactions and elimination reactions often compete with each other.

6.19A SN2 VERSUS E2
1. Since eliminations occur best by an E2 path when carried out with a high concentration of a strong base (and thus a high concentration of a strong nucleophile), substitution reactions by an SN2 path often compete with the elimination reaction. 1) When the nucleophile (base) attacks a β carbon atom, elimination occurs. 2) When the nucleophile (base) attacks the carbon atom bearing the leaving group, substitution results. (a) elimination E2
X H Nu
C C

(a)
Nu −

H

C C

(b)

(b) substitution S N2

C C

+

X−

2. Primary halides and ethoxide: CH3CH2O−Na+ + CH3CH2Br

substitution is favored

55oC (−NaBr)

C2H5OH

CH3CH2OCH2CH3 + H2C

CH2

3. Secondary halides:

elimination is favored

~ 52 ~

C2H5Ο − Na+ + CH3CHCH3 Br

C2H5OH 55oC (−NaBr)

CH3CHCH 3 +
O C2H5 SN2 (21%)

H2C

CHCH3

E2 (79%)

4. Tertiary halides:

no SN2 reaction, elimination reaction is highly favored

CH3
C2H5Ο − Na+ + CH3CCH3 Br

C2H5OH 25oC (−NaBr)

CH3 CH3CCH3
O C2H5 SN2 (9%)

+ H2C

CHCH3

E2 (91%) C2H5OH

CH3
C2H5Ο − Na+ + CH3CCH3 Br

C2H5OH 55oC (−NaBr)

CH3 H2C CCH3 +
E2 + E1 (100%)

1) Elimination is favored when the reaction is carried out at higher temperature. i) Eliminations have higher free energies of activation than substitutions because eliminations have a greater change in bonding (more bonds are broken and formed). ii) Eliminations have higher entropies than substitutions because eliminations have a greater number of products formed than that of starting compounds). 2) Any substitution that occurs must take place through an SN1 mechanism.

6.19B TERTIARY HALIDES: SN1 VERSUS E1
1. E1 reactions are favored: 1) with substrates that can form stable carbocations. 2) by the use of poor nucleophiles (weak bases). 3) by the use of polar solvents (high dielectric constant). 2. It is usually difficult to influence the relative position between SN1 and E1 products.
~ 53 ~

3. SN1 reaction is favored over E1 reaction in most unimolecular reactions. 1) In general, substitution reactions of tertiary halides do not find wide use as synthetic methods. 2) Increasing the temperature of the reaction favors reaction by the E1 mechanism at the expense of the SN1 mechanism. 3) If elimination product is desired, it is more convenient to add a strong base and force an E2 reaction to take place.

6.20 OVERALL SUMMARY
Table 6.7
CH3X Methyl

Overall Summary of SN1, SN2, E1 and E2 Reactions
RCH2X 1° RR’CHX 2° only RR’R”CX 3°

Bimolecular reactions
Gives mainly SN2

SN1/E1 or E2

reactions

Gives SN2

except with a hindered strong base [e.g., (CH3)3CO–] and then gives mainly E2

with weak bases (e.g., I–, CN–, RCO2–) and mainly E2 with strong bases (e.g., RO–)

Gives mainly SN2

In solvolysis gives SN1/E1, and at lower temperatures SN1 is favored. When a strong base (e.g., RO–) is used E2 predominates

No SN2 reaction.

~ 54 ~

Table 6D
Halide type

Reactivity of alkyl halides toward substitution and elimination
SN1 SN2 E1 E2

Primary halide Does not occur
Can occur under solvolysis conditions in polar solvents

Highly favored Favored by good nucleophiles in polar aprotic solvents

Does not occur Can occur under solvolysis conditions in polar solvents Occurs under solvolysis conditions

Occurs when strong, hindered bases are used

Secondary halide

Favored when strong bases are used Highly favored when bases are used

Tertiary halide

Favored by nonbasic nucleophiles in polar solvents

Does not occur

Table 6E
Reaction

Effects of reaction variables on substitution and elimination reactions
Solvent Nucleophile/base

Leaving group Strong effect; reaction favored by good leaving group Strong effect; reaction favored by good leaving group Strong effect; reaction favored by good leaving group Strong effect; reaction favored by good leaving group

Substrate structure
Strong effect; reaction favored by 3°, allylic, and benzylic substrates Strong effect; reaction favored by 1°, allylic, and benzylic substrates Strong effect; reaction favored by 3°, allylic, and benzylic substrates Strong effect; reaction favored by 3° substrates

SN1

Very strong effect; reaction favored by polar solvents Strong effect; reaction favored by polar aprotic solvents Very strong effect; reaction favored by polar solvents Strong effect; reaction favored by polar aprotic solvents

Weak effect; reaction favored by good nucleophile/weak base Strong effect; reaction favored by good nucleophile/ weak base Weak effect; reaction favored by weak base Strong effect; reaction favored by poor nucleophile/ strong base

SN2

E1

E2

~ 55 ~

ALKENES AND ALKYNES I. PROPERTIES AND SYNTHESIS
7.1 INTRODUCTION

1. Alkenes are hydrocarbons whose molecules contain the C–C double bond. 1) olefin: i) Ethylene was called olefiant gas (Latin: oleum, oil + facere, to make) because gaseous ethane (C2H4) reacts with chlorine to form C2H4Cl2, a liquid (oil).

H C H C

H H Ethene

H C H C

CH3 H C C H H Propene

Ethyne

2. Alkynes are hydrocarbons whose molecules contain the C–C triple bond. 1) acetylenes:

7.1A PHYSICAL PROPERTIES OF ALKENES AND ALKYNES
1. Alkenes and alkynes have physical properties similar to those of corresponding alkanes. 1) Alkenes and alkynes up to four carbons (except 2-butyne) are gases at room temperature. 2) Alkenes and alkynes dissolve in nonpolar solvents or in solvents of low polarity. i) Alkenes and alkynes are only very slightly soluble in water (with alkynes being slightly more soluble than alkenes). ii) Alkenes and alkynes have densities lower than that of water.

7.2

NOMENCLATURE OF ALKENES AND CYCLOALKENES
~1~

1. Determine the base name by selecting the longest chain that contains the double

bond and change the ending of the name of the alkane of identical length from -ane to -ene. 2. Number the chain so as to include both carbon atoms of the double bond, and begin numbering at the end of the chain nearer the double bond. bond as a prefix: 3. Indicate the location of the substituent groups by numbering of the carbon atoms to which they are attached. 4. Number substituted cycloalkenes in the same way that gives the carbon atoms of the double bond the 1 and 2 positions and that also gives the substituent groups the lower numbers at the first point of difference. 5. Name compounds containing a double bond and an alcohol group as alkenols (or cycloalkenols) and give the alcohol carbon the lower number. 6. Two frequently encountered alkenyl groups are the vinyl group and allyl group. 7. If two identical groups are on the same side of the double bond, the compound can be designated cis; if they are on the opposite sides it can be designated trans. Designate the location of the double bond by using the number of the first atom of the double

7.2A THE (E)-(Z) SYSTEM FOR DESIGNATING ALKENE DIASTEREOMERS
1. Cis- and trans- designations the stereochemistry of alkene diasteroemers are unambiguous only when applied to disubstituted alkenes.
Br C H 2. The (E)-(Z) system: C F Cl A

Cl Higher priority Higher priority Br

C C

F

Cl > F Br > H
~2~

F

C

Cl Higher priority

H

Higher priority C H Br (E)-2-Bromo-1-chloro-1-fluroethene

(Z)-2-Bromo-1-chloro-1-fluroethene

1) The group of higher priority on one carbon atom is compared with the group of higher priority on the other carbon atom: i) (Z)-alkene: If the two groups of higher priority are on the same side of the If the two groups of higher priority are on opposite side of the double bond (German: zusammen, meaning together). ii) (E)-alkene: double bond (German: entgegen, meaning opposite).
H3C C C CH3 CH3 > H H3C C C H

H H (Z)-2-Butene (cis-2-butene)
Cl C C Cl Cl > H Br > Cl

H CH3 (E)-2-Butene (trans-2-butene)
Cl C C Br

H Br (E)-1-Bromo-1,2-dichloroethene

H Cl (Z)-1-Bromo-1,2-dichloroethene

7.3

RELATIVE STABILITIES OF ALKENES

7.3A HEATS OF HYDROGENATION
1. The reaction of an alkene with hydrogen is an exothermic reaction; the enthalpy change involved is called the heat of hydrogenation. 1) Most alkenes have heat of hydrogenation near –120 kJ mol–1.

C

C

+ H

H

Pt

C H

C H

∆H° ≈ – 120 kJ mol–1

2) Individual alkenes have heats of hydrogenation may differ from this value by more than 8 kJ mol–1. 3) The differences permit the measurement of the relative stabilities of alkene
~3~

isomers when hydrogenation converts them to the same product.
CH3CH2CH CH2 + H2 Pt CH3CH2CH2CH3 Butane Pt ∆Ho = −127 kJ mol-1

1-Butene (C4H8) H3C C C CH3 + H2

CH3CH2CH2CH3 Butane

∆Ho = −120 kJ mol-1

H H cis-2-Butene (C4H8)

H3C C C

H + H2 Pt CH3CH2CH2CH3 Butane ∆Ho = −115 kJ mol-1

H CH3 trans-2-Butene (C4H8) 2. In each reaction: 1) The product (butane) is the same.

2) One of the reactants (hydrogen) is the same. 3) The different amount of heat evolved is related to different stabilities (different heat contents) of the individual butenes.

Figure 7.1

An energy diagram for the three butene isomers. stability is trans-2-butene > cis-2-butene > 1-butene.
~4~

The order of

4) 1-Butene evolves the greatest amount of heat when hydrogenated, and trans-2-butene evolves the least. i) 1-Butene must have the greatest energy (enthalpy) and be the least stable isomer. ii) trans-2-Butene must have the lowest energy (enthalpy) and be the most stable isomer. 3. Trend of stabilities:
H3CH2C C C CH3 + H2

trans isomer > cis isomer
Pt CH3CH2CH2CH2CH3 ∆Ho = −120 kJ mol-1 Pentane

H H cis-3-Pentene

H3CH2C C C

H + H2 Pt o -1 CH3CH2CH2CH2CH3 ∆H = −115 kJ mol

H CH3 trans-3-Pentene

Pentane

4. The greater enthalpy of cis isomers can be attributed to strain caused by the crowding of two alkyl groups on the same side of the double bond.

Figure 7.2

cis- and trans-Alkene isomers. strain.

The less stable cis isomer has greater

7.3B RELATIVE STABILITIES FROM HEATS OF COMBUSTION
1. When hydrogenation os isomeric alkenes does not yield the same alkane, heats of
~5~

combustion can be used to measure their relative stabilities. 1) 2-Methylpropene cannot be compared directly with other butene isomers.
CH3 + H2 H3CC CH2 2-Methylpropene CH3 CH3CHCH3 Isobutane

Pt

2) Isobutane and butane do not have the same enthalpy so a direct comparison of heats of hydrogenation is not possible. 2. 2-Methylpropene is the most stable of the four C4H8 isomers:

CH3CH2CH
H3C

CH2 + 6 O2
CH3

4 O2 + 4 H2O

∆Ho = −2719 kJ mol-1

C
H H3C

C
H H

+ 6 O2

4 O 2 + 4 H 2O

∆Ho = −2712 kJ mol-1

C
H

C
CH3

+ 6 O2

4 O 2 + 4 H 2O

∆Ho = −2707 kJ mol-1

CH3 H3CC CH2 + 6 O2 4 O2 + 4 H2O ∆Ho = −2703 kJ mol-1

3. The stability of the butene isomers: CH3 H3CC CH2
H3C H H3C CH3

>
H

C

C
CH3

>
H

C

C
H

> CH3CH2CH

CH2

7.3C OVERALL RELATIVE STABILITIES OF ALKENES
1. The greater the number of attached alkyl groups (i.e., the more substituted the carbon atoms of the double bond), the greater is the alkene’s stability.

~6~

R R

R > R

R R

R > H

R R

H > H

R H

H > R

R H

R > H

R H

H > H

H H

H H

Tetrasubstituted

Trisubstituted

Disubstituted

Monosubstituted Unsubstituted

7.4

CYCLOALKENES

1. The rings of cycloalkenes containing five carbon atoms or fewer exist only in the cis form. H H2C H2C C C H H2C C H2 H H2 C H
H 2C H 2C H2 C H

H 2C

C C

H

H

C H2

H

Cyclopropene

Cyclobutene Figure 7.3

Cyclopentene

Cyclohexene

cis-Cycloalkanes.

2. There is evidence that trans-cyclohexene can be formed as a very reactive short-lived intermediate in some chemical reactions. H2C H2C H
Figure 7.4

C C

H CH2 CH2

Hypothetical trans-cyclohexene. This molecule is apparently too highly strained to exist at room temperature.

3. trans-Cycloheptene has been observed spectroscopically, but it is a substance with very short lifetime and has not been isolated. 4. trans-Cyclooctene has been isolated. 1) The ring of trans-cyclooctene is large enough to accommodate the geometry required by trans double bond and still be stable at room temperature.
~7~

2) trans-Cyclooctene is chiral and exists as a pair of enantiomers. H2 C C HH2C H2 C C CH2H

H2C HC HC H2C

CH2 CH2 CH2 CH2

H2C

CH2 H C C H2

H H2C C C H2

CH2

CH2 H2C

cis-Cyclooctene Figure 7.5

trans-Cyclooctene

The cis- and trans forms of cyclooctene.

7.5

SYNTHESIS OF ALKENES VIA ELIMINATION REACTIONS

1. Dehydrohalogenation of Alkyl Halides
H

H C C

H

base
− HX

H C H C

H H

H

H

X

2. Dehydration of Alcohols
H

H C C

H

H+, heat
− HOH

H C H C

H H

H

H

OH

3. Debromination of vic-Dibromides
Br

H C C

H

H

Zn, CH3CH2OH

H C H C

H H

H

Br

− ZnBr2

7.6

DEHYDROHALOGENATION OF ALKYL HALIDES
~8~

1. Synthesis of an alkene by dehydrohalogenation is almost always better achieved by an E2 reaction: B−

H

C

β

C

α

E2

C

C

+ B H + X−

X

2. A secondary or tertiary alkyl halide is used if possible in order to bring about an E2 reaction. 3. A high concentration of a strong, relatively nonpolarizable base, such alkoxide ion, is used to avoid E1 reaction. 4. A relatively polar solvent such as an alcohol is employed. 5. To favor elimination generally, a relatively high temperature is used. 6. Sodium ethoxide in ethanol and potassium tert-butoxide in tert-butyl alcohol are typical reagents. 7. Potassium hydroxide in ethanol is used sometimes: OH– + C2H5OH H2O + C2H5O–

7.6A E2 REACTIONS: THE ORIENTATION OF THE DOUBLE BOND IN THE PRODUCT ZAITSEV’S RULE
1. For some dehydrohalogenation reactions, a single elimination product is possible:. C2H5O−Νa+ C2H5OH 55oC

CH3CHCH3 Br CH3 CH3CCH3 Br

CH2

CHCH3 79% CH3

C2H5O−Νa+ C2H5OH 55oC

CH2

C 100%

CH3

~9~

CH3(CH2)15CH2CH2Br

(CH3)3CO− K+ (CH3)3COH 40oC

CH3(CH2)15CH 85%

CH2

2. Dehydrohalogenation of many alkyl halides yields more than one product:
(a) H CH2 (b) B − CH3CH C Br H (a) CH3 (a) 2-Bromo-2-methylbutane (b) CH3 CH3 2-Methyl-2-butene (b) CH2 CH3 2-Methyl-1-butene CH3CH2C + H B + CH3CH C + H B + Br −

Br −

1) When a small base such as ethoxide ion or hydroxide ion is used, the major product of the reaction will be the more stable alkene.
CH3 CH3CH2O− + CH3CH2C Br CH3 CH3 CH2 + CH3CH2C CH3

70oC CH3CH CH3 CH3CH2OH

C

2-Methyl-2-butene 2-Methyl-1-butene (69%) (31%) (more stable) (less stable) i) The more stable alkene has the more highly substituted double bond.

2. The transition state for the reaction: δ− H C2H5O− + C C Br

C2H5O H C C δ− C2H5OΗ + C

C + Br−

Br Transition state for an E2 reaction The carbon-carbon bond has some of the character of a double bond.
~ 10 ~

1) The transition state for the reaction leading to 2-methyl-2-butene has the

developing character of a double bond in a trisubstituted alkene. 2) The transition state for the reaction leading to 2-methyl-1-butene has the developing character of a double bond in a disubstituted alkene. 3) Because the transition state leading to 2-methyl-2-butene resembles a more stable alkene, this transition state is more stable.

Figure 7.6 i)

Reaction (2) leading to the the more stable alkene occurs faster than reaction (1) leading to the less stable alkene; ∆G‡(2) is less than ∆G‡(1).

Because this transition state is more stable (occurs at lower free energy), the free energy of activation for this reaction is lower and 2-methyl-2-butene is formed faster.

4) These reactions are known to be under kinetic control. 3. Zaitsev rule: an elimination occurs to give the most stable, more highly

substituted alkene 1) Russian chemist A. N. Zaitsev (1841-1910). 2) Zaitsev’s name is also transliterated as Zaitzev, Saytzeff, or Saytzev.
~ 11 ~

7.6B AN EXCEPTION TO ZAITSEV’S RULE
1. A bulky base such as potassium tert-butoxide in tert-butyl alcohol favors the formation of the less substituted alkene in dehydrohalgenation reactions. CH3 H3C C O CH3CH2
−

CH3 C CH3

CH3

o Br 75 C CH3CH (CH3)3COH

CH3 C

CH3 CH3 2-Methyl-2-butene 2-Methyl-1-butene (27.5%) (72.5%) (more substituted) (less substituted)

+ CH3CH2C

CH2

1) The reason for leading to Hofmann’s product: i) The steric bulk of the base. ii) The association of the base with the solvent molecules make it even larger. iii) tert-Butoxide removes one of the more exposed (1°) hydrogen atoms instead of the internal (2°) hydrogen atoms due to its greater crowding in the transition state.

7.6C THE STEREOCHEMISTRY OF E2 REACTIONS: THE ORIENTATION OF GROUPS IN THE TRANSITION STATE
1. Periplannar: 1) The requirement for coplanarity of the H–C–C–L unit arises from a need for proper overlap of orbitals in the developing π bond of the alkene that is being formed. 2) Anti periplannar conformation: i) The anti periplannar transition state is staggered (and therefore of lower energy) and thus is the preferred one.

~ 12 ~

B−

H C C

B−

H C C

L

L Anti periplanar transition state (preferred) 3) Syn periplannar conformation: i)

Syn periplanar transition state (only with certain rigid molecules)

The syn periplannar transition state is eclipsed and occurs only with rigid molecules that are unable to assume the anti arrangement.

2. Neomenthyl chloride and menthyl chloride:

H3C Cl

CH(CH3)2

H3C Cl

CH(CH3)2

Neomenthyl chloride

H3C Cl

CH(CH3)2

H3C

CH(CH3)2 Cl

Menthyl chloride

1) The β-hydrogen and the leaving group on a cyclohexane ring can assume an anti periplannar conformation only when they are both axial:

B

−

H H H H H

H

H H H

Cl Here the β-hydrogen and the chlorine are both axial. This allow an antiperiplanar transition state.

Cl

H

A Newman projection formula shows that the β-hydrogen and the chlorine are anti periplanar when they are both axial.

2) The more stable conformation of neomenthyl chloride: i) The alkyl groups are both equatorial and the chlorine is axial. ii) There also axial hydrogen atoms on both C1 and C3.
~ 13 ~

ii) The base can attack either of these hydrogen atoms and achieve an anti periplannar transition state for an E2 reaction. ii) Products corresponding to each of these transition states (2-menthene and 1-menthene) are formed rapidly. v) 1-Menthene (with the more highly substituted double bond) is the major product (Zaitsev’s rule).

A Mechanism for the Elimination Reaction of Neomenthyl Chloride
E2 Elimination Where There Are Two Axial Cyclohexane β-Hydrogens
− (a)

(a)

Et−O Et−O − (b) H H3C
4 3

H
1

H3C H CH(CH3)2

4 3 2

1

CH(CH3)2

2

1-Menthene (78%) (more stable alkene)

H Cl (b) Neomenthyl chloride Both green hydrogens are anti to the chlorine in this the more stable conformatio. Elimination by path (a) leads to 1-menthene; by path (b) to 2-menthene. H3C
4 3 2 1

CH(CH3)2

2-Menthene (22%) (less stable alkene)

~ 14 ~

A Mechanism for the Elimination Reaction of Menthyl Chloride
E2 Elimination Where The Only Eligible Axial Cyclohexane β-Hydrogen is From a Less Stable Conformer H H3C
4 3 2

H
1

CH3 ClCH(CH3)2 H
−

Cl H

H H Menthyl chloride (more stable conformation) Elimination is not possible for this conformation because no hydrogen is anti to the leaving group.

H CH(CH3)2 H Et−O Menthyl chloride (less stable conformation) Elimination is possible for this conformation because the green hydrogen is anti to the chlorine.

H3C

4 3 2

1

CH(CH3)2 2-Menthene (100%)

3) The more stable conformation of menthyl chloride: i) The alkyl groups and the chlorine are equatorial. conformation in which the large isopropyl group and the methyl group are also axial. ii) This conformation is of much higher energy, and the free energy of activation for the reaction is large because it includes the energy necessary for the conformational change. ii) Menthyl chloride undergoes an E2 reaction very slowly, and the product is entirely 2-menthene (Hofmann product). ii) For the chlorine to become axial, menthyl chloride has to assume a

~ 15 ~

7.7

DEHYDRATION OF ALCOHOLS

1. Dehydration of alcohols: 1) Heating most alcohols with a strong acid causes them to lose a molecule of water and form an alkene:

C H

C OH

HA heat

C

C

+ H2O

2. The reaction is an elimination and is favored at higher temperatures. 1) The most commonly used acids in the laboratory are Brønsted acids ––– proton donors such as sulfuric acid and phosphoric acid. 2) Lewis acids such as alumina (Al2O3) are often used in industrial, fas phase dehydrations. 3. Characteristics of dehydration reactions: 1) The experimental conditions –– temperature and acid concentration –– that are required to bring about dehydration are closely related to the structure of the individual alcohol. i) Primary alcohols are the most difficult to dehydrate:
H H H C H C H H + H2O

concd H C C H H2SO4 180oC H O H Ethanol (a 1o alcohol)

ii) Secondary alcohols usually dehydrate under milder conditions: OH 85% H3PO4 165-170oC Cyclohexanol
~ 16 ~

+ H 2O Cyclohexene (80%)

iii) Tertiary alcohols are usually dehydrated under extremely mild conditions: CH3 H3C C OH CH3 tert-Butyl alcohol CH2 H3C C + H2O CH3

20% aq. H2SO4 85oC

2-Methylpropene (84%)

iv) Relative ease of order of dehydration of alcohols: R R o R OH > R o H OH > R o C

C

C

OH

R 3 Alcohol

H 2 Alcohol

H 1 Alcohol

2) Some primary and secondary alcohols also undergo rearrangements of their carbon skeleton during dehydration. i) Dehydration of 3,3-dimethyl-2-butanol: CH3 C CH3 CH3

CH3 85% H3PO4 C CH3 C CH3 + HC H 3C o C H 3C C C 2 80 C H 3C OH CH3 CH3 3,3-Dimethyl-2-butanol 2,3-Dimethyl-2-butene 2,3-Dimethyl-1-butene (80%) (20%) ii) The carbon skeleton of the reactant is C C C C C C while that of the products is C C C C C C

7.7A MECHANISM OF ALCOHOL DEHYDRATION: AN E1 REACTION
1. The mechanism is an E1 reaction in which the substrate is a protonated alcohol (or an alkyloxonium ion).
~ 17 ~

Step 1
H3C

CH3 C O H + H CH3

H O
+

CH3H H3C C O
+

H + H

O H

H

CH3 Protonated alcohol or alkyloxonium ion

1) In step 2, the leaving group is a molecule of water. 2) The carbon-oxygen bond breaks heterolytically. 3) It is a highly endergonic step and therefore is the slowest step.

Step 2
H3C

CH3H C O
+

CH3 H H3C CH3 A carbocation H + O H C+ + O H CH2 H 3C CH3 2-Methylpropene C + H H O
+

H

CH3

Step 3

H 2C H 3C C+

H CH3

H

7.7B CARBOCATION STABILITY AND THE TRANSITION STATE
1. The order of stability of carbocations is 3° > 2° > 1° > methyl: R C+ R 3 o R > R > R 2 o H H > R > 1 o H H > > H H Methyl C+

C+

C+

~ 18 ~

A Mechanism for the Reaction
Acid-Catalyzed Dehydration of Secondary or Tertiary Alcohols: An E1 Reaction

Step 1
R C o R O H + H A fast C C

H O
+

C

H

+

A−

H R' Strong acid 2 or 3o Alcohol (R' may be H) (typically sulfuric or phosphoric acid)

H R' Protonated alcohol Conjugate base

The alcohol accepts a proton from the acid in a fast step.

Step 2
R C H C R' H O
+

R H slow (rate determining) C H C+ R' +

H O H

The protonated alcohol loses a molecule of water to become a carbocation. This step is slow and rate determining

Step 3
R A
−

R fast C C + H A

+

C H

C+ R'

R' Alkene The carbocation loses a proton to a base. In this step, the base may be another molecule of the alcohol, water, or the conjugate base of the acid. The proton transfer results in the formation of the alkene. Note that the overall role of the acid is catalytic (it is used in the reaction and regenerated).

2. The order of free energy of activation for dehydration of alcohols is 3° > 2° > 1° > methyl:

~ 19 ~

Figure 7.7

Free-energy diagrams for the formation of carbocations from protonated tertiary, secondary, and primary alcohols. The relative free energies of activation are tertiary < secondary « primary.

3. Hammond-Leffler postulate: 1) There is a strong resemblance between the transition state and the cation product. 2) The transition state that leads to the 3° carbocation is lowest in free energy because it resembles the most stable product. 3) The transition state that leads to the 1° carbocation is highest in free energy because it resembles the least stable product. 4. Delocalization of the charge stabilizes the transition state and the carbocation. H C O
+

H H C δ+ + +

H C+ Carbocation + O H

O

δ+

H

Protonated alcohol

Transition state

1) The carbon begins to develop a partial positive charge because it is losing the electrons that bonded it to the oxygen atom. 2) This developing positive charge is most effectively delocalized in the transition

state leading to a 3° carbocation because of the presence of three electron-releasing alkyl groups.
~ 20 ~

δ+ R δ+ R

H O δ+ δ+ R

H O δ+ H H R C δ+ H O δ+ C

δ+

H

δ+ R

C

δ+

H

δ+ R

H Transition state leading to 2o carbocation

H Transition state leading to 1o carbocation (least stable)

Transition state leading to 3o carbocation (most stable)

3) Because this developing positive charge is least effectively delocalized in the transition state leading to a 1° carbocation, the dehydration of a 1° alcohol proceeds through a different mechanism ––– an E2 mechanism.

7.7C A MECHANISM FOR DEHYDRATION OF PRIMARY ALCOHOLS: AN E2 REACTION A Mechanism for the Reaction
Dehydration of a Primary Alcohol: An E2 Reaction H C C O H + H A fast C H C H O
+

H

+

A−

H H Primary alcohol

Strong acid (typically sulfuric or phosphoric acid) The alcohol accepts a proton from the acid in a fast step. H H O
+

H H Protonated alcohol Conjugate base

A− +

C H

C H

H

R' Alkene A base removes a hydrogen from the β carbon as the double bond forms and the protonated hydroxyl group departs. (The base may be another molecule of the alcohol or the conjugate base of the acid)

slow rate determining

R C C + H A +

H O H

7.8

CARBOCATION STABILITY AND THE OCCURRENCE OF
~ 21 ~

MOLECULAR REARRANGEMENTS
7.8A REARRANGEMENTS DURING DEHYDRATION OF SECONDARY ALCOHOLS
CH3 C CH3 CH3

C CH3 C CH3 CH3 85% H3PO4 + HC H 3C o H 3C C C C 2 80 C H 3C CH3 CH3 OH 3,3-Dimethyl-2-butanol 2,3-Dimethyl-2-butene 2,3-Dimethyl-1-butene (major product) (minor product)

Step 1
H3C H3C

CH3 C C O CH3 H 3C H 3C C C
+

H CH3 + H H O H H3C H3C

CH3 C C
+

H CH3 + O H

OH2 Protonated alcohol CH3
H

Step 2

CH3

H 3C H 3C o C

C+

CH3

+

O

H

OH2

H A 2 carbocation

1. The less stable, 2° carbocation rearranges to a more stable 3° carbocation.

Step 3
H 3C H 3C o CH3 C C+ CH3 H 3C H 3C

δ+

+ + CH3 C CH3 Cδ+

H A 2 carbocation (less stable)

H Transition state

H 3C H 3C o C

+

C

CH3 CH3

H A 3 carbocation (more stable)

2. The methyl group migrates with its pair of electrons, as a methyl anion, –:CH3 (a methanide ion). 3. 1,2-Shift: 4. In the transition state the shifting methyl is partially bonded to both carbon atoms
~ 22 ~

by the pair of electrons with which it migrates. skeleton.

It never leaves the carbon

5. There two ways to remove a proton from the carbocation: 1) Path (b) leads to the highly stable tetrasubstituted alkene, and this is the path followed by most of the carbocations. 2) Path (a) leads to a less stable, disubstituted alkene and produces the minor product of the reaction. 3) The formation of the more stable alkene is the general rule (Zaitsev’s rule) in

the acid-catalyzed dehydration reactions of alcohols. Step 4
(a)
(a) A
−

CH3 H2C H CH3 (b) H3C C C CH3 Less stable alkene + HA

(b) +

H CH2 H3C

C

C

CH3 (minor product) CH3 C C

CH3

CH3 More stable alkene

CH3 (major product) 6. Rearrangements occur almost invariably when the migration of an alkanide ion or hydride ion can lead to a more stable carbocation. CH3 H3C H3C o C

C+

CH3

methanide migration

H 2 carbocation H C CH3

H3C H3C o C

+

C

CH3 CH3

H 3 carbocation C
+

H C

H3C H3C o C+

hydride migration

H 2 carbocation
~ 23 ~

H3C H3C o CH3

H 3 carbocation

CH3 CH CH3

OH

H+ , heat (−H2O) + CH3 CH3

CH3 + CH CH3 2o Carbocation CH3 CH3

CH3 CH CH3
+

H

7.8B REARRANGEMENTS AFTER DEHYDRATION OF A PRIMARY ALCOHOL
1. The alkene that is formed initially from a 1° alcohol arises by an E2 mechanism. 1) An alkene can accept a proton to generate a carbocation in a process that is essentially the reverse of the deprotonation step in the E1 mechanism for dehydration of an alcohol. 2) When a terminal alkene protonates by using its π electrons to bond a proton at the terminal carbon, a carbocation forms at the second carbon of the chain (The carbocation could also form directly from the 1° alcohol by a hydride shift from its β-carbon to the terminal carbon as the protonated hydroxyl group departs). 3) Various processes can occur from this carbocation: i) A different β-hydrogen may be removed, leading to a more stable alkene than the initially formed terminal alkene. ii) A hydride or alkanide rearrangement may occur leading to a more stable carbocation, after which elimination may be completed. iii) A nucleophile may attack any of these carbocations to form a substitution product. v) Under the high-temperature conditions for alcohol dehydration the principal products will be alkenes rather than substitution products.

~ 24 ~

A Mechanism for the Reaction
Formation of a Rearranged Alkene During Dehydration of a Primary Alcohol R R C H C H C O H + H A H E2 C C C H + H O H + H A

R H H R H Primary alcohol The initial alkene (R may be H) The primary alcohol initially undergoes acid-catalyzed dehydration by an E2 mechanism R C H R C C H H + H A H protonation C
+C

R H C H H + A−

R

The π electrons of the initial alkene can then be used to form a bond with a proton at the terminal carbon, forming a secondary or tertiary carbocation. R C A− + H
+C

R H C H H deprotonation C C C H H + H A

R

R H Final alkene

A different β -hydrogen can be removed from the carbocation, so as to form a more highly substituted alkene than the initial alkene. This deprotonation step is the same as the usual completion of an E1 elimination. (This carbocation could experience other fates, such as further rearrangement before elimination or substitution by an SN1 process.)

~ 25 ~

7.9

ALKENES BY DEBROMINATION OF VICINAL DIBROMIDES

1. Vicinal (or vic) and geminal (or gem) dihalides: X

C

C

C

C

X X A vic-dihalide

X A gem-dihalide

1) vic-Dibromides undergo debromination: acetone

C

C

+

2 NaI

C

C

+ I2 + 2 NaBr

Br Br C C

+

Zn

Br Br

CH3CO2H or CH3CH2OH

C

C

+

ZnBr2

A Mechanism for the Reaction
Mechanism:

Step 1
Br I−

+

C

C
Br

C

C

+

I

Br

+

Br −

An iodide ion become bonded to a bromine atom in a step that is, in effect, an SN2 attack on the bromine; removal of the bromine brings about an E2 elimination and the formation of a bouble bond.

Step 2

I−

+

I

Br

I

I

+

Br −

Here, an SN2-type attack by iodide ion on IBr leads to the formation of I2 and a bromide ion.

~ 26 ~

1. Debromination by zinc takes place on the surface of the metal and the mechanism is uncertain. 1) Other electropositive metals (e.g., Na, Ca, and Mg) also cause debromination of

vic-dibromide.
2. vic-Debromination are usually prepared by the addition of bromine to an alkene. 3. Bromination followed by debromination is useful in the purification of alkenes and in “protecting” the double bond.

7.10 SYNTHESIS OF ALKYNES BY ELIMINATION REACTIONS
1. Alkynes can be synthesized from alkenes. H RCH CHR + H C R R C

Br2

Br Br vic-Dibromide
1) The vic-dibromide is dehydrohalogenated through its reaction with a strong base. 2) The dehydrohalogenation occurs in two steps. be carried out consecutively in a single mixture. i) The strong base, NaNH2, is capable of effecting both dehydrohalogenations in a single reaction mixture. ii) At least two molar equivalents of NaNH2 per mole of the dihalide must be used, and if the product is a terminal alkyne, three molar equivalents must be used because the terminal alkyne is deprotonated by NaNH2 as it is formed in the mixture. iii) Dehydrohalogenations with NaNH2 are usually carried out in liquid ammonia or in an inert medium such as mineral oil. Depending on conditions, these two dehydrohalogenations may be carried out as separate reactions, or they may

~ 27 ~

A Mechanism for the Reaction
Dehydrohalogenation of vic-Dibromides to form Alkynes Reaction: H RC H
− CR + 2 NH2

RC

CR + 2 NH3 + 2 Br−

Br Br Mechanism:
Step 1

H H N− + R H C

H C R

R C Br C

H + H R N H Ammonia Bromide ion H + Br −

Br Br

Amide ion vic-Dibromide The strongly basic amide ion brings about an E2 reaction.
Step 2

Bromoalkene

R C C

H +

−

N

H

R

C

C

R + H

N

H +

Br −

R Br H Bromoalkene Amide ion A second E2 reaction produces the alkyne.

Alkyne

H Ammonia Bromide ion

2. Examples: CH3CH2CH CH2 CH3CH2CH + H3CH2CC Br H3CH2CC C − Na+ Br2 CCl4 CH3CH2CHCH2Br Br NaNH2 mineral oil 110-160 oC NH4Cl

NaNH2 mineral oil 110-160 oC CH NaNH2

CHBr CH2

H3CH2CC

H3CH2CC
~ 28 ~

CH + NH3 + NaCl

3. Ketones can be converted to gem-dichloride through their reaction with phosphorus pentachloride which can be used to synthesize alkynes. O C CH3 PCl5 (−POCl3) 0 oC Cl 1. 3 NaNH2 mineral oil C heat CH3 Cl 2. H+ C CH

Cyclohexyl methyl ketone

A gem-dichloride (70-80%)

Cyclohexylene (46%)

7.11 THE ACIDITY OF TERMINAL ALKYNES
1. The hydrogen atoms of ethyne are considerably more acidic than those of ethane or ethane: H H C C H H pKa = 25 C C H H H H C H C H

pKa = 44

H H pKa = 50

1) The order of basicities of anions is opposite that of the relative acidities of the hydrocarbons.
Relative Basicity of ethanide, ethenide, and ethynide ions:

CH3CH2:–

> CH2=CH:–

> HC≡C:–

Relative Acidity of hydrogen compounds of the first-row elements of the periodic table:

H–OH > H–OR > H–C≡CR > H–NH2 > H–CH=CH2 > H–CH2CH3
Relative Basicity of hydrogen compounds of the first-row elements of the periodic table:
–

:OH < –:OR < –:C≡CR < –:NH2 < –:CH=CH2 < –:CH2CH3
~ 29 ~

2) In solution, terminal alkynes are more acidic than ammonia, however, they are less acidic than alcohols and are less acidic than water. 3) In the gas phase, the hydroxide ion is a stronger base than the acetylide ion. i) In solution, smaller ions (e.g., hydroxide ions) are more effectively solvated than larger ones (e.g., ethynide ions) and thus they are more stable and therefore less basic. ii) In the gas phase, large ions are stabilized by polarization of their bonding electrons, and the bigger a group is the more polarizable it will be and consequently larger ions are less basic

7.12 REPLACEMENT OF THE ACETYLENEIC HYDROGEN ATOM OF TERMINAL ALKYNES
1. Sodium alkynides can be prepared by treating terminal alkynes with NaNH2 in liquid ammonia. H–C≡C–H + NaNH2
CH3C≡C–H + NaNH2 liq. NH3 liq. NH3 H–C≡C:– Na+ + NH3 CH3C≡C:– Na+ + NH3

1) The amide ion (ammonia, pKa = 38) is able to completely remove the acetylenic protons of terminal alkynes (pKa = 25). 2. Sodium alkynides are useful intermediates for the synthesis of other alkynes.

R

C

C − Na+

+

R'CH2

Br

R

C

C

CH2R' + NaBr

Sodium alkynide

1° Alkyl halide

Mono- or disubstituted acetylene

CH3CH2C

C − Na+ + CH3CH2

Br

CH3CH2C

CCH2CH3 + NaBr

3-Hexyne (75%)
~ 30 ~

3. An SN2 reaction: R' RC C Na+ Sodium alkynide
−

C

Br

H H 1o Alkyl halide

nucleophilic substitution S N2

RC

C

CH2R' + NaBr

4. This synthesis fails when secondary or tertiary halides are used because the alkynide ion acts as a base rather than as a nucleophile, and the major results is an E2 elimination. H R' E2 RC CH + R'CH

RC

C−

H

C

C Br H R'' o 2 Alkyl halide

CHR'' + Br−

7.13 HYDROGENATION OF ALKENES
1. Catalytic hydrogenation (an addition reaction): 1) One atom of hydrogen adds to each carbon of the double bond. 2) Without a catalyst the reaction does not take place at an appreciable rate. CH2=CH2 + H2 Ni, Pd or Pt 25 oC Ni, Pd or Pt 25 oC CH3–CH3

CH3CH=CH2 + H2

CH3CH2–CH3

2. Saturated compounds: 3. Unsaturated compounds: 4. The process of adding hydrogen to an alkene is a reduction.
~ 31 ~

7.14 HYDROGENATION: THE FUNCTION OF THE CATALYST
1. Hydrogenation of an alkene is an exothermic reaction (∆Η° ≈ –120 kJ mol–1).

R–CH=CH–R + H2

hydrogenation

R–CH2–CH2–R + heat

1) Hydrogenation reactions usually have high free energies of activation. 2) The reaction of an alkene with molecular hydrogen does not take place at room temperature in the absence of a catalyst, but it often does take place at room temperature when a metal catalyst is added.

Figure 7.8

Free-energy diagram for the hydrogenation of an alkene in the presenceof a catalyst and the hypothetical reaction in the absence of a catalyst. The free energy of activation [∆G‡(1)] is very much larger than the largest free energy of activation for the catalyzed reaction [∆G‡(2)].

2. The most commonly used catalysts for hydrogenation (finely divided platinum, nickel, palladium, rhodium, and ruthenium) apparently serve to adsorb hydrogen molecules on their surface. 1) Unpaired electrons on the surface of the metal pair with the electrons of
~ 32 ~

hydrogen and bind the hydrogen to the surface. 2) The collision of an alkene with the surface bearing adsorbed hydrogen causes adsorption of the alkene. 3) A stepwise transfer of hydrogen atoms take place, and this produces an alkane before the organic molecule leaves the catalyst surface. 4) Both hydrogen atoms usually add form the same side of the molecule (syn addition).

Figure 7.9

The mechanism for the hydrogenation of an alkene as catalyzed by finely divided platinum metal: (a) hydrogen adsorption; (b) adsorption of the alkene; (c) and (d), stepwise transfer of both hydrogen atoms to the same face of the alkene (syn addition).

C +
H

C
H

Pt
H

C

C
H

Catalytic hydrogenation is a syn addition.

7.14A SYN AND ANTI ADDITIONS
1. Syn addition:

~ 33 ~

C

C

+ X

Y X

C

C Y

A syn addition

2. Anti addition: Y C C + X Y X C C A anti addition

7.15 HYDROGENATION OF ALKYNES
1. Depending on the conditions and the catalyst employed, one or two molar equivalents of hydrogen will add to a carbon–carbon triple bond. 1) A platinum catalyst catalyzes the reaction of an alkyne with two molar equivalents of hydrogen to give an alkane. CH3C≡CCH3 Pt H2 [CH3CH=CHCH3] Pt H2 CH3CH2CH2CH3

7.15A SYN ADDITION OF HYDROGEN: SYNTHESIS OF CIS-ALKENES
1. A catalyst that permits hydrogenation of an alkyne to an alkene is the nickel boride compound called P-2 catalyst.

O Ni OCCH 3
2

NaBH4 C2H5OH

Ni2B P-2

1) Hydrogenation of alkynes in the presence of P-2 catalyst causes syn addition of hydrogen to take place, and the alkene that is formed from an alkyne with an internal triple bond has the (Z) or cis configuration. 2) The reaction take place on the surface of the catalyst accounting for the syn
~ 34 ~

addition. CH3CH2C CCH2CH3 H2/Ni2B (P-2) syn addition H3CH2C C C CH2CH3

3-Hexyne

H H (Z)-3-Hexene (cis-3-hexene) (97%)

2. Lindlar’s catalyst: metallic palladium deposited on calcium carbonate and is poisoned with lead acetate and quinoline. H2, Pd/CaCO3 (Lindlar's catalyst) quinoline (syn addition) R C H C H R

R

C

C

R

7.15B ANTI ADDITION OF HYDROGEN: SYNTHESIS OF TRANS-ALKENES
1. An anti addition of hydrogen atoms to the triple bond occurs when alkynes are reduced with lithium or sodium metal in ammonia or ethylamine at low temperatures. 1) This reaction, called a dissolving metal reduction, produces an (E)- or

trans-alkene.
1. Li, C2H5NH2, −78oC 2. NH4Cl CH3(CH2)2 C H C (CH2)2CH3 H

CH3(CH2)2 C

C (CH2)2CH3

4-Octyne

(E)-4-Octyne (trans-4-Octyne) (52%)

~ 35 ~

A Mechanism for the Reduction Reaction
The Dissolving Metal Reduction of an Alkyne R Li + R C C R C C
−

H

NHEt

R C C

H

R R Radical anion Vinylic radical A lithium atom donates an electron to The radical anion acts as a base and removes a the π bond of the alkyne. An electron proton from a molecule pair shifts to one carbon as the of the ethylamine. hybridization states change to sp2. R C C R H Li
−

R C C

H R H NHEt

R C C

H

R H trans-Vinylic anion trans-Alkene Vinylic radical The anion acts as a base and A second lithium atom donates an electron to removes a proton from a second molecule of ethylamine. the vinylic radical.

7.16 MOLECULAR FORMULAS OF HYDROCARBONS: THE INDEX OF HYDROGEN DEFICIENCY
1. 1-Hexene and cyclohexane have the same molecular formula (C6H12): CH2=CHCH2CH2CH2CH3 1-Hexene Cyclohexane

1) Cyclohexane and 1-hexene are constitutional isomers. 2. Alkynes and alkenes with two double bonds (alkadienes) have the general formula CnH2n–2. 1) Hydrocarbons with one triple bond and one double bond (alkenynes) and alkenes
~ 36 ~

with three double bonds have the general formula CnH2n–4. CH2=CH–CH=CH2 1,3-Butadiene (C4H6) CH2=CH–CH=CH–CH=CH2 1,3,5-Hexatriene (C6H8)

3. Index of Hydrogen Deficiency (degree of unsaturation, the number of double-bond equivalence): 1) It is an important information about its structure for an unknown compound. 2) The index of hydrogen deficiency is defined as the number of pair of hydrogen atoms that must be subtracted from the molecular formula of the corresponding alkane to give the molecular formula of the compound under consideration. 3) The index of hydrogen deficiency of 1-hexene and cyclohexane: C6H14 = formula of corresponding alkane (hexane) C6H12 = formula of compound (1-hexene and cyclohexane) H2 = difference = 1 pair of hydrogen atoms Index of hydrogen deficiency = 1 4. Determination of the number of rings: 1) Each double bond consumes one molar equivalent of hydrogen; each triple bond consumes two. 2) Rings are not affected by hydrogenation at room temperature. CH2=CH(CH2)3CH3 + H2
Pt 25 oC CH3(CH2)4CH3

+

H2

Pt 25 oC Pt 25 oC

No reaction

+

H2

Cyclohexene
CH2=CHCH=CHCH2CH3 + 2 H2 Pt 25 oC CH3(CH2)4CH3

1,3-Hexadiene
~ 37 ~

4. Calculating the index of Hydrogen Deficiency (IHD): 1) For compounds containing halogen atoms: simply count the halogen atoms as

hydrogen atoms.
C4H6Cl2 = C4H8

⇒

IHD = 1

2) For compounds containing oxygen atoms: ignore the oxygen atoms and

calculate the IHD from the remainder of the formula.
C4H8O = C4H8 CH2=CHCH2CH2OH

⇒

IHD = 1

O
CH3CH2=CHCH2OH CH3CH2CCH3

O
CH3CH2CH2CH

O

O
CH3

and so on

3) For compounds containing nitrogen atoms: subtract one hydrogen for each

nitrogen atom, and then ignore the nitrogen atoms.
C4H9N = C4H8 CH2=CHCH2CH2NH2

⇒

IHD = 1

NH
CH3CH2=CHCH2NH2 CH3CH2CCH3

NH
CH3CH2CH2CH

H

CH3 N and so on

N

H

~ 38 ~

SUMMARY OF METHODS FOR THE PREPARATION OF ALKENES AND ALKYNES
1. Dehydrohalogenation of alkyl halides (Section 7.6)

General Reaction
H C C X base heat (−HX) C C

Specific Examples
CH3CH2CHCH3 Br CH3CH2CHCH3 Br C2H5O−Νa+ C2H5OH H3CHC CHCH 3 + H3CH2CHC (19%) + H3CH2CHC CH2 CH2

(cis and trans, 81%) H3CHC CHCH3

(CH3)3CO−Κ+ (CH3)3COH

Disubstituted alkenes Monosubstituted alkene (cis and trans, 47%) (53%)

2. Dehydration of alcohols (Section 7.7 and 7.8)

General Reaction

C H
Specific Examples

C OH

acid heat (−H2O)

C

C

CH3CH2OH
CH3 H3CC OH CH3

concd H2SO4 180 oC

CH2=CH2

+

H2O

20% H2SO4 85 oC

CH3 H3CC CH2 + H2O

~ 39 ~

SUMMARY OF METHODS FOR THE PREPARATION OF ALKENES AND ALKYNES
3. Debromination of vic-dibromides (Section 7.9)

General Reaction
Br C C Br 4. Hydrogenation of alkynes (Section 7.15) Zn CH3CO2H C C + ZnBr2

General Reaction

H2/Ni2B (P-2) (syn addition) R C C R' Li or Na NH3 or RNH2 (anti additon) 5. Dehydrohalogenation of vic-dibromides (Section 7.15) General Reaction Br H R C H C Br
− R + 2 NH2

R C C

R'

H H (Z)-Alkene R C C H

R' H (E)-Alkene

RC

CR + 2 NH3 + 2 Br−

~ 40 ~

ALKENES AND ALKYNES II. ADDITION REACTIONS
THE SEA: A TREASURY OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS

Electron micrograph of myosin 1. The concentration of halides in the ocean is approximately 0.5 M in chloride, 1mM in bromide, and 1µM in iodide. 2. Marine organisms have incorporated halogen atoms into the structures of many of their metabolites: 3. For the marine organisms that make the metabolites, some of these molecules are part of defense mechanisms that serve to promote the species’ survival by deterring predators or inhibiting the growth of competing organisms. 4. For humans, the vast resource of marine natural products shows great potential as a source of new therapeutic agents. 1) Halomon: in preclinical evaluation as a cytotoxic agent against certain tumor cell types.
~1~

2) Tetrachloromertensene: 3) (3R)- and (3S)-Cyclocymopol monomethyl ether: show agonistic or antagonistic effects on the human progesterone receptor, depending on which enantiomer is used 4) Dactylyne: an inhibitor of pentobarbital metabolism 5) (3E)-Laureatin: 6) Kumepaloxane: a fish antifeedant synthesized by the Guam bubble snail Haminoea cymbalum, presumably as a defense mechanism for the snail. 7) Brevetoxin B: associated with deadly “red tides”. 8) Eleutherobin: a promising anticancer agent.

OCH3

Br Cl Cl Br
Halomon

Cl

Cl

Br
3

Cl

Cl Cl
Tetrachloromertensene

Br OH
Cyclocymopol monomethyl ether

Br O Br
Dactylyne

Cl

Br

O O Br
(3E)-Laureatin
HO O

H O O O H H O H H O H H O H O H O H H O H H H O O

H O

Brevetoxin B
~2~

Cl Br

Kumepaloxane

5. The biosynthesis of halogenated marine natural products: 1) Some of their halogens appear to have been introduced as electrophiles rather than as Lewis bases or nucleophiles, which is their character when they are solutes in seawater. 2) Many marine organisms have enzymes called haloperoxidases that convert nucleophilic iodide, bromide, or chloride anions into electrophilic species that react like I+, Br+ or Cl+. 3) In the biosynthetic schemes proposed for some halogenated natural products, positive halogen intermediates are attacked by electrons from the π bond of an alkene or alkyne in an addition reaction.

8.1

INTRODUCTION:
C C +

ADDITIONS TO ALKENES
A B addition C C

A

B

H

X

H

C

C

X

Alkyl halide (Section 8.2, 8.3, and 10.9) Alkyl hydrogen sulfate (Section 8.4) Alcohol (Section 8.5) Dihaloakane (Section 8.6, 8.7)

H C C

OSO3H

H

C

C

OSO3H

Alkene

H OH HA (cat.) X X

H

C

C

OH

X

C

C
~3~

X

8.1A CHARACTERISTICS OF THE DOUBLE BOND:
1. An addition results in the conversion of one π bond and one σ bond into two σ bonds: 1) π bonds are weaker than that of σ binds ⇒ energetically favorable.

C

C

+

X

Y

C X

C Y

π bond

σ bond

2σ bonds Bond formed

Bonds broken

2. The electrons of the π bond are exposed ⇒ the π bond is particularly susceptible to electrophiles (electron-seeking reagents).

An electrostatic potential map for ethane shows the higher density of negative charge in the region of the π bond. 1) Electrophilic: i) electron-seeking.

The electron pair of the π bond is distributed throughout both lobes of the π molecular orbital.

2) Electrophiles include: Positive reagents: protons (H+). positive). iii) Lewis acids: BF3 and AlCl3. iv) Metal ions that contain vacant orbitals: the silver ion (Ag+), the mercuric ion (Hg2+), and the platinum ion (Pt2+).
~4~

ii) Neutral reagents: bromine (because it can be polarized so that one end is

8.1B THE MECHANISM OF THE ADDITION OF HX TO A DOUBLE BOND:
1. The H+ of HX reacts with the alkene by using the two electons of the π bond to form a σ bond to one of the carbon atoms ⇒ leaves a vacant p orbital and a + charge on the other carbon ⇒ formation of a carbocation and a halide ion:

2. The carbocation is highly reactive and combines with the halide ion:

8.1C ELECTROPHILES ARE LEWIS ACIDS:
1. Electrophiles: molecules or ions that can accept an electron pair ⇒ Lewis acids. 2. Nucleophiles: molecules or ions that can furnish an electron pair ⇒ Lewis bases. 3. Any reaction of an electrophile also involves a nucleophile. 4. In the protonation of an alkene: 1) The electrophile is the proton donated by an acid. 2) The nucleophile is the alkene.

~5~

H X H +

C

C

C

C+

+

X−

Electrophile Nucleophile

5. The carbocation reacts with the halide in the next step:
H C C
+

H + X− C

X C

Electrophile Nucleophile

8.2

ADDITION OF HYDROGEN HALIDES TO ALKENE: MARKOVNIKOV’S RULE

1. Hydrogen halides (HI, HBr, HCl, and HF) add to the double bond of alkenes:

C

C

+

HX

C

C

H
2. The addition reactions can be carried out:

X

1) By dissolving the HX in a solvent such as acetic acid or CH2Cl2. 2) By bubbling the gaseous HX directly into the alkene and using the alkene itself as the solvent. i) HF is prepared as polyhydrogen fluoride in pyridine.

3. The order of reactivity of the HX is HI > HBr > HCl > HF: i) Unless the alkene is highly substituted, HCl reacts so slowly that the reaction is not an useful preparative method. ii) HBr adds readily, but, unless precautions are taken, the reaction may follow an alternate course.
~6~

4. Adding silica gel or alumina to the mixture of the alkene and HCl or HBr in CH2Cl2 increases the rate of addition dramatically and makes the reaction an easy one to carry out. 5. The regioselectivity of the addition of HX to an unsymmetrical alkenes: i) H2C The addition of HBr to propene: the main product is 2-bromopropane. CHCH3 + HBr CH3CHCH3 Br 2-Bromopropane (little BrCH2CH2CH3)

1-Bromopropane

ii) The addition of HBr to 2-methylpropene: the main product is tert-butyl bromide. H3C C H3C CH2 + HBr H3C CH3 C CH3 Br tert-Butyl bromide CH3 (little H3C CH CH2 Br )

2-Methylpropene (isobutylene)

Isobutyl bromide

8.2A MARKOVNIKOV’S RULE:
1. Russian chemist Vladimir Markovnikov in 1870 proposed the following rule: 1) “If an unsymmetrical alkene combines with a hydrogen halide, the halide

ion adds to the carbon atom with fewer hydrogen atoms” that already has the greater number of hydrogen atoms).
CH2 CHCH 3 H Br

(The addition of

HX to an alkene, the hydrogen atom adds to the carbon atom of the double

Carbon atom with the greater number of hydrogen atoms i)

CH2 H

CHCH3 Br

Markovnikov addition:

ii) Markovnikov product:
~7~

A Mechanism for the Reaction
Addition of a Hydrogen Halide an Alkene H

Step 1

C

C + H

X

slow

+C

C

+

X−

The π electron of the alkene form a bond with a proton from HX to form a carboncation and a halide ion. H H fast C C
+

Step 2

X− +

C

C

X The halide ion reacts with the carboncation by donating an electron pair; the result is an alkyl halide.

Figure 8.1

Free-energy diagram for the addition of HX to an alkene. The free energy of activation for step 1 is much larger than that for step 2.
~8~

2. Rate-determining step: 1) Alkene accepts a proton from the HX and forms a carbocation in step 1. 2) This step is highly endothermic and has a high free energy of activation ⇒ it takes place slowly. 3. Step 2: 1) The highly reactive carbocation stabilizes itself by combining with a halide ion. 2) This exothermic step has a very low free energy of activation ⇒ it takes place rapidly.

8.2B THEORETICAL EXPLANATION OF MARKOVNIKOV’S RULE:
1. The step 1 of the addition reaction of HX to an unsymmetrical alkene could conceivably lead to two different carbocations: H X H + CH3CH CH2 CH3CH CH2 + 1o Carbocation (less stable)
+

X−

CH3CH CH2 + H

X

CH3CH

+

CH2 H +

X−

2o Carbocation (more stable) 2. These two carbocations are not of equal stability. 1) The 2° carbocation is more stable ⇒ accounts for the correct predication of the overall addition by Markovnikov’s rule.

~9~

X CH3CH CH2 HBr slow

− + CH3CH2CH2 Br

CH3CH2CH2Br 1-Bromopropane (little formed)

1o
+

CH3CHCH 3 2 Step 1 o Br−

CH3CHCH3

Br 2-Bromopropane (main product) Step 2

2) The more stable 2° carbocation is formed preferentially in the first step ⇒ the chief product is 2-bromopropane. 3. The more stable carbocation predominates because it is formed faster.

Figure 8.2

Free-energy diagrams for the addition of HBr to propene. less than ∆G‡(1°).

∆G‡(2°) is

1) The transition state resembles the more stable 2° carbocation ⇒ the reaction leading to the 2° carbocation (and ultimately to 2-bromopropane) has the lower free energy of activation.
~ 10 ~

2) The transition state resembles the less stable 1° carbocation ⇒ the reaction leading to the 1° carbocation (and ultimately to 1-bromopropane) has a higher free energy of activation. 3) The second reaction is much slower and does not compete with the first one. 4. The reaction of HBr with 2-methylpropene produces only tert-butyl bromide. 1) The difference between a 3° and a 1° carbocation. 2) The formation of a 1° carbocation is required ⇒ isobutyl bromide is not obtained as a product of the reaction. 3) The reaction would have a much higher free energy of activation than that leading to a 3° carbocation.

A Mechanism for the Reaction
Addition of HBr to 2-Methylpropene This reaction takes place:
CH3 H 3C C CH2 H Br o H 3C
+C

CH3 CH2 H Br − H 3C C CH3

H 3C

3 Carbocation (more stable carbocation) This reaction does not occur appreciably:

Br tert-Butyl bromide Actual product

CH3 H3C C CH2 H Br X H3C

CH3 C

CH2

+

CH3 X H3C CH CH2 Br Isobutyl bromide Not formed

Br − H 1o Carbocation (less stable carbocation)

5. When the carbocation initially formed in the addition of HX to an alkene can rearrange to a more stable one ⇒ rearrangements invariably occur.
~ 11 ~

8.2C MODERN STATEMENT OF MARKOVNIKOV’S RULE:
1. In the ionic addition of an unsymmetrical reagent to a double bond, the positive portion of the adding reagent attaches itself to a carbon atom of the double bond so as to yield the more stable carbocation as an intermediate.

1) This is the step that occurs first (before the addition of the negative portion of the adding reagent) ⇒ it is the step that determines the overall orientation of the reaction. H3C C H3C 2-methylpropene δ+ δ−

H3C
+C

CH3 CH2 Cl − I H3C C Cl 2-Chloro-1-iodo-2-methylpropane CH2 I

CH2 + I

Cl

H3C

8.2D REGIOSELECTIVE REACTIONS:
1. When a reaction that can potentially yield two or more constitutional isomers actually produces only one (or a predominance of one), the reaction is said to be regioselective.

8.2E AN EXCEPTION TO MARKOVNIKOV’S RULE:
1. When alkenes are treated with HBr in the presence of peroxides (i.e., compounds with the general formula ROOR) the addition occurs in an anti-Markovnikov manner in the sense that the hydrogen atom becomes attached to the carbon atom with fewer hydrogen atoms.
CH3CH CH2 + HBr ROOR CH3CH2CH2Br

1) This anti-Markovnikov addition occurs only when HBr is used in the presence

of peroxides and does not occur significantly with HF, HCl, and HI even when peroxides are present.
~ 12 ~

8.3

STEREOCHEMISTRY OF THE IONIC ADDITION TO AN ALKENE

1. The addition of HX to 1-butene leads to the formation of 2-halobutane:

CH3CH2CH

CH2 + HX

* CH3CH2CHCH3 X

1) The product has a stereocenter and can exist as a pair of enantiomers. 2) The carbocation intermediate formed in the first step of the addition is trigonal plannar and is achiral. 3) When the halide ion reacts with this achiral carbocation in the second step,

reaction is equally likely at either face.
i) The reactions leading to the two enantiomers occur at the same rate, and the enantiomers are produced in equal amounts as a racemic form.

The Stereochemistry of the Reaction
Ionic Addition to an Alkene
(a)

X
C 2H 5 C H CH3

(a) H C2H5 CH CH2
− C 2H 5 C + + X

(S)-2-Halobutane (50% )
(b) H CH3

H

(b) H Achiral, trigonal planar carbocation

X

CH2

C 2H 5 C

1-Butene accepts a proton from HX to form an achiral carbocation.

X (R)-2-Halobutane (50% ) The carbocation reacts with the halide ion at equal rates by path (a) or (b) to form the enantiomers as a racemate.

8.4

ADDITION OF SULFURIC ACID TO ALKENES
~ 13 ~

1. When alkenes are treated with cold concentrated sulfuric acid, they dissolve because they react by addition to form alkyl hydrogen sulfates. 2. The mechanism is similar to that for the addition of HX: 1) In the first step, the alkene accepts a H+ form sulfuric acid to form a

carbocation.
2) In the second step, the carbocation reacts with a hydrogen sulfate ion to form an

alkyl hydrogen sulfate.
O C C +H O S O
Alkene Sulfuric acid Carbocation

H OH
+C

O +
−

HO3SO OH C

H C

C

O

S O

Hydrogen sulfate ion Alkyl hydrogen sulfate

Soluble in sulfuric acid

3. The addition of H2SO4 is regioselective and follows Markovnikov’s rule: H C H3C CH2 H
+C

H CH2 H − OSO3H H3C C CH3

H

OSO3H

H3C

OSO3H Isopropyl hydrogen sulfate

2o Carbocaion (more stable carbocation)

8.4A ALCOHOLS FROM ALKYL HYDROGEN SULFATES:
1. Alkyl hydrogen sulfates can be easily hydrolyzed to alcohols by heating them with water. CH3CH CH2 cold H2SO4 CH3CHCH 3

H2O, heat

CH3CHCH3 + H2SO4

OSO3H

OH

1) The overall result of the addition of sulfuric acid to an alkene followed by
~ 14 ~

hydrolysis is the Markovnikov addition of H– and –OH.

8.5

ADDITION OF WATER TO ALKENES: ACID-CATALYZED HYDRATION

1. The acid-catalyzed addition of water to the double bond of an alkene is a method for the preparation of low molecular weight alcohols that has its greatest utility in large-scale industrial processes. 1) The acids most commonly used to catalyze the hydration of alkenes are dilute solutions of sulfuric acid and phosphoric acid. 2) The addition of water to a double bond is usually regioselective and follows Markovnikov’s rule.

C

C

+

HOH

H3O+

C H

C OH CH3

H3C C CH2 + HOH H3C 2-Methylpropene (isobutylene)

H3O+ 25oC

H3C

C

CH2 H

OH tert-Butyl alcohol

2. The acid-catalyzed hydration of alkenes follows Markovnikov’s rule ⇒ the reaction does not yield 1° alcohols except in the special case of the hydration of ethene.
H 2C CH2 + HOH H3PO4 300oC CH3CH2OH

3. The mechanism for the hydration of an alkene is the reverse of the mechanism for the dehydration of an alcohol.

~ 15 ~

A Mechanism for the Reaction
Acid-Catalyzed Hydration of an Alkene

Step 1
CH3 H3C C CH2 H H O
+

H

slow

H2C H3C C+

H +

H O H

CH3

The alkene accepts a proton to form the more stable 3° carbocation.

Step 2

CH3 H3C C+ CH3 +

H O H

fast

CH3H H3C C O
+

H

CH3

The carbocation reacts with a molucule of water to form a protonated alcohol.

Step 3

CH3H H3C C O
+

H H + O H fast H3C

CH3 C O H + H CH3

H O
+

H

CH3

A transfer of a proton to a molecule of water leads to the product.

4. The rate-determining step in the hydration mechanism is step 1: the formation of the carbocation ⇒ accounts for the Markovnikov addition of water to the double bond. 1) The more stable tert-butyl cation is formed rather than the much less stable isobutyl cation in step 1 ⇒ the reaction produces tert-butyl alcohol.

~ 16 ~

CH3 H 3C C CH2 H

H O
+

H

very slow

CH3 H 3C C H + CH2+

H O H

For all practiacl purposes this reaction does not take place because it produces a 1° carbocation. 5. The ultimate products for the hydration of alkenes or dehydration of alcohols are governed by the position of an equilibrium. 1) The dehydration of an alcohol is best carried out using a concentrated acid so that the concentration of water is low. i) The water can be removed as it is formed, and it helps to use a high temperature. 2) The hydration of an alkene is best carried out using dilute acid so that the concentration of water is high. i) It helps to use a lower temperature.

6. The reaction involves the formation of a carbocation in the first step ⇒ the carbocation rearranges to a more stable one if such a rearrangement is possible. CH3 H3C C CH CH2 CH3 3,3-Dimethyl-1-butene OH H3C C CH CH3

H2SO4 H2O

CH3 CH3 2,3-Dimethyl-2-butanol (major product)

7. Oxymercuration-demercuration allows the Markovnikov addition of H– and –OH without rearrangements. 8. Hydroboration-oxidation permits the anti-Markovnikov and syn addition of H– and –OH without rearrangements.

~ 17 ~

8.6

ADDITION OF BROMINE AND CHLORINE TO ALKENES

1. Alkenes react rapidly with chlorine and bromine in non-nucleophilic solvents to form vicinal dihalides.

CH3CH

CHCH3 +

Cl2

−9oC

CH3CH Cl

CHCH3 (100%) Cl CH2 (97%) Cl

CH3CH2CH

CH2 +

Cl2

−9oC

CH3CH2CH Cl

+

Br2

−5oC CCl4

Br H + enantiomer (95%) H Br trans-1,2-Dibromocyclohexane (as a racemic form)

2. A test for the presence of carbon-carbon multiple bonds:

C

C

+ Br2

room temperature in the dark, CCl4

C

C

An alkene Bromine (colorless)(red brown)

Br Br vic-Dibromide (colorless)

Rapid decolorization of Br2/CCl4 is a test for alkenes and alkynes.

1) Alkanes do not react appreciably with bromine or chlorine at room temperature and in the absence of light. room temperature Br2 + R H in the dark, CCl4 Alkane Bromine (colorless) (red brown) no appreciable reaction

8.6A MECHANISM OF HALOGEN ADDITION:
1. In the first step, the π electrons of the alkene double bond attack the halogen. (In

the absence of oxygen, some reactions between alkenes and chlorine proceed
~ 18 ~

through a radical mechanism)

An Ionic Mechanism for the Reaction
Addition of Bromine to an Alkene Step 1
Br − Bromide ion

C

C

C
+

C Br

+

δ+ Br δ− Br

Bromonium ion

A bromine molecule becomes polarized as it approaches the alkene. The polarized bromine molecule transfers a positive bromine atom (with six electrons in its valence shell) to the alkene resulting in the formation of a bromonium ion.

Step 2

Br
C C +

Br − Br Bromide ion

C

C

Br + Bromonium ion

vic-Dibromide

A bromide ion attacks at the back side of one carbon (or the other) of the bromonium ion in an SN2 reacion causing the ring to open and resulting in the formation of a vic-dibromide.

1) The bromine molecule becomes polarized as the π electrons of the alkene approaches the bromine molecule. 2) The electrons of the Br–Br bond drift in the direction of the bromine atom more distant from the approaching alkene ⇒ the more distant bromine develops a

partial negative charge; the nearer bromine becomes partially positive.
3) Polarization weakens the Br–Br bond, causing it to break heterolytically ⇒ a bromide ion departs, and a bromonium ion forms.
~ 19 ~

C

C

Br

δ+

Br

δ−

+

Br
C
+ Br
−

Br
C C

+

+ Br −

Bromonium ion

i)

In the bromonium ion a positively charged bromine atom is bonded to two carbon atoms by twwo pairs of electrons: one pair from the π bond of the alkene, the other pair from the bromine atom (one of its unshared pairs) ⇒ all the atoms of the bromonium ion have an octet of electrons.

2. In the second step, the bromide ion produced in step 1 attacks the back side of one of the carbon atoms of the bromonium ion. 1) The nucleophilic attack results in the formation of a vic-dibromide by opening the three-membered ring. 2) The bromide ion acts as a nucleophile while the positive bromine of the bromonium ion acts as a leaving group.

8.7

STEREOCHEMISTRY OF THE ADDITION OF HALOGENS TO ALKENES

1. Anti addition of bromine to cyclopentene: H H H

Br
+ enantiomer

Br2 CCl4

Br H trans-1,2-Dibromocyclopentane

1) A bromonium ion formed in the first step. 2) A bromide ion attacks a carbon atom of the ring from the opposite side of the bromonium ion. 3) Nucleophilic attack by the bromide ion causes inversion of the configuration of
~ 20 ~

the carbon being attacked which leads to the formation of one enantiomer of trans-1,2-dibromocyclopentane. 4) Attack of the bromide ion at the other carbon of the bromonium ion results in the formation of the other enantiomer.

Br − H
+

H

H

H H

H

Bottom attack

H Br Br

H

Br

Br+

Br Br cis-1,2-Dibromocyclopentane (not formed)
−

Cyclopentene

Carbocation intermediate

H

Br

Br

Top Br H attack trans-1,2-Dibromocyclopentane Br −

Br

H

(b)

H

(b) (a)

H

(a)

H

Br

H

Br

Br+ Bromonium ion

Br

H

trans-1,2-Dibromocyclopentane enantiomers 2. Anti addition of bromine to cyclohexene:

~ 21 ~

Br −
6 1 2 3

Br2
6 1 2

3

inversion at C1

Br

Cyclohexene

Br Bromonium ion inversion at C2
+

Br Diaxial conformation trans-1,2Dibromocyclohexane

Br Br Br Br trans-1,2-Dibromocyclohexane 1) The product is a racemate of the trans-1,2-dibromocyclohexane. 2) The initial product of the reaction is the diaxial conformer. i) They rapidly converts to the diequatorial form, and when equilibrium is reached the diequatorial form predominates. ii) When cyclohexane derivatives undergo elimination, the required conformation is the diaxial one. Br Br Diequatorial conformation

8.7A STEREOSPECIFIC REACTIONS
1. A reaction is stereospecific when a particular stereoisomeric form of the starting material reacts gives a specific stereoisomeric form of the product. 2. When bromine adds to trans-2-butene, the product is (2R,3S)-2,3-dibromobutane, the meso compound. Reaction 1 H3C H C C H Br2 CH3 CCl4 Br Br CH3 H C C

trans-2-Butene

H CH3 (2R,3S)-2,3-Dibromobutane (a meso compound)
~ 22 ~

Br Me H Me C H C H Me Br Br Me H C
+

C

+

Me H H Me Br

Br C C H Me

C
−

Br C Br

trans-2-butene

H Me

Br C Me H C

H

Me

Br

anti-addition 3. When bromine adds to cis-2-butene, the product is a racemic form of (2R,3R)-2,3-dibromobutane and (2S,3S)-2,3-dibromobutane. Reaction 2 H3C H3C C C H Br2 H CCl4 H Br CH3 H C C Br H + Br CH3 Br C C

cis-2-Butene

CH3 (2S,3R)

H CH3 (2S,3S) H C C Br H Me

Br H Me H H C C Me Me cis-2-butene Br Br H Me C
+

C

+

Me H Me

C
−

Br + Br H Me C C

Br C Br

H Me

H

Me

Br

anti-addition

~ 23 ~

A Stereochemistry of the Reaction
Addition of Bromine to cis- and trans-2-Butene cis-2-Butene reacts with bromine to yield the enantiomeric 2,3-dibromobutanes: HCH Br (a) 3 C C − Br H (a) (b) H 3C Br H H CH3 H 3C H (2R,3R-)2,3-Dibromobutane H C C C C CH3 (chiral) H 3C Br Br H + δ+ Br H 3C (b) Bromonium ion C C (achiral) H δ− Br CH3 Br (2S,3S)-2,3-Dibromobutane (chiral)

The bromonium ion reacts with the cis-2-butene reacts with bromine to yield an achiral bromonium ion and bromide ions at equal rates by paths (a) and (b) to yield the two enantiomers in a bromide ion. [Reaction at the other face of the alkene (top) would equal amounts (i.e., as the racemic form). yield the same bromonium ion.] trans-2-Butene reacts with bromine to yield meso-2,3-dibromobutane.: CH3 Br (a) H C C − Br H (a) (b) H3C Br H CH3 H3C H (R,S-)2,3-Dibromobutane CH3 C C C C H H (meso) H3C Br Br H + δ+ Br H3C (b) Bromonium ion C C (chiral) CH δ− Br H 3 Br (R,S)-2,3-Dibromobutane (meso)

trans-2-Butene reacts with bromine yo yield chiral bromonium ions and bromide ions. [Reaction at the other face (top) would yield the enantiomer of the bromonium ion as shown here.]

When the bromonium ions react by either path (a) or path (b), they yiled the same achiral meso compound. [Reaction of the enantiomer of the intermediate bromonium ion would produce the same result.]

~ 24 ~

8.8

HALOHYDRIN FORMATION

1. When an alkene is reacted bromine in aqueous solution (rather than CCl4), the major product is a halohydrin (halo alcohol).

C

C

+ X2 + H2O X = Cl or Br

C

C

+

C

C

+ HX

X OH Halohydrin (major)

X X vic-Dihalide (minor)

A Mechanism for the Reaction
Halohydrin formation from an Alkene
Step 1

C δ+ X δ− X

C

C X
+

C

+

X−

Halonium ion

This step is the same as for halogen addition to an alkene
Step 2 and 3

H C X
+

O C + O H H X C C

+

H

O H

H C X

H O C + H O H
+

H

Protonated Halohydrin halohydrin The protonated hallohydrin loses a Here, however, a water molecule acts as the nuclephile and attacks a proton (it is transferred to a molecule of water). This step produces the carbon of the ring, causing the halohydrin and hydronium ion. formation of a protonated halohydrin.

Halonium ion

1) Water molecules far numbered halide ions because water is the solvent for the
~ 25 ~

reaction. 2. If the alkene is unsymmetrical, the halogen ends up on the carbon atom with the greater number of hydrogen atoms.

1) The intermediate bromonium ion is unsymmetrical. i) The more highly substituted carbon atom bears the greater positive charge because it resembles the more stable carbocation. ii) Water attacks this carbon atom preferentially. H3C C H3C CH2 CH3 C CH2 Br δ+
+OH2

Br2

H3C

δ+

OH2

H3C

C CH3

CH2Br H3C

−H+
OH C CH2Br

CH3 (73%) iii) The greater positive charge on the 3° carbon atom permits a pathway with a lower free energy of activation even though attack at the 1° carbon atom is less hindered.

The Chemistry of Regiospecificity in Unsymmetrically Substituted Bromonium Ions: Bromonium Ions of Ethene, Propene, and 2-Methylpropene
1. When a nucleophile reacts with a bromonium ion, the addition takes place with Markovnikov regiochemistry. 1) In the formation of bromohydrin, bromine bonds at the least substituted carbon (from nucleophilic attack by water), and the hydroxyl group bonds at the more substituted carbon (i.e., the carbon that accommodated more of the positive charge in the bromonium ion). 2. The relative distributions of electron densities in the bromonium ions of ethane,
~ 26 ~

propene, and 2-methylpropene:

Red indicates relatively negative areas and blue indicates relatively positive (or less negative) areas. Figure 8.A As alkyl substitution increases, carbon is able to accommodate greater positive charge and bromine contributes less of its electron density. 1) As alkyl substitution increases in bromonium ions, the carbon having greater substitution requires less stablization by contribution of electron density from bromine. 2) In the bromonium ion of ethene (I), the bromine atom contributes substantial electron density. 3) In the bromonium ion of 2-methylpropene (III): i) The tertiary carbon can accommodate substantial positive charge, and hence most of the positive charge is localized there (as is indicated by deep blue at the tertiary carbon in the electrostatic potential map). ii) The bromine retains the bulk of its electron density (as indicated by the mapping of red color near the bromine). ii) The bromonium ion of 2-methylpropene has essentially the charge distribution of a tertiary carbocation at its carbon atoms. 4) The bromonium ion of propene (II), which has a secondary carbon, utilizes some electron density from the bromine (as indicated by the moderate extent of yellow near the bromine)
~ 27 ~

3. Nucleophile reacts with bromonium ions II or III at the carbon of each that bears the greater positive charge, in accord with Markovnikov regiochemistry. 4. The C–Br bond lengths of bromonium ions I, II, and III:

Figure 8.B The carbon-bromine bond length (shown in angstroms) at the central carbon increases as less electron density from the bromine is needed to stabilize the positive charge. A lesser electron density contribution from bromine is needed because additional alkyl groups help stabilize the charge 1) In the bromonium ion of ethene (I), the C–Br bond lengths are identical (2.06Å). 2) In the bromonium ion of propene (II), the C–Br bond involving the 2° carbon is 2.17Å, whereas the one with the 1°carbon is 2.03Å. i) The longer bond length to the 2° carbon is consistent with the lesser contribution of electron density from the bromine to the 2° carbon, because the 2° carbon can accommodate the charge better than the 1° carbon. 3) In the bromonium ion of 2-methylpropene (III), the C–Br bond involving the 3° carbon is 2.39Å, whereas the one with the 1°carbon is 1.99Å. i) The longer bond length to the 3° carbon indicates that significantly less contribution of electron density from the bromine to the 3° carbon, because the 3° carbon can accommodate the charge better than the 1° carbon. ii) The bond at the 1° carbon is like that expected for typical alkyl bromide. 5. The lowest unoccupied molecular orbital (LUMO) of ethane, propene, and 2-methylpropene: 1) The lobes of the LUMO on which we should focus on are those opposite the three membered ring portion of the bromonium ion.
~ 28 ~

Figure 8.C With increasing alkyl substitution of the bromonium ion, the lobe of the LUMO where electron density from the nucleophile will be contributed shifts more and more to the more substituted carbon. 2) In the bromonium ion of ethene (I), equal distribution of the LUMO lobe near the two carbons where the nucleophile could attack. 3) In the bromonium ion of propene (II), the corresponding LUMO lobe has more of its volume associated with the more substituted carbon, indicating that electron density from the nucleophile will be best accommodated here. 4) In the bromonium ion of 2-methylpropene (III) has nearly all of the volume from this lobe of the LUMO associate with the 3° carbon and virtually none associated with the 1° carbon.

8.9

DIVALENT CARBON COMPOUNDS:

CARBENES

1. Carbenes: compounds in which carbon forms only two bonds. 1) Most carbenes are highly unstable compounds that are capable of only fleeting existence. 2) The reactions of carbenes are of great synthetic use in the preparation of compounds that have three-membered rings.

~ 29 ~

8.9A STRUCTURE AND REACTIONS OF METHYLENE
1. Methylene (:CH2), the simplest carbene, can be prepared by the decomposition of diazomethane (CH2N2).
−

CH2

N

+

N

heat or light

CH2 Methylene

+

N

N

Diazomethane

Nitrogen

2. The structure of diazomethane is a resonance hybrid of three structures:
−

CH2

N I

+

N

CH2

N II

+

N

−

−

CH2

N III

N

+

3. Methylene adds to the double bond of alkenes to form cyclopropanes:

C

C

+

CH2

C

C

C Alkene Methylene H H Cyclopropane

8.9B REACTIONS OF OTHER CARBENES: DIHALOCARBENES
1. Most reactions of dihalocarbenes are stereospecific.

C

C + CCl2

C

C

C Cl Cl

The addition of :CX2 is stereospecific. If the R groups of the alkene are trans in the product, they will be trans in the product. (If the R groups were initially cis, they would be cis in the product)

2. Dichlorocarbenes can be synthesized by the α elimination of hydrogen chloride from chloroform. R O − K+ + H CCl3 R O Η+
−

CCl3 + K+

slow Dichlorocarbene

− CCl2 + Cl

~ 30 ~

1) Compounds with a β-hydrogen react by β elimination preferentially. 2) Compounds with no β-hydrogen but with an α-hydrogen react by α

elimination.
3. A variety of cyclopropane derivatives has been prepared by generating dichlorocarbene in the presence of alknenes. H KOC(CH3)3 CHCl3 (59% ) H Cl Cl

7,7-Dichlorobicyclo[4,1,0]heptane

8.9C CARBENOIDS: THE SIMMONS-SMITH CYCLOPROPANE SYNTHESIS
1. H. E. Simmons and R. D. Smith of the DuPont Company had developed a useful cyclopropane synthesis by reacting a zinc-copper couple with an alkene. 1) The diiodomethane and zinc react to produce a carbene-like species called a carbenoid. CH2I2 + Zn(Cu) ICH2ZnI A carbeniod

2) The carbenoid then brings about the stereospecific addition of a CH2 group directly to the double bond.

8.10 OXIDATION OF ALKENES: SYN-HYDROXYLATION
1. Potassium permanganate or osmium tetroxide oxidize alkenes to furnish 1,2-diols (glycols).

~ 31 ~

H2C

CH2 + KMnO4

cold OH− , Η 2O

H2C

CH2

Ethene

OH OH 1,2-Ethanediol (ethylene glycol) CH3CH CH2

CH3CH

CH2

1. OsO4, pyridine 2. Na2SO3/H2O or NaHSO3/H2O

Propene

OH OH 1,2-Propaneiol (propylene glycol)

8.10A MECHANISMS FOR SYN-HYDROXYLATION OF ALKENES
1. The mechanism for the syn-hydroxylation of alkenes: OH− H2O several steps

C + O

C

C O

C O Mn O−

C

C

+

MnO2

O Mn O− O

OH OH

O

C O O +

C O O

pyridine

C O

C O Os

NaHSO3 H2O

C

C

+ Os

OH OH

Os

O O An osmate ester H H H2O OH− O O Mn O− O HO OH cis-1,2-Cyclopentanediol (a meso compound) H H

+ H H

MnO4−

cold

~ 32 ~

+ OsO4 H H

cold

H

H

NaHSO4 H2O

H

H

O Os O

O O

HO OH cis-1,2-Cyclopentanediol (a meso compound)

2. Osmium tetroxide gives the higher yields. 1) Osmium tetroxide is highly toxic and is very expensive ⇒ Osmium tetroxide is used catalytically in conjunction with a cooxidant. 3. Potassium permanganate is a very powerful oxidizing agent and is easily causing

further oxidation of the glycol.
1) Limiting the reaction to hydroxylation alone is often difficult but usually attempted by using cold, dilute, and basic solutions of potassium permanganate.

8.11 OXIDATIVE CLEAVAGE OF ALKENES
1. Alkenes with monosubstituted carbon atoms are oxidatively cleaved to salts of carboxylic acids by hot basic permangnate solutions.

CH3CH

CHCH3

KMnO4, OH −, H2O heat

O 2 CH3C O Acetate ion
−

H+

O 2 CH3C OH Acetic acid

(cis or trans)

1) The intermediate in this reaction may be a glycol that is oxidized further with cleavage at the carbon-carbon bond. 2) Acidification of the mixture, after the oxidation is complete, produces 2 moles of acetic acid for each mole of 2-butene. 2. The terminal CH2 group of a 1-alkene is completely oxidized to carbon dioxide and water by hot permanganate. 3. A disubstituted carbon atom of a double bond becomes the carbonyl group of a
~ 33 ~

ketone.

CH3 CH3CH2C CH2

1. KMnO4, OH− , heat 2. H3O+

CH3 CH3CH2C O + O C O + H2O

4. The oxidative cleavage of alkenes has been used to establish the location of the double bond in an alkene chain of ring.

8.11A OZONOLYSIS OF ALKENES
1. Ozone reacts vigorously with alkenes to form unstable initial ozonides (molozonides) which rearrange spontaneously to form ozonides. 1) The rearrangement is thought to go through dissociation of the initial ozonide into reactive fragments that recombine to give the ozonide.

A Mechanism for the Reaction
Ozonide Formation from an Alkene

C
−

C O O

C O O

C O

C O

+
−

C O
+O

O

Ozone adds to the alkene to form an initial ozonide.

Initial ozonide

The initial ozonide fragments.

C

O
−

C
+O

C

O

C

O The fragments recombine to form the ozonide.

O O Ozonide

2. Ozonides are very unstable compounds and low molecular weight ononides often explode violently.
~ 34 ~

1) Ozonides are not usually isolated but are reduced directly by treatment with znic and acetic acid (HOAc). 2) The reduction produces carbonyl compounds (aldehydes or ketones) that can be safely isolated and identified. O

C O

C O

+ Zn

HOAc

C

O

+

O

C

+ Zn(HOAc)2

Ozonide

Aldehydes and/or ketones

3-28-02 3. The overall process of onzonolysis is: R C R' C H R" 1. O3, CH2Cl2, −78 oC 2. Zn/HOAc R C R' O + O C H R"

1) The –H attached to the double bond is not oxidized to –OH as it is with permanganate oxidations CH3 CH3C CHCH3 2-Methyl-2-butene CH3 CH3C CH CH2 3-Methyl-1-butene 1. O3, CH2Cl2, −78 oC 2. Zn/HOAc 1. O3, CH2Cl2, −78 oC 2. Zn/HOAc CH3 CH3C O Acetone CH3 O CH3C CH + + O CH3CH

Acetaldehyde O HCH

Isobutyraldehyde Formaldehyed

8.12 ADDITION OF BROMINE AND CHLORINE TO ALKYNES
1. Alkynes show the same kind of reactions toward chlorine and bromine that alkenes do: They react by addition. 1) With alkynes, the addition may occur once or twice depending on the number of molar equivalents of halogen employed.
~ 35 ~

C

C

Br2 CCl4

Br C C Br Dibromoalkene Cl C C Cl Dichloroalkene

Br2 CCl4

Br Br C C

Br Br Tetrabromoalkane Cl Cl C C

C

C

Cl2 CCl4

Cl2 CCl4

Cl Cl Tetrachloroalkane

2. It is usually possible to prepare a dihaloalkene by simply adding one molar equivalent of the halogen. Br2 (1 mol) CCl4 0 oC CH3CH2CH2CH2CBr CBrCH2OH (80%)

H3CH2CH2CH2CC

CCH2OH

3. Most additions of chlorine and bromine to alkynes are anti additions and yield trans-dihaloalkenes. HO2C

C

C

CO2H

Br2

HO2C C Br C

Br CO2H

Acetylenedicarboxylic acid

(70%)

8.13 ADDITION OF HYDROGEN HALIDES TO ALKYNES
1. Alkynes react with HCl and HBr to form haloalkenes or geminal dihalides depending on whether one or two molar equivalents of the hydrogen halide are used. 1) Both additions are regioselective and follow Markovnikov’s rule:

~ 36 ~

H C C HX C C X Haloalkene

H HX C H

X C X

gem-Dihalide

2) The H atom of the HX becomes attached to the carbon atom that has the greater number of H atoms. Br C4H9C CH HBr C4H9 C Br 2-Bromo-1-hexene CH2 HBr C4H9 C CH3

Br 2,2-Dibromohexane

2. The addition of HBr to an alkyne can be facilitated by using acetyl bromide (CH3COBr) and alumina instead of aqueous HBr. 1) CH3COBr acts as an HBr precursor by reacting with alumina to generate HBr. 2) The alumina increases the rate of reaction. Br C CH2 C5H11 (82%)

C5H11C

CH

"HBr" CH3COBr/alumina CH2Cl2

3. Anti-Markovnikov addition of HBr to alkynes occur when peroxides are present. 1) These reactions take place through a free radical mechanism. CH3CH2CH2CH2C CH HBr peroxides CH3CH2CH2CH2CH CHBr (74%)

8.14 OXIDATIVE CLEAVAGE OF ALKYNES
1. Treating alkynes with ozone or with basic potassium permanganate leads to
~ 37 ~

cleavage at the C≡C.

R

C

C

R'

1. O3 2. HOAc

RCO2H + R'CO2H RCO2H + R'CO2H

R

C

C

1. KMnO4, OH− R' 2. H+

8.15 SYNTHETIC STRATEGIES REVISITED
1. Four interrelated aspects to be considered in planning a synthesis: 1) Construction of the carbon skeleton. 2) Functional group interconversion. 3) Control of regiochemistry. 4) Control of stereochemistry. 2. Synthesis of 2-bromobutane from compounds of two carbon atoms or fewer:
Retrosynthetic Analysis

CH3CH2CHCH 3 Br
Synthesis

CH3CH2CH CH2 + H

Br

Markovnikov addition

CH3CH2CH CH2 + H

Br

no peroxide

CH3CH2CHCH3 Br

Target molecule

Precursor

3. Synthesis of 1-butene from compounds of two carbon atoms or fewer:
Retrosynthetic Analysis

CH3CH2CH CH3CH2C

CH2 CH

CH3CH2C

CH

+ H2 CH

CH3CH2Br + NaC
~ 38 ~

NaC
Synthesis

CH

HC

CH + NaNH2

HC

C

+− H + Na NH2

liq. NH3 −33 C liq. NH3 −33oC o HC

C − Na+

+− CH3CH2 Br + Na C

CH

CH3CH2C

CH

CH3CH2C 4. Disconnection:

CH + H2

Ni2B (P-2)

CH3CH2CH CH2

1) Warren, S. “Organic Synthesis, The Disconnection Approach”; Wiley: New York, 1982. Warren, S. “Workbook for Organic Synthesis, The Disconnection

Approach”; Wiley: New York, 1982.
CH3CH2 C i) CH CH3CH2 +
+
−

C

CH

The fragments of this disconnection are an ethyl cation and an ethynide anion.

ii) These fragments are called synthons (synthetic equivalents).
CH3CH2 ≡ CH3CH2Br
+

−

C

CH ≡ Na+− C

CH

5. Synthesis of (2R,3R)-2,3-butanediol and (2S,3S)-2,3-butanediol from compounds of two carbon atoms or fewer: 1) Synthesis of 2,3-butanediol enantiomers: syn-hydroxylation of trans-2-butene.

Retrosynthetic Analysis

~ 39 ~

CH3 H HO C H C

H H 3C

C C

OH

H CH3 C C H 3C H

H CH3 CH3 H OH HO C C HO CH3 H CH3 (S,S)-2,3-butanediol H HO C C

H CH3 (R,R)-2,3-butanediol

OH H3C

OH

trans-2-Butene syn-hydroxylation at either face of the alkene

Synthesis

H CH3 C C H3C H trans-2-Butene 1. OsO4 2. NaHSO3, H2O

HO

CH3 H C C CH3 OH

H

CH3 OH C H CH3 C

H

HO

(R,R) (S,S) Enantiomeric 2,3-butanediols

i)

This reaction is stereospecific and produces the desired enantiomeric 2,3-butanediols as a racemic mixture (racemate).

2) Synthesis of trans-2-butene: Retrosynthetic Analysis H CH3 C C H3C H trans-2-Butene Synthesis anti-addition CH3 C C + H2

CH3 2-Butyne

~ 40 ~

CH3 C C CH3 2-Butyne 3) Synthesis of 2-butyne: Retrosynthetic Analysis
H 3C C C CH3 H 3C C

H CH3 1. Li,EtNH2 2. NH4Cl anti addition of H2 C C H3C H trans-2-Butene

C − Na+ + CH3

I

H3C
Synthesis
H 3C C

C

C − Na+

H3C

C

C

H + NaNH2

C

H

1. NaNH2/liq. NH3 2. CH3I

H 3C

C

C

CH3

4) Synthesis of propyne:

Retrosynthetic Analysis
H C C CH3 H C C − Na+ + CH3 I

Synthesis
H C C H 1. NaNH2/liq. NH3 2. CH3I H C C CH3

The Chemistry of Cholesterol Biosynthesis: Elegant and Familiar Reactions in Nature

~ 41 ~

H3C H3C CH3 HO H3C Squalene H3C CH3 H HO H H Cholesterol CH3 Lanosterol

1. Cholesterol is the biochemical precursor of cortisone, estradiol, and testosterone. 1) Cholesterol is the parent of all of the steroid hormones and bile acids in the body. 2. The last acyclic precursor of cholesterol biosynthesis is squalene, consisting of a linear polyalkene chain of 30 carbons. 3. From squalene, lanosterol, the first cyclic precursor, is created by a remarkable set of enzyme-catalyzed addition reactions and rearrangements that create four fused rings and seven stereocenters. 1) In theory, 27 (or 128) stereoisomers are possible. 4. Polyene Cyclization of Squalene to Lanosterol 1) The sequence of transformations from squalene to lanosterol begins by the enzymatic oxidation of the 2,3-double bond of squalene to form (3S)-2,3-oxidosqualene [also called squalene 2,3-epoxide]. 2) A cascade of alkene addition reactions begin through a chair-boat-chair conformation transition state. i) Protonation of (3S)-2,3-oxidosqualene by squalene oxidocyclase gives the oxygen a formal positive charge and converts it to a good leaving group.
~ 42 ~

ii) Protonation of (3S)-2,3-oxidosqualene by squalene oxidocyclase gives the oxygen a formal positive charge and converts it to a good leaving group.

Squalene Oxidocyclase Enz−H CH3 O
3 2 7 10

CH3
19

CH3
6 11

H3C H3C
15 14

CH3

CH3 (3S)-2,3-Oxidosqualene CH3 H
6 7 11 10

CH3

18

CH3 H3C + CH3 19
15 14 18

CH3 HO

CH3 H

H3C CH3 Protosteryl cation

H

iii) The protonated epoxide makes the tertiary carbon (C2) electron deficient (resembling a 3° carbocation), and C2 serves as the electrophile for an addition with the double bond between C6 and C7 in the squalene chain ⇒ another 3° carbocation begins to develop at C6. iv) The C6 carbocation is attacked by the next double bond, and so on for two more alkene additions until the exocyclic tertiary proteosteryl cation results. 4. An Elimination Reaction Involving a Sequence of 1,2-Methanide and 1,2-Hydride Rearrangements 1) The subsequent transformations involved a series of migrations (carbocation rearrangements) followed by removal of a proton to form an alkene. i) The process begins with a 1,2-hydride shift from C17 to C18, leading to development of positive charge at C17. ii) The developing positive charge at C17 facilitates another hydride shift from C13 to C17 which is accompanied by methyl shift from C14 to C13 and C8 to C14.
~ 43 ~

iii) Finally, enzymatic removal of a proton from C9 forms the C8-C9 double bond leading to lanosterol. B CH3 HO H 3C CH3 H
10 5 9 8

CH3 H 3C CH3 18+
14 13 17

CH3 H

Protosteryl cation CH3
10 9 8

CH3

H CH3
18 17

CH3
13 14

CH3 CH3

CH3 HO H 3C

H

H Lanosterol

CH3

5. The remaining steps to cholesterol involve loss of three carbons through 19 oxidation-reduction steps:

H3C H3C CH3 HO H3C CH3 Lanosterol 19 steps HO CH3 H

H3C H H Cholesterol and

6. Biosynthetic reactions occur on the basis of the same fundamental principles reaction pathways in organic chemistry.

8.16 SUMMARY OF KEY REACTIONS
Summary of Addition Reactions of Alkenes

~ 44 ~

H2/Pt, Ni, or Pd
Syn addition

H

CH3 Hydrogenation

HX (X = Cl, Br, I or OSO3H) Markovnikov addition

H H

H X Ionic Addition of HX

H HBr, ROOR anti-Markovnikov addition H3O+/H2O Markovnikov addition H H Br H H

CH3 H Free Radical Addition of HBr CH3 OH Hydration CH3 X Halogenation

X2 (X = Cl, Br) H CH3 Anti addition

X H

CH3 OH Halohydrin Formation

X2/H2O Anti addition, follows Markovnikov's rule CH2I2/Zn(Cu) (or other conditions)
Syn addition

X H

CH3 H Carbene Addition

Cold dil. KMnO4 or 1. OsO4, 2. NaHSO3
Syn addition

CH2 H CH3 Syn Hydroxylation HO OH Oxidative Cleavage CH3 Ozonlysis CH3

1. KMnO4, OH− , heat 2. H3O+ 1. O3, 2. Zn/HOAc OO H
~ 45 ~

OO HO

A summary of addition reactions of alkenes with 1-methylcyclopentene as the organic substrate. A bond designated means that the stereochemistry of the group is unspecified. For brevity the structure of only one enantiomer of the product is shown, even though racemic mixtures would be produced in all instances in which the product is chiral.

Summary of Addition Reactions of Alkynes
H2/NiB2 (P-2 catalyst) Syn addition R C H R C H C R C H H Hydrogenation R

Li/NH3 (or RNH2) Anti addition

H2/Pt R C C R X2 (one molar equiv.) Anti addition

R R C X R C H R C HO

CH2 X C R X C R

CH2 R *

X2

RCX2CX2R

Halogenation

HX (one molar equiv.) Anti addition

HX

RCH2CX2R

Addition of HX

1. O3, 2. HOAc or 1. KMnO4, OH− , 2. H3O+

OH OO C R Oxidation

~ 46 ~

RADICAL REACTIONS
CALICHEAMICIN γ1I: A RADICAL DEVICE FOR

SLICING THE BACKBONE OF DNA
1. Calicheamicin γ1I binds to the minor groove of DNA where its unusual enediyne moiety reacts to form a highly effective device for slicing the backbone of DNA. 1) Calicheamicin γ1I and its analogs are of great clinical interest because they are extraordinarily deadly for tumor cells. 2) They have been shown to initiate apoptosis (programmed cell death). 2. Bacteria called Micromonospora echinospora produce calicheamicin γ1I as a natural metabolite, presumably as a chemical defense against other organisms.

HO Me I O Me O HO MeO OMe OH calicheamicin γ 1I O S OMe OH Me MeS S H S O N HO O MeO H O O

O

CO2Me NH

O

O

H Me N

3. The DNA-slicing property of calicheamicin γ1I arises because it acts as a molecular machine for producing carbon radicals. 1) A carbon radical is a highly reactive and unstable intermediate that has an unpaired electron. 2) A carbon radical can become a stable molecule again by removing a proton and one electron (i.e., a hydrogen atom) from another molecule. 3) The molecule that lost the hydrogen atom becomes a new radical intermediate.
~1~

4) When the radical weaponry of each calicheamicin γ1I is activated, it removes a hydrogen atom from the backbone of DNA. 5) This leaves the DNA molecule as an unstable radical intermediate, which in turn results in double strand cleavage of the DNA and cell death.

HO

O

O S H S SMe calicheamicin γ 1I Bergman cycloaromatization

CO2Me 1. nucleophilic attack NH 2. conjugate Sugar addition

HO

S

O O Sugar H CO2Me N H

HO

S DNA

O O Sugar H CO2Me N H O2 DNA diradical DNA double strand cleavage

HO

S

O O Sugar H CO2Me N H

4. The total synthesis of calicheamicin γ1I by the research group of K. C. Nicolaou (The Scripps Research Institute, University of California, San Diego) represents a stunning achievement in synthetic organic chemistry.

~2~

10.1 INTRODUCTION:
1. Ionic reactions are those in which covalent bonds break heterolytically, and in which ions are involved as reactants, intermediates, or products. 1) Heterolytic bond dissociation (heterolysis): electronically unsymmetrical bond breaking ⇒ produces ions. 2) Heterogenic bond formation: electronically unsymmetrical bond making. 3) Homolytic bond dissociation (homolysis): electronically symmetrical bond breaking ⇒ produces radicals (free radicals). 4) Hemogenic bond formation: electronically symmetrical bond making. homolysis A B i)

A + B Radicals

Single-barbed arrows are used for the movement of a single electron.

10.1A PRODUCTION OF RADICALS
1. Energy must be supplied by heating or by irradiation with light to cause homolysis of covalent bonds. 1) Homolysis of peroxides:

R

O O

R

heat

2 R

O

Dialkyl peroxide

Alkxoyl radicals

2) Homolysis of halogen molecules: heating or irradiation with light of a wave length that can be absorbed by the halogen molecules. homolysis heat or light 2 X

X X

10.1B REACTIONS OF RADICALS:
~3~

1. Almost all small radicals are short-lived, highly reactive species. 2. They tend to react in a way that leads to pairing of their unpaired electron. 1) Abstraction of an atom from another molecule: i) Hydrogen abstraction:

General Reaction X + H R Alkane Specific Example
Cl + H CH3 Methane Cl H + CH3

XH +

R

Alkyl radical

Methyl radical

2) Addition to a compound containing a multiple bond to produce a new, larger radical:

R C C

R C C

Alkene

New radical

The Chemistry of Radicals in Biology, Medicine, and Industry
1. Radical reactions are of vital importance in biology and medicine. 1) Radical reactions are ubiquitous (everywhere) in living things, because radicals are produced in the normal course of metabolism. 2) Radical are all around us because molecular oxygen ( O diradical. 3) Nitric oxide ( N systems.
~4~

O ) is itself a

O ) plays a remarkable number of important roles in living

i)

Although in its free form nitric oxide is a relatively unstable and potentially toxic gas, in biological system it is involved in blood pressure regulation and blood clotting, neurotransmission, and the immune response against tumor

cells. ii) The 1998 Nobel Prize in Medicine was awarded to the scientists (R. F. Furchgott, L. J. Ignarro, and F. Murad) who discovered that NO is an important signaling molecule (chemical messenger). 2. Radical are capable of randomly damaging all components of the body because they are highly reactive. 1) Radical are believed to be important in the “aging process” in the sense that radicals are involved in the development of the chronic diseases that are life limiting. 2) Radical are important in the development of cancers and in the development of atherosclerosis (動脈粥樣硬化). 3. Superoxide ( O2− ) is a naturally occurring radical and is associated with both the immune response against pathogens and at the same time the development of certain diseases. 1) An enzyme called superoxide dismutase regulates the level of superoxide in the body. 4. Radicals in cigarette smoke have been implicated in inactivation of an antiprotease in the lungs which leads to the development of emphysema (氣腫). 5. Radical reactions are important in many industrial processes. 1) Polymerization: polyethylene (PE), Teflon (polytetrafluoroethylene, PTFE), polystyrene (PS), and etc. 2) Radical reactions are central to the “cracking” process by which gasoline and other fuels are made from petroleum. 3) Combustion process involves radical reactions.
~5~

Table 10.1

Single-Bond Homolytic Dissociation Energies ∆H° at 25°C

A B
Bond Broken (shown in red) H–H D–D F–F Cl–Cl Br–Br I–I H–F H–Cl H–Br H–I CH3–H CH3–F CH3–Cl CH3–Br CH3–I CH3–OH CH3–OCH3 CH3CH2–H CH3CH2–F CH3CH2–Cl CH3CH2–Br CH3CH2–I CH3CH2–OH CH3CH2–OCH3 CH3CH2CH2–H CH3CH2CH2–F CH3CH2CH2–Cl CH3CH2CH2–Br CH3CH2CH2–I CH3CH2CH2–OH CH3CH2CH2–OCH3 (CH3)2CH–H (CH3)2CH–F kJ mol–1
435 444 159 243 192 151 569 431 366 297 435 452 349 293 234 383 335 410 444 341 289 224 383 335 410 444 341 289 224 383 335 395 439

A + B
Bond Broken (shown in red) (CH3)2CH–Br (CH3)2CH–I (CH3)2CH–OH (CH3)2CH–OCH3 (CH3)2CHCH2–H (CH3)3C–H (CH3)3C–Cl (CH3)3C–Br (CH3)3C–I (CH3)3C–OH (CH3)3C–OCH3 C6H5CH2–H CH2=CHCH2–H CH2=CH–H C6H5–H HC C H CH3–CH3 CH3CH2–CH3 CH3CH2CH2–H CH3CH2–CH2CH3 (CH3)2CH–CH3 (CH3)3C–CH3 HO–H HOO–H HO–OH (CH3)3CO–OC(CH3)3
O C6H5CO O OCC6H5

kJ mol–1
285 222 385 337 410 381 328 264 207 379 326 356 356 452 460 523 368 356 356 343 351 335 498 377 213 157

139 184 431 364

CH3CH2O–OCH3 CH3CH2O–H

~6~

(CH3)2CH–Cl

339

O CH3C H

10.2 HOMOLYTIC BOND DISSOCIATION ENERGIES
1. Bond formation is an exothermic process:

H• + H• Cl• + Cl•

H–H Cl–Cl

∆H° = – 435 kJ mol–1 ∆H° = – 243 kJ mol–1

2. Bond breaking is an endothermic process:

H–H Cl–Cl

H• + H• Cl• + Cl•

∆H° = + 435 kJ mol–1 ∆H° = + 243 kJ mol–1

3. The hemolytic bond dissociation energies, ∆H°, of hydrogen and chlorine:

H–H
(∆H° = 435 kJ mol–1)

Cl–Cl
(∆H° = 243 kJ mol–1)

10.2A HOMOLYTIC BOND DISSOCIATION ENERGIES AND HEATS OF REACTION:
1. Bond dissociation energies can be used to calculate the enthylpy change (∆H°) for a reaction. 1) For bond breaking ∆H° is positive and for bond formation ∆H° is negative.

H

H

+

Cl

Cl

2H

Cl

∆H° = 435 kJ mol–1 ∆H° = 243 kJ mol–1 +678 kJ mol–1 is required for bond cleavage.

(∆H° = 431 kJ mol–1) × 2 – 862 kJ mol–1 is evolved in bond formation.

i)

The overall reaction is exothermic:
∆H° = (– 862 kJ mol–1 + 678 kJ mol–1) = – 184 kJ mol–1

ii) The following pathway is assumed in the calculation:

H–H
~7~

2 H•

Cl–Cl
2 H• + 2 Cl•

2 Cl• 2 H–Cl

10.2B HOMOLYTIC BOND DISSOCIATION ENERGIES AND THE RELATIVE STABILITIES OF RADICALS:
1. Bond dissociation energies can be used to eatimate the relative stabilities of radicals. 1) ∆H° for 1° and 2° C–H bonds of propane:

CH3CH2CH2–H
(∆H° = 410 kJ mol–1) 2) ∆H° for the reactions:

(CH3)2CH–H
(∆H° = 395 kJ mol–1)

CH3CH2CH2–H

CH3CH2CH2• + H• Propyl radical (a 1° radical)

∆H° = + 410 kJ mol–1

(CH3)2CH–H

(CH3)2CH• + H• Isopropyl radical (a 2° radical)

∆H° = + 395 kJ mol–1

3) These two reactions both begin with the same alkane (propane), and they both produce an alkyl radical and a hydrogen atom. 4) They differ in the amount of energy required and in the type of carbon radical produced. 2. Alkyl radicals are classified as being 1°, 2°, or 3° on the basis of the carbon atom that has the unpaired electron. 1) More energy must be supplied to produce a 1° alkyl radical (the propyl radical) from propane than is required to produce a 2° carbon radical (the isopropyl radical) from the same compound ⇒ 1° radical has greater potential energy
⇒ 2° radical is the more stable radical.

3. Comparison of the tert-butyl radical (a 3° radical) and the isobutyl radical (a 1° radical) relative to isobutene:
~8~

1) 3° radical is more than the 1° radical by 29 kJ mol–1.
CH3 H 3C C H CH3 H3C C H CH2 H CH2 H CH3 CH3CCH3 + H
∆H° = + 381 kJ mol–1

tert-Butyl radical (a 3o radical) CH3 CH3CCH2 + H
∆H° = + 410 kJ mol–1

H Isobutyl radical (a 1o radical)

1o radical CH3CH2CH2 + H 2o radical

1o radical 3o radical CH3

CH3 CH3CHCH2 + H

CH3CHCH3 + H 15 kJ mol−1 PE ∆Ho = +410 kJ mol−1 ∆Ho = +395 kJ mol−1 PE

29 kJ mol−1 CH3CCH3 + H ∆Ho = +410 kJ mol−1 ∆Ho = +381 kJ mol−1

CH3 CH3CH2CH2 CH3CHCH3

Figure 10.1 (a) Comparison of the potential energies of the propyl radical (+H•) and the isopropyl radical (+H•) relative to propane. The isopropyl radical –– a 2° radical –– is more stable than the 1° radical by 15 kJ mole–1. (b) Comparison of the potential energies of the tert-butyl radical (+H•) and the isobutyl radical (+H•) relative to isobutane. The 3° radical is more stable than the 1° radical by 29 kJ mole–1. 4. The relative stabilities of alkyl radicals:
~9~

Tertiary C C C C

> >

Secondary C C C H

> >

Primary H C C H

> >

Methyl H H C H

1) The order of stability of alkyl radicals is the same as for carbocations. i) Although alkyl radicals are uncharged, the carbon that bears the odd electrons is electron deficient. ii) Electron-releasing alkyl groups attached to this carbon provide a stabilizing effect, and more alkyl groups that are attached to this carbon, the more stable the radical is.

10.3 THE REACTIONS OF ALKANES WITH HALOGENS
1. Methane, ethane, and other alkanes react with fluorine, chlorine, and bromine. 1) Alkanes do not react appreciably with iodine. 2) With methane the reaction produces a mixture of halomethanes and a HX.

H H C H + X2

heat

H H Halomethane

X H Dihalomethane

X X Trihalomethane

X X Tetrahalo- Hydrogen methane halide

or light H Methane Halogen

H C X+ H C X +H C X + X C X + H X

(The sum of the number of moles of each halogenated methane produced equals the number of moles of methane that reacted.) 2. Halogentaiton of an alkane is a substitution reaction. R–H + X2 R–X + H–X

10.3A MULTIPLE SUBSTITUTION REACTIONS VERSUS SELECTIVITY
~ 10 ~

1. Multiple substitutions almost always occur in the halogenation of alkanes. 2. Chlorination of methane: 1) At the outset, the only compounds that are present in the mixture are chlorine and methane ⇒ the only reaction that can take place is the one that produces chloromethane and hydrogen chloride.
H H C H H + Cl2 heat or light H H C H Cl + H Cl

2) As the reaction progresses, the concentration of chloromethane in the mixture increases and a second substitution reaction begins to occur ⇒ Chloromethane reacts with chlorine to produce dichloromethane.

H H C H Cl + Cl2

heat or light

H H C Cl Cl + H Cl

3) The dichloromethane produced can then react to form trichloromethane. 4) The trichloromethane, as it accumulates in the mixture, can react to produce tetrachloromethane. 3. Chlorination of most of higher alkanes gives a mixture of isomeric monochloro products as well as more highly halogenated compounds. 1) Chlorine is relatively unselective ⇒ it does not discriminate greatly among the different types of hydrogen atoms (1°, 2°, and 3°) in an alkane. CH3 CH3CHCH3 Isobutane CH3 CH3CHCH2Cl + CH3 Cl

Cl2 light

CH3CHCH3 + polychlorinated + H products Cl Isobutyl chloride tert-Buty chloride (23%) (48%) (29%)

4. Alkane chlorinations usually give a complex mixture of products ⇒ they are not
~ 11 ~

generally useful synthetic methods for the preparation of a specific alkyl chloride. 1) Halogenation of an alkane (or cycloalkane) with equivalent hydrogens:
CH3 H3C C CH3 + Cl2 CH3 Neopentane (excess) CH3 H3C C CH2Cl + H Cl CH3 Neopentyl chloride

heat or light

5. Bromine is generally less reactive toward alkanes than chlorine ⇒ bromination is more regio-selective.

10.4 CHLORINATION OF METHANE: MECHANISM OF REACTION
1. Several important experimental observations about halogenation reactions: CH4 + Cl2 CH3Cl + HCl (+ CH2Cl2, CHCl3, and CCl4)

1) The reaction is promoted by heat or light. i) At room temperature methane and chlorine do not react at a perceptible rate as long as the mixture is kept away from light. ii) Methane and chlorine do react at room temperature if the gaseous reaction mixture is irradiated with UV light. iii) Methane and chlorine do react in the dark if the gaseous reaction mixture is heated to temperatures greater than 100°C. 2) The light-promoted reaction is highly efficient.

10.4A A MECHANISM FOR THE HALOGENATION REACTION:
1. The chlorination (halogenation) reaction takes place by a radical mechanism. 2. The first step is the fragmentation of a chlorine molecule, by heat or light, into two chlorine atoms.
~ 12 ~

1) The frequency of light that promotes the chlorination of methane is a frequency that is absorbed by chlorine molecules and not by methane molecules.

A Mechanism for the Reaction
Radical Chlorination of Methane Reaction: CH4 + Cl2 Mechanism:
Step 1 (chain-initiating step –– radicals are created)

heat or light

CH3Cl + HCl

Cl Cl

heat or light

Cl

+

Cl

Under the influence of heat or light a molecule of chlorine dissociates; each atom takes one of the bonding electrons.

This step produces two highly reactive chlorine atoms.

Step 2 (chain-propagating step –– one radical generates another)

H
Cl

H H
Cl H

+ H

C

+

C

H

H H This step produces a molecule of A chlorine atom abstracts a hydrogen atom from a methane molucule. hydrogen chloride and a methyl radical.
Step 3 (chain-propagating step –– one radical generates another)

H H C H + Cl Cl H

H C Cl + Cl

H A methyl radical abstracts a This step produces a molecule of methyl chloride and a cholrine atom. The chlorine chlorine atom from a atom can now cause a repetition of Step 2. chlorine molecule.

3. With repetition of steps 2 and 3, molecules of chloromethane and HCl are
~ 13 ~

procuded ⇒ chain reaction. 1) The chain reaction accounts for the observation that the light-promoted reaction is highly efficient. 4. Chain-terminating steps: used up one or both radical intermediates. H H C H H H C H Cl + + H Cl H C H H + Cl H H C Cl H H H C C H H Cl Cl H

1) Chloromethan and ethane, formed in the terminating steps, can dissipate their excess energy through vibrations of their C–H bonds. 2) The simple diatomic chlorine that is formed must dissipate its excess energy rapidly by colliding with some other molecule or the walls of the container. Otherwise it simply flies apart again. 5. Mechanism for the formation of CH2Cl2:
Cl H H Cl H + H H + H Cl Cl Cl C Cl H + Cl C Cl

Step 2a

Cl

+ H

C H

H

Step 3a

Cl

C

10.5 CHLORINATION OF METHANE: ENERGY CHANGES
~ 14 ~

1. The heat of reaction for each individual step of the chlorination:

Chain Initiation Step 1
Cl–Cl (∆H° = 243) 2 Cl•

∆H° = + 243 kJ mol–1

Chain Propagation Step 2
CH3–H + •Cl (∆H° = 435) CH3• + Cl–Cl (∆H° = 243) CH3• + H–Cl (∆H° = 431) CH3–Cl + •Cl (∆H° = 349)

∆H° = + 4 kJ mol–1 ∆H° = – 106 kJ mol–1

Step 3

Chain Termination
CH3• + •Cl CH3• + CH3• •Cl + •Cl CH3–Cl (∆H° = 349) CH3–CH3 (∆H° = 368) Cl–Cl (∆H° = 243)

∆H° = – 349 kJ mol–1 ∆H° = – 368 kJ mol–1 ∆H° = – 243 kJ mol–1

2. In the chain-initiating step only the bond between two chlorine atoms is broken, and no bonds are formed. 1) The heat of reaction is simply the bond dissociation energy for a chlorine molecule, and it is highly endothermic. 3. In the chain-terminating steps bonds are formed, but no bonds are borken. 1) All of the chain-terminating steps are highly exothermic. 4. In the chain-propagating steps, requires the breaking of one bond and the formation of another. 1) The value of ∆H° for each of these steps is the difference between the bond dissociation energy of the bond that is broken and the bond dissociation energy for the bond that is formed. 5. The addition of chain-propagating steps yields the overall equation for the chlorination of methane:
~ 15 ~

CH3–H + •Cl CH3• + Cl–Cl CH3–H + Cl–Cl

CH3• + H–Cl CH3–Cl + •Cl CH3–Cl + H–Cl

∆H° = + 4 kJ mol–1 ∆H° = – 106 kJ mol–1 ∆H° = – 102 kJ mol–1

1) The addition of the values of ∆H° for the chain-propagating steps yields the overall value of ∆H° for the reaction.

10.5A THE OVERALL FREE-ENERGY CHANGE:
1. For many reactions the entropy change is so small that the term T∆S° is almost zero, and ∆G° is approximately equal to ∆H° in ∆G° = ∆H° – T∆S°. 2. Degrees of freedom are associated with ways in which monement or changes in

relative position can occur for a molecule and its constituent atoms.

Figure 10.2 Translational, rotational, and vibrational degrees of freedom for a simple diatomic molecule. 3. The reaction of methane with chlorine: CH4 + Cl2 CH3Cl + HCl

1) 2 moles of the products are formed from 2 moles of the reactants ⇒ the number of translational degrees of freedom available to products and reactants are the same. 2) CH3Cl is a tetrahedral molecule like CH4, and HCl us a diatomic molecule like Cl2 ⇒ the number of vibrational and rotational degrees of freedom available to products and reactants are approximately the same. 3) The entropy change for this reaction is quite small, ∆S° = + 2.8 J K–1 mol–1 ⇒ at
~ 16 ~

room temperature (298 K) the T∆S° term is 0.8 kJ mol–1. 4) The enthalpy change for the reaction and the free-energy change are almost equal ⇒ ∆H° = – 102.5 kJ mol–1 and ∆G° = – 103.3 kJ mol–1. 5) In situation like this one it is often convenient to make predictions about whether a reaction will proceed to completion on the basis of ∆H° rather than ∆G° since
∆H° values are readily obtained from bond dissociation energies.

10.5B ACTIVATION ENERGIES:
1. It is often convenient to estimate the reaction rates simply on energies of activation, Eact, rather than on free energies of activation, ∆G‡. 2. Eact and ∆G‡ are close related and both measure the difference in energy between the reactants and the transition state. 1) A low energy of activation ⇒ a reaction will take place rapidly. 2) A high energy of activation ⇒ a reaction will take place slowly. 3. The energy of activation for each step in chlorination:

Chain Initiation Step 1
Cl2 2 Cl•

Eact = + 243 kJ mol–1

Chain Propagation Step 2 Step 3
CH3–H + •Cl CH3• + Cl–Cl CH3• + H–Cl CH3–Cl + •Cl

Eact = + 16 kJ mol–1 Eact = ~ 8 kJ mol–1

1) The energy of activation must be determined from other experimental data. 2) The energy of activation cannot be directly measured –– it is calculated. 4. Principles for estimating energy of activation: 1) Any reaction in which bonds are broken will have an energy of activation greater than zero. i) This will be true even if a stronger bond is formed and the reaction is exothermic. ii) Bond formation and bond breaking do not occur simultaneously in the
~ 17 ~

transition state. iii) Bond formation lags behind, and its energy is not all available for bond breaking. 2) Activation energies of endothermic reactions that involve both bond formation and bond rupture will be greater than the heat of reaction, ∆H°. CH3–H + •Cl (∆H° = 435) CH3–H + •Br (∆H° = 435) i) CH3• + H–Cl (∆H° = 431) CH3• + H–Br (∆H° = 366)

∆H° = + 4 kJ mol–1 Eact = + 16 kJ mol–1 ∆H° = + 69 kJ mol–1 Eact = + 78 kJ mol–1

This energy released in bond formation is less than that required for bond breaking for the above two reactions ⇒ they are endothermic reactions.

Figure 10.3 Potential energy diagrams (a) for the reaction of a chlorine atom with methane and (b) for the reaction of a bromine atom with methane. 3) The energy of activation of a gas-phase reaction where bonds are broken homolytically but no bonds are formed is equal to ∆H°. i) This rule only applies to radical reactions taking place in the gas phase. Cl–Cl (∆H° = 243) 2 •Cl

∆H° = + 243 kJ mol–1 Eact = + 243 kJ mol–1
~ 18 ~

Figure 10.4 Potential energy diagram for the dissociation of a chlorine molecule into chlorine atoms. 4) The energy of activation for a gas-phase reaction in which radicals combine to form molecules is usually zero. 2 CH3• CH3–CH3 (∆H° = 368)

∆H° = – 368 kJ mol–1 Eact = 0 kJ mol–1

Figure 10.5 Potential energy diagram for the combination of two methyl radicals to form a molecule of ethane.

10.5C REACTION OF METHANE WITH OTHER HALOGENS:
1. The reactivity of one substance toward another is measured by the rate at which the two substances react. 1) Fluorine is most reactive –– so reactive that without special precautions mixtures
~ 19 ~

of fluorine and methane explode. 2) Chlorine is the next most reactive –– chlorination of methane is easily controlled by the judicious control of heat and light. 3) Bromine is much less reactive toward methane than chlorine. 4) Iodine is so unreactive that the reaction between it and methane does not take place for all practical purposes. 2. The reactivity of halogens can be explained by their ∆H° and Eact for each step: 1) FLUORINATION:

∆H° (kJ mol–1) Eact (kJ mol–1)

Chain Initiation
F2 2 F• + 159 + 159

Chain Propagation
F• + CH3–H CH3• + F–F H–F + CH3• – 134 + 5.0 Small

CH3–F + F• – 293 Overall ∆H° = – 427

i)

The chain-initiating step in fluorination is highly endothermic and thus has a high energy of activation.

ii) One initiating step is able to produce thousands of fluorination reactions ⇒ the high activation energy for this step is not an obstacle to the reaction. iii) Chain-propagating steps cannot afford to have high energies of activation. iv) Both of the chain-propagating steps in fluorination have very small energies of activation. v) The overall heat of reaction, ∆H°, is very large ⇒ large quantity of heat is evolved as the reaction occurs ⇒ the heat may accumulate in the mixture faster than it dissipates to the surroundings ⇒ causing the reaction temperature to rise

⇒ a rapid increase in the frequency of additional chain-initiating steps that would generate additional chains. vi) The low energy of activation for the chain-propagating steps and the large
~ 20 ~

overall heat of reaction ⇒ high reactivity of fluorine toward methane.. vii) Fluorination reactions can be controlled by diluting both the hydrocarbon and the fluorine with an inert gas such as helium or the reaction can be carried out in a reactor packed with copper shot to absorb the heat produced. 2) CHLORINATION:

∆H° (kJ mol–1) Eact (kJ mol–1)

Chain Initiation
Cl2 2 Cl• + 243 + 243

Chain Propagation
Cl• + CH3–H CH3• + Cl–Cl H–Cl + CH3• +4 + 16 Small

CH3–Cl + Cl• – 106 Overall ∆H° = – 102

i)

The higher energy of activation of the first chain-propagating step in chlorination (16 kJ mol–1), versus the lower energy of activation (5.0 kJ mol–1) in fluorination, partly explains the lower reactivity of chlorine.

ii) The greater energy required to break the Cl–Cl bond in the initiating step (243 kJ mol–1 for Cl2 versus 159 kJ mol–1 for F2) has some effect, too. iii) The much greater overall heat of reaction in fluorination probably plays the greatest role in accounting for the much greater reactivity of fluorine. 3) BROMINATION:

∆H° (kJ mol–1) Eact (kJ mol–1)

Chain Initiation
Br2 2 Br• + 192 + 192

Chain Propagation
Br• + CH3–H CH3• + Br–Br H–Br + CH3• CH3–Br + Br•
~ 21 ~

+ 69 – 100

+ 78 Small

Overall ∆H° = – 31 i) The chain-initiating step in bromination has a very high energy of activation (Eact = 78 kJ mol–1) ⇒ only a very tiny fraction of all of the collisions between bromine and methane molecules will be energetically effective even at a temperature of 300 °C. ii) Bromine is much less reactive toward methane than chlorine even though the net reaction is slightly exothermic. 4) IODINATION:

∆H° (kJ mol–1) Eact (kJ mol–1)

Chain Initiation
I2 2 I• + 151 + 151

Chain Propagation
I• + CH3–H CH3• + I–I H–I + CH3• + 138 + 140 Small

CH3–I + I• – 84 Overall ∆H° = + 54

i)

The I–I bond is weaker than the F–F bond ⇒ the chain-initiating step is not responsible for the observed reactivities: F2 > Cl2 > Br2 > I2.

ii) The H-abstraction step (the first chain-propagating step) determines the order of reactivity. iii) The energy of activation for the first chain-propagating step in iodination reaction (140 kJ mol–1) is so large that only two collisions out of every 1012 have sufficient energy to produce reactions at 300 °C. 5) The halogenation reactions are quite similar and thus have similar entropy changes ⇒ the relative reactivities of the halogens toward methane can be compared on energies only.

~ 22 ~

10.6 HALOGENATION OF HIGHER ALKANES
1. Ethane reacts with chlorine to produce chloroethane:

A Mechanism for the Reaction
Radical Chlorination of Ethane Reaction: CH3CH3 + Cl2 Mechanism: Chain Initiation Cl Cl heat or light Cl + Cl heat or light CH3CH2Cl + HCl

Chain Propagation

Step 2 Step 3

CH3CH2 H + Cl

CH3CH2

+

Cl H

CH3CH2

+

Cl Cl

CH3CH2 Cl +

Cl

Chain propagation continues with Step 2, 3, 2, 3, an so on. Chain Termination CH3CH2
CH3CH2 +

+ Cl

CH3CH2 Cl
CH3CH2 CH2CH3

CH2CH3

Cl

+

Cl

Cl Cl

2. Chlorination of most alkanes whose molecules contain more than two carbon atoms gives a mixture of isomeric monochloro products (as well as more highly chlorinated compounds).
~ 23 ~

1) The percentages given are based on the total amount of monochloro products formed in each reaction.
CH3CH2CH3 Propane CH3 CH3CHCH3 Isobutane CH3 CH3CCH2CH3 H 2-Methylbutane Cl2 light, 25 oC CH3CH2CH2Cl Propyl chloride (45%) Cl2 light, 25 oC CH3 CH3CHCH2Cl Isobutyl chloride (63%) Cl2 300 oC CH3 ClCH2CCH2CH3 1-Chloro-2methyllbutane (30%) CH3 + CH3CCHCH 3 + + + + CH3CHCH 3

Cl Isopropyl chloride (55%) CH3 CH3CCH3

Cl tert-butyl chloride (37%) CH3 CH3CCH2CH3 Cl 2-Chloro-2-methylbutane (22%) CH3 CH3CCH2CH2Cl 1-Chloro-3-methylbutane (15%)

Cl 2-Chloro-3-meyhylbutane (33%)

2) 3° hydrogen atoms of an alkane are most reactive, 2° hydrogen atoms are next most reactive, and 1° hydrogen atoms are the least reactive. 3) Breaking a 3° C–H bond requires the least energy, and breaking a 1° C–H bond requires the most energy. 4) The step in which the C–H bond is broken determines the location or orientation of the chlorination ⇒ the Eact for abstracting a 3° hydrogen atom to be the least and the Eact for abstracting a 1° hydrogen atom to be greatest ⇒ 3° hydrogen atoms should be most reactive, 2° hydrogen atoms should be the next most reactive, and 1° hydrogen atoms should be the the least reactive. 5) The difference in the rates with which 1°, 2°, and 3° hydrogen atoms are
~ 24 ~

replaced by chlorine are not large ⇒ chlorine does not discriminate among the different types of hydrogen atoms to render chlorination of higher alknaes a generally useful laboratory synthesis.

10.6A SELECTIVITY OF BROMINE
1. Bromine is less reactive toward alkanes in general than chlorine, but bromine is more selective in the site of attack when it does react. 2. The reaction of isobutene and bromine gives almost exclusive replacement of the 3° hydrogen atom.
CH3 CH3CCH2H H Br2 light, 127 oC CH3 CH3CCH3 + Br (>99%) CH3 CH3CHCH 2Br (trace)

i)

The ratio for chlorination of isobutene: CH3 CH3CCH2H H Cl2 hν, 25 oC CH3 CH3CCH3 + Cl (37%) CH3 CH3CHCH2Cl (63%)

3. Fluorine is much more reactive than chlorine ⇒ fluorine is even less selective

than chlorine.

10.7 THE GEOMETRY OF ALKYL RADICALS
1. The geometrical structure of most alkyl radicals is trigonal planar at the carbon having the unpaired electron. 1) In an alkyl radical, the p orbital contains the unpaired electron.

~ 25 ~

(a)

(b)

Figure 10.6 (a) Drawing of a methyl radical showing the sp2-hybridized carbon atom at the center, the unpaired electron in the half-filled p orbital, and the three pairs of electrons involved in covalent bonding. The unpaired electron could be shown in either lobe. (b) Calculated structure for the methyl radical showing the highest occupied molecular orbital, where the unpaired electron resides, in red and blue. The region of bonding electron density around the carbons and hydrogens is in gray.

10.8 REACTIONS THAT GENERATE TETRAHEDRAL STEREOCENTERS
1. When achiral molecules react to produce a compound with a single tetrahedral stereocenter, the product will be obtained as a racemic form. 1) The radical chlorination of pentane: CH3CH2CH2CH2CH3 Pentane (achiral) Cl2 (achiral) CH3CH2CH2CH2CH2Cl + CH3CH2CH2* ClCH3 CH 1-Chloropentane (achiral) + CH3CH2CHClCH2CH3 3-Chloropentane (achiral) 1) Neither 1-chloropentane nor 3-chloropentane contains a stereocenter, but 2-chloropentane does, and it is obtained as a racemic form. (±)-2-Chloropentane (a racemic form)

~ 26 ~

A Mechanism for the Reaction
The Stereochemistry of Chlorination at C2 of Pentane

C2 CH3CH2CH2CH2CH3 Cl CH3 CH3 C H 3C

Cl

+ Cl

C

Cl2

Cl2

H CH2CH2CH3

H CH2CH2CH3
Trigonal planar radical (achiral)

H H3CH2CH2C
(50%)

C

Cl + Cl

(S)-2-Chloropentane (50%)

(R)-2-Chloropentane

Enantiomers Abstraction of a hydrogen atom from C2 produces a trigonal planar radical that is achiral. This radical is achiral then reacts with chlorine at either face [by path (a) or path (b)]. Because the radical is achiral the probability of reaction by either path is the same; therefore, the two enantiomers are produced in equal amounts, and a racemic form of 2-chloropentane results.

10.8A GENERATION OF A SECOND STEREOCENTER IN A RADICAL HALOGENATION:
1. When a chiral molecule reacts to yield a product with a second stereocenter: 1) The products of the reactions are diastereomeric (2S,3S)-2,3-dichloropentane and (2S,3R)-2,3-dichloropentane. i) The two diastereomers are not produced in equal amounts. equally likely. iii) The presence of a stereocenter in the radical (at C2) influences the reaction that introduces the new stereocenter (at C3).
~ 27 ~

ii) The intermediate radical itself is chiral ⇒ reactions at the two faces are not

2) Both of the 2,3-dichloropentane diastereomers are chiral ⇒ each exhibits optical activity. i) The two diastereomers have different physical properties (e.g., m.p. & b.p.) and are separable by conventional means (by GC, LC, or by careful fractional distillation).

A Mechanism for the Reaction
The Stereochemistry of Chlorination at C3 of (S)-2-Chloropentane

H

CH3 Cl C CH2 CH2 CH3 Cl

H Cl + Cl

CH3 Cl C C Cl2 H

H

CH3 Cl C C H CH2 CH3 Cl2

H H

CH3 Cl C C Cl + Cl

CH2 CH3

CH2 CH3

(2S,3S)-2,3-Dichloropentane (chiral)

Trigonal planar radical (chiral)

(2S,3R)-2,3-Dichloropentane (chiral)

Diastereomers Abstraction of a hydrogen atom from C3 of (S)-2-chloropentane produces a radical that is chiral (it contains a stereocenter at C2). This chiral radical can then react with chlorine at one face [path (a)] to produce (2S,3S)-2,3-dichloropentane and at the other face [path (b)] to yield (2S,3R)-2,3-dichloropentane. These two compounds are diastereomers, and they are not produced in equal amounts. Each product is chiral, and each alone would be optically active.

~ 28 ~

10.9 REDICAL ADDITION TO ALKENES: THE ANTI-MARKOVNIKOV ADDITION OF HYDROGEN BROMIDE
1. Kharasch and Mayo (of the University of Chicago) found that when alkenes that contained peroxides or hydroperoxides reacted with HBr ⇒ anti-Markovnikov addition of HBr occurred.
R O O R R O O H

An organic peroxide

An organic hydroperoxide

1) In the presence of peroxides, propene yields 1-bromopropane. CH3CH=CH2 + HBr

ROOR

CH3CH2CH2BrAnti-Markovnikov addition

2) In the absence of peroxides, or in the presence of compounds that would “trap” radicals, normal Markovnikov addition occurs. CH3CH=CH2 + HBr no peroxides CH3CHBrCH2–H Markovnikov addition

2. HF, HCl, and HI do not give anti-Markovnikov addition even in the presence of peroxides. 3. Step 3 determines the final orientation of Br in the product because a more stable
2° radical is produced and because attack at the 1° carbon is less hindered. x Br + H2C

CH CH3

x

CH2 CH CH3 Br

1) Attack at the 2° carbon atom would have been more hindered.

~ 29 ~

A Mechanism for the Reaction
Anti-Markovnikov Addition
Chain Initiation Step 1 R

O O

R

heat

2R

O

∆H° ≅ + 150 kJ mol–1

Heat brings about homolytic cleavage of the weak oxygen-oxygen bond.
Step 2 R
O + H Br R O H + Br
∆H° ≅ – 96 kJ mol–1

Eact is low The alkoxyl radical abstracts a H-atom from HBr, producing a Br-atom.

Step 3

Br + H2C

CH CH3

Br CH2 CH CH3 2° radical

A Br-atom adds to the double bond to produce the more stable 2° radical.

Step 4

Br CH2 CH CH3 + H Br

Br CH2 CH CH3 + Br H 1-Bromopropane

The 2° radical abstracts a H-atom from HBr. This leads to the product and regenerates a Br-atom. Then repetitions of steps 3 and 4 lead to a chain reaction.

10.9A SUMMARY OF MARKOVNIKOV VERSUS ANTI-MARKOVNIKOV ADDITION OF HBr TO ALKENES
1. In the absence of peroxides, the reagent that attacks the double bond first is a proton. 1) Proton is small ⇒ steric effects are unimportant. 2) Proton attaches itself to a carbon atom by an ionic mechanism to form the more stable carbocation ⇒ Markovnikov addition.
Ionic addition
~ 30 ~

H2C

CHCH3

H

Br

H

CH2CHCH3

+

Br−

H

CH2CHCH3

More stable carbocation

Br Markovnikov product

2. In the presence of peroxides, the reagent that attacks the double bond first is the larger bromine atom. 1) Bromine attaches itself to the less hindered carbon atom by a radical mechanism to form the more stable radical intermediate ⇒ anti-Markovnikov addition.
Radical addition

H2C

CHCH3

Br Br

CH2CHCH3

H

Br

Br

CH2CHCH3 + Br

More stable radical 4-23-02

H anti-Markovnikov product

10.10 RADICAL POLYMERIZATION OF ALKENES: CHAIN-GROWTH POLYMERS
1. Polymers, called macromolecules, are made up of many repeating subunits (monomers) by polymerization reactions. 1) Polyethylene (PE): Monomeric units m H2C CH2 Ethylene monomer

polymerization

CH2CH2

(m and n are large numbers)

( CH2CH2 )n CH2CH2 Polyethlene polymer

2. Chain-growth polymers (addition polymers): 1) Ethylene polymerizes by a radical mechanism when it is heated at a pressure of 1000 atm with a small amount of an organic peroxide. 2) The polyethylene is useful only when it has a molecular weight of nearly 1,000,000. 3) Very high molecular weight polyethylene can be obtained by using a low concentration of the initiator ⇒ initiates the polymerization of only a few chains and ensures that each will have a large excess of the monomer available.
~ 31 ~

A Mechanism for the Reaction
Radical Polymerization of Ethene
Chain Initiation

O
Step 1 R

O O O C R

O 2R C O 2 CO2 + 2 R

C

Diacyl peroxide
Step 2 R + H2C

CH2

R CH2 CH2

The diacyl peroxide dissociates to produce radicals, which in turn initiate chains.
Chain Propagation Step 3 R CH2
CH2 + n H2C CH2 R ( CH2CH2 )n CH2CH2

Chain propagation by adding successive ethylene units, until their growth is stopped by combination or disproportionation.

Chain Termination Step 4
2 R ( CH2CH2 )n CH2CH2 combination disproportionation R ( CH2CH2 )n CH2CH2

2

R ( CH2CH2 )n CH CH2 + R ( CH2CH2 )n CH2CH3

The radical at the end of the growing polymer chain can also abstract a hydrogen atom from itself by what is called “back biting.” This leads to chain branching.

Chain Branching

R

CH2 H CH2CH CH2 ( CH2CH2 )n

RCH2CH ( CH2CH2 )n CH2CH2 H H2C CH2 RCH2CH ( CH2CH2 )n CH2CH2 H CH2 CH2 etc.

~ 32 ~

3. Polyethylene has been produced commercially since 1943. 1) PE is used in manufacturing flexible bottles, films, sheets, and insulation for electric wires. 2) PE produced by radical polymerization has a softening point of about 110°C. 4. PE can be produced using Ziegler-Natta catalysts (organometallic complexes of transition metals) in which no radicals are produced, no back biting occurs, and, consequently, there is no chain branching. 1) The PE is of higher density, has a higher melting point, and has greater strength.

Table 10.2
Monomer CH2=CHCH3 CH2=CHCl
CH2=CHCN CF2=CF2
CH3 H2C CCO2CH3

Other Common Chain-Growth Polymers
Polymer ( CH2
( CH2 ( CH2
( CF2 ( CH2

Names Polypropylene
Poly(vinyl chloride), PVC Polyacrylonitrile, Orlon
Polytetrafluoroethene, Teflon Poly(methyl methacrylate), Lucite, Plexiglas, Perspex

CH )n CH3
CH )n Cl CH )n CN
CF2 )n CH3 C )n CO2CH3

10.11 OTHER IMPORTANT RADICAL CHAIN REACTIONS
10.11A MOLECULAR OXYGEN AND SUPEROXIDE
1. Molecular oxygen in the ground state is a diradical with one unpaired electron on
~ 33 ~

each oxygen. 1) As a radical, oxygen can abstract hydrogen atoms just like other radicals. 2. In biological systems, oxygen is an electron acceptor. 1) Molecular oxygen accepts one electron and becomes a radical anion called superoxide ( O2 ). 2) Superoxide is involved in both positive and negative physiological roles: i) The immune system uses superoxide in its defense against pathogens. associated with aging and oxidative damage to healthy cells. 3) The enzyme superoxide dismutase regulates the level of superoxide by catalyzing conversion of superoxide to hydrogen peroxide and molecular oxygen. i) Hydrogen peroxide is also harmful because it can produce hydroxyl (HO•) radicals. ii) The enzyme catalase helps to prevent release of hydroxyl radicals by converting hydrogen peroxide to water and oxygen. ii) Superoxide is suspected of being involved in degenerative disease processes
−

2 O2− + 2 H+

superoxide dismutase catalase

H2O2 + O2

2 H2O2

2 H2O + O2

10.11B COMBUSTION OF ALKANES
1. When alkanes react with oxygen a complex series of reactions takes place, ultimately converting the alkane to CO2 and H2O.

R H R R

+ +

O2 O2 H

R R R

+ OO

OOH

Initiating Propagating

OO + R

OOH + R

2. The O–O bond of an alkyl hydroperoxide is quite weak, and it can break and produce radicals that can initiate other chains:
~ 34 ~

RO–OH

RO• + •OH

10.11C AUTOXIDATION
1. Linoleic acid is a polyunsaturated fatty acid (compound containing two or more double bonds) occurs as an ester in polyunsaturated fats. H CH3(CH2)4 H HH C H H (CH2)7CO2R' Linoleic acid (as an ester)

2. Polyunsaturated fats occur widely in the fats and oils that are components of our diet and are widespread in the tissues of the body where they perform numerous vital functions. 3. The hydrogen atoms of the –CH2– group located between the two double bonds of linoleic ester (Lin–H) are especially susceptible to abstraction by radicals. 1) Abstraction of one of these hydrogen atoms produces a new radical (Lin•) that can react with oxygen in autoxidation. 2) The result of autoxidation is the formation of a hydroperoxide. 4. Autoxidation is a process that occurs in many substances: 1) Autoxidation is responsible for the development of the rancidity that occurs when fats and oils spoil and for the spontaneous combustion of oily rags left open to the air. 2) Autoxidation occurs in the body which may cause irreversible damage.

~ 35 ~

Step 1 Chain initiation H HH

H

− ROH

H CH3(CH2)4 H

HH C H

H (CH2)7CO2R'

CH3(CH2)4 H RO

C H

(CH2)7CO2R' H CH3(CH2)4 HH C H

(CH2)7CO2R'

Step 2 Chain Propagation O H CH3(CH2)4 O HH C H H O O HH C H H (CH2)7CO2R'

H (CH2)7CO2R' CH3(CH2)4

Step 3 Chain Propagation
O Lin H O HH C H HO O Another radical H HH + C Lin (CH2)7CO2R'

H CH3(CH2)4

H (CH2)7CO2R' CH3(CH2)4

H Hydrogen abstraction from another molecular of the linoleic ester

H A hydroperoxide

Figure 10.7 Autoxidation of a linoleic acid ester. In step 1 the reaction is initiated by the attack of a radical on one of the hydrogen atoms of the –CH2– group between the two double bonds; this hydrogen abstraction produces a radical that is a resonance hybrid. In step 2 this radical reacts with oxygen in the first of two chain-propagating steps to produce an oxygen-containing radical, which in step 3 can abstract a hydrogen from another molecule of the linoleic ester (Lin–H). The result of this second chain-propagating step is the formation of a hydroperoxide and a radical (Lin•) that can bring about a repetition of step 2.

~ 36 ~

10.11D ANTIOXIDANTS
1. Autoxidation is inhibited by antioxidants. 1) Antioxidants can rapidly “trap” peroxyl radicals by reacting with them to give stabilized radicals that do not continue the chain. 2. Vitamin E (α-tocopherol) is capable of acting as a radical trap which may inhibit radical reactions that could cause cell damage. 3. Vitamin C is also an antioxidant (supplements over 500 mg per day may have prooxidant effect). 4. BHT is added to foods to prevent autoxidation. CH3 HO

H3C CH3

O

CH3 Vitamin E (α-tocophero)

OH (CH3)3C C(CH3)3 O O

OH CH CH2OH

CH3 BHT (butylated hydroxytoluene)

HO

OH Vitamin C

10.11E OZONE DEPLETION AND CHLOROFLUOROCARBONS (CFCs):
1. In the stratosphere at altitudes of about 25 km, very high energy UV light converts diatomic oxygen (O2) into ozone (O3).

Step 1

O2 + hν

O+O
~ 37 ~

Step 2 Step 3

O + O2 + M O3 + hν

O3 + M + heat O2 + O + heat

1) M is some other particle that can absorb some of the energy released in step 2. 2) The ozone produced in step 2 can also interact with high energy UV light give molecular oxygen and an oxygen atom in step 3. 3) The oxygen atom formed in step 3 can cause a repetition of step 2, and so forth. 4) The net result of these steps is to convert highly energetic UV light into heat. 2. Production of freons or chlorofluorocarbons (CFCs) (chlorofluoromethane and chlorofluoroethanes) began in 1930 and the world production reached 2 billion pounds annually by 1974. 1) Freons have been used as refrigerants, solvents, and propellants in aerosol cans. 2) Typical freons are trichlorofluoromethane, CFCl3 (called Freon-11) and dichlorodifluoromethane, CF2Cl2 (called Freon-12). 3) In the stratosphere freon is able to initiate radical chain reactions that can upset the natural ozone balance (1995 Nobel Prize in Chemistry was awarded to P. J. Crutzen, M. J. Molina, and F. S. Rowland). 4) The reactions of Freon-12:

Chain Initiation Step 1
CF2CCl2 + hν CF2CCl• + Cl•

Chain Propagation Step 2 Step 3
Cl• + O3 ClO• + O ClO• + O2 O2 + Cl•

3. In 1985 a hole was discovered in the ozone layer above Antarctica. 1) The “Montreal Protocol” was initiated in 1987 which required the reduction of production and consumption of chlorofluorocarbons.

i)

.
~ 38 ~

–
−1

− ↕

° •

⇒ ±
⇒ ⇐

Å
⇑

é
⇓

ö

ø

←

↑

→

↓

↔

•●

≡

‡

⇔ ¯

~ 39 ~

ALCOHOLS AND ETHERS
MOLECULAR HOSTS
1. The cell membrane establishes critical concentration gradients between the interior and exterior of cells. 1) An intracellular to extracellular difference in sodium and potassium ion concentrations is essential to the function of nerves, transport of important nutrients into the cell, and maintenance of proper cell volume. i) Discovery and characterization of the actual molecular pump that establishes the sodium and potassium concentration gradient (Na+, K+-ATPase) earned Jens Skou (Aarhus University, Denmark) one half of the 1997 Nobel Prize in Chemistry. synthesis. 2. There is a family of antibiotics (ionophores) whose effectiveness results from disrupting this crucial ion gradient. 3. Monesin binds with sodium ions and carries them across the cell membrane and is called a carrier ionophore. 1) Other ionophore antibiotics such as gramicidin and valinomycin are channel-forming ionophores because they open pores that extend through the membrane. 2) The ion-transporting ability of monensin results principally from its many ether functional groups, and it is an example of a polyether antibiotic. i) The oxygen atoms of these molecules bind with metal ions by Lewis acid-base interactions. ii) Each monensin molecule forms an octahedral complex with a sodium ion. iii) The complex is a hydrophobic “host” for the ion that allows it to be carried as a “guest” of monensin from one side of the nonpolar cell membrane to the other. iv) The transport process destroys the critical sodium concentration gradient
~1~

The other half went to Paul D. Boyer (UCLA) and John E.

Walker (Cambridge) for elucidating the enzymatic mechanism of ATP

needed for cell function.

H3C H3CH2C H3C O H H H3C O OH CH2 OH CH3 Monensin H HC CH3 H3C O H O O H CH3 OCH3 CO2−

Carrier (left) and channel-forming modes of transport ionophors. 4. Crown ethers are molecular “hosts” that are also polyether ionophores. 1) Crown ethers are useful for conducting reactions with ionic reagents in nonpolar solvents. 2) The 1987 Nobel Prize in Chemistry was awarded to Charles J. Pedersen, Donald J. Cram, and Jean-Marie Lehn for their work on crown ethers and related compounds (host-guest chemisty).

11.1 STRUCTURE AND NOMENCALTURE
1. Alcohols are compounds whose molecules have a hydroxyl group attached to a saturated carbon atom.
~2~

1) Compounds in which a hydroxyl group is attached to an unsaturated carbon atom of a double bond (i.e., C=C–OH) are called enols.
CH3
CH3CHCH3

CH3CCH3 OH

CH3OH Methanol (methyl alcohol)

CH3CH2OH Ethanol (ethyl alcohol) a 1° alcohol

OH

2-Propanol 2-Methyl-2propanol (isopropyl alcohol) (tert-butyl alcohol) a 2° alcohol a 3° alcohol

CH2OH CH2=CHCH2OH H–C≡CCH2OH

Benzyl alcohol a benzylic alcohol

2-Propenol (allyl alcohol) an allylic alcohol

2-Propynol (propargyl alcohol)

2) Compounds that have a hydroxyl group attached directly to a benzene ring are called phenols.

OH

H 3C

OH Ar–OH

Phenol

p-Methylphenol (p-Cresol)

General formula

2. Ethers are compounds whose molecules have an oxygen atom bonded to two carbon atom. 1) The hydrocarbon groups may be alkyl, alkenyl, vinyl, alkynyl, or aryl. CH3CH2–O–CH2CH3 CH2=CHCH2–O–CH3

Diethyl ether

Allyl methyl ether

OCH3 CH2=CH–O–CH=CH2

Divinyl ether

Methyl phenyl ether (Anisole)

~3~

11.1A NOMENCLATURE OF ALCOHOLS
1. The hydroxyl group has precedence over double bonds and triple bonds in deciding which functional group to name as the suffix.
CH3CHCH2CH CH2 OH 2. In common radicofunctional nomenclature alcohols are called alkyl alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, and so on.
1 2 3 4 5

4-Penten-2-ol

11.1B NOMENCLATURE OF ETHERS
1. Simple ethers are frequently given common radicofunctional names. 1) Simply lists (in alphabetical order) both groups that are attached to the oxygen atom and adds the word ether.

CH3 C 6H 5O
CH3CH2–O–CH3 CH3CH2–O–CH2CH3

C CH3

CH3

Ethyl methyl ether

Diethyl ether

tert-Butyl phenyl ether

2. IUPAC substitutive names are used for more complicated ethers and for compounds with more than one ether linkage. 1) Ethers are named as alkoxyalkanes, alkoxyalkenes, and alkoxyarenes. 2) The RO– group is an alkoxy group. CH3CHCH2CH2CH3 OCH3

H 3C

OCH2CH3 CH3–O–CH2CH2–O–CH3

2-Methoxypentane

1-Ethoxy-4-methylbenzene

1,2-Dimethoxyethane

3. Cyclic ethers can be names in several ways. 1) Replacement nomenclature: relating the cyclic ether to the corresponding
~4~

hydrocarbon ring system and use the prefix oxa- to indicate that an oxygen atom replaces a CH2 group. 2) Oxirane: a cyclic three-membered ether (epoxide). 3) Oxetane: a cyclic four-membered ether. 4) Common names: given in parentheses.
O O

Oxacyclopropane or oxirane (ethylene oxide)
O

Oxacyclobutane or oxetane
O

O

Oxacyclopentane (tertahydrofuran)

1,4-Dioxacyclohexane (1,4-dioxane)

4. Tetrahydrofuran (THF) and 1,4-dioxane are useful solvents.

11.2 PHYSICAL PROPERTIES OF ALCOHOLS AND ETHERS
1. Ethers have boiling points that are comparable with those of hydrocarbons of the same molecular weight. 1) The b.p. of diethyl ether (MW = 74) is 34.6 °C; that of pentane (MW = 74) is 36 °C. 2. Alcohols have much higher b.p. than comparable ethers or hydrocarbons. 1) The b.p. of butyl alcohol (MW = 74) is 117.7 °C. 2) The molecules of alcohols can associate with each other through hydrogen

bonding, whereas those of ethers and hydrocarbons cannot.
3. Ethers are able to form hydrogen bonds with compounds such as water. 1) Ethers have solubilities in water that are similar to those of alcohols of the same molecular weight and that are very different from those of hydrocarbons.
~5~

2) Diethyl ether and 1-butanol have the same solubility in water, approximately 8 g per 100 mL at room temperature. water. H 3C Pentane, by contrast, is virtually insoluble in

H O H O
CH3

O
CH3

H

Hydrogen bonding between molecules of methanol Table 11.1 NAME
Dimethyl ether Ethyl methyl ether Diehyl ether Dipropyl ether Diisopropyl ether Dibutyl ether 1,2-Dimethoxyethane Tetrahydrofuran

Physical Properties of Ethers mp (°C)
–138

FORMULA
CH3OCH3 CH3OCH2CH3 CH3CH2OCH2CH3 (CH3CH2CH2)2O (CH3)2CHOCH(CH3)2 (CH3CH2CH2CH2)2O CH3OCH2CH2OCH3 O

bp (°C)
–24.9 10.8

Density d420 (g mL–1)

0.661 0.697 0.714 0.736 0.725 0.769 0.863 0.888

–116 –122 –86 –97.9 –68 –108

34.6 90.5 68 141 83 65.4

1,4-Dioxane Anisole (methoxybenzene)

O

O

11

101

1.033

OCH3

–37.3

158.3

0.994

~6~

Table 11.2 Compound Monohydroxy Alcohols
CH3OH CH3CH2OH CH3CH2CH2OH CH3CH(OH)CH3 CH3CH2CH2CH2OH Methanol Ethanol

Physical Properties of Alcohols mp bp(°C) (°C) (1 atm) Density d420 (g mL–1)

Name

Water Solubility (g 100 mL–1 H2O)

–97 –117 –126 –90

64.7 78.3 97.2 82.3 117.7 99.5 82.5 156.5 176 195 212 228 97 140

0.792 0.789 0.804 0.786 0.810 0.802 0.808 0.789 0.817 0.819 0.822 0.825 0.827 0.829 0.855 0.949

∞ ∞ ∞ ∞ 8.3 10.0 26.0 ∞ 2.4 0.6 0.2 0.05

Propyl alcohol Butyl alcohol

Isopropyl alcohol –88

CH3CH(CH3)CH2OH Isobutyl alcohol (CH3)3COH CH3(CH2)3CH2OH CH3(CH2)4CH2OH CH3(CH2)5CH2OH CH3(CH2)6CH2OH CH3(CH2)7CH2OH CH3(CH2)8CH2OH CH2=CHCH2OH OH tert-Butyl alcohol

–108 108.0 25 –52 –34 –15 –5.5 6 –129 –19

CH3CH2CH(OH)CH3 sec-Butyl alcohol –114 Pentyl alcohol Hexyl alcohol Heptyl alcohol Octyl alcohol Nonyl alcohol Decyl alcohol Allyl alcohol Cyclopentanol

–78.5 138.0

∞

OH C6H5CH2OH
Diols and Triols

Cyclohexanol Benzyl alcohol

24 –15

161.5 205

0.962 1.046

3.6 4

CH2OHCH2OH CH3CHOHCH2OH CH2OHCH2CH2OH

Ethylene glycol Propylene glycol Trimethylene glycol

–12.6 –59 –30 18
~7~

197 187 215 290

1.113 1.040 1.060 1.261

∞ ∞ ∞ ∞

CH2OHCHOHCH2OH Glycerol

4. Methanol, ethanol, both propanols, and tert-butyl alcohol are completely miscible with water. 1) The remaining butyl alcohols have solubilities in water between 8.3 and 26.0 g per 100 mL. 2) The solubility of alcohols in water gradually decreases as the hydrocarbon portion of the molecule lengthens.

11.3 IMPORTANT ALCOHOLS AND ETHERS
11.3A METHANOL
1. At one time, most methanol was produced by the destructive distillation of wood (i.e., heating wood to a high temperature in the absence of air) ⇒ “wood alcohol”. 1) Today, most methanol is prepared by the catalytic hydrogenation of carbon monoxide. CO + 2 H2 300-400oC 200-300 atm ZnO-Cr2O3 CH3OH

2. Methanol is highly toxic ⇒ ingestion of small quantities of methanol can cause blindness; large quantities cause death. 1) Methanol poisoning can also occur by inhalation of the vapors or by prolonged exposure to the skin.

11.3B ETHANOL
1. Ethanol can be made by fermentation of sugars, and it is the alcohol of all alcoholic beverages. 1) Sugars from a wide variety of sources can be used in the preparation of alcoholic beverages. 2) Often, these sugars are from grains ⇒ “grain alcohol”.
~8~

2. Fermentation is usually carried out by adding yeast to a mixture of sugars and water. 1) Yeast contains enzymes that promote a long series of reactions that ultimately convert a simple sugar (C6H12O6) to ethanol and carbon dioxide. C6H12O6 yeast 2 CH3CH2OH + 2 CO2

2) Enzymes of the yeast are deactivated at higher ethanol concentrations ⇒ fermentation alone does not produce beverages with an ethanol content greater than 12-15%. 3) To produce beverages of higher alcohol content (brandy, whiskey, and vodka) the aqueous solution must be distilled. 4) The “proof” of an alcoholic beverage is simply twice the percentage of ethanol (by volume) ⇒ 100% proof whiskey is 50% ethanol. 5) The flavors of the various distilled liquors result from other organic compounds that distill with the alcohol and water. 3. An azeotrope of 95% ethanol and 5% water boils at a lower temperature (78.15°C) than either pure ethanol (bp 78.3°C) or pure water (bp 100°C). 1) Azeotrope can also have boiling points that are higher than that of either of the pure components. 2) Benzene forms an azeotrope with ethanol and water that is 7.5% water which boils at 64.9°C ⇒ allows removal of the water from 95% ethanol. 3) Pure ethanol is called absolute alcohol. 4. Most ethanol for industrial purposes is produced by the acid-catalyzed hydration of ethene. CH2=CH2 + H2O CH3CH2OH

Acid

5. Ethanol is a hypnotic (sleep producer). 1) Ethanol depresses activity in the upper brain even though it gives the illusion of being a stimulant.
~9~

2) Ethanol is toxic.

In rats the lethal dose of ethanol is 13.7 g/Kg of body weight.

3) Abuse of ethanol is a major drug problem in most countries.

11.3C ETHYLENE GLYCOL
1. Ethylene glycol (HOCH2CH2OH) has a low molecular weight and a high boiling point and is miscible with water ⇒ ethylene glycol is an ideal automobile antifreeze. 1) Ethylene glycol is toxic.

11.3D DIETHYL ETHER
1. Diethyl ether is a very low-boiling, highly flammable liquid ⇒ open flames or sparks from light switches can cause explosive combustion of mixture of diethyl ether and air. 2. Most ethers react slowly with oxygen by a radical process called autooxidation to form hydroperoxides and peroxides.
Step 1 R

+

H C

OR' OR' R H + C

Step 2

OR' + O2 C

O C

O OR'

O
Step 3a

O OR' +

C

H C

O OR' C

OH OR' + C

OR'

A hydroperoxide or
Step 3b

O C

O OR' + C

OR' R'O C O O C OR'

3. These hydroperoxides and peroxides, which often accumulate in ethers that have been left standing for long periods in contact with air, are dangerously explosive.
~ 10 ~

1) They often detonate without warning when ether solutions are distilled to near dryness ⇒ test for and decompose any ether peroxides before a distillation is carried out. 4. Diethyl ether was first used as a surgical anesthetic by C. W. Long of Jefferson, Georgia, in 1842 and shortly after by J. C. Waren of the Massachusetts General Hospital in Boston. 1) The most popular modern anesthetic is halothane (CF3CHBrCl). not flammable. Halothane is

11.4 SYNTHESIS OF ALCOHOLS FROM ALKENES
1. Acid-Catalyzed Hydration of Alkenes: 1) Water adds to alkenes in the presence of an acid catalyst following Markovnikov’s rule. i) The reaction is reversible. +H2O

C

C + HA

C H

+

C +A

−

−H2O

C

C

+ A−

C C H O

+ HA

Alkene

H O H + H

H Alcohol

2) Because rearrangements often occur, the acid-catalyzed hydration of alkenes has limited usefulness as a laboratory method. 2. Oxymercuration-Demercuration: 1) Oxymercuration-demercuration gives Markovnikov addition of H– and –OH to an alkene, yet it is not complicated by rearrangement. 3. Hydroboration-Oxidation: 1) Hydroboration-oxidation gives anti-Markovnikov but syn addition of H– and –OH to an alkene.
~ 11 ~

11.5 ALCOHOLS FROM ALKENES THROUGH OXYMERCURATION-DEMERCURATION
1. Alkenes react with Hg(OAc)2 in a mixture of THF and water to produce (hydroxyalkyl)mercury compounds. 2. The (hydroxyalkyl)mercury compounds can be reduced to alcohols with NaBH4.
Step 1: Oxymercuration

O C C + H2O + Hg OCCH3
2

O THF C C O + CH3COH

OH Hg OCCH3
Step 2: Demercuration

O

C

C

− O + OH + NaBH4

C

C

+ Hg + CH3CO−

OH Hg OCCH3

OH H

3. Both steps can be carried out in the same vessel, and both reactions take place very rapidly at room temperature or below. 1) Oxymercuration usually goes to completion within a period of 20 s to 10 min. 2) Demercuration normally requires less than an hour. 3) The overall reaction gives alcohols in very high yields, usually greater than 90%. 4. Oxymercuration-demercuration is highly regioselective. 1) The H– becomes attached to the carbon atom of the double with the greater number of hydrogen atoms: H C R C H 1. Hg(OAc)2/THF-H2O 2. NaBH4, OH− R H C H C H

+ H HO H

OH H

~ 12 ~

5. Specific examples: CH3(CH2)2CH CH2 1-Pentene
Hg(OAc)2

THF-H2O (15s) CH3(CH2)2CH

CH3(CH2)2CH CH2 + Hg

OH− OH HgOAc (1 h)

CH2

NaBH4

OH H 2-Pentanol (93% ) CH3 HO Hg(OAc)2 CH3 HgOAc HO CH3 H + Hg H

C

C

NaBH4 OH (6 min)
−

C

THF-H2O (20s) 1-Methylcyclopentene

H

1-Methylcyclopentanol

6. Rearrangements of the carbon skeleton seldom occur in oxymercurationdemercuration.

CH3 CH3C CH CH2 CH3 3,3-Dimethyl-1-butene

1. Hg(OAc)2/THF-H2O 2. NaBH4, OH−

CH3 CH3C

H CH C H

CH3 OH H 3,3-Dimethyl-2-butanol (94%)

1) 2,3-Dimethyl-2-butanol can not be detected by gas chromatography (GC) analysis. 2) 2,3-Dimethyl-2-butanol is the major product in the acid-catalyzed hydration of 3,3-dimethyl-1-butene. 7. Solvomercuration-demercuration: Hg(O2CCF3)2/THF-ROH C solvomercuration OR C C NaBH4, OH − OR C C

C

Alkene

demercuration HgO2CCF3 (Alkoxyalkyl)mercuric trifluoroacetate
~ 13 ~

H Ether

A Mechanism for the Reaction
Oxymercuration
Step 1

Hg(OAc)2

+

HgOAc + –OAc

Mercuric acetate dissociates to form an Hg+OAc ion and an acetate ion.

CH3
Step 2

CH3 CH CH2 + Hg+OAc H3C CH3

H3C

C CH3

C CH CH2 HgOAc δ+ δ+

3,3-Dimethyl-1-butene

Mercury-bridged carbocation

The electrophilic HgOAc+ ion accepts a pair of electrons from the alkene to form a mercury-bridged carbocation. In this carbocation, the positive charge is shared between the 2° carbon atom and the mercury atom. The charge on the carbon atom is large enough to account for the Markovnikov orientation of the addition, but not large enough for a rearrangement to occur.
CH3
Step 3

O H

H H 3C

CH3 OH2 C CH3 CH CH2 HgOAc

+

H 3C

C CH CH2 δ+ CH3

HgOAc δ+ A water molecule attacks the carbon bearing the partial positive charge. CH3 OH2
Step 4
+

O H

H H3C

CH3 OH C CH CH2 + H O+ H

H3C

C CH3

CH CH2

HgOAc

CH3 H HgOAc (Hydroxyalkyl)mercury compound

An acid-base reaction transfers a proton to another water molecule (or to an acetate ion). This step produces the (hydroxyalkyl)mercury compound.

8. Mercury compounds are extremely hazardous.

~ 14 ~

11.6 HYDROBORATION: SYNTHESIS OF ORGANOBORANES
1. Hydroboration, discovered by Herbert C. Brown of Purdue University (co-winner of the Nobel Prize for Chemistry in 1979), involves an addition of a H–B bond (a boron hydride) to an alkene.

C

C

+

H

B

hydroboration

C H

C B

Alkene

Boron hydride

Organoborane

2. Hydroboration can be carried out by using the boron hydride (B2H6) called diborane. 1) It is much more convenient to use a THF solution of diborane.

B2H6 + 2 O Diborane THF

2

O BH3 THF : BH3

+ −

BH3 is a Lewis acid (because the boron has only six electrons in its valence shell). It accepts an electron pair from the oxygen atom of THF.

2) Solutions containing the THF:BH3 complex is commercially available. 3) Hydroboration reactions are usually carried out in ether: either in (C2H5)2O, or in some higher molecular weight ether such as “diglyme” [(CH3OCH2CH2)2O, diethylene glycol dimethyl ether].

3. Great care must be used in handling diborane and alkylboranes because they ignite spontaneously in air (with a green flame). inert atmosphere and with care. The solution of THF:BH3 is considerably less prone to spontaneous ignition but still must be used in an

11.6A MECHANISM OF HYDROBORATION
1. When an 1-alkene is treated with a solution containing the THF:BH3 complex, the
~ 15 ~

boron hydride adds successively to the double bonds of three molecules of the alkene to form a trialkylborane: More substituted CH3CH CH2 + H BH2 Less substituted CH3CHCH2 BH2 H CH3CH CH2 (CH3CH2CH2)2BH CH3CH CH2

(CH3CH2CH2)2B Tripropylborane 2. The boron atom becomes attached to the less substituted carbon atom of the double bond. 1) Hydroboration is regioselective and is anti-Markovnikov.

CH3 CH3CH2C 1%

Less substituted CH2 99 %

CH3 CH3C 2%

Less substituted CHCH 3 98 %

2) The observed regioselectivity of hydroboration results in part from steric factors –– the bulky boron-containing group can approach the less substituted carbon atom more easily. 3. Mechanism of hydroboration: 1) In the first step, the π electrons of the double bond adds to the vacant p orbital of BH3. 2) In the second step, the π complex becomes the addition product by passing through a four-center transition state in which the boron atom is partially bonded to the less substituted carbon atom of the double bond. i) Electrons shift in the direction of the boron atom and away from the more substituted carbon atom of the double bond. ii) This makes the more substituted carbon atom develop a partial positive charge, and because it bears an electron-releasing alkyl group, it is better able to accommodate this positive charge.
~ 16 ~

3) Both electronic and steric factors accounts for the anti-Markovnikov orientation of the addition.

A Mechanism for the Reaction
Hydroboration
H3C H H H H3C H H H H3C δ+ H C C H H H Bδ− H H Four-center transition state
+ +

C H + B H

C H

C H B

C H

H π complex

Addition takes place through the initial formation of a π complex, which changes into a cyclic four-center transition state with the boron atom adding to the less hindered carbon atom. The dashed bonds in the transition state represent bonds that are partially formed or partially broken.

H3C H C

H C H

H B H H The transition state passes over to become an alkylborane. The other B−H bonds of the alkylborane can undergo similar additions, leading finally to a trialkylborane.

11.6B THE STEREOCHEMISTRY OF HYDROBORATION
1. The transition state for the hydroboration requires that the boron atom and the hydrogen atom add to the same face of the double bond ⇒ a syn addition.

C

C

syn addition H

C

C B

~ 17 ~

syn addition H CH3 anti-Markovnikov

H B

CH3 + enantiomer H

B

11.7 ALCOHOLS FROM ALKENES THROUGH HYDROBORATION-OXIDATION
1. Addition of the elements of water to a double bond can be achieved through hydroboration, followed by oxidation and hydorlysis of the organoboron intermediate to an alcohol and boric acid. H2O2/OH THF:BH3 (CH3CH2CH2)3B 3 CH3CH CH2 Hydroboration Oxidation Tripropylborane Propene
−

3 CH3CH2CH2OH Propyl alcohol

A Mechanism for the Reaction
Oxidation of Trialkylboran R R B R +
−

R O O H R
−

R O O H R B O R + −O H

B

R

Trialkyl- Hydroperoxide Unstable intermediate Borate ester borane ion The boron atom accepts an electron An alkyl group migrates from pair from the hydroperoxide ion to boron to the adjacent oxygen form an unstable intermediate. atom as a hydroxide ion depatrs.

2. The alkylborane produced in the hydroboration, without isolation, are oxidized and hydrolyzed to alcohols in the same reaction vessel by the addition of hydrogen peroxide in aqueous base.
~ 18 ~

R3B

H2O2 NaOH, 25 oC oxidation

3R

OH

+ Na3BO3

3. The alkyl migration takes place with retention of configuration of the alkyl group which leads to the formation of a trialkyl borate, an ester, B(OR)3.

1) The ester then undergoes basic hydrolysis to produce three molecules of alcohol and a borate ion. B(OR)3 + 3 OH– H2O 3 R–OH + BO33–

4. The net result of hydroboration-oxidation is an anti-Markovnikov addition of water to a double bond. 5. Two complementary orientations for the addition of water to a double bond: 1) Acid-catalyzed hydration (or oxymercuration-demercuration) of 1-hexene:

CH3CH2CH2CH2CH CH2 1-Hexene

H3O+, H2O

CH3CH2CH2CH2CHCH3 2-Hexanol OH

2) Hydroboration-oxidation of 1-hexene: CH3CH2CH2CH2CH CH2
1-Hexene

2. H2O2, OH−

1. THF:BH3

CH3CH2CH2CH2CH2CH2OH
1-Hexanol (90%)

3) Other examples of hydroboration-oxidation of alkenes: CH3 H3C C CHCH 3 1. THF:BH3 CH3 H3C C CHCH 3 H OH 3-Methyl-2-butanol (59%)

2. H2O2, OH−

2-Methyl-2-butene

~ 19 ~

1. THF:BH3 CH3
1-Methylcyclopentene

H

CH3 + enantiomer

2. H2O2, OH−

H OH trans-2-Methylcyclopentanol (86%)

11.7A THE STEREOCHEMISTRY OF HYDROBORATION
1. The net result of hydroboration-oxidation is a syn addition of –H and –OH to a double bond.

Figure 11.1 The hydroboration-oxidation of 1-methylcyclopentene. The first reaction is a syn addition of borane. (In this illustration we have shown the boron and hydrogen both entering from the bottom side of 1-methylcyclopentene. The reaction also takes place from the top side at an equal rate to produce the enantiomer.) In the second reaction the boron atom is replaced by a hydroxyl group with retention of configuration. The product is a trans compound (trans-2-methylcyclopentanol), and the overall result is the syn addition of –H and –OH.

11.7B PROTONOLYSIS OF ORGANOBORANES
1. Heating an organoborane with acetic acid causes cleavage of the C–B bond: 1) This reaction also takes place with retention of configuration ⇒ the stereochemistry of the reaction is like that of the oxidation of organoboranes ⇒ it can be very useful in introducing deuterium or tritium in a specific way.

~ 20 ~

R

B

CH3CO2H heat

R

H + CH3C O O

B

Organoborane

Alkane

11.8 REACTIONS OF ALCOHOLS
1. The oxygen atom of an alcohol polarizes both the C–O bond and the O–H bond:

C O H δ− δ+ δ+

The functional group of an alcohol

An electrostatic potential map for methanol

1) Polarization of the O–H bond makes the hydrogen partially positive ⇒ alcohols are weak acids. 2) The OH– is a strong base ⇒ OH– is a very poor leaving group. 3) The electron pairs on the oxygen atom make it both basic and nucleophilic. i) In the presence of strong acids, alcohols act as bases and accept protons:

H
C

O H + H

A

C

O H + A−
+

Alcohol

Strong acid

Protonated alcohol

2. Protonation of the alcohol converts a poor leaving group (OH–) into a good one (H2O). 1) It also makes the carbon atom even more positive (because –OH2+ is more electron withdrawing than –OH) ⇒ the carbon atom is more susceptible to nucleophilic attack ⇒ Substitution reactions become possible (SN2 or SN1, depending on the class of alcohol).
~ 21 ~

H Nu:
−

+

C

O H

+

S N2

H Nu
C +

O H

Protonated alcohol
2) Alcohols are nucleophiles ⇒ they can react with protonated alcohols to afford ethers.

H R O
+ C

H O H
+

S N2

H R O+ C
+

O H

Protonated alcohol

H Protonated ether

3) At a high enough temperature, and in the absence of a good nucleophile, protonated alcohols are capable of undergoing E1 or E2 reactions.

11.9 ALCOHOLS AS ACIDS
1. Alcohols have acidities similar to that of water. 1) Methanol is a slightly stronger acid than water but most alcohols are somewhat weaker acids.

Table 11.3

pKa Values for Some Weak Acids Acid pKa
15.5 15.74 15.9 18.0

CH3OH H2O CH3CH2OH (CH3)3COH

2) The lesser acidity of sterically hindered alcohols such as tert-butyl alcohol arises from solvation effects. i) With unhindered alcohols, water molecules are able to surround and solvate the
~ 22 ~

negative oxygen of the alkoxide ion formed ⇒ solvation stabilizes the alkoxide ion and increases the acidity of the alcohol.

H
R

H
R

O

H +

O H

O−

+ H

O H

+

Alcohol

Alkoxide ion (stablized by solution)

ii) If the R– group of the alcohol is bulky, solvation of the alkoxide ion is hindered ⇒ the alkoxide ion is not so effectively stabilized ⇒ the alcohol is a weaker acid. 2. Relative acidity of acids:
Relative Acidity

H2O > ROH > RC≡CH > H2 > NH3 > RH
Relative Basicity

R– > NH2– > H– > RC≡C– > RO– > HO–
3. Sodium and potassium alkoxides are often used as bases in organic synthesis.

11.10 CONVERSION OF ALCOHOLS INTO MESYLATES AND TOSYLATESS
1. Alcohols react with sulfonyl chlorides to form sulfonates. 1) These reactions involve cleavage of the O–H bond of the alcohol and not the C–O bond ⇒ no change of configuration would have occurred if the alcohol had been chiral.
O CH3S Cl + H OCH2CH3 Ethanol base (−HCl) O CH3S OCH2CH3

O Methanesulfonyl chloride

O Ethyl methanesulfonate (ethyl mesylate)
~ 23 ~

O CH3 S Cl + H OCH2CH3 Ethanol

base (−HCl)

O CH3 S OCH2CH3

O p-Toluenesulfonyl chloride

O Ethyl p-toluenesulfonate (ethyl tosylate)

2. The mechanism for the sulfonation of alcohols:

A Mechanism for the Reaction
Conversion of an Alcohol into an Alkyl Methanesulfonate O CH3S Cl + H O R O− S R Me O S O R O+ H

Me

O Methanesulfonyl Alcohol The intermediate chloride loses a chloride ion. The alcohol oxygen attacks the O sulfur atom of the sulfonyl chloride. Me S O

O+ O H Cl

B Loss of a proton leads to the product. R + H B

−

O Alkyl methanesulfonate

3. Sulfonyl chlorides are usually prepared by treating sulfonic acids with phosphorus pentachloride. O CH3 S OH + PCl5 CH3 O S Cl + POCl3 + HCl

O p-Toluenedulfonic acid

O p-toluenesulfonyl chloride (tosyl chloride)

4. Abbreviations for methanesulfonyl chloride and p-toluenesulfonyl chloride are “mesyl chloride” and “tosyl chloride”, respectively. 1) Methanesulfonyl group is called a “mesyl” group and p-toluenesulfonyl group is
~ 24 ~

called a “tosyl” group. 2) Methanesulfonates are known as “mesylates” and p-toluenesulfonates are known as “tosylates”.

O H3C S or Ms− CH3

O S or Ts−

O The mesyl group O H3C S OR or MsOR CH3

O The tosyl group O S OR or TsOR

O An alkyl mesylate

O An alkyl tosylate

11.11 MESYLATES AND TOSYLATES IN SN2 REACTIONS
1. Alkyl sulfonates are frequently used as substrates for nucleophilic substitution reactions.
O R' S O
− CH2R + Nu

O RH2C Nu + R' S O−

O Alkyl sulfonate (tosylate, mesylate, etc.)

O Sulfonate ion (very weak base −−− a good leaving group)

2. The trifluoromethanesulfonate ion (CF3SO2O–) is one of the best of all known leaving groups. 1) Alkyl trifluoromethanesulfonates –– called alkyl triflates –– react extremely rapidly in nucleophilic substitution reactions. 2) The triflate ion is such a good leaving group that even vinylic triflatres undergo SN1 reactions and yield vinylic cations.

~ 25 ~

OSO2CF3 C C

solvolysis

C

C+

+

−

OSO2CF3

Vinylic triflate

Vinylic cation

Triflate ion

3. Alkyl sulfonates provide an indirect method for carrying out nucleophilic substitution reactions on alcohols. R C H + Cl Ts retention −HCl R H R' Nu C R C H + R'
−

Step 1

H R' Nu

O R + H R'

O

Ts

Step 2

−

C

O

Ts

inversion S N2

O

Ts

1) The alcohol is converted to an alkyl sulfonate first and then the alkyl sulfonate is reacted with a nucleophile. 2) The first step –– sulfonate formation –– proceeds with retention of configuration because no bonds to the stereocenter are broken. 3) The second step –– if the reaction is SN2 –– proceeds with inversion of configuration. 4) Allkyl sulfonates undergo all the nucleophilic substitution reactions that alkyl halides do.

The Chemistry of Alkyl Phosphates
1. Alcohols react with phosphoric acid to yield alkyl phosphates:
O ROH ROH RO P OH RO P OH ROH + HO P OH (−H2O) (−H2O) (−H2O) OH OR OH Dialkyl hydrogen Phosphoric Alkyl dihydrogen phosphate acid phosphate O O O RO P OR OR Trialkyl phosphate

1) Esters of phosphoric acids are important in biochemical reactions (triphosphate
~ 26 ~

esters are especially important). 2) Although hydrolysis of the ester group or of one of the anhydride linkages of an alkyl triphosphate is exothermic, these reactions occur very slowly in aqueous solutions. 3) Near pH 7, these phosphates exist as negatively charged ions and hence are much less susceptible to nucleophilic attack ⇒ Alkyl triphosphates are relatively stable compounds in the aqueous medium of a living cell. 2. Enzymes are able to catalyze reactions of these triphosphates in which the energy made available when their anhydride linkages break helps the cell make other chemical bonds. O ROH + HO Ester linkage O RO P OH O O OH Anhydride linkage O OH OH P O P H2O slow O RO P OH O RO P OH O OH + HO O P OH OH + HO P OH O O OH O P OH O OH OH O O P OH O P OH OH OH P O P

11.12 CONVERSION OF ALCOHOLS INTO ALKYL HALIDES
1. Alcohols react with a variety of reagents to yield alkyl halides. 1) Hydrogen halides (HCl, HBr, or HI):
CH3 H3C C

OH + HCl (concd)

CH3

25 C 94%

o

CH3 H3C C CH3

Cl + H2O

CH3CH2CH2CH2OH + HBr (concd)

reflux

CH3CH2CH2CH2Br (95%)

~ 27 ~

2) Phosphorous tribromide (PBr3):
3 (CH3)2CHCH2OH + PBr3 3) Thionyl chloride (SOCl2): H3CO CH2OH + SOCl2 pyridine H3CO CH2Cl + HCl + SO2 (forms a salt with pyridine) −10 to 0 oC 4h 3 (CH3)2CHCH 2Br + H3PO3 (55-60%)

(an organic base) (91%)

11.13 ALKYL HALIDES FROM THE REACTION OF ALCOHOLS WITH HYDROGEN HALIDES
1. When alcohols react with a HX, a substitution takes place producing an RX and H2O: R OH + HX R X + H2O

1) The order of reactivity of the HX is: HI > HBr > HCl (HF is generally unreactive). 2) The order of reactivity of alcohols is: 3° > 2° > 1° < methyl. 2. The reaction is acid catalyzed. ROH + NaX
H2SO4

RX + NaHSO4 + H2O

11.13A MECHANISMS OF THE REACTIONS OF ALCOHOLS WITH HX
1. 2°, 3°, allylic, and benzylic alcohols appear to react by an SN1 mechanism. 1) The porotonated alcohol acts as the substrate.
CH3

Step 1

H3C

C

O

H + H

O H

+

H

fast

CH3H H 3C C O
+

H +

O H

H

CH3

CH3
~ 28 ~

CH3H
Step 2

H 3C

C

O

+

H

slow

CH3 H 3C C+ CH3 + O H H

CH3 CH3
Step 3

H 3C

C+

+

Cl −

fast

CH3 H 3C C CH3 Cl

CH3 i)

The first two steps are the same as in the mechanism for the dehydration of an alcohol ⇒ the alcohol accepts a proton and then the protonated alcohol dissociates to form a carbocation and water.

ii) In step 3, the carbocation reacts with a nucleophile (a halide ion) in an SN1 reaction. 2. Comparison of dehydration and RX formation from alcohols: 1) Dehydration is usually carried out in concentrated sulfuric acid. i) The only nucleophiles present in the reaction mixture are water and hydrogen sulfate (HSO4–) ions. ii) Both are poor nucleophiles and both are usually present in low concentrations ⇒ The highly reactive carbocation stabilizes itself by losing a proton and becoming an alkene ⇒ an E1 reaction. 2) Conversion of an alcohol to an alkyl halide is usually carried out in the presence of acid and in the presence of halide ions. i) The only nucleophiles present in the reaction mixture are water and hydrogen sulfate (HSO4–) ions. ii) Halide ions are good nucleophiles and are present in high concentrations ⇒ Most of the carbocations stabilize themselves by accepting the electron pair of a halide ion ⇒ an SN1 reaction. 3. Dehydration and RX formation from alcohols furnish another example of the competition between nucleophilic substitution and elimination.
~ 29 ~

1) The free energies of activation for these two reactions of carbocations are not very different from one another. 2) In conversion of alcohols to alkyl halides (substitution), very often, the reaction is accompanied by the formation of some alkenes (elimination). 4. Acid-catalyzed conversion of 1° alcohols and methanol to alkyl halides proceeds through an SN2 mechanism. H X− + R o H O
+

H H X C H R + O H

C

H (protonated 1 alcohol or methanol)

H (a good leaving group)

1) Although halide ions (particularly I– and Br–) are strong nucleophiles, they are not strong enough to carry out substitution reactions with alcohols directly. H Br
−

H O H X Br C H R +
−

+

R

C H

O

H

5. Many reactions of alcohols, particularly those in which carbocations are formed, are accompanied by rearrangements.

6. Chloride ion is a weaker nucleophile than bromide and iodide ions ⇒ chloride does not react with 1° or 2° alcohols unless zinc chloride or some Lewis acid is added to the reaction. 1) ZnCl2, a good Lewis acid, forms a complex with the alcohol through association with an lone-pair electrons on the oxygen ⇒ provides a better leaving group for the reaction than H2O.
R O H
−

+ ZnCl2

R

O+ ZnCl2 H

Cl

−

+

R

O+ ZnCl2 H
~ 30 ~

−

Cl

− R + [Zn(OH)Cl2]

[Zn(OH)Cl2]– + H+

ZnCl2 + H2O

11.14 ALKYL HALIDES FROM THE REACTION OF ALCOHOLS WITH PBr3 OR SOCl2
1. 1° and 2° alcohols react with phosphorous tribromide to yield alkyl bromides. 3R OH + PBr3 3R Br + H3PO3

(1oor 2o) 1) The reaction of an alcohol with PBr3 does not involve the formation of a carbocation and usually occurs without rearrangement ⇒ PBr3 is often preferred for the formation of an alcohol to the corresponding alkyl bromide. 2. The mechanism of the reaction involves the initial formation of a protonated alkyl dibromophosphite by a nucleophilic displacement on phosphorus: O+ PBr2 +
−

RCH2OH + Br

P Br

Br

RCH2

Br

H Protonated alkyl dibromophosphite

1) Then a bromide ion acts as a nucleophile and displaces HOPBr2. Br
−

+ RCH2

O+ PBr2 H

RCH2Br + HOPBr2

A good leaving group i) The HOPBr2 can react with more alcohol ⇒ 3 mol of alcohol is converted to 3 mol of alkyl bromide by 1 mol of PBr3. 3. Thionyl chloride (SOCl2) converts 1° and 2° alcohols to alkyl chlorides (usually without rearrangement):
~ 31 ~

R OH + SOCl2 (1oor 2o) i)

reflux

R

Cl + HCl + SO2

A 3° amine is added to promote the reaction by reacting with the HCl. R3N: + HCl R3NH+ + Cl–

4. The reaction mechanism involves the initial formation of the alkyl chlorosulfite:
+

Cl S Cl O
−

RCH2OH + Cl

S O

Cl Cl

RCH2

O H

RCH2 Cl−

O

+

Cl S O

H

RCH2

O

S

+ HCl

O Alkyl chlorosulfite i) Then a chloride ion (from R3N: + HCl R3NH+ + Cl–) can bring about

an SN2 displacement of a very good leaving group, ClSO2–, which, by decomposing (to SO2 and Cl– ion), helps drive the reaction to completion. Cl + RCH2 O S O Cl S O SO2

Cl

−

RCH2Cl + O

−

+ Cl−

11.15 SYNTHESIS OF ETHERS
11.15A ETHERS BY INTERMOLECULAR DEHYDRATION OF ALCOHOLS
1. Alcohols can dehydrate to form alkenes. R–OH + HO–R

H+ −H2O

R–O–R

1) Dehydration to an ether usually takes place at a lower temperature than dehydration to an alkene.
~ 32 ~

i)

The dehydration to an ether can be aided by distilling the ether as it is formed.

ii) Et2O is the predominant product at 140°C; ethane is the major product at 180°C H2SO4 CH3CH2OH 180 oC H2SO4 140 oC

CH2 CH2 Ethene CH3CH2OCH2CH3 Diethyl ether

2. The formation of the ether occurs by an SN2 mechanism with one molecule of the alcohol acting as the nucleophile and with another protonated molecule of the alcohol acting as the substrate.

A Mechanism for the Reaction
Intermolecular Dehydration of Alcohols to Form an Ether
Step 1 RCH2

O

H + H

OSO3H

RCH2

O

+

H +

−

OSO3H

H This is an acid-base reaction in which the alcohol accepts a proton from the sulfuric acid.
RCH2 O H + RCH2 O
+

Step 2

H

RCH2

O

+

CH2R + O H

H

H

H

Another molecule of alcohol acts as a nucleophile and attacks the protonnated alcohol in SN2 reaction.
Step 3 RCH2

O

+

CH2R + O H

H

RCH2

O

CH2R + H

O+ H H

H

Another acid-base reaction converts the protonated ether to an ether by transferring a proton to a molecule of water (or to another molecule of alcohol).

1) Attempts to synthesize ethers with 2° alkyl groups by intermolecular dehydration
~ 33 ~

of 2° alcohols are usually unsuccessful because alkenes form too easily ⇒ This method of preparing ethers is of limited usefulness. 2) This method is not useful for the preparation of unsymmetrical ethers from 1° alcohols because the reaction leads to a mixture of products: ROR ROH + R'OH 1o alcohol H2SO4 ROR' R'OR' H2O

11.15B THE WILLIAMSON SYNTHESIS OF ETHERS
1. Williamson Ether synthesis:

A Mechanism for the Reaction
The Williamson Ether Synthesis

R

O − Na+

+

R'

L

R

O

R' +

Na+ − L

Alkyl hslide, Sodium (or potassium) alkyl sulfonate, or dialkyl sulfate alkoxide

Ether

The alkoxide ion reacts with the substrate in an SN2 reaction, with the resulting formation of the ether. The substrate must bear a good leaving group. Typical substrates are alkyl halides, alkyl sulfonates, and dialkyl sulfates, i.e. –L = −Br , −I , –OSO2R", or –OSO2OR"

2. The usual limitations of SN2 reactions apply: 1) Best results are obtained when the alkyl halide, sulfonate, or sulfate is 1° (or methyl). 2) If the substrate is 3°, elimination is the exclusive result. 3) Substitution is favored over elimination at lower temperatures.
~ 34 ~

3. Example of Williamson ether synthesis:
CH3CH2CH2OH Propyl alcohol NaH CH3CH2CH2O −Na
+

+

H

H

Sodium propoxide 70% CH3CH2I
+ − CH3CH2CH2OCH2CH3 + Na I

Ethyl propyl ether

11.15C TERT-BUTYL ETHERS BY ALKTLATION OF ALCOHOLS. PROTECTING GROUPS
1. 1° alcohols can be converted to tert-butyl ethers by dissolving them in a strong acid such as sulfuric acid and then adding isobutylene to the mixture (to minimize dimerization and polymerization of the isobutylene). CH3 RCH2O CCH3 CH3

RCH2OH + H2C

CCH3 CH3

H2SO4

tert-butyl protecting group

1) The tert-butyl protecting group can be removed easily by treating the ether with dilute aqueous acid. 2. Preparation of 4-pentyn-1-ol from 3-bromo-1-propanol and sodium acetylide: 1) The strongly basic sodium acetylide will react first with the hydroxyl group.
HOCH2CH2CH2Br + NaC 3-Bromo-1-proponal CH NaOCH2CH2CH2Br + HC CH

2) The –OH group has to be protected first.
HOCH2CH2CH2Br

1. H2SO4 2.H2C
C(CH3)2

(CH3)3COCH2CH2CH2Br

NaC

CH

H3O+ (CH3)3COCH2CH2CH2C CH H2O

HOCH2CH2CH2C CH + (CH3)3COH 4-Pentyn-1-ol

~ 35 ~

11.15D SILYL ETHER PROTECTING GROUPS
1. A hydroxyl group can also be protected by converting it to a silyl ether group. 1) tert-butyldimethylsilyl ether group [tert-butyl(CH3)2Si–O–R, or TBDMS–O–R]: i) Triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, and others can be used. ii) The tert-butyldimethylsilyl ether is stable over a pH range of roughly 4~12. iii) The alcohol is allowed to react with tert-butylchlorodimethylylsilane in the presence of an aromatic amine (a base) such as imidazole or pyridine.
CH3 R O H + Cl Si C(CH)3 CH3

imidazole DMF (−HCl)

CH3 R O Si C(CH)3 CH3

tert-butylchlorodimethylsilane (TBDMSCl)

(R−O−TBDMS)

iv) The TBDMS group can be removed by treatment with fluoride ion (tetrabutylammonium fluoride):
CH3 R O Si C(CH)3 CH3 Bu4N F THF
+ −

CH3 R O H + F Si C(CH)3 CH3

(R−O−TBDMS) 2. Converting an alcohol to a silyl ether makes it much more volatile ⇒ can be analyzed by gas chromatography. 1) Trimethylsilyl ethers are often used for this purpose.

11.16 REACTIONS OF ETHERS
1. Dialkyl ethers react with very few reagents other than acids. 1) Reactive sites of a dialkyl ether: C–H bonds and –O– group. 2) Ethers resist attack by nucleophiles and by bases. 3) The lack of reactivity, coupled with the ability of ethers to solvate cations makes ethers especially useful as solvents for many reactions.
~ 36 ~

2. The oxygen of the ether linkage makes ethers basic ⇒ Ethers can react with proton donors to form oxonium salts. CH3CH2OCH2CH3 + HBr H3CH2C
O
+

CH2CH3Br−

H An oxonium salt

3. Heating dialkyl ethers with very strong acids (HI, HBr, and H2SO4) cleaves the ether linkage: CH3CH2OCH2CH3 + 2 HBr 2 CH3CH2Br + H2O
Cleavage of an ether

A Mechanism for the Reaction
Ether Cleavage by Strong Acids

Step 1

CH3CH2OCH2CH3 + HBr

H3CH2C

O

+

CH2CH3 + Br

−

H H3CH2C Ethanol O + CH3CH2Br H Ethyl bromide

In step 2 the ethanol (just formed) reacts with HBr (present in excess) to form a second molar equivalent of ethyl bromide.

Step 2
H3CH2C O +H H Br Br − +H3CH2C O+ H H CH3CH2−Br + O H H

1) The reaction begins with formation of an oxonium ion. 2) An SN2 reaction with a bromide ion acting as the nucleophile produces ethanol and ethyl bromide. 3) Excess HBr reacts with the ethanol produced to form the second molar equivalent of ethyl bromide.
~ 37 ~

11.17 EPOXIDES
1. Epoxides are cyclic ethers with three-membered rings (IUPAC: oxiranes).

C O

C

H2C

2

O IUPAC nomenclature: oxirane Common name: ethylene oxide

1

CH2

3

An epoxide 2. Epoxidation: Syn addition

1) The most widely used method for synthesizing epoxides is the reaction of an alkene with an organic peroxy acid (peracid). O RCH CHR + R'C An alkene O OH epoxidation O RHC CHR + R'C OH O An epoxide (or oxirane)

A peroxy acid

A Mechanism for the Reaction
Alkene Epoxidation C C Alkene O R' C C O O + C R'

+

O H

C O

Proxy acid

Epoxide

O H Carboxylic acid

The peroxy acid transfers an oxygen atom to the alkene in a cyclic, single-step mechanism. The result is the syn addition of the oxygen to the alkene, with formation of an epoxide and a carboxylic acid. 3. Most often used peroxy acids for epoxidation: 1) MCPBA: Meta-ChloroPeroxyBenzoic Acid (unstable). 2) MMPP: Magnesium MonoPeroxyPhthalate.
~ 38 ~

O C O C O O O
−

OH Mg2+

Cl

C

OH

O m-Chloroperoxybenzoic acid (MCPBA) 4. Example:

Magnesium monoperoxyphthalate (MMPP)

2

H MMPP O CH3CH2OH 85% H 1,2-Epoxycyclohexane Cyclohexene (cyclohexene oxide) 5. The epoxidation of alkenes with peroxy acids is stereospecific: 1) cis-2-Butene yields only cis-2,3-dimethyloxirane; trans-2-butene yields only the racemic trans-2,3-dimethyloxiranes. H 3C H + R O COOH H H 3C O CH3

C C

H 3C H cis-2-Butene H 3C H + R

H cis-2,3-Dimethyloxirane (a meso compound) H O CH3 + H 3C H

C C

O COOH

H CH3 trans-2-Butene

O H 3C H CH3 H Enantiomeric trans-2,3-dimethyloxiranes

~ 39 ~

The Chemistry of The Sharpless Asymmetric Epoxidation
1. In 1980, K. B. Sharpless (then at the Massachusetts Institute of Technology, presently at the University of California San Diego, Scripps research Institute; co-winner of the Nobel Prize for Chemistry in 2001) and co-workers reported the “Sharpless asymmetric epoxidation”. 2. Sharpless epoxidation involves treating an allylic alcohol with titanium(IV) tetraisopropoxide [Ti(O–iPr)4], tert-butyl hydroperoxide [t-BuOOH], and a specific enantiomer of a tartrate ester.

O OH tert-BuOOH, Ti(O−Pri)4 CH2Cl2 , −20 oC (+)-diethyl tartate 77% yield 95% enantiomeric excess Geraniol 3. The oxygen that is transferred to the allylic alcohol to form the epoxide is derived from tert-butyl hydroperoxide. 4. The enantioselectivity of the reaction results from a titanium complex among the reagents that includes the enantiomerically pure tartrate ester as one of the ligands.
D-(−)-diethyl tartrate (unnatural) .. ":O:" R2 R3 R1 OH t-BuOOH, Ti(OPr-i)4 CH2Cl2, −20 oC R2 O
3

OH

R1 OH

":O:" .. L-(+)-diethyl tartrate (natural)

R 70-87% yields > 90% e.e.

“The First Practical Methods for Asymmetric Epoxidation” Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-5976.
~ 40 ~

5. The tartrate (either diethyl or diisopropyl ester) stereoisomer that is chosen depends on the specific enantiomer of the epoxide desired. 1) It is possible to prepare either enantiomer of a chiral epoxide in high enantiomeric excess:

(+)-dialkyl tartrate Sharpless asymmetric epoxidation OH (−)-dialkyl tartrate Sharpless asymmetric epoxidation

O OH (S)-Methylglycidol O OH (R)-Methylglycidol

6. The synthetic utility of chiral epoxy alcohol synthons produced by the Sharpless asymmetric epoxidation has been demonstrated in enantioselective syntheses of many important compounds. 1) Polyether antibiotic X-206 by E. J. Corey (Harvard University): OH H O OH Antibiotic X-206 O H H O OH H O H O OH HO O O OH 2) Commercial synthesis of the gypsy moth pheromone (7R,8S)-disparlure by J. T. Baker: H O H
~ 41 ~

H

(7R,8S)-Disparlure

3) Zaragozic acid A (which is also called squalestatin S1 and has been shown to lower serum cholesterol levels in test animals by inhibition of squalene biosynthesis) by K. C. Nicolaou (University of California San Diego, Scripps Research Institute): O O HO2C HO2C O OH OH

OCOCH 3

Zaragozic acid A (squalestatin S1)

O CO2H

11.18 REACTIONS OF EPOXIDES
A Mechanism for the Reaction
Acid-Catalyzed Ring Opening of an Epoxide
+

C O

C

+ H

O H

H

C

C O+

+ O H

H

Epoxide

H Protonated epoxide

The acid reacts with the epoxide to produce a protonated epoxide. H C C O+ + O H C O C
+

H

O H

H C H O

O C

H + H O H
+

H

H O H H Protonated Weak Protonated epoxide nucleophile glycol

Glycol

The protonated epoxide reacts with the weak nucleophile (water) to form a protonated glycol, which then transfers a proton to a molecule of water to form the glycol and a hydronium ion.
~ 42 ~

1. The highly strained three-membered ring of epoxides makes them much more reactive toward nucleophilic substitution than other ethers. 1) Acid catalysis assists epoxide ring opening by providing a better leaving group (an alcohol) at the carbon atom undergoing nucleophilic attack. 2. Epoxides Can undergo base-catalyzed ring opening:

A Mechanism for the Reaction
Base-Catalyzed Ring Opening of an Epoxide

R

O +

−

C

C

RO

C

C

O

−

H

OR RO C +R C O− OH

O Strong nucleophile Epoxide

An alkoxide ion

A strong nucleophile such as an alkoxide ion or a hydroxide ion is able to open the strained epoxide ring in a direct SN2 reaction. 1) If the epoxide is unsymmetrical, the nucleophile attacks primarily at the less substituted carbon atom in base-catalyzed ring opening.

1o Carbon atom is less hindered H3CH2C O + H 2C O Methyloxirane H3CH2CO
−

CHCH3

H3CH2CO

CH2 CH O CH3

−

H

OCH2CH3

CH2 CH OH + H3CH2C

O−

CH3 1-Ethoxy-2-propanol 2) If the epoxide is unsymmetrical, the nucleophile attacks primarily at the more substituted carbon atom in acid-catalyzed ring opening.

~ 43 ~

CH3 CH3OH + H3C C O i) CH2

HA

CH3 H 3C C CH2 OH OCH3

Bonding in the protonated epoxide is unsymmetrical, which the more highly substituted carbon atom bearing a considerable positive charge; the reaction is SN1 like. CH3 This carbon resembles a 3o carbocation CH3 CH2 H3C H C
+

CH3OH + H3C

δ+

C

CH2 OH

O δ+ H Protonated epoxide

OCH3

The Chemistry of Epoxides, Carcinogens, and Biological Oxidation
1. Certain molecules from the environment becomes carcinogenic by “activation” through metabolic processes that are normally involved in preparing them for excretion. 2. Two of the most carcinogenic compounds known: dibenzo[a,l]pyrene, a polycyclic aromatic hydrocarbon (PAH) and aflatoxin B1, a fungal metabolite. 1) During the course of oxidative processing in the liver and intestines, these molecules undergo epoxidation by enzymes called P450 cytochromes. i) The epoxides are exceptionally reactive nucleophiles and it is precisely because of this that they are carcinogenic. ii) The epoxides undergo very facile nucleophilic substitution reactions with DNA. iii) Nucleophilic sites on DNA react to open the epoxide ring, causing alkylation of the DNA by formation of a covalent bond with the carcinogen. iv) Modification of the DNA in this way causes onset of the disease state.

~ 44 ~

deoxyadenosine adduct DNA enzymatic epoxidation ("activation") HO Dibenzo[a,l]pyrene OH Dibenzo[a,l]pyrene-11,12-diol-13,14-epoxide O

2) The normal pathway toward excretion of foreign molecules like aflatoxin B1 and dibenzo[a,l]pyrene, however, also involves nucleophilic substitution reactions of their epoxides.
CO2−
+

H3N O

H N

O N H SH O O H O H O N H S H O OCH3 O CO2−

O H O H O Aflatoxin B1

O

Galutathione enzymatic epoxidation ("activation")

OCH3 CO2−
+

epoxide ring opening by glutathion CO2− O

H3N O

H N

O

HO O Afltatoxin B1-gultathione adduct H i)
~ 45 ~

O

OCH3

One pathway involves opening of the epoxide ring by nucleophilic substitution

with glutathione. ii) Glutathion is a relatively polar molecule that has a strongly nucleophilic sulfhydryl (thiol) group. iii) The newly formed covalent derivative is readily excreted through aqueous pathways because it is substantially more polar than the original epoxide.

11.18A POLYETHER FORMATION
1. Treating ethylene oxide with sodium methoxide (in the presence of a small amount of methanol) can result in the formation of a polyether. H3C O − + H2C O H3C H3C O O CH2 CH2 O CH2 CH2 O − n CH2

H3C

O

CH2

CH2 O − + H2C O etc. CH3OH O−

CH2

CH2 CH2 O

CH2 CH2 OH + H3C

Poly(ethylene glycol) (a polyether) 1) This an example of anionic polymerization. i) The polymer chains continue to grow until methanol protonates the alkoxide group at the end of the chain. ii) The average length of the growing chains and, therefore, the average molecular weight of the polymer can be controlled by the amount of methanol present. iii) The physical properties of the polymer depend on its average molecular weight. 2) Polyethers have high water solubilities because of their ability to form multiple hydrogen bonds to water molecules. i) Marketed commercially as carbowaxes, these polymers have a variety of uses, ranging from use in gas chromatography columns to applications in cosmetics.

~ 46 ~

11.19 ANTI HYDROXYLATION OF ALKENES VIA EPOXIDES
1. Epoxidation of cyclopentene produces 1,2-epoxycyclopentane: O + H H Cyclopentene R C O O H H H + R O C O H

O 1,2-Epoxycyclopentane

2. Acid-catalyzed hydrolysis of 1,2-epoxycyclopentane yields a trans-diol, trans-1,2-cyclopentanediol. H H H H H O+ + H H
+

H H O+ H O

H H

H

O H

enantiomer + H O H

O

O

H

HO

H

H HO trans-1,2-Cyclopentanediol

1) Water acting as a nucleophile attacks the protonated epoxide from the side opposite the epoxide group. 2) The carbon atom being attacked undergoes an inversion of configuration. 3) Attack at the other carbon atom produces the enantiomeric form of trans-1,2-cyclopentanediol. 3. Epoxidation followed by acid-catalyzed hydrolysis constitutes a method for anti hydroxylation of a double bond.

~ 47 ~

H H H3CH H CH3 HA H2O H3CH O C O
+

H

H (a)

O+ H H 3C C C

H CH3

C

C

C

H CH3

C C H OH OH H 3C (2R,3R)-2,3-Butanediol H
−

A

−

HO

H CH3

H (b) H H 3C HO
+O

O cis-2,3-Dimethyloxirane

H

C

C

A

H H 3C

OH C C

H CH3

H HO CH3 (2S,3S)-2,3-Butanediol

Figure 11.2 Acid-catalyzed hydrolysis of cis-2,3-dimethyloxirane yields (2R,3R)-2,3-butanediol by path (a) and (2S,3S)-2,3-butanediol by path (b). H H H3C H C H CH3 H3C HA H C H2O O H H CH3 H O+ C C H CH3 A
−

HO C C

H CH3

H3C H

C

C O
+

H3C OH OH H (2R,3S)-2,3-Butanediol H
−

H C C H H HO HO CH3 CH3 (2R,3S)-2,3-Butanediol These moleculea are identical: they both represent the meso compound (2R,3S)-2,3-butanediol. C H3C H C
+O

O One trans-2,3dimethyloxirane enantiomer

H

A

H3C H

OH

Figure 11.3 The acid-catalyzed hydrolysis of one trans-2,3-dimethyloxirane enantiomer produces the meso (2R,3S)-2,3-butanediol by path (a) or path (b). Hydrolysis of the other enantiomer (or the racemic modification) would yield the same product.

~ 48 ~

H3C H C C H3C H 1. RC(O)OOH 2. HA, H2O (anti hydroxylation)

HO

CH3 H C C OH

H

CH3 OH C C

cis-2-Butene
H CH3 C C H3C H

H CH3 CH3 (R,R) (S,S) Enantiomeric 2,3-butanediols H HO HO CH3 H C H CH3 C

1. RC(O)OOH 2. HA, H2O (anti hydroxylation)

HO

trans-2-Butene

meso-2,3-Butanediols

Figure 11.4 The overall result of epoxidation followed by acid-catalyzed hydrolysis is a stereospecific anti hydroxylation of the double bond. cis-2-Butene yields the enantiomeric 2,3-butanediols; trans-2-butene yields the meso compound.

11.20 CROWN ETHERS: NUCLEOPHILIC SUBSTITUTION REACTIONS IN RELATIVELY NONPOLAR APROTIC SOLVENTS BY PHASE-TRANSFER CATALYSIS
1. SN2 reactions take place much more rapidly in polar aprotic solvents. 1) In polar aprotic solvents the nucleophile is only very slightly solvated and is, consequently, highly reactive. 2) This increased reactivity of nucleophile is a distinct advantage ⇒ Reactions that might have taken many hours or days are often over in a matter of minutes. 3) There are certain disadvantages that accompany the use of solvents such as DMSO and DMF. i) These solvents have very high boiling points, and as a result they are often difficult to remove after the reaction is over. ii) Purification of these solvents is time consuming, and they are expensive. iii) At high temperatures certain of these polar aprotic solvents decompose.
~ 49 ~

2. In some ways the ideal solvent for an SN2 reaction would be a nonpolar aprotic solvent such as a hydrocarbon or a relatively nonpolar chlorinated hydrocarbon. 1) They have low boiling points, they are inexpensive, and they are relatively stable. 2) Hydrocarbon or chlorinated hydrocarbon were seldom used for nucleophilic substitution reactions because of their inability to dissolve ionic compounds. 3. Phase-transfer catalysts are used with two immiscible phases in contact ––– often an aqueous phase containing an ionic reactant and an organic (benzene, CHCl3, etc.) containing the organic substrate. 1) Normally the reaction of two substances in separate phases like this is inhibited because of the inability of the reagents to come together. 2) Adding a phase-transfer catalyst solves this problem by transferring the ionic reactant into the organic phase. i) Because the reaction medium is aprotic, an SN2 reaction occurs rapidly.

4. Phase-transfer catalysis:

Figure 11.5 Phase-transfer catalysis of the SN2 reaction between sodium cyanide and an alkyl halide.
~ 50 ~

1) The phase-transfer catalyst (Q+X–) is usually a quaternary ammonium halide (R4N+X–) such as tetrabutylammonium halide (CH3CH2CH2CH2)4N+X–. 2) The phase-transfer catalyst causes the transfer of the nucleophile (e.g. CN–) as an ion pair [Q+CN–] into the organic phase. 3) This transfer takes place because the cation (Q+) of the ion pair, with its four alkyl groups, resembles a hydrocarbon in spite of its positive charge. i) It is said to be lipophilic –– it prefers a nonpolar environment to an aqueous one. 4) In the organic phase the nucleophile of the ion pair (CN–) reacts with the organic substrate RX. 5) The cation (Q+) [and anion (X–)] then migrate back into the aqueous phase to complete the cycle. i) This process continues until all of the nucleophile or the organic substrate has reacted. 5. An example of phase-transfer catalysis: 1) The nucleophilic substitution reaction of 1-chlorooctane (in decane) and sodium cyanide (in water): CH3(CH2)6CH2Cl (in decane) i) R4N+Br− aqueous NaCN, 105 oC CH3(CH2)6CH2CN

The reaction (at 105 °C) is complete in less than 2 h and gives a 95% yield of the substitution product.

6. Many other types of reactions than nucleophilic substitution are also amenable to phase-transfer catalysis. 1) Oxidation of alkenes dissolved in benzene can be accomplished in excellent yield using potassium permanganate (in water) when a quaternary ammonium salt is present.

~ 51 ~

CH3(CH2)5CH CH2 (in benzene) i)

R4N+Br− aqueous KMnO4, 35 oC

CH3(CH2)5CO2H + HCO2H (99%)

Potassium permanganate can be transferred to benzene by quaternary ammonium salts to give “purple benzene” which can be used as a test reagent for unsaturated compounds ⇒ the purple color of KMnO4 disappears and the solution becomes brown (MnO2).

11.20A CROWN ETHERS
1. Crown ethers are also phase-transfer catalysts and are able to transport ionic compounds into an organic phase. 1) Crown ethers are cyclic polymers of ethylene glycol such as 18-crown-6: O O O O 18-Crown-6 2) Crown ethers are named as x-crown-y where x is the total number of atoms in the ring and y is the number of oxygen atoms. 3) The relationship between crown ether and the ion that is transport is called a host-guest relationship. i) The crown ether acts as the host, and the coordinated cation is the guest. O O K
+

O O K+ O O O O

2. The Nobel Prize for Chemistry in 1987 was awarded to Charles J. Pedersen (retired from DuPont company), Donald J. Cram (retired from the University of California, Los Angeles), and Jean-Marie Lehn (Louis Pasteur University, Strasbourg, France) for their development of crown ethers and other molecules “with structure specific interactions of high selectivity”. 1) Their contributions to our understanding of what is now called “molecular
~ 52 ~

recognition” have implications for how enzymes recognize their substrates, how hormones cause their effects, how antibodies recognize antigens, how neurotransmitters propagate their signals, and many other aspects of biochemistry. 3. When crown ethers coordinate with a metal cation, they thereby convert the metal ion into a species with a hydrocarbonlike exterior. 1) The 18-crown-6 coordinates very effectively with potassium ions because the cavity size is correct and because the six oxygen atoms are ideally situated to donate their electron pairs to the central ion. 4. Crown ethers render many salts soluble in nonpolar solvents. 1) Salts such as KF, KCN, and CH3CO2K can be transferred into aprotic solvents by using catalytic amounts of 18-crown-6. 2) In the organic phase the relatively unsolvated anions of these salts can carry out a nucleophilic substitution reaction on an organic substrate.
RCH2X + K+CN− C6H5CH2Cl + K+F− 18-crown-6 benzene 18-crown-6 benzene RCH2CN + K+X− C6H5CH2F + K+Cl− (100%)

+ KMnO4

dicyclohexano-18-crown-6 benzene HO2C (90%)

O

O O O O O Dicyclohexano-18-crown-6 O

~ 53 ~

11.20B TRANSPORT ANTIBIOTICS AND CROWN ETHERS
1. There are several antibiotics called ionophores, most notably nonactin and

valinomycin, that coordinate with metal cations in a manner similar to that of crown ether. 2. Normally, cells must maintain a gradient between the concentrations of sodium and potassium ions inside and outside the cell wall. 1) Potassium ions are “pumped” in; sodium ions are pumped out. 2) The cell membrane, in its interior, is like a hydrocarbon, because it consists in this region primarily of the hydrocarbon portions of lipids. 3) The transport of hydrated sodium and potassium ions through the cell membrane is slow, and this transport requires an expenditure of energy by the cell. 3. Nonactin upsets the concentration gradient of these ions by coordinating more strongly with potassium ions than with sodium ions. 1) Because the potassium ions are bound in the interior of the nonactin, this host-guest complex becomes hydrocarbonlike on its surface and passes readily through the interior of the membrane. 2) The cell membrane thereby becomes permeable to potassium ions, and the essential concentration gradient is destroyed. H3C O O H3C H O H O H H CH3 O CH3 O O CH3 O O O H O H O CH3 CH3

H H

Nonactin

~ 54 ~

11.21 SUMMARY OF REACTIONS OF ALKENES, ALCOHOLS, AND ETHERS
H2SO4 ,140oC (Section 11.15A) H2SO4 ,180oC (Section 7.7) Na or NaH (Section 6.16B and 11.9) TsCl (Section 11.10) CH3CH2OH MsCl (Section 11.10) HX (Section 11.13) PBr3 (Section 11.14) SOCl2 (Section 11.14) CH2C(CH3)2/H2SO4 (Section 11.15C) TBDMSCl (Section 11.15D) HX (X = Br, I) (Section 11.16)

CH3CH2OCH2CH3 O H2C CH2

2 CH3CH2X ROH, H+ ROCH2CH2OH ROCH2CH2OH

RCOOH (Section 11.17)

H2C O

CH2

(Section 11.18) ROH, H− (Section 11.18)

RCH2X HX (X=Br,I) CH3CH2X CH3CH2ONa CH3CH2OCH2R (Section 11.15B ) (Section 11.18) + RCH2X CH3CH2OTs CH3CH2OMs CH3CH2X CH3CH2Br CH3CH2Cl CH3 CH3CH2OCCH3 CH3 CH3CH2OTBDMS H3O+/H2O (Section 11.15C) Bu4N F , THF (Section 11.15D)
+ −

Nu− (Nu− = OH−, I−, CN−, etc.) (Section 11.11) Nu− (Nu− = OH−, I−, CN−, etc.) (Section 11.11)

CH3CH2Nu

CH3CH2Nu

RONa (Section 11.15B)

CH3CH2OR

CH3 CH3CH2OH + HOCCH3 CH3 CH3CH2OH + FTBDMS

Figure 11.6 Summary of importrant reactions of alcohols and ethers starting with ethanol.

~ 55 ~

11.21A ALKENES IN SYNTHESIS
Me H Hydration Markovnikov (Section 11.5)

1. Hg(OAc)2 , THF-H2O 2. NaBH4, OH−

(

H HO means indefinite stereochemistry) Me H Syn addition of hydrogen (Section 11.6 and 11.7)

CH3CO2H H THF:BH3 Me H Me H H2O2 OH− Me H H

H Me RCO2OH H /ROH
+

B H

H HO

Hydration Syn hydrogen (Section 11.6 OH and 11.7) Anti Hydroxylation (Section 11.19) Anti Hydroxylation (Section 11.18 and 11.19)

H3O O RO Me
−

+

H

Me Me OH− OR HO

RO

H

OH OH

Me

OH HO

H

H

Figure 11.7 Summary of importrant reactions of alcohols and ethers starting with ethanol.

~ 56 ~

ALCOHOLS FROM CARBONYL COMPOUNDS. OXIDATION-REDUCTION AND ORGANOMETALLIC COMPOUNDS
THE TWO ASPECTS OF THE COENZYME NADH
1. The role of many of the vitamins in our diet is to become coenzymes for enzymatic reactions. 1) Coenzymes are molecules that are part of the organic machinery used by some enzymes to catalyze reactions. 2. The vitamins niacin (nicotinic acid, 菸鹼酸) and its amide niacin amide are precursors to the coenzyme nicotinamide adenine dinucleotide.

O OH N Niacin (Nicotinic acid) N

O NH2 N Nicotine N N CH3 N

NH2 N N Adenine

Nicotinamide

H

O C NH2 O
−

H

H O C

NH2

O
−

O P O P

CH2 N O H H H OH H OH

+

O P O P

CH2 N O H H H OH H OH

O O

O O

−

O

O

CH2 Adenine O H H H OH H OH

−

O

O

CH2 Adenine O H H H OH H OH

nicotinamide adenine dinucleotide

reduced nicotinamide adenine dinucleotide
~1~

NAD+

NADH

H

O C NH2
NAD+

N R 1) Soybeans are one dietary source of niacin. 3. NAD+ is the oxidized form while NADH is the reduced form of the coenzyme. 1) NAD+ serves as an oxidizing agent. 2) NADH is a reducing agent that acts as an electron donor and frequently as a biochemical source of hydride (“H–”).

+

12.1 INTRODUCTION
1. Carbonyl compounds include aldehydes, ketones, carboxylic acids, and esters. R
C O

R C O C O R' A ketone

R C O HO A carboxylic

R C O R'O A carboxylate ester

H The carbonyl group An aldehyde

12.1A STRUCTURE OF THE CARBONYL
1. The carbonyl carbon atom is sp2 hybridized ⇒ it and the three groups attached to it lie in the same plane. 1) A trigonal plannar structure ⇒ the bond angles between the three attached atoms are approximately 120°.

~2~

2. The carbon-oxygen double bond consists of two electrons in a σ bond and two electrons in a π bond. 1) The π bond is formed by overlap of the carbon p orbital with a p orbital from the oxygen atom. 2) The electron pair in the π bond occupies both lobes (above and below the plane of the σ bonds).

The π bonding molecular orbital of formaldehyde (HCHO). The electron pair of the π bond occupies both lobes.
3. The more electronegative oxygen atom strongly attracts the electrons of both the σ bond and the π bond, causing the carbonyl group to be highly polarized ⇒ the carbon atom bears a substantial positive charge and the oxygen bears a substantial negative charge. 1) Resonance structures for the carbonyl group:

C

O

+C

O−

or

C

δ+

O

δ−

Resonance structure for the carbonyl group

Hybrid

2) Carbonyl compounds have rather large dipole moments as a result of the polarity of the carbon-oxygen bond.

~3~

H3 C

+¡÷ H

+¡÷ H3C
O

C

δ+

O

δ−

C
H

C H3C

O

H3 C

Formaldehyde µ = 2.27 D

Acetone µ = 2.88 D

An electrostatic potential map for acetone

12.1B REACTION OF CARBONYL COMPOUNDS WITH NUCLEOPHILES
1. One of the most important reactions of carbonyl compounds is the nucleophilic addition to the carbonyl group. 1) The carbonyl carbon bears a partial positive charge ⇒ the carbonyl group is susceptible to nucleophilic attack. 2) The electron pair of the nucleophile forms a bond to the carbonyl carbon atom. 3) The carbonyl carbon can accept this electron pair because one pair of electrons of the carbon-oxygen group double bond can shift out to the oxygen.
−
δ+ δ−

Nu:

+

C

O

Nu

C

O−

2. The carbon atom undergoes a change in its geometry and its hybridization state during the reaction. 1) It goes from a trigonal planar geometry and sp2 hybridization to a tetrahedral geometry and sp3 hybridization. 2) The electron pair of the nucleophile forms a bond to the carbonyl carbon atom. 3. Two important nucleophiles that add to carbonyl compounds: 1) Hydride ions form compounds such as NaBH4 or LiAlH4. 2) Carbanions form compounds such as RLi or RMgX. 4. Oxidation of alcohols and reduction of carbonyl compounds:

~4~

H R C O H

[O] oxidation reduction [H]

R C H An aldehyde O

H A primary alcohol

12.2 OXIDATION-REDUCTION REACTIONS IN ORGANIC CHEMISTRY
1. Reduction of an organic molecule usually corresponds to increasing its hydrogen content or to decreasing its oxygen content.

1) Converting a carboxylic acid to an aldehyde is a reduction:
Oxygen content decreases O R C OH O R C H

[H] reduction

[H] stands for a reduction of the compound 2) Converting an aldehyde to an alcohol is a reduction: Hydrogen content increases O R C H

[H] reduction

RCH2OH

3) Converting a n alcohol to an alkane is a reduction:
Oxygen content decreases RCH2OH [H] reduction

RCH3

2. Oxidation of an organic molecule usually corresponds to increasing its oxygen content or to decreasing its hydrogen content.
~5~

R

CH3

[O] [H] R

CH2OH

[O] [H] R

O C H

[O] [H] R

O C OH Highest oxidation state

Lowest oxidation state

[O] stands for an oxidation of the compound 1) Oxidation of an organic compound may be more broadly defined as a reaction that increases its content of any element more electronegative than carbon.

Ar

CH3

[O] [H] Ar CH2Cl

[O] [H] Ar CHCl2

[O] [H] Ar CCl3

3. When an organic compound is reduced the reducing agent must be oxidized. When an organic compound is oxidized the oxidizing agent must be reduced. 1) The oxidizing and reducing agents are often inorganic compounds.

12.3 ALCOHOLS BY REDUCTION OF CARBONYL COMPOUNDS
1. Primary and secondary alcohols can be synthesized by the reduction of a variety of compounds that contain the carbonyl group. O R C OH Carboxylic acid O R C OR' Ester O R C H Aldehyde [H] R CH2OH 1o Alcohol [H] R CH2OH + R'OH 1o Alcohol [H] R CH2OH 1o Alcohol

~6~

O R C R' [H] R Ketone

OH CH R' 2o Alcohol

2. Reduction of carboxylic acids are the most difficult, but they can be accomplished with the powerful reducing agent lithium aluminum hydride (LiAlH4, abbreviated LAH).
4 RCO2H + 3 LiAlH4 Lithium aluminum hydride CH3 H3C C CO2H Et2O [(RCH2O)4Al]Li + 4 H2 + 2 LiAlO2 4 RCH2OH + Al2(SO4)3 + Li2SO4 CH3 H3C C CH2OH

H2O/H2SO4

1. LiAlH4/Et2O

2. H2O/H2SO4 CH3 92% 2,2-Dimethylpropanoic acid

CH3 Neopentyl alcohol

3. Esters can be reduced by high-pressure hydrogenation (a reaction preferred for industrial processes and often referred to as “hydrogenolysis” because the C–O bond is cleaved in the process), or through the use of LiAlH4.

O R C OR' + H2 CuO-CuCr2O4 175 oC 5000 psi RCH2OH + R'OH

O R C OR'

1. LiAlH4/Et2O 2. H2O/H2SO4

RCH2OH + R'OH

1) The latter method is the one most commonly used now in small-scale laboratory syntheses. 4. Aldehydes and ketones can be reduced to alcohols by hydrogenation, or sodium in alcohol, and by the use of LiAlH4. 1) The most often used reducing agent is sodium borohydride (NaBH4).
~7~

O 4R C H + NaBH4 + 3 H2O O H3CH2CH2C Butanal C H NaBH4 H2O 85% 4 RCH2OH + NaH2BO3

CH3CH2CH2CH2OH 1-Butanol

H2CH3C

C

CH3

NaBH4 H2O 87%

H3CH2C

CH CH3

O 2-Butanone

OH 2-Butanol

5. The key step in the reduction of a carbonyl compound by either LiAlH4 or NaBH4 is the transfer of a hydride ion from the metal to the carbonyl carbon. 1) The hydride ion acts as a nucleophile.

A Mechanism for the Reaction
Reduction of Aldehydes and Ketones by Hydride Transfer R BH3 H + R H C O− H OH H R C O H

δ+ δ−

C

O

R' Hydride transfer

R' Alkoxide ion

R' Alcohol

6. NaBH4 is a less powerful reducing agent than LiAlH4. 1) LiAlH4 reduces acids, esters, aldehydes, and ketones. 2) NaBH4 reduces only aldehydes and ketones.

~8~

Reduced by LiAlH4 Recuced by NaBH4 O R C O− < R O C OR' < R O C R' < R O C H

Ease of reduction 7. LiAlH4 reacts violently with water ⇒ reductions with LiAlH4 must be carried out in anhydrous solutions, usually in anhydrous ether. 1) Ethyl acetate is added cautiously after the reaction is over to decompose excess LiAlH4, then water is added to decompose the aluminum complex. 2) NaBH4 reductions can be carried out in water or alcohol solutions.

The Chemistry of Alcohol Dehydrogenase
1. When the enzyme alcohol dehydrogenase converts acetaldehyde to ethanol, NADH acts as a reducing agent by transferring a hydride from C4 of the nicotinamide ring to the carbonyl group of acetaldehyde. 1) The nitrogen of the nicotinamide ring facilitates this process by contributing its nonbonding electron pair to the ring, which together with loss of the hydride converts the ring to the energetically more stable ring found in NAD+. 2) The ethoxide anion resulting from hydride transfer to acetaldehyde is then protonated by the enzyme to form ethanol.

~9~

R

N

H 2N HS O re Part of NADH

H HR H 3C C O H+ NH2 H O HS + C H 3C OH Ethanol S Zn2+ S Cys N His Cys

R NAD
+

N

+

HR

2. Although the carbonyl group of acetaldehyde that accepts the hydride is inherently electrophilic, the enzyme enhances this property by providing a zinc ion as a Lewis acid to coordinate with the carbonyl oxygen. 1) The Lewis acid stabilizes the negative charge that develops on the oxygen in the transition state. 2) The role of the enzyme’s protein scaffold is to hold the zinc ion, coenzyme, and substrate in the three-dimensional array required to lower the energy of the transition state. 3) The reaction is reversible and when the relative concentration of ethanol is high, alcohol dehydrogenase carries out the oxidation of ethanol ⇒ alcohol dehydrogenase is important in detoxication.

The Chemistry of Stereoselective Reductions of Carbonyl Groups
1. Enantioselectivity: 1) Depending on the structure about the carbonyl group that is being reduced, the tetrahedral carbon that is formed by transfer of a hydride could be a new stereocenter.
~ 10 ~

i)

Achiral reagents like NaBH4 and LiAlH4, react with equal rates at either face of an achiral trigonal planar substrate, leading to a racemic form of the product.

ii) Reactions involving a chiral reactant typically lead to a predominance of one enantiomeric form of a chiral product ⇒ an enantioselective reaction.

2) When enzymes like alcohol dehydrogenase, are chiral, reduce carbonyl groups using coenzyme NADH, they discriminate between the two faces of the trigonal planar carbonyl substrate, such that a predominance of one of the two possible stereoisomeric forms of the tetrahedral product results. i) If the original reactant was chiral, the formation of the new stereocenter may result in preferential formation of one diastereomer of the product ⇒ a diastereoselectiv reaction.

3. Re and si face of a trigonal planar center: 1) Re is clockwise, si is counterclockwise. re face (when looking at this face there is a clockwise sequence of priorities) si face (when looking at this face there is a counterclockwise sequence of priorities

R

2

R1

C

O

The re and si faces of a carbonyl group (Where O > R1 > R2 in terms of Cahn-Inglod-Prelog priorities)
4. The preference of many NADH-dependent enzymes for either re or si face of their respective substrates is known ⇒ some of these enzymes become exceptionally useful stereoselective reagents for synthesis. 1) Yeast alcohol dehydrogenase is one of the most widely used enzymes. 2) Extremozymes, enzymes from thermophilic bacteria, have become important in synthetic chemistry. i) Use of heat-stable enzymes allows reactions to be completed faster due to the rate-enhancing factor of elevated temperature (over 100 °C in some cases), although greater enantioselectivity is achieved at lower temperature.
~ 11 ~

O

Thermoanaerobium brockii 85% yield

HO

H

95% enantiomeric excess
5. Chiral reducing agents: 1) Chiral reducing agents derived from aluminum or boron reducing agents that involve one or more chiral organic ligands. 2) S-Alpine-borane and R-Alpine-borane are derived from either (–)-α-pinene or (+)-α-pinene and 9-borabicyclo[3.3.1]nonane (9-BBN).

H B H B B 9-BBN R-Alpine-BoraneTM O (S)-(−)Aline-Borane 60-65% yield 97% enantiomeric excess HO H B

D CH3 Cl H CH3 B

B H

O R

D C R (R) H RL

OH H

Ipc O RL

OH C (S) RS

favored

RS
~ 12 ~

Cl H CH3 B RL OBn Ipc O RS less favored H C RS (R) RL OH

OBn

OBn

B

H

B

t-BuLi

B H NB-EnantrideTM

Li

nopol benzyl ether

NB-EnantraneTM

3) Reagents derived from LiAlH4 and chiral amines have also been developed. 4) Often it is necessary to test several reaction conditions in order to achieve optimal stereoselectivity. 5. Prochirality 1) For a given enzymatic reaction only one specific hydride from C4 in NADH is transferred. HR
R N H 2N

HS O

Nicotinamide ring NADH, showing the pro-R and pro-S hydrogens
2) The hydrogens at C4 of NADH are prochiral. 3) Pro-R and pro-S hydrogens: i) If the configuration is R when the hydrogen is “replaced” by a group of higher priority than hydrogen it is a pro-R hydrogen. ii) If the configuration is S when the hydrogen is “replaced” by a group of higher priority than hydrogen it is a pro-S hydrogen.
~ 13 ~

3) Pro-chiral center: i) Addition of a group to a trigonal planar atom or replacement of one of two identical groups at a tetrahedral atom leads to a new stereocenter ⇒ a

prochiral center.

12.4 OXIDATION OF ALCOHOLS
12.4A OXIDATION OF PRIMARY ALCOHOLS TO ALDEHYDES: RCH2OH → RCHO
1. 1° alcohols can be oxidized to aldehydes and carboxylic acids.

O
R CH2OH 1° Alcohol [O] R C H Aldehyde [O]

O
R C OH Carboxylic acid

2. The oxidation of aldehydes to carboxylic acids in aqueous solutions usually takes place with less powerful agents than those required to oxidize 1° alcohols to aldehydes ⇒ it is difficult to stop the oxidation at the aldehyde stage. 1) Dehydrogenation of an organic compound corresponds to oxidation, whereas hydrogenation corresponds to reduction. 3. A variety of oxidizing agents are available to prepare aldehydes from 1° alcohols such as pyridinium chlorochromate (PCC) and pyridinium dichromate (PDC). 1) PCC is prepared by dissolving CrO3 in hydrochloric acid and then treated with pyridine.

CrO3 + HCl +

N Pyridine (C5H5N)

N H CrO3Cl− Pyridinium chlorochromate (PCC)

+

H2Cr2O7 +

N
~ 14 ~

N H Cr2O72−
2

+ +

Pyridine 2) PCC does not attack double bonds. CH3 (C2H5)2C CH2OH + 2-Ethyl-2-methyl-1-butanol PCC

Pyridinium dichromate (PDC)

CH2Cl2 25 oC

CH3 O (C2H5)2C CH 2-Ethyl-2-methylbutanal

3) PCC and PDC are cancer suspect agents and must be dealt with care. 4. One reason for the success of oxidation with PCC is that the oxidation can be carried out in a solvent such as CH2Cl2, in which PCC is soluble. 1) Aldehydes themselves are not nearly so easily oxidized as are the aldehyde hydrates, RCH(OH)2, that form when aldehydes are dissolved in water, the usual

medium for oxidation by PCC. RCHO + H2O RCH(OH)2

12.4B OXIDATION OF PRIMARY ALCOHOLS TO CARBOXYLIC ACIDS: RCH2OH → RCO2H
1. 1° alcohols can be oxidized to carboxylic acids by potassium permanganate. 1) The reaction is usually carried out in basic aqueous solution from which MnO2 precipitates as the oxidation takes place. 2) After the oxidation is complete, filtration allows removal of the MnO2 and acidification of the filtrate gives the carboxylic acid.
R CH2OH + KMnO4 OH− H2O heat RCO2− K+ + MnO2 H3O+ RCO2H

12.4C OXIDATION OF SECONDARY ALCOHOLS TO KETONES
1. 2° alcohols can be oxidized to ketones.
~ 15 ~

1) The reaction usually stop at the ketone stage because further oxidation requires the breaking of a C–C bond.

OH R CH R' [O] R 2° Alcohol

O C R' Ketone

2. Various oxidizing agents based on chromium(VI) have been used to oxidize 2° alcohols to ketones. 1) The most commonly used reagent is chromic acid (H2CrO4). 2) Chromic acid is usually prepared by adding chromium(VI) oxide (CrO3) or sodium dichromate (Na2Cr2O7) to aqueous sulfuric acid. 3) Oxidation of 2° alcohols are generally carried out in acetone or acetic acid solutions. R 3 R' CHOH + 2 H2CrO4 + 6 H+ 3 R' R C O + 2 Cr3+ + 8 H2O

4) As chromic acid oxidizes the alcohol to ketone, chromium is reduced from the +6 oxidation state (H2CrO4) to the +3 oxidation state (Cr3+). 3. Chromic acid oxidations of 2° alcohols generally give ketones in excellent yields if the temperature is controlled. OH H2CrO4 Acetone 35 oC Cyclooctanol Cyclooctanone O

4. The use of CrO3 in aqueous acetone is usually called the Jones oxidation. 1) Jones oxidation rarely affects double bonds present in the molecule.

12.4D MECHANISM OF CHROMATE OXIDATION
1. The mechanism of chromic acid oxidations of alcohols:
~ 16 ~

1) The first step is the formation of a chromate ester of the alcohol. 2) The chromate ester is unstable and is not isolated. It transfers a proton to a base (usually water) and simultaneously eliminates an HCrO3– ion.

A Mechanism for the Reaction
Chromate Oxidations: Formation of the Chromate Ester
Step 1
H H3C C H3C H O + H O O Cr O O
−

H H O H3C C O+ H H3C H H O
+

O Cr O H H O+ H O− O H

H

H H The alcohol donates an electron pair to the One oxygen loses a proton; chromium atom, as an oxygen accepts a proton. another oxygen accepts a proton. O H3C C H3C H O O H Cr H O− H3C C O O H + O Cr O O

+

O

H

H H3C H H Chromate ester A molecule of water departs as a leaving group as a chromium-oxygen double bond forms.

A Mechanism for the Reaction
Chromate Oxidations: The Oxidation Step

Step 2

~ 17 ~

O H3C C H3C H O H The chromium atom departs with a pair of electrons that formerly belonged to the alcohol; the alcohol is thereby oxidized and the chromium reduced. H O Cr O H O H3C C H3C O + O Cr O H O + H O+ H H

3) The overall result of second step is the reduction of HCrO4– to HCrO3–, a two electron (2 e–) change in the oxidation state of chromium, from Cr(VI) to Cr(IV). 4) At the same time the alcohol undergoes a 2 e– oxidation to the ketone. 5) The remaining steps of the mechanism are complicated which involve further oxidations (and disproportionations), ultimately, converting Cr(IV) compounds to Cr3+ ions. 2. The aldehydes initially formed are easily oxidized to carboxylic acids in aqueous solutions. 1) The aldehyde initially formed from a 1° alcohol reacts with water to form an aldehyde hydrate. 2) The aldehyde hydrate can then react with HCrO4– (and H+) to form a chromate ester, and this can then be oxidized to the carboxylic acid. 3) In the absence of water (i.e., using PCC in CH2Cl2), the aldehyde hydrate does not form ⇒ further oxidation does not happen.

~ 18 ~

R H O H H R C H H O H O O H O Cr OH O C O

R H

O− C O
+

R H R C

O

H

HCrO4− , H+

H O C

H O H Aldehyde hydrate + HCrO3− + H3O+

O H Carboxylic acid

3. The chromate ester from 3° alcohols does not bear a hydrogen that can be eliminated, and therefore no oxidation takes place. R C R O R + H
−

O O Cr O O H + H+

R C R

R O O Cr OH O + H2O

3°Alcohol

This chromate ester cannot undergo elimination of H2CrO3

12.4E A CHEMICAL TEST FOR PRIMARY AND SECONDARY ALCOHOLS
1. The relative ease of oxidation of 1° and 2° alcohols compared with the difficulty of oxidizing 3° alcohols forms the basis for a convenient chemical test. 1) 1° and 2° alcohols are rapidly oxidized by a solution of CrO3 in aqueous sulfuric acid. 2) Chromic oxide (CrO3) dissolves in aqueous sulfuric acid to give a clear orange solution containing Cr2O72– ions. 3) A positive test is indicated when this clear orange solution becomes opaque and takes on a greenish cast within 2 s.

~ 19 ~

RCH2OH or + CrO3/aqueous H2SO4 R CHOH R Clear orange solution i)

Cr3+ and oxidation products

Greenish opaque solution

This color change, associated with the reduction of Cr2O72– to Cr3+, forms the basis for “Breathalyzer tubes” used to detect intoxicated motorists. In the Breathalyzer the dichromate salt is coated on granules of silica gel.

ii) This test not only can distinguish 1° and 2° alcohols from 3° alcohols it also can distinguish them from other compounds except aldehydes..

12.4F SPECTROSCOPIC EVIDENCE FOR ALCOHOLS
1. Alcohols give rise to O–H stretching absorptions from 3200 to 3600 cm–1 in infrared spectra. 2. The alcohol hydroxyl hydrogen typically produced a broad 1H NMR signal of variable chemical shift which can be eliminated by exchange with deuterium from D2O. 3) The 13C NMR spectrum of an alcohol sows a signal between δ 50 and δ 90 for the alcohol carbon.
4) Hydrogen atoms on the carbon of a 1° or 2° alcohol produce a signal in the 1H

NMR spectrum between δ 3.3 and δ 4.0 that integrates for 2 or 1 hydrogens, respectively

12.5 ORGANOMETALLIC COMPOUNDS
1. Compounds that contain carbon-metal bonds are called organometallic compounds. 1) The nature of the C–M bond varies widely, ranging from bonds that are essentially ionic to those that are primarily covalent.
~ 20 ~

2) The structure of the organic portion of the organometallic compound has some effects on the nature of the C–M bond, the identity of the metal itself is of far greater importance. i) C–Na and C–K bonds are largely ionic in character.

ii) C–Pb, C–Sn, C–Tl, and C–Hg bonds are essentially covalent. iii) C–Li and C–Mg bonds lie in between these two extremes. δ− δ+

+ C− M

C

M

C M Primarily covalent (M = Pb, Sn, Hg, or Tl)

Primarily ionic (M = Na+ or K+)

(M = Mg or Li)

2. The reactivity of organometallic compounds increases with the percent ionic character of the C–M bond. 1) Alkylsodium and alkylpotassium compounds are highly reactive and are among the most powerful of bases ⇒ they react explosively with water and burst into flame when exposed to air. 2) Organomercury and organolead compounds are much less reactive ⇒ they are often volatile and are stable in air. i) They are all poisonous and are generally soluble in nonpolar solvents.

ii) Tetraethyllead has been replaced by other antiknock agent such as tert-butyl methyl ether (TBME). 3. Organolithium and organomagnesium compounds are of great importance in organic synthesis. i) They are relatively stable in ether solutions. iii) Their C–M bonds have considerable ionic character ⇒ the carbon atom that is bonded to the metal atom of an organolithium or organomagnesium compound is a strong base and powerful nucleophile.

~ 21 ~

12.6 PREPARATION OF ORGANOLITHIUM AND ORGANOMAGNESIUM COMPOUNDS
12.6A ORGANOLITHIUM COMPOUNDS
1. Organolithium compounds are often prepared by the reduction of organic halide with lithium metal. 1) These reductions are usually carried out in ether solvents and care must be taken to exclude moisture since organolithium compounds are strong bases. i) Most commonly used solvents are diethyl ether and tetrahydrofuran.

CH3CH2OCH2CH3 Diethyl ether (Et2O)

O Tetrahydrofuran (THF)

ii) Most organolithium compounds slowly attack ethers by bringing about an elimination reaction. R : Li + H δ− δ+

CH2

CH2 OCH2CH3

RH + H2C

− CH2 + Li+ OCH2CH3

iii) Ether solutions of organolithium reagents are not usually stored but are used immediately after preparation. iv) Organolithium compounds are much more stable in hydrocarbon solvents. 2) Examples of organolithium compounds prepared in ether
−10 oC Et2O 80-90%

CH3CH2CH2CH2Br + 2 Li Butyl bromide
R X + 2 Li (or Ar−X)

CH3CH2CH2CH2Li + LiBr Butylithium
R Li + LiX (or ArLi)

Et2O

3) The order of reactivity of halides is RI > RBr > RCl (Alkyl and aryl fluorides are seldom used in the preparation of organolithium compounds).
~ 22 ~

12.6B GRIGNARD REAGENTS
1. Organomagnesium halides were discovered by the French chemist Victor Grignard in 1900. 1) Grignard received the Nobel Prize in 1912 and organomagnesium halides are now called Grignard reagents. 2) Grignard reagents have great use in organic synthesis. 2. Grignard reagents are usually prepared by the reaction of an organohalide and magnesium metal (turnings) in an ether solvent.
RX + Mg ArX + Mg Et2O Et2O RMgX ArMgX

Grignard reagents

1) The order of reactivity of halides with magnesium is RI > RBr > RCl (very few organomagnesium fluorides have been prepared). i) Aryl Grignard reagents are more easily prepared from aryl bromides and aryl iodides than from aryl chlorides, which react very sluggishly. 3. Grignard reagents are seldom isolated but are used for further reactions in ether solution. CH3X + Mg Et2O 35 oC CH3MgX Methylmagnesium iodide (95%) C6H5MgX Phenylmagnesium bromide (95%)

C6H5X +

Mg

Et2O 35 oC

4. The actual structures of Grignard reagents are more complex than the general formula RMgX indicates. 1) Experiments done with radioactive magnesium have established that, for most
~ 23 ~

Grignard reagents, there is an equilibrium between an alkylmagnesium halide and a dialkylmagnesium. 2 RMgX Alkylmagnesium halide + R2Mg Dialkylmagnesium MgX2

2) For convenience, RMgX is used for the Grignard reagent. 5. A Grignard reagent forms a complex with its ether solvent:

R C6H5 R

O Mg O

R X R

1) Complex formation with molecules of ether is an important factor in the formation and stability of Grignard reagents. 2) Organomagnesium compounds can be prepared in nonethereal solvents, but the preparations are more difficult. 6. The mechanism for the formation of Grignard reagents might involve radicals:
R X + Mg R + MgX R + MgX RMgX

12.7 REACTIONS OF ORGANOLITHIUM AND ORGANOMAGNESIUM COMPOUNDS
12.7A REACTIONS WITH COMPOUNDS CONTAINING ACIDIC HYDROGEN ATOMS
1. Grignard reagents and organolithium compounds are very strong bases ⇒ they react with any compound that has a hydrogen attached to an electronegative atom such as oxygen, nitrogen, or sulfur.
~ 24 ~

R MgX and R Li

δ−

δ+

δ− δ+

1) The reactions of Grignard reagents with water and alcohols are simply acid-base reactions ⇒ the Grignard reagent behaves as if it contained an carbanion. δ− δ+

H OH R MgX + Grignard reagent Water (stronger base) (stronger acid) δ− δ+

HO − + Mg2+ + X − R H + Alkane Hydroxide ion (weaker acid) (weaker base) RO − + Mg2+ + X − R H + Alkane Alkoxide ion (weaker acid) (weaker base)

H OR R MgX + Grignard reagent Alcohol (stronger base) (stronger acid)

2) Grignard reagents and organolithium compounds abstract protons that are much less acidic than those of water and alcohols ⇒ a useful way to prepare alkynylmagnesium halides and alkynyllithium. δ− δ+ δ− δ+

R C C H + R' MgX Terminal alkyne Grignard reagent (stronger base) (stronger acid) δ− δ+

R' H + R C C MgX Alkynylmagnesium halide Alkane (weaker base) (weaker acid) δ− δ+

R C C H + R' Li Terminal alkyne Alkyllithium (stronger acid) (stronger base)

R C C Li Alkynyllithium (weaker base)

+

R' H Alkane (weaker acid)

2. Grignard reagents and organolithium compounds are powerful nucleophiles.

12.7B REACTIONS OF GRIGNARD REAGENTS WITH OXIRANES (EPOXIDES)
1. Grignard reagents carry out nucleophilic attack at a saturated carbon when they react with oxiranes ⇒ a convenient way to synthesize 1° alcohols.

~ 25 ~

R MgX + H2C

δ−

δ+

δ+

δ+

CH2 O δ−

R

CH2CH2

2+ − O Mg X
−

H+

R

CH2CH2 OH

Oxirane
Specific Examples
C6H5MgBr + H2C O CH2 Et2O C6H5CH2CH2OMgBr H+

A primary alcohol

C6H5CH2CH2OH

1) Grignard reagents react primarily at the less-substituted ring carbon of substituted oxirane.

Specific Examples
C6H5MgBr + H2C CH O CH3 Et2O C6H5CH2CHOMgBr CH3 H+ C6H5CH2CHOH CH3

12.7C REACTIONS OF GRIGNARD REAGENTS WITH CARBONYL COMPOUNDS
1. The most important reactions of Grignard reagents and organolithium compounds are the nucleophilic attack to the carbonyl group.

A Mechanism for the Reaction
The Grignard Reaction Reaction: RMgX + C O 1. ether 2. H3O+X − R C O H + MgX2

Mechanism:

Step 1

~ 26 ~

R MgX

δ−

δ+

+

C

O

R

C

O − Mg2+X −

Grignard reagent Carbonyl compound

Halomagnesium alkoxide

The strongly nucleophilic Grignard reagent uses its electron pair to form a bond to the carbon atom. One electron pair of the carbonyl group shifts out to the oxygen. This reaction is a nucleophilic addition to the carbonyl group, and it results in the formation of an alkoxide ion associated with Mg2+ and X−.

Step 2
R C
2+ − O − Mg X + H − O+ H + X

R

C

O

H + O H

H + MgX2

Halomagnesium alkoxide

H

Alcohol

In the second step, the addition of aqueous HX causes protonation of the alkoxide ion; this leads to the formation of the alcohol and MgX2.

12.8 ALCOHOLS FROM GRIGNARD REAGENTS
1. Grignard Reagents React with Formaldehyde to Give a 1° Alcohol. H C O R H Fromaldehyde H C H O MgX
+

R MgX +

δ−

δ+

H3O

H R o C

OH

H 1 alcohol

2. Grignard Reagents React with All Other Aldehydes to Give 2° Alcohols. R' R MgX + C δ− δ+

R' O R C H O MgX

H3O

+

R' R o C

OH

H Higher aldehyde

H 2 alcohol

~ 27 ~

3. Grignard Reagents React with Ketones to Give 3° Alcohols. R' R MgX + C δ− δ+

R' O R C R" O MgX

H3O+

R' R o C

OH

R" Ketone

R" 3 alcohol

4. Esters React with Two Molar Equivalents of a Grignard Reagent to Form 3° Alcohols.

R' R MgX + C δ− δ+

R' O R C O O MgX R"

−R"OMgX spontaneously

R' C R Ketone O

R"O Ester RMgX

Initial product (unstable) R' H3O+ R C OMgX R o R' C OH

R Salt of an alcohol (not isolated)

R 3 alcohol

1) The initial addition product is unstable and loses a magnesium alkoxide to form a ketone which is more reactive toward Grignard reagents than esters. 2) A second molecule of the Grignard reagentadds to the carbonyl group as soon as the ketone is formed in the mixture. 3) After hydrolysis, the product is a 3° alcohol with two identical alkyl groups. SPECIFIC EXAMPLES GRIGNARD REAGENT CARBONYL REACTANT FINAL PRODUCT

Reaction with formaldehyde
H C6H5MgBr + C O H Phenylmagnesium Fromaldehyde bromide Et2O C6H5CH2 OMgBr H3O+

C6H5CH2OH Benzyl alcohol (90%)

Reaction with a higher aldehyde
~ 28 ~

H3C CH3CH2MgBr + C O H Ethylmagnesium Acetaldehyde bromide Et2O

CH3 CH3CH2C H OMgX

H3O+

CH3 CH3CH2CHOH 2-Butanol (80%)

Reaction with a ketone
H3C CH3CH2CH2CH2MgBr + C CH3 O Et2O CH3CH2CH2CH2C OMgX CH3 CH3CH2CH2CH2C OH CH3 2-Methyl-2-hexanol (92%) CH3

H3C Butylmagnesium bromide Acetone

NH4Cl H2O

Reaction with an ester
CH3CH2MgBr H3C + C CH3 O CH3CH2 C OMgBr −C2H5OMgBr

CHO OCH2CH3 Ethylmagnesium 2 5 bromide Ethyl acetate CH3 H3C CH3 CH3CH2MgBr NH4Cl C O CH3CH2C OMgX H O CH3CH2C OH 2 CH3CH2 CH CH CH CH
2 3 2

3

3-Methyl-3-pentanol (67%)

12.8A PLANNING A GRIGNARD SYNTHESIS
C6H5 CH3CH2 C OH 1. We can use a ketone with two ethyl groups (3-pentanone) and allow it to react
~ 29 ~

CH2CH3

3-Phenyl-3-pentanol

with phenylmagnesium bromide:

Analysis
C6H5 CH3CH2 C OH CH2CH3 CH3CH2 C O CH2CH3 + C6H5MgBr

Synthesis
C6H5MgBr + CH3CH2 Phenylmagnesium bromide C CH2CH3 1. Et2O 2. NH4Cl H2O C6H5 CH3CH2 C CH2CH3 OH 3-Phenyl-3-pentanol

O 3-Pentanone

2. We can use a ketone containing an ethyl groups and a phenyl group (ethyl phenyl ketone) and allow it to react with ethylmagnesium bromide:

Analysis
C6H5 CH3CH2 C OH CH2CH3 CH3CH2 C6H5 C O + CH3CH2MgBr

Synthesis
C6H5 CH3CH2MgBr + C O CH3CH2 Ethylmagnesium Ethyl phenyl ketone bromide 1. Et2O 2. NH4Cl H2O C6H5 CH3CH2 C CH2CH3 OH 3-Phenyl-3-pentanol

3. We can use an ester of benzoic acid and allow it to react with two molar equivalents of ethylmagnesium bromide:

Analysis
C6H5 CH3CH2 C OH CH2CH3 C6H5
~ 30 ~

O C OCH3 + 2 CH3CH2MgBr

Synthesis
O 2 CH3CH2MgBr + Ethylmagnesium bromide C6H5 OCH3 2. NH4Cl H 2O Methyl benzoate C 1. Et2O CH3CH2 C6H5 C CH2CH3 OH 3-Phenyl-3-pentanol

4. All these methods will be likely to give the desired compound in greater than 80% yields.

12.8B RESTRICTIONS ON THE USE OF GRIGNARD REAGENTS
1. The Grignard reagent is a very powerful base ⇒ it is not possible to prepare a Grignard reagent from an organic group that contains an acidic hydrogen. 2. Grignard reagents are powerful nucleophiles ⇒ it is not possible to prepare a Grignard reagent from any organic halide that contains a carbonyl, epoxy, nitro, or cyano group. –OH, O CH , –NH2, O CR , –NHR, O COR , –CO2H, O CNH2 , –NO2, –C≡N,
C O Grignard reagents containing these groups cannot be prepared. C

–SO3H,

–SH,

–C≡C–

This means that when we prepare Grignard reagents, we are effectively limited to alkyl halides or tro analogous organic halides containing C=C bonds, internal triple bonds, ether linkages, and –NR2 groups.
3. Grignard reactions are so sensitive to acidic compounds that special care must be taken to exclude moisture from the apparatus and anhydrous ether must be used as the solvent. 4. Acetylenic Grignard reagents:
~ 31 ~

C6H5C

CH + C2H5MgBr O

C6H5C

CMgBr + C2H6¡ô

C6H5C

CMgBr + C2H5CH

2. H3O (52 %)

+

C6H5C

C

CHC2H5 OH

5. Care must be taken in designing syntheses involving Grignard reagents ⇒ the reacting electrophile can not contain an acidic group. 1) The following reaction would take place when 4-hydroxy-2-butanone is treated with methylmagnesium bromide: CH3MgBr + HOCH2CH2CCH3 O 4-Hydroxy-2-butanone rather than: CH3 CH3MgBr + HOCH 2CH2CCH3 O HOCH 2CH2CCH3 OMgBr ¡ô CH4 + BrMgOCH2CH2CCH3 O

2) Two equivalents of methylmagnesium bromide can be utilized to effect the following reaction: CH3 CH3 2 CH3MgBr 2 NH4Cl HOCH2CH2CCH3 BrMgOCH2CH2CCH3 HOCH2CH2CCH3 H 2O − CH4 O OMgBr OH

12.8C THE USE OF LITHIUM REAGENTS
1. Organolithium reagents (Rli) react with carbonyl compounds in the same way as Grignard reagents.

~ 32 ~

R Li

δ−

δ+

+

C

O

R

C

O Li

H3O+

R

C

OH

Organolithium Aldehyde reagent or ketone

Lithium alkoxide

Alcohol

1) Organolithium reagents are somewhat more reactive than Grignard reagents.

12.8D THE USE OF SODIUM ALKYNIDES
1. Sodium alkynides react with aldehydes and ketones to yield alcohols.
NaNH2 −NH3 CH3 O H3CC C C CH3 ONa

H3CC CH3 CH3

CH

H3CC

CNa CH3 H3CC C C CH3 OH

H3CC

δ− δ+

C Na + C

H3O+

12.9 LITHIUM DIALKYLCUPERATES: THE COREY-POSNER, WHITESIDES-HOUSE SYNTHESIS
1. A highly versatile method for the synthesis of alkanes and other hydrocarbons from organic halides has been developed by E. J. Corey (Harvard University, Nobel Prize for Chemistry in 1990), G. H. Posner (The Johns Hopkins University), and by G. M. Whitesides (Harvard University) and H. O. House (Georgia Institute of Technology). R X + R' X several steps (− 2 X) R R'

1) The transformation of an alkyl halide into a lithium dialkylcuprate (R2CuLi) requires two steps: i) The alkyl halide is treated with lithium metal in an ether solvent to give an alkyllithium, RLi.
~ 33 ~

R

X + 2 Li

diethyl ether

RLi + LiX Alkyllithium

ii) Then the alkyllithium is treated with cuprous iodide (CuI) to furnish the lithium dialkylcuprate.
2 RLi + CuI Alkyllithium R2CuLi + LiI Lithium dialkylcuprate

2) One alkyl group of the lithium dialkylcuprate undergoes a coupling reaction with the second alkyl halide (R’–X) to afford an alkane. R2CuLi + R' X Lithium dialkylcuprate Alkyl halide i) R R' + Alkane RCu + LiX

For the last step to give a good yield of the alkane, the alkyl halide R’–X must be either a methyl halide, a 1° alkyl halide, or a 2° cycloalkyl halide.

ii) The alkyl groups of the lithium dialkylcuprate may be methyl, 1°, 2°, or 3°. iii) The two alkyl groups being coupled need not be different. 3) The overall scheme for this alkane synthesis: CuI R'X RLi R2CuLi Alkyllithium Lithium dialkylcuprate Li/Et2O R X An alkyl halide R' X A methyl, 1o alkyl, or 2o cycloalkyl halide R R' + RCu + LiX Alkane

There are organic strating materials. The R− and R'− groups need not be different. 4) Examples: H3C I Li Et2O CH3Li CuI (CH3)2CuLi CH3CH2CH2CH2CH2I H3C CH2CH2CH2CH2CH3 Hexane (98 %)

~ 34 ~

CH3CH2CH2CH2Br

Li Et2O

CH3CH2CH2CH2Li

CuI

(CH3CH2CH2CH2)2CuLi

CH3CH2CH2CH2CH2Br

H3CH2CH2CH2C CH2CH2CH2CH2CH3 Nonane (98 %)

2. Lithium dialkylcuprates couple with other organic groups: I + (CH3)2CuLi Et2O CH3 + Methylcyclohexane (75 %) Br + (CH3)2CuLi Et2O CH3 + CH3Cu + LiBr CH3Cu + LiI

3-Methylcyclohexene (75 %) 1) Lithium dialkylcuprates couple with phenyl and vinyl halides:

(CH3CH2CH2CH2)2CuLi + I

Et2O

H3CH2CH2CH2C Butylbenzene (75 %)

3. Summary of the coupling reactions of lithium dialkylcuprates:

~ 35 ~

CH3X or R'CH2X X

R

CH3 or R'CH2

R

R R2CuLi X R X R

12.10 PROTECTING GROUPS

12.11 SUMMARY OF REACTIONS

~ 36 ~

12.11A OVERALL SUMMARY OF REDUCTION REACTIONS (SECTION 12.3)
NaBH4 LiAlH4

O

OH H R
C

OH H R
C

Aldehydes

R

C

H

H O OH R' R
C

H OH R' R OH
C

Ketones

R

C

R'

H O

H R
C

Esters

R

C

OR'

—

H + HOR’ OH

H O

Carboxylic acids

R

C

OH

—

R

C

H

H
Hydrogens in blue are added during the reaction workup by water or aqueous acid.

12.11B OVERALL SUMMARY OF OXIDATION REACTIONS (SECTION 12.4)
Reactant
OH

PCC
O

H2CrO4
O H R C O R' R C R' OH R

KMnO4
O C O R C R' OH

1° alcohols

R

C H OH

H

R

C O

2° alcohols

R

C H OH

R'

R

C

3° alcohols

R

C R"

R'

—

—

—

~ 37 ~

12.11C FORMATION OF ORGANOLITHIUM AND GRIGNARD REAGENTS (SECTION 12.3)
R—X + 2 Li R—X + Mg R—Li + LiX R—MgX

12.11D REACTIONS OF GRIGNARD AND ORGANOLITHIUM REAGENTS (SECTION 12.7 AND 12.8)
HA O
1. 2. H3O+ (attack at least hindered carbon)

R

H + M+A−

R

C

C

OH

O
1. H C H 2. H3O
+

OH
H C H

O R M (M = Li or MgBr)
1. R' C H 2. H3O+ R'

R OH
C H

O
1. R' C R" 2. NH4Cl, H2O

R OH R
C R"

O
1. R' C OR"2. NH4Cl, H2O R'

R' OH C

R + HOR"

R

12.11E COREY-POSNER, WHITESIDE-HOUSE SYNTHESIS (SECTION 12.9)
2 RLi + CuI

R2CuLi

R' X (R' = 1o or 2o, cyclic)

R—R’ + RCu + LiX

~ 38 ~

CONJUGATED UNSATURATED SYSTEMS
MOLECULES WITH THE NOBEL PRIZE IN THEIR SYNTHETIC LINEAGE (ANCESTRY)
1. The Diels-Alder reaction: 1) Otto Diels and Kurt Alder won the Nobel Prize for Chemistry in 1950 for developing this reaction. 2) It can form a six-membered ring with as many as four new stereocenters created in a single stereospecific step from acyclic precursors. 3) It also produces a double bond that can be used to introduce other functionality. 2. Molecules that have been synthesized using Diels-Alder reaction include:

HO

MeO OMe N H H
H N CH3

N

MeO H

OMe

H

H MeO2C Reserpine OMe O O

HO

Morphine

O O CH3 H O H H O Cortisone CH3 CH2OH OH O CH3 H CH3 O CH2OH OH H H

1) Morphine (M. Gates): the hypnotic sedative used after many surgical procedures. 2) Reserpine (R. B. Woodward): a clinically used antipypertensive agent. 3) Chlesterol (R. B. Woodward): precursor of all steroids in the body.
~1~

Cortisone (R. B. Woodward): an antiinflammatory agent. 4) Prostaglandins F2α and E2 (E. J. Corey): members of a family of hormones that mediate blood pressure, smooth muscle contraction, and inflammation (Section 13.11D). 5) Vitamin B12 (A. Eschenmoser and R. B. Woodward): used in the production of blood and nerve cells (Section 4.20). 6) Taxol (K. C. Nicolaou): a potent cancer chemotherapy agent.

13.1 INTRODUCTION
1. Species that have a p orbital on an atom adjacent to a double bond: 1) The p orbital may have a single electron as in the allyl radical (CH2=CHCH2•). 2) The p orbital may be vacant as in the allyl cation (CH2=CHCH2+). 3) The p orbital may contain a pair of electrons as in the allyl anion (CH2=CHCH2:–). 4) It may be the p orbital of another double bond as in 1,3-butadiene (CH2=CH–CH=CH2). 2. Conjugated unsaturated systems: systems that have a p orbital on an atom adjacent to a double bond ––– molecules with delocalized π bonds. 3. Conjugation gives these systems special properties: 1) Conjugated radicals, ions, or molecules are more stable than nonconjugated ones. 2) Conjugated molecules absorb energy in the ultraviolet and visible regions of the electromagnetic spectrum. 3) Conjugation allows molecules to undergo unusual reactions.

13.2 ALLYLIC SUBSTITUTION AND THE ALLYL RADICAL
~2~

1. Addition of halogen to the double bond takes place when propene reacts with bromine or chlorine at low temperatures. low temperature CCl4 (addition reaction)

H 2C

CH CH3 + X2 Propene

H 2C X

CH CH3 X

2. Substitution occurs when propene reacts with bromine or chlorine at very high temperatures or under very low halogen concentration.

H2C

CH CH3 + X2 Propene

high temperature or low conc. of X2 (substitution reaction)

H2C

CH CH2X + HX

3. Allylic substitution: any reaction in which an allylic hydrogen atom is replaced.
H C H H C C H H H Allylic hydrogen atoms

13.2A ALLYLIC CHLORINATION (HIGH TEMPERATURE)
1. Propene undergoes allylic chlorination when propene and chlorine react in the gas phase at 400°C ––– the “Shell Process”.
400 oC gas phase

H 2C

CH CH3 + Cl2 Propene

H 2C

CH CH2Cl + HCl

3-Chloropropene (allyl chloride)

2. The mechanism for allylic substitution: 1) Chain-initiating Step
Cl Cl 2) First Chain-propagating Step
~3~

hν

2 Cl

H C H C H

H H CH Cl

H C H C

H + H Cl C H

H Allyl radical

3) Second Chain-propagating Step
H C H C CH2 Cl Cl H H C C H + Cl

H CH2 Cl Allyl chloride

3. Bond dissociation energies of C–H bonds: CH2=CHCH2—H Propene (CH3)3C—H Isobutane (CH3)2CH—H Propane CH3CH2CH2—H Propane CH2=CH—H Ethene CH2=CHCH2• + Allyl radical (CH3)3C• + 3° Radical H• H• H• H•

∆H° = 360 kJ mol–1 ∆H° = 380 kJ mol–1 ∆H° = 395 kJ mol–1 ∆H° = 410 kJ mol–1 ∆H° = 452 kJ mol–1

(CH3)2CH• + 2° Radical

CH3CH2CH2• + 1° Radical CH2=CH• + Vinyl radical H•

1) An allylic C–H bond of propene is broken with greater ease than even the 3° C–H bond of isobutene and with far greater ease than a vinylic C–H bond.

H 2C

CH

CH2

H + X

H 2C

CH

CH2

+ H X

Eact is low

H 3C

CH

CH

H + X

H 3C

CH

CH

+ H X

Eact is high

~4~

Figure 13.1 The relative stability of the allyl radical compared to 1°, 2°, 3°, and vinyl radicals. (The stabilities of the radicals are relative to the hydrocarbon from which was formed, and the overall order of stability is allyl > 3° > 2° > 1° > vinyl). 2) Relative stability of radicals: allylic or allyl > 3° > 2° > 1° > vinyl or vinylic

13.2B ALLYLIC BROMINATION WITH N-BROMOSUCCINIMIDE (LOW CONCENTRATION OF Br2)
1. Propene undergoes allylic bromination when treated with N-bromosuccinimide (NBS) in CCl4 in the presence of peroxides or light. O CH2 CH CH3 + N Br light or ROOR CCl4 CH2 CH CH2Br + O N H O Succinimide

O N-Bromosuccinimide (NBS)

3-Bromopropene (allyl bromide)

1) The reaction is initiated by the formation of a small amount of Br•. 2) The main propagation steps:
~5~

H2C

CH

CH2

H + Br

H2C H 2C

CH

CH2 CH2

+ H Br

H 2C

CH

CH2 + Br

Br

CH

Br + Br

3) NBS is nearly insoluble in CCl4 and provides a constant but very low concentration of bromine in the reaction mixture. i) NBS reacts very rapidly with the HBr formed in the substitution reaction ⇒ each molecule of HBr is replaced by one molecule of Br2. O N Br + HBr O O N H + Br2 O

ii) In a nonpolar solvent and with a very low concentration of bromine, very little bromine adds to the double bond; it reacts by substitution and replaces an

allylic hydrogen atom. 2. Why does a low concentration of bromine favor allylic substitution over addition? 1) The mechanism for addition of Br2 to a double bond:

Br

Br +

C C

+

Br

C C

+ Br−

C Br C

Br

i)

In the first step only one atom of the bromine molecule becomes attached to the alkene in a reversible step.

ii) The other atom (now the bromide ion) becomes attached in the second step. iii) If the concentration of bromine is low, the equilibrium for the first step will lie far to the left. Even when the bromonium ion forms, the probability of its
~6~

finding a bromide ion in its vicinity is low. ⇒ These two factors slow the addition so that allylic substitution competes successfully. 2. The use of a nonpolar solvent slows addition. 1) There are no polar solvent molecules to solvate (and thus stabilize) the bromide ion formed in the first step, the bromide ion uses a bromine molecule as a substitute. ⇒ In a nonpolar solvent the rate equation is second order with respect to bromine. C C nonpolar solvent C C

2 Br2 +

+

Br

− + Br3

rate = k

C C

[Br2]2

i)

The low bromine concentration has a more pronounced effect in slowing the rate of addition.

3. Why a high temperature favors allylic substitution over addition? 1) The addition reaction has a substantial negative entropy change ⇒ At low temperatures, the T∆S° term in ∆G° = ∆H° – T∆S°, is not large enough to offset the favorable ∆H° term. 2) At high temperatures, the T∆S° term becomes more significant, ∆G° becomes more positive ⇒ the equilibrium becomes more unfavorable.

13.3 THE STABILITY OF THE ALLYL RADICAL
13.3A MOLECULAR ORBITAL DESCRIPTION OF THE ALLYL RADICAL
1. As the allylic hydrogen atom is abstracted from propene, the sp3-hybridized carbon atom of the methyl group changes its hybridization state to sp2.
~7~

1) The p orbital of this new sp2-hybridized carbon atom overlaps with the p orbital of the central carbon atom ⇒ in the allyl radical three p orbitals overlap to form a set of π MOs that encompass all three carbon atoms. 2) The new p orbital of the allyl radical is conjugated with those of the double bond ⇒ the allyl radical is a conjugated unsaturated system.
+ δ X +

sp2 Hybridized

H

C 1 H

C

H
2 3C

X

H H C 1 C δC 2 3 H H H C 1 H C
2 3C

H

H 3 sp Hybridized

H

H H

3) The unpaired electron of the allyl radical and the two electrons of the π bond are delocalized over all three carbon atoms.

i)

This delocalization of the unpaired electron accounts for the greater stability of the allyl radical when compared to 1°, 2°, and 3° radicals.

ii) Although some delocalization occurs in 1°, 2°, and 3° radicals, delocalization is not as effective because it occurs through σ bonds.
6-11-02

2. Formation of three π MOs of the allyl radical: 1) The bonding π MO is of lowest energy ⇒ it encompasses all three carbon atoms and is occupied by two spin-paired electrons. i) The bonding π orbital is the result of having p orbitals with lobes of the same sign overlap between adjacent carbon atoms ⇒ increases the π electron density in the regions between the atoms. 2) The nonbonding π orbital is occupied by one unpaired electron, and it has a node at the central carbon atom ⇒ the unpaired electron is located in the vicinity of carbon 1 and 3 only. 3) The antibonding π MO results when orbital lobes of opposite sign overlap between adjacent carbon atoms ⇒ there is a node between each pair of carbon atoms.
~8~

i)

The antibonding orbital of the allyl radical is of highest energy and is empty in the ground state of the radical.

Figure 13.2 Combination of three atomic p orbitals to form three π molecular orbitals in the allyl radical. The bonding π molecular orbital is formed by the combination of the three p orbitals with lobes of the same sign overlapping above and below the plane of the atoms. The nonbonding π molecular orbital has a node at C2. The antibonding π molecular orbital has two nodes: between C1 and C2, and between C2 and C3. The shapes of molecular orbitals for the allyl radical calculated using quantum mechanical principles are shown alongside the schematic orbitals.

3. The structure of allyl radical given by MO theory:
H H
1/2

C H

1

C

2

3 H C 1/2

H

1) The dashed lines indicate that both C–C bonds are partial double bonds ⇒ there is a π bond encompassing all three atoms.

i)

The symbol 1/2• besides the C1 and C3 atoms ⇒ the unpaired electron spends
~9~

its time in the vicinity of C1 and C3 ⇒ the two ends of allyl radical are equivalent.

13.3B RESONANCE DESCRIPTION OF THE ALLYL RADICAL
1. Resonance structures of the allyl radical: H H C H
1

H
2

H C H H H C H
1

H
2

C

C H

3

H

H

C H

C

C

C H

3

H

⇒

H
1/2

C H

1

C

2

3 H C 1/2

A

B

C

H

1) Only the electrons are moved but not the atomic nuclei. i) In resonance theory, when two structures can be written for a chemical entity that differ only in the positions of the electrons, the entity can not be

represented by either structure alone but is a hybrid of both. ii) Structure C blends the features of both resonance structures A and B. iii) The resonance theory gives the same structure of the allyl radical as in the MO approach ⇒ the C–C bonds of the allyl radical are partial double bonds and the unpaired electron is associated only with C1 and C3 atoms. iv) Resonance structures A and B are equivalent ⇒ C1 and C3 are equivalent. 2) The resonance structure shown below is not a proper resonance structure because resonance theory dictates that all resonance structures must have the same number of unpaired electrons.

i)

This structure indicates that an unpaired electron is associated with C2. CH2 CH CH2 (an incorrect resonance structure)

2. In resonance theory, when equivalent structures can be written for a chemical species, the chemical species is much more stable than any resonance structure (when taken alone) would indicate.

1) Either A or B alone resembles a 1° radical.
~ 10 ~

2) Since A and B are equivalent resonance structures, the allyl radical should be much more stable than either, that is, much more stable than a 1° radical ⇒ the allyl radical is even more stable than a 3° radical.

13.4 THE ALLYL CATION
1. The allyl cation (CH2=CHCH2+) is an unusually stable carbocation ⇒ it is more stable than a 2° carbocation and is almost as stable as a 3° carbocation.

1) The relative order of carbocation stability:
C C C C H
+

C CHCH2 > C
+

H C+ > CH2 H CH
+

C

>C

C + > CH2 C

C+ > C H

Substituted allylic >

3° >

Allyl

>

2°

>

1°

>

Vinyl

1. MO description of the allyl cation:

~ 11 ~

Figure 13.3 The π molecular orbitals of the allyl cation. The allyl cation, like the allyl radical, is a conjugated unsaturated system. The shapes of molecular orbitals for the allyl cation calculated using quantum mechanical principles are shown alongside the schematic orbitals.
1) The bonding π molecular orbital of the allyl cation contains two spin-paired electrons. 2) The nonbonding π molecular orbital of the allyl cation is empty. 3) Removal of an electron from an allyl radical gives the allyl cation ⇒ the electron is removed from the nonbonding π molecular orbital.

CH2 i)

CHCH2

CH2

CHCH2

+

Removal of an electron from a nonbonding orbital requires less energy than removal of an electron from a bonding orbital.

ii) The positive charge on the allyl cation is effectively delocalized between C1 and C3. iii) The ease of removal of a nonbonding electron and the delocalization of charge account for the unusual stability of the allyl cation in MO theory.

2. Resonance theory depicts the allyl cation as a hybrid of structures D and E: H H C H
1

H
2

H
2

C

C+ H

3

H

H

+C

1

C

C H

3

H

H

1/2 +C

1

C

2

C 1/2 + H

3

H

D

H

E

H

F

1) D and E are equivalent resonance structures ⇒ the allyl cation should be unusually stable. 2) The positive charge is located on C3 in D and on C1 in E ⇒ the positive charge is delocalized over both carbon atoms and C2 carries none of the positive charge. 3) The hybrid structure F includes charge and bond features of both D and E.

~ 12 ~

13.5 SUMMARY OF RULES FOR RESONANCE
13.5A RULES FOR WRITING RESONANCE STRUCTURES
1. Resonance structures exist only on paper.

1) Resonance structures are useful because they allow us to describe molecules, radicals, and ions for which a single Lewis structure is inadequate. 2) Resonance structures or resonance contributors are connected by double-headed arrows (↔) ⇒ the real molecule, radical, or ion is a hybrid of all of them.
2. In writing resonance structures, only electrons are allowed to be moved.

1) The positions of the nuclei of the atoms must remain the same in all of the structures.
CH3 CH CH 1
+

CH2

CH3 CH CH 2

CH2

+

CH2 CH2 CH 3

+

CH2

These are resonance structures for the allylic cation formed when 1,3-butadiene accepts a prooton.

This is not a proper resonance structure for the allylic cation because a hydrogen atom has been moved.

2) Only the electrons of π bonds and those of lone pairs are moved. 3. All of the structures must be proper Lewis structures.
H H C
−

O

+

H

This not a proper resonance structure for methanol because carbon has five bonds. Elements of the first major row of the periodic table cannot have more than eight electrons in their valence.

H

4. All structures must have the same number of unpaired electrons. CH CH

H2C

CH2

H2C

CH2

This is not a proper resonance structure for the allyl radical because it does not contain the same number of unpaired electrons as CH2=CHCH2•.
~ 13 ~

5. All atoms that are a part of the delocalized system must be in a plane or be nearly planar. 1) 2,3-Di-tert-butyl-1,3-butadiene behaves like a nonconjugated dienes because the bulky tert-butyl groups twist the structure and prevent the double bonds from lying in the same plane ⇒ the p orbitals at C2 and C3 do not overlap and delocalization (and therefore resonance) is prevented.

(H3C)3C C H2C C

CH2 C(CH3)3

6. The energy of the actual molecule is lower than the energy that might be estimated for any contributing structure.
1) Structures 4 and 5 resembles 1° carbocations and yet the allyl cation is more stable than a 2° carbocation ⇒ resonance stabilization.
CH2 CH 4 CH2
+

CH2

+

CH 5

CH2

or Resonance structures for benzene Representation of hybrid

7. Equivalent resonance structures make equal contributions to the hybrid, and a system described by them has a large resonance stabilization. 8. For nonequivalent resonance structures, the more stable a structure is the greater is its contribution to the hybrid. 1) Structures that are not equivalent do not make equal contributions. 2) Cation A is a hybrid of structures 6 and 7. i) Structure 6 makes greater contribution than 7 because 6 is a more stable 3° carbocation while 7 is a 1° cation.
~ 14 ~

CH3 CH3 a CH3 CH c CH3 CH CH2 CH3 C 7 CH CH2
+

δ+

C

b

A

δ+

CH2

d

CH3

C
+

6

ii) Structure 6 makes greater contribution means that the partial positive charge on carbon b of the hybrid will be larger than the partial positive charge on carbon

d. iii) It also means that the bond between carbon atoms c and d will be more like a double bond than the bond between carbon atoms b and c.

13.5B ESTIMATING THE RELATIVE STABILITY OF RESONANCE STRUCTURES
1. The more covalent bonds a structure has, the more stable it is. CH2 CH 8 This is structure is the most stable because it contains more covalent bonds. 2. Structures in which all of the atoms have a complete valence shell of electrons are especially stable and make large contributions to the hybrid. 1) Structure 12 makes a larger stabilizing contribution to the cation below than 11 because all of the atoms of 12 have a complete valence shell. i) 12 has more covalent bonds than 11. H2C
+

CH

CH2

−

CH2

CH 9

CH

CH2

+

CH2

+

CH CH 10

CH2

−

O

CH3

H2C

O

+

CH3

11 This carbon atom has only six electrons. 3. Charge separation decreases stability.

12 The carbon atom has eight electrons.

1) Separating opposite charges requires energy.
~ 15 ~

i)

Structures in which opposite charges are separated have greater energy than those that have no charge separation.
−

H2C

CH Cl 13

CH2

CH 14

Cl

13.6 ALKADIENES AND POLYUNSATURATED HYDROCARBONS
1. Alkadiene and alkatriene ⇒ diene and triene; alkadiyne and alkenyne ⇒ diyne and enyne. CH2 C CH2 1,2-Propadiene (allene)
1 2 3

CH2 CH CH CH2 1,3-Butadiene

1

2

3

4

HC

5

C CH2 CH CH2 1-Penten-4-yne
H C4
3C 1 CH3

4

3

2

1

H

H3C 6 C
4

C

3

H CH
2

5C

C

4

H C
3 2

H 3C 6 H
1
5C

H3C 5 (3Z)-1,3-Pentadiene (cis-1,3-pentadiene)
H3C 1
2C

CH2

1

H

C

H

C2

CH3 H (2E,4E)-2,4-Hexadiene (trans,trans-2,4-hexadiene)

H H (2Z,4E)-2,4-Hexadiene (cis,trans-2,4-hexadiene)

H C3
4C

H C5
6C

H

H C7

2 1 6 5 3 4 2 1

3 4 5 6

H

8 CH3 H (2E,4E,6E)-2,4,6-Octatriene (trans,trans,trans-2,4,6-octatriene)

1,3-Cyclohexadiene 1,4-Cyclohexadiene

2. The multiple bonds of polyunsaturated compounds are classified as being cumulated, conjugated, or isolated.

1) The double bonds of allene are said to be cumulated because one carbon (the central carbon) participates in two double bonds. i) Hydrocarbons whose molecules have cumulated double bonds are called cumulenes. ~ 16 ~

ii) The name allene is used as a class name for molecules with two cumulated double bonds.
CH2=C=CH2

C

C

C

Allene

A cumulated diene

iii) Appropriately substituted allenes give rise to chiral molecules. iv) Cumulated dienes have had some commercial importance, and cumulated double bonds are occasionally found in naturally occurring molecules. vi) In general, cumulated dienes are less stable than isolated dienes. 2) An example of a conjugated diene is 1,3-butadiene. i) In conjugated polyenes the double and single bonds alternate along the chain.
C C C C

CH2=CH—CH=CH2 1,3-Butadiene

A cconjugated diene

3) If one or more saturated carbon atoms intervene between the double bonds of an alkadiene, the double bonds are said to be isolated.

C

C

C

C

(CH2)n An isolated diene (n ≠ 0) i)

CH2=CH—CH2—CH=CH2 1,4-Pentadiene

The double bonds of isolated double dienes undergo all of the reactions of alkenes.

13.7 1,3-BUTADIENE:

ELECTRON DELOCALIZATION

13.7A BOND LENGTH OF 1,3-BUTADIENE
~ 17 ~

1. The bond length of 1,3-butadiene:
CH2 CH CH CH2 1.34 Å 1.47 Å 1.34 Å 1) The C1―C2 bond and the C3―C4 bond are (within experimental error) the same length as the C–C double bond of ethene. 2) The central bond of 1,3-butadiene (1.47 Å) is considerably shorter than the single bond of ethane (1.54 Å). i) All of the carbon atoms of 1,3-butadiene are sp2 hybridized ⇒ the central bond results from overlapping sp2 orbitals. ii) A σ bond that is sp3-sp3 is longer ⇒ the central bond results from overlapping sp2 orbitals.
1 2 3 4

3) There is a steady decrease in bond length of C–C single bonds as the hybridization state of the bonded atoms changes from sp3 to sp.

Table13.1

Carbon-Carbon Single Bond Lengths and Hybridization State Hybridization State sp3-sp3 Sp2-sp3 Sp2-sp2 sp-sp3 sp-sp2 sp-sp

Compound
H3C―CH3 H2C=CH―CH3 H2C=CH―CH=CH2 HC≡C―CH3 HC≡C―CH=CH2 HC≡C―C≡CH

Bond Length (Å)
1.54 1.50 1.47 1.46 1.43 1.37

13.7B CONFORMATIONS OF 1,3-BUTADIENE
1. There are two possible planar conformations of 1,3-butadiene: the s-cis and the s-trans conformations.

rotate about 3 C2−C3 s-cis Conformation of 1,3-butadiene s-trans Conformation of 1,3-butadiene
~ 18 ~

2

3

2

1) The s-trans conformation of 1,3-butadiene is the predominant one at room temperature.

13.7C MOLECULAR ORBITALS OF 1,3-BUTADIENE
1. The central carbon atoms of 1,3-butadiene are close enough for overlap to occur between the p orbitals of C2 and C3.

Figure 13.4 The p orbitals of 1,3-butadiene, stylized as spheres. (See Figure 13.5 for the shapes of calculated molecular orbitals for 1,3-butadiene.) 1) This overlap is not as great as that between the orbitals of C1 and C2. 2) The C2–C3 overlap gives the central bond partial double bond character and allows the four π electrons of 1,3-butadiene to be delocalized over all four atoms. 2. The π molecular orbitals of 1,3-butadiene: 1) Two of the π molecular orbitals of 1,3-butadiene are bonding molecular orbitals. i) In the ground state these orbitals hold the four π electrons with two spin-paired electrons in each. 2) The other two π molecular orbitals are antibonding molecular orbitals. i) In the ground state these orbitals are unoccupied.

3) An electron can be excited from the highest occupied molecular orbital (HOMO) to the lowest unoccupied molecular orbital (LUMO) when 1,3-butadiene absorbs light with wavelength of 217 nm.

~ 19 ~

Figure 13.5 Formation of the π molecular orbitals of 1,3-butadiene from four isolated p orbitals. The shapes of molecular orbitals for 1,3-butadiene calculated using quantum mechanical principles are shown alongside the schematic orbitals.

13.8 The Stability of Conjugated Dienes
1. Conjugated alkadienes are thermodynamically more stable than isolated alksdienes. Table13.2 Heats of Hydrogenation of Alkenes and Alkadienes H2 (mol) 1 1 1 2 2 2 2
~ 20 ~

Compound 1-Butene 1-Pentene trans-2-Pentene ∆H° (kJ mol–1) –127 –126 –115 –239 –226 –254 –253

1,3-Butadiene trans-1,3-Pentadiene 1,4-Pentadiene 1,5-Hexadiene

2. Comparison of the heat of hydrogenation of 1,3-butadiene and 1-butene:
∆H° (kJ mol–1)

2 CH2=CHCH2CH3 + 2 H2 1-Butene CH2=CHCH=CH2 + 2 H2 1,3-Butadiene

2 CH3CH2CH2CH3

(2 × –127) = –254

2 CH3CH2CH2CH3

= –239 Difference 15 kJ mol–1

1) Hydrogenation of 1,3-butadiene liberates 15 kJ mol–1 less than expected ⇒ conjugation imparts some extra stability to the conjugated system.

Figure 13.6 Heats of hydrogenation of 2 mol of 1-butene and 1 mol of 1,3-butadiene. 3. Assessment of the conjugation stabilization of trans-1,3-pentadiene: CH2=CHCH2CH3 1-Pentene CH3CH2 C H H2C CH C H C CH3 C CH3 H
∆H° = –226 kJ mol–1 ∆H° = –126 kJ mol–1

H
∆H° = –115 kJ mol–1

Sum = –241 kJ mol–1

trans-2-Pentene

Diffference = –15 kJ mol–1
~ 21 ~

trans-1,3-Pentadiene

1) Conjugation affords trans-1,3-pentadiene an extra stability of 15 kJ mol–1 ⇒

conjugated dienes are more stable than isolated dienes.
4. What is the source of the extra stability associated with conjugated dienes?. 1) In part from the stronger central bond that they contain (sp2-sp2 C–C bond). 2) In part from the additional delocalization of the π electrons that occurs in conjugated dienes.

13.9 ULTRAVIOLET-VISIBLE SPECTROSCOPY
13.9A UV-VIS SPECTROPHOTOMERS

13.9B ABSORPTION MAXIMA FOR NONCONJUGATED AND CONJUGATED DIENES 13.9C ANALYTICAL USES OF UV-VIS SPECTROSCOPY

13.10 ELECTROPHILIC ATTACK ON CONJUGATED DIENES: 1,4-ADDITION
1. 1,3-butadiene reacts with one molar equivalent of HCl to produce two products: 3-chloro-1-butene and 1-chloro-2-butene. CH2 CH CH CH2 HCl 25 oC CH3 CH CH CH2 + CH3 CH CH CH2

1,3-Butadiene 1) 1,2-Addition:

Cl 3-Chloro-1-butene

Cl 1-Chloro-2-butene

~ 22 ~

CH2

1

CH CH + H Cl

2

3

CH2

4

1,2-addition

CH2 H

CH CH

CH2

Cl 3-Chloro-1-butene

2) 1,4-Addition: CH2
1

CH CH + H Cl

2

3

CH2

4

1,4-addition

CH2 H

CH CH

CH2

Cl 1-Chloro-2-butene

2. 1,4-Addition can be attributed directly to the stability and delocalized nature of allylic cation. 1) The mechanism for the addition of HCl:

Step 1

CH2

CH CH H Cl

CH2

CH3 CH CH
+

CH2

− CH3 CH CH CH2 + Cl

+

An allylic cation equivalent to CH3 CH CH CH2 δ+ δ+

Step 2 δ+ (a) CH CH2 + Cl − (b) δ+ CH2 H CH2 H

CH CH Cl CH CH

CH2 1,2-Addition CH2 1,4-Addition Cl

CH3 CH (a)

(b)

2) In step 1, a proton adds to one of the terminal carbon atoms of 1,3-butadiene to form the more stable carbocation ⇒ a resonance stabilized allylic cation. i) Addition to one of the inner carbon atoms would have produced a much less 1° cation, one that could not be stabilized by resonance.

CH2

CH CH H Cl

CH2

X

CH2 CH2 CH
+

CH2 + Cl −

A 1o carbocation

~ 23 ~

3. 1,3-Butadiene shows 1,4-addition reactions with electrophilic reagents other than HCl. CH2=CHCH=CH2

HBr 40oC Br2

CH3CHBrCH=CH2 + CH3CH=CHCH2Br (20%) (80%)

CH2=CHCH=CH2

−15oC

CH2BrCHBrCH=CH2 + CH2BrCH=CHCH2Br (54%) (46%)

4. Reactions of this type are quite general with other conjugated dienes. 1) Conjugated trienes often show 1,6-addition. Br Br2 CHCl3 (>68%) Br

13.10A KINETIC CONTROL VERSUS THERMODYNAMIC CONTROL OF A CHEMICAL REACTION
1. The relative amounts of 1,2- and 1,4-addition products obtained from the addition of HBr to 1,3-butadiene are dependent on the reaction temperature. 1) When 1,3-butadiene and HBr react at a low temperature (–80 °C) in the absence of peroxides, the major reaction is 1,2-addition ⇒ 80% of the 1,2-product and only 20% of the 1,4-product. 2) At higher temperature (40 °C) the result is reversed: the major reaction is 1,4-addition ⇒ 80% of the 1,4-product and only about 20% of the 1,2-product. 3) When the mixture formed at the lower temperature is brought to higher temperature, the relative amounts of the two products change. i) This new reaction mixture eventually contains the same proportion of products given by the reaction carried out at the higher temperature.

~ 24 ~

−80oC CH2 CHCH CH2 + HBr 40 C o CH3CHCH Br (80%) CH3CHCH Br (20%)

CH2 + CH3CH 40oC

CHCH2 Br

(20%)

CH2 + CH3CH

CHCH2 Br

(80%)

ii) At the higher temperature and in the presence of HBr, the 1,2-adduct rearranges to 1,4-product and that an equilibrium exists between them.

CH3CHCH

CH2

40oC, HBr

CH3CH

CHCH2

Br 1,2-Addition product

Br 1,4-Addition product

iii) The equilibrium favors the 1,4-addition product ⇒ 1,4-adduct must be more stable. 2. The outcome of a chemical reaction can be determined by relative rates of competing reactions and by relative stabilities of the final products. 1) At lower temperature, the relative amounts of the products of the addition are determined by the relative rates at which the two additions occur; 1,2-addition occurs faster so the 1,2-addition product is the major product. 2) At higher temperature, the relative amounts of the products of the addition are determined by the position of an equilibrium; 1,4-addition product is the more stable, so it is the major product. 3) The step that determines the overall outcome of the reaction is the step in which the bybrid allylic cation combines with a bromide ion:
Br− CH3 CH δ+ CH3CHCH

CH2

CH HBr

CH2 Br− CH2

δ+

Br 1,2 Product CH3CH CHCH2 Br 1,4 Product
~ 25 ~

This step determines the regioselectivity of the reaction.

CH2

CHCH

Figure 13.10 A schematic free-energy versus reaction coordinate diagram for the 1,2 and 1,4 addition of hbr to 1,3-butadiene. An allylic carbocation is common to both pathways. The energy barrier for attack of bromide on the allylic cation to form the 1,2-addition product is less than that to form the 1,4-addition product. The 1,2-addition product is kinetically favored. The 1,4-addition product is more stable, and so it is the thermodynamically favored product.

~ 26 ~

Special Topic A

CHAIN-GROWTH POLYMERS
A.1 INTRODUCTION
A.1A POLYMER AGE
1. 石器時代 ⇒ 陶器時代 ⇒ 銅器時代 ⇒ 鐵器時代 ⇒ 聚合物時代 1) The development of the processes by which synthetic polymers are made was responsible for the remarkable growth of the chemical industry in the twentieth century. 2) Although most of the polymeric objects are combustible, incineration is not always a feasible method of disposal because of attendant air pollution ⇒ “Biodegradable plastics”.

聚合物材料與結構材料比較表
伸張強度 1 鋁合金 鋼(延伸) Kevlar® 聚乙烯 1. 相對於鋁合金 2. Kevlar®﹕ 聚對苯二甲醯對二胺基苯 1.0 5.0 5.4 5.8 單位重量伸張強度 1 1.0 1.7 10.0 15.0

~1~

一些簡單的聚合物 ––– 顯示聚合物可配合各種需求
R1 R2 R1 R2 R1 R2

R3 R1, R2, R3, R4 H, H, H, H

R4
名稱

R3

R4

n

R3
產品

R4 1982 年美國產量 5,700,000 公噸

聚乙烯 (Polyethylene) 聚四氯乙烯 (Teflon) (Polytetrafluoroethylene) 聚丙烯 (Polypropylene) 聚氯乙烯 (Polyvinylchloride)

塑膠袋；瓶 子；玩具 廚具；絕緣 地毯(室內、室 外)；瓶子 塑膠膜；唱 片；水電管 絕緣 (隔熱)；

F, F, F, F

H, H, H, CH3

1,600,000 公噸

H, H, H, Cl

2,430,000 公噸

H, H, H, C6H5

聚苯乙烯 (Polystyrene)

傢俱；包裝材 料

2,326,000 公噸

H, H, H, CN

聚丙烯氰 (Polyacrylonitrile) 聚乙酸乙烯酯 (Polyvinyl acetate) 聚二氯乙烯 (Polyvinylidine chloride)

毛線；編織 物；假髮 黏著劑；塗 料；磁碟片 食物包裝材料

920,000 公噸

H, H, H, OCOCH3

500,000 公噸

H, H, Cl, Cl

(如 Saran®)

H, H, CH3, COOCH3

玻璃替代物； 聚甲基丙烯酸甲酯 (Polymethyl methacrylate) 保齡球；塗料

~2~

A.1B NATURALLY OCCURRING POLYMERS
1. Proteins –– silk, wool. 2. Carbohydrates (polysaccharides) –– starches, cellulose of cotton and wood.

~3~

A.1C CHAIN-GROWTH POLYMERS
1. Polypropylene is an example of chain-growth polymers (addition polymers): polymerization

H 2C

CH CH3

CH2CH CH3

CH2CH CH3 n CH2CH CH3

Propylene

Polypropylene

A.1D MECHANISM OF POLYMERIZATION
1. The addition reactions occur through radical, cationic, or anionic mechanisms: 1) Radical Polymerization

C C R + C C R C C R C C C C

C C etc.

2) Cationic Polymerization

C C R+ + C C R C C+ R C C C C+

C C etc.

3) Anionic Polymerization

C C Z:−+ C C Z C C:− Z C C C C:−

C C etc.

~4~

A.1E RADICAL POLYMERIZATION
1. Poly(vinyl chloride) (PVC): n H 2C CH CH2CH Cl n Poly(vinyl chloride) (PVC)

Cl Vinyl chloride

1) PVC has a molecular weight of about 1,500,000 and is a hard, brittle, and rigid. 2) PVC is used to make pipes, rods, and compact discs. 3) PVC can be softened by mixing it with esters (called plasticizers). i) The softened material is used for making “vinyl leather”, plastic raincoats, shower curtains, and garden hoses. 4) Exposure to vinyl chloride has been linked to the development of a rare cancer of the liver called angiocarcinoma [angiotensin: 血管緊張素、血管緊張； carcinoma: 癌] (first noted in 1974 and 1975 among workers in vinyl chloride factories). i) Standards have been set to limit workerrs’ exposure to less than one part per million (ppm) average over an 8-h day. ii) The US Food and Drug Administration (FDA) has banned the use of PVC in packing materials for food. 2. Polyacrylonitrile (Orlon):

n H 2C

CH

FeSO4 H−O−O−H

CH2CH CN n Polyacrylonitrile (Orlon)

CN Acrylonitrile

1) Polyacrylonitrile decomposes before it melts ⇒ melt spinning cannot be used for the production of fibers.
~5~

2) Polyacrylonitrile is soluble in N,N-dimethylformamide (DMF) ⇒ the solution can be used to spin fibers. 3) Polyacrylonitrile fibers are used in making carpets and clothing. 3. Polytetrafluoroethylene (Teflon, PTFE): n F2C FeSO4 H−O−O−H CF2CF2

CF2

n

Tetrafluoroethylene

Polyetrafluoroethylene (Teflon)

1) Teflon is made by polymerizing tetrafluoroethylene in aqueous suspension. 2) The reaction is highly exothermic ⇒ water helps to dissipate the heat that is produced. 3) Teflon has a melting point (327 °C) that is unusually high for an addition polymer. 4) Teflon is highly resistant to chemical attack and has a low coefficient of friction ⇒ Teflon is used in greaseless bearings, in liners for pots and pans, and in many special situations that require a substance that is highly resistant to corrosive chemicals. 4. Poly(vinyl alcohol):

n H2C

CH O C

CH2CH O O C On Poly(vinyl acetate) H3C

HO− H 2O

CH2CH OH n

H3C

Vinyl acetate

Polyvinyl alcohol

1) Vinyl alcohol is an unstable compound that tautomerizes spontaneously to acetaldehyde.

H2C

CH

H3C

CH

OH Vinyl alcohol
~6~

O Acetaldehyde

i)

Poly(vinyl alcohol), a water-soluble polymer, cannot be made directly ⇒ polymerization of vinyl acetate to poly(vinyl acetate) followed by hydrolysis to poly(vinyl alcohol).

ii) The hydrolysis is rarely carried to completion because the presence of a few ester groups helps confer water solubility of the product. iii) The ester groups apparently helps keep the polymer chain apart, and this permits hydration of the hydroxyl groups. 2) Poly(vinyl alcohol) in which 10% of the ester groups remain dissolves readily in water. 3) Poly(vinyl alcohol) is used to manufacture water-soluble films and adhesives. 4) Poly(vinyl acetate) is used as an emulsion in water-based paints. 5. Poly(methyl methacrylate):
CH3 n H2C H3CO C C O CH3 CH2C C H3CO O n Methyl methacrylate

Poly(methyl methacrylate)

1) Poly(methyl methacrylate) has excellent optical properties and is marketed under the names Lucite, Plexiglas, and Perspex. 6. Copolymer of vinyl chloride and vinylidene chloride:

Cl H2C C + H2C CH R Cl Cl Vinylidene chloride Vinyl chloride (excess)

Cl CH2 C CH2CH

Cl Cl Saran Wrap

1) Saran Wrap used in food packing is made by polymerizing a mixture in which the vinylidene chloride predominates.
~7~

~8~

A.1F CATIONIC POLYMERIZATION
1. Alkenes polymerize when they are treated with strong acids:
Step 1 H

O + BF3 H

H

O H

+

BF3 CH3 H3C C+ CH3

−

Step 2 H

O H

+

BF3 + H2C

−

CH3 C CH3

CH3
Step 3 H3C

CH3 C CH3
CH3

CH3H H 3C C C

CH3 C+ CH3

C+

+ H 2C

CH3
Step 4

CH3H

CH3H H 3C C C

CH3 C+ CH3

H2C

C CH3

CH3H H 3C C C

CH3H C C

CH3 C+ CH3

etc.

CH3H

CH3H

CH3H

1) The catalysts used for cationic polymerizations are usually Lewis acids that contain a small amount of water.

A.1G ANIONIC POLYMERIZATION
1. Alkenes containing electron-withdrawing groups polymerize in the presence of strong bases:
H2N
−

+ H 2C
CH2

CH CN

NH3

H2N

CH2

CH CN

−

H2N

CH2

CH CN

−

CHCN H2N

CH2

CH CH2 CN

CH CN

−

etc.

1) Anionic polymerization of acrylonitrile is less important in commercial production than the radical process.
~9~

A.2 STEREOCHEMISTRY OF CHAIN-GROWTH POLYMERIZATION
1. Head-to-tail polymerization of propylene produces a polymer in which every other atom is a stereocenter. 2. Many of the physical properties of propylene produced in this way depend on the stereochemistry of these stereocenters.

CH2

CH CH3

polymerization (head to tail)

CH2CHCH2CHCH2CHCH2CH CH3 CH3 CH3 CH3

¡¯

¡¯

¡¯

¡¯

A.2A ATACTIC POLYMERS
1. The stereochemistry at the stereocenters is random, the polymer is said to be atactic (a, without + Greek: taktikos, order).

H H H H3C H

H H H CH3 H3C H

H

H CH3 H H

H H H CH3

H CH3 H H H CH3

CH3

H CH3

H H CH3

H CH3 H3C H

Figure 10.1 Atactic polypropylene. chain is used for clarity.

(In this illustration a “stretched” carbon

1) In atactic polypropylene the methyl groups are randomly disposed on either side of the stretched carbon chain ⇒ (R-S) designations along the chain is random. 2) Polypropylene produced by radical polymerization at high pressure is atactic. 3) Atactic polymer is noncrystalline ⇒ it has a low softening point and has poor mechanical properties.

A.2B SYNDIOTACTIC POLYMERS
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1. The stereochemistry at the stereocenters alternates regularly from one side of the stretched chain to the other is said to be syndiotactic (syndio: two together) ⇒ (R-S) designations along the chain would alternate (R), (S), (R), (S), (R), (S) and ao on. H H H H3C H H CH3 H H H CH3 H H H CH3 H H H CH3 H H H CH3 H H CH3 H CH3

H CH3 H3C H

H CH3 H3C H

Figure 10.2 Syndiotactic polypropylene.

A.2C ISOTACTIC POLYMERS
1. The stereochemistry at the stereocenters is all on one side of the stretched chain is said to be isotactic (iso: same). H H H H3C H H CH3 H3C H H H H CH3 H3C H H H H CH3 H3C H H H H CH3 H3C H H H H CH3 CH3 H3C H H H

Figure 10.3 Isotactic polypropylene.

1) The configuration of the stereocenters are either all (R) or all (S) depending on which end of the chain is assigned higher preference.

A.2D ZIEGLER-NATTA CATALYSTS
1. Karl Ziegler (a German chemist) and Giulio Natta (an Italian chemist) announced
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independently in 1953 the discovery of catalysts that permit stereochemical control of polymerization reactions ⇒ they were awarded the Nobel Prize in
Chemistry for their discoveries in 1963.

1) The Ziegler-Natta catalysts are prepared from transition metal halides and a reducing agent ⇒ the catalysts most commonly used are prepared from titanium tetrachloride (TiCl4) and a trialkylaluminum (R3Al). 2. Ziegler-Natta catalysts are generally employed as suspended solids ⇒ polymerization probably occurs at metal atoms on the surfaces of the particles. 1) The mechanism for the polymerization is an ionic mechanism. 2) There is evidence that polymerization occurs through an insertion of the alkene monomer between the metal and the growing polymer chain. 3. Both syndiotactic and isotactic polypropylene have been made using Ziegler-Natta catalysts. 1) The polymerizations occur at much lower pressures, and the polymers that are produced are much higher melting than atactic polypropylene. i) Isotactic polypropylenemelts at 175 °C.

4. Syndiotactic and isotactic polymers are much more crystalline than atactic polymers. 1) The regular arrangement of groups along the chains allows them to fit together better in a crystal structure. i) Isotactic polypropylenemelts at 175 °C.

5. Atactic poly(methyl methacrylate) is a noncrystalline glass. 1) Syndiotactic and isotactic poly(methyl methacrylate) are crystalline and melt at 160 and 200 °C, respectively.

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