xxxiv INTRODUCTION really did not speak to the question of vital force,and he knew this.The problem was that at the time there were no sources of ammonium cyanate that did not involve such savory starting materials as horns and blood-surely"vital"materials.The real coup de grace for vitalism came some years later when Adolph Wilhelm Hermann Kolbe(1818-1884)synthesized acetic acid from elemental carbon and inorganic materials in 1843-1844(see structures below). 0 H.C OH H,NT >NH2 Acetic Acid Urea Despite the demise of the vital-force idea,carbon-containing molecules certain- ly do have a strong connection to living things,including ourselves.Indeed,carbon provides the backbone for all the molecules that make up the soft tissues of our bod- ies.Our ability to function as living,sentient creatures depends on the properties of carbon-containing organic molecules,and we are about to embark on a study of their structures and transformations. Organic chemistry has come far from the days when chemists were simply col- lectors of observations.In the beginning,chemistry was largely empirical,and the questions raised were,more or less,along the lines of"What's going to happen if I mix this stuff with that stuff?"or"I wonder how many different things I can isolate from the sap of this tree?"Later,it became possible to collate knowledge and to begin to rationalize the large numbers of collected observations.Questions now could be expanded to deal with finding similarities in different reactions,and chemists began to have the ability to make predictions.Chemists began the transformation from the hunter-gatherer stage to modern times,in which we routinely seek to use what we know to generate new knowledge. Many advances have been critical to that transformation;chief among them is our increased analytical ability.Nowadays the structure of a new compound,be it isolated from tree sap or produced in a laboratory,cannot remain a mystery for long. Today,the former work of years can often be accomplished in hours.This expertise has enabled chemists to peer more closely at the wby questions,to think more deeply about reactivity of molecules.This point is important because the emergence of uni- fying principles has allowed us to teach organic chemistry in a different way,to teach in a fashion that largely frees students from the necessity to memorize organic chem- istry.That is what this book tries to do:to teach concepts and tools,not vast com- pendia of facts.The aim of this book is to provide frameworks for generalizations, and the discussions of topics are all designed with this aim in mind. We will see organic molecules of all types in this book.Organic compounds range in size from hydrogen(H2)-a kind of honorary organic molecule even though it doesn't contain carbon-to the enormously complex biomolecules,which typically contain thousands of atoms and have molecular weights in the hundreds of thou- sands.Despite this diversity,and the apparent differences between small and big mol- ecules,the study of all molecular properties always begins the same way,with structure.Structure determines reactivity,which provides a vehicle for navigating from the reactions of one kind of molecule to another and back again.So,early on, this book deals extensively with structure. What Do Organic Chemists Do?Structure determination has traditionally been one of the things that practicing organic chemists do with their lives.In the early
really did not speak to the question of vital force, and he knew this. The problem was that at the time there were no sources of ammonium cyanate that did not involve such savory starting materials as horns and blood—surely “vital” materials. The real coup de grâce for vitalism came some years later when Adolph Wilhelm Hermann Kolbe (1818–1884) synthesized acetic acid from elemental carbon and inorganic materials in 1843–1844 (see structures below). Despite the demise of the vital-force idea, carbon-containing molecules certainly do have a strong connection to living things, including ourselves. Indeed, carbon provides the backbone for all the molecules that make up the soft tissues of our bodies. Our ability to function as living, sentient creatures depends on the properties of carbon-containing organic molecules, and we are about to embark on a study of their structures and transformations. Organic chemistry has come far from the days when chemists were simply collectors of observations. In the beginning, chemistry was largely empirical, and the questions raised were, more or less, along the lines of “What’s going to happen if I mix this stuff with that stuff?” or “I wonder how many different things I can isolate from the sap of this tree?”Later, it became possible to collate knowledge and to begin to rationalize the large numbers of collected observations. Questions now could be expanded to deal with finding similarities in different reactions, and chemists began to have the ability to make predictions. Chemists began the transformation from the hunter–gatherer stage to modern times, in which we routinely seek to use what we know to generate new knowledge. Many advances have been critical to that transformation; chief among them is our increased analytical ability. Nowadays the structure of a new compound, be it isolated from tree sap or produced in a laboratory, cannot remain a mystery for long. Today, the former work of years can often be accomplished in hours. This expertise has enabled chemists to peer more closely at the why questions, to think more deeply about reactivity of molecules.This point is important because the emergence of unifying principles has allowed us to teach organic chemistry in a different way, to teach in a fashion that largely frees students from the necessity to memorize organic chemistry. That is what this book tries to do: to teach concepts and tools, not vast compendia of facts. The aim of this book is to provide frameworks for generalizations, and the discussions of topics are all designed with this aim in mind. We will see organic molecules of all types in this book. Organic compounds range in size from hydrogen (H 2)—a kind of honorary organic molecule even though it doesn’t contain carbon—to the enormously complex biomolecules, which typically contain thousands of atoms and have molecular weights in the hundreds of thousands. Despite this diversity, and the apparent differences between small and big molecules, the study of all molecular properties always begins the same way, with structure. Structure determines reactivity, which provides a vehicle for navigating from the reactions of one kind of molecule to another and back again. So, early on, this book deals extensively with structure. What Do Organic Chemists Do? Structure determination has traditionally been one of the things that practicing organic chemists do with their lives. In the early CO H3C OH CO H2N NH2 Acetic Acid Urea xxxiv INTRODUCTION
INTRODUCTION XXXV days,such activity took the form of uncovering the gross connectivity of the atoms in the molecule in question:What was attached to what?Exactly what are those molecules isolated from the Borneo tree or made in a reaction in the lab?Such ques- tions are quickly answered by application of today's powerful spectroscopic tech- niques,or,in the case of solids,by X-ray diffraction crystallography.And small details of structure lead to enormous differences in properties:morphine,a pain-killing agent in wide current use,and heroin,a powerfully addictive narcotic,differ only by the presence of two acetyl groups(CH3CO units),a tiny difference in their large and complex structures. Today,much more subtle questions are being asked about molecular structure. How long can a bond between atoms be stretched before it goes,"Boing,"in its quiet, molecular voice,and the atoms are no longer attached?How much can a bond be squeezed?How much can a bond be twisted?These are structural questions,and reveal much about the properties of atoms and molecules-in other words,about the constituents of us and the world around us. Many chemists are more concerned with how reactions take place,with the study of "reaction mechanisms."Of course,these people depend on those who study struc- ture;one can hardly think about how reactions occur if one doesn't know the detailed structures-connectivity of atoms,three-dimensional shape-of the molecules involved.In a sense,every chemist must be a structural chemist.The study of reac- tion mechanisms is an enormously broad subject.It includes people who look at the energy changes involved when two atoms form a molecule or,conversely,when a molecule is forced to come apart to its constituent atoms,as well as those who study the reactions of the huge biomolecules of our bodies-proteins and polynucleotides. How much energy is required to make a certain reaction happen?Or,how much energy is given off when it happens?You are familiar with both kinds of processes. For example,burning is clearly a process in which energy is given off as both heat and light. Chemists also want to know the details of how molecules come together to make other molecules.Must they approach each other in a certain direction?Are there catalysts-molecules not changed by the reaction-that are necessary?There are many such questions.A full analysis of reaction mechanism requires a knowledge of the structures and energies of all molecules involved in the process,including species called intermediates,molecules of fleeting existence that cannot usually be isolated because they go on quickly to other species.One also must have an idea of the structure and energy of the highest energy point in a reaction,called the tran- sition state.Such species cannot be isolated-they are energy maxima,not energy minima-but they can be studied nonetheless.We will see how. Still other chemists focus on synthesis.The goal in such work is the construc- tion of a target molecule from smaller,available molecules.In earlier times the rea- son for such work was sometimes structure determination.One set out to make a molecule one suspected of being the product of some reaction of interest.Now,deter- mination of structure is not usually the goal.And it must be admitted that Nature is still a much better synthetic chemist than any human.There is simply no contest; evolution has generated systems exquisitely designed to make breathtakingly com- plicated molecules with spectacular efficiency.We cannot hope to compete.Why, then,even try?The reason is that there is a cost to the evolutionary development of synthesis,and that is specificity.Nature can make a certain molecule in an extraor- dinarily competent way,but Nature can't make changes on request.The much less efficient syntheses devised by humans are far more flexible than Nature's,and one
days, such activity took the form of uncovering the gross connectivity of the atoms in the molecule in question: What was attached to what? Exactly what are those molecules isolated from the Borneo tree or made in a reaction in the lab? Such questions are quickly answered by application of today’s powerful spectroscopic techniques, or, in the case of solids, by X-ray diffraction crystallography. And small details of structure lead to enormous differences in properties: morphine, a pain-killing agent in wide current use, and heroin, a powerfully addictive narcotic, differ only by the presence of two acetyl groups (CH 3CO units), a tiny difference in their large and complex structures. Today, much more subtle questions are being asked about molecular structure. How long can a bond between atoms be stretched before it goes,“Boing,”in its quiet, molecular voice, and the atoms are no longer attached? How much can a bond be squeezed? How much can a bond be twisted? These are structural questions, and reveal much about the properties of atoms and molecules—in other words, about the constituents of us and the world around us. Many chemists are more concerned with how reactions take place, with the study of “reaction mechanisms.”Of course, these people depend on those who study structure; one can hardly think about how reactions occur if one doesn’t know the detailed structures—connectivity of atoms, three-dimensional shape—of the molecules involved. In a sense, every chemist must be a structural chemist. The study of reaction mechanisms is an enormously broad subject. It includes people who look at the energy changes involved when two atoms form a molecule or, conversely, when a molecule is forced to come apart to its constituent atoms, as well as those who study the reactions of the huge biomolecules of our bodies—proteins and polynucleotides. How much energy is required to make a certain reaction happen? Or, how much energy is given off when it happens? You are familiar with both kinds of processes. For example, burning is clearly a process in which energy is given off as both heat and light. Chemists also want to know the details of how molecules come together to make other molecules. Must they approach each other in a certain direction? Are there catalysts—molecules not changed by the reaction—that are necessary? There are many such questions. A full analysis of reaction mechanism requires a knowledge of the structures and energies of all molecules involved in the process, including species called intermediates, molecules of fleeting existence that cannot usually be isolated because they go on quickly to other species. One also must have an idea of the structure and energy of the highest energy point in a reaction, called the transition state. Such species cannot be isolated—they are energy maxima, not energy minima—but they can be studied nonetheless. We will see how. Still other chemists focus on synthesis. The goal in such work is the construction of a target molecule from smaller, available molecules. In earlier times the reason for such work was sometimes structure determination. One set out to make a molecule one suspected of being the product of some reaction of interest. Now, determination of structure is not usually the goal. And it must be admitted that Nature is still a much better synthetic chemist than any human. There is simply no contest; evolution has generated systems exquisitely designed to make breathtakingly complicated molecules with spectacular efficiency. We cannot hope to compete. Why, then, even try? The reason is that there is a cost to the evolutionary development of synthesis, and that is specificity. Nature can make a certain molecule in an extraordinarily competent way, but Nature can’t make changes on request. The much less efficient syntheses devised by humans are far more flexible than Nature’s, and one INTRODUCTION xxxv
xxxvi INTRODUCTION reason for the chemist's interest in synthesis is the possibility of generating molecules of Nature in systematically modified forms.We hope to make small changes in the structures and to study the influence on biological properties induced by those changes.In that way it could be possible to find therapeutic agents of greatly increased efficiency,for example,or to stay ahead of microbes that become resistant to certain drugs.Nature can't quickly change the machinery for making an antibi- otic molecule to which the microbes have become resistant,but humans can. What's Happening Now?It's Not All Done.In every age,some people have felt that there is little left to be done.All the really great stuff is behind us,and all we can hope for is to mop up some details;we won't be able to break really new ground.And every age has been dead wrong in this notion.By contrast,the slope of scientific discovery continues to increase.We learn more every year,and not just details.Right now the frontiers of molecular biology-a kind of organic chemistry of giant molecules,we would claim-are the most visibly expanding areas,but there is much more going on. In structure determination,completely new kinds of molecules are appearing.For example,just a few years ago a new form of carbon,the soccer ball-shaped C6o,was synthesized in bulk by the simple method of vaporizing a carbon rod and collect- ing the products on a cold surface.Even more recently it has been possible to cap- ture atoms of helium and argon inside the soccer ball.These are the first neutral compounds of helium ever made.Molecules connected as linked chains or as knot- ted structures are now known.What properties these new kinds of molecules will have no one knows.Some will certainly turn out to be mere curiosities,but others will influence our lives in new and unexpected ways. The field of organic reaction mechanisms continues to expand as we become bet- ter able to look at detail.For example,events on a molecular time scale are becom- ing visible to us as our spectrometers become able to look at ever smaller time periods. Molecules that exist for what seems a spectacularly short time-microseconds or nanoseconds-are quite long-lived if one can examine them on the femtosecond time scale.Indeed,the Nobel Prize in Chemistry in 1999 was given to Ahmed H.Zewail (b.1946)of Caltech for just such work.Nowadays we are moving ever further into the strange realm of the attosecond time regime.We are sure to learn much more about the details of the early stages of chemical reactions in the next few years. At the moment,we are still defining the coarse picture of chemical reactions. Our resolution is increasing,and we will soon see micro details we cannot even imag- ine at the moment.It is a very exciting time.What can we do with such knowledge? We can't answer that question yet,but chemists are confident that with more detailed knowledge will come an ability to take finer control of the reactions of molecules. At the other end of the spectrum,we are learning how macromolecules react,how they coil and uncoil,arranging themselves in space so as to bring two reactive mol- ecules to just the proper orientation for reaction.Here we are seeing the bigger pic- ture of how much of Nature's architecture is designed to facilitate positioning and transportation of molecules to reactive positions.We are learning how to co-opt Nature's methods by modifying the molecular machinery so as to bring about new results. We can't match Nature's ability to be specific and efficient.Over evolutionary time,Nature has just had too long to develop methods of doing exactly the right thing.But we are learning how to make changes in Nature's machinery-biomole- cules-that lead to changes in the compounds synthesized.It is likely that we will
reason for the chemist’s interest in synthesis is the possibility of generating molecules of Nature in systematically modified forms. We hope to make small changes in the structures and to study the influence on biological properties induced by those changes. In that way it could be possible to find therapeutic agents of greatly increased efficiency, for example, or to stay ahead of microbes that become resistant to certain drugs. Nature can’t quickly change the machinery for making an antibiotic molecule to which the microbes have become resistant, but humans can. What’s Happening Now? It’s Not All Done. In every age, some people have felt that there is little left to be done. All the really great stuff is behind us, and all we can hope for is to mop up some details; we won’t be able to break really new ground. And every age has been dead wrong in this notion. By contrast, the slope of scientific discovery continues to increase. We learn more every year, and not just details. Right now the frontiers of molecular biology—a kind of organic chemistry of giant molecules, we would claim—are the most visibly expanding areas, but there is much more going on. In structure determination, completely new kinds of molecules are appearing. For example, just a few years ago a new form of carbon, the soccer ball–shaped C60, was synthesized in bulk by the simple method of vaporizing a carbon rod and collecting the products on a cold surface. Even more recently it has been possible to capture atoms of helium and argon inside the soccer ball. These are the first neutral compounds of helium ever made. Molecules connected as linked chains or as knotted structures are now known. What properties these new kinds of molecules will have no one knows. Some will certainly turn out to be mere curiosities, but others will influence our lives in new and unexpected ways. The field of organic reaction mechanisms continues to expand as we become better able to look at detail. For example, events on a molecular time scale are becoming visible to us as our spectrometers become able to look at ever smaller time periods. Molecules that exist for what seems a spectacularly short time—microseconds or nanoseconds—are quite long-lived if one can examine them on the femtosecond time scale. Indeed, the Nobel Prize in Chemistry in 1999 was given to Ahmed H. Zewail (b. 1946) of Caltech for just such work. Nowadays we are moving ever further into the strange realm of the attosecond time regime. We are sure to learn much more about the details of the early stages of chemical reactions in the next few years. At the moment, we are still defining the coarse picture of chemical reactions. Our resolution is increasing, and we will soon see micro details we cannot even imagine at the moment. It is a very exciting time. What can we do with such knowledge? We can’t answer that question yet, but chemists are confident that with more detailed knowledge will come an ability to take finer control of the reactions of molecules. At the other end of the spectrum, we are learning how macromolecules react, how they coil and uncoil, arranging themselves in space so as to bring two reactive molecules to just the proper orientation for reaction. Here we are seeing the bigger picture of how much of Nature’s architecture is designed to facilitate positioning and transportation of molecules to reactive positions. We are learning how to co-opt Nature’s methods by modifying the molecular machinery so as to bring about new results. We can’t match Nature’s ability to be specific and efficient. Over evolutionary time, Nature has just had too long to develop methods of doing exactly the right thing. But we are learning how to make changes in Nature’s machinery—biomolecules—that lead to changes in the compounds synthesized. It is likely that we will xxxvi INTRODUCTION
INTRODUCTION xxxvii be able to co-opt Nature's methods,deliberately modified in specific ways,to retain the specificity but change the resulting products.This is one frontier of synthetic chemistry. The social consequences of this work are surely enormous.We are soon going to be able to tinker in a controlled way with much of Nature's machinery.How does humankind control itself?How does it avoid doing bad things with this power? Those questions are not easy,but there is no hiding from them.We are soon going to be faced with the most difficult social questions of human history,and how we deal with them will determine the quality of the lives of us and our children.That's one big reason that education in science is so important today.It is not that we will need more scientists;rather it is that we must have a scientifically educated popu- lation in order to deal sensibly with the knowledge and powers that are to come.So, this book is not specifically aimed at the dedicated chemist-to-be.That person can use this book,but so can anyone who will need to have an appreciation of organic chemistry in his or her future-and that's nearly everyone these days. How to Study Organic Chemistry Work with a Pencil.We were taught very early that"Organic chemistry must be read with a pencil."Truer words were never spoken.You can't read this book,or any chemistry book,in the way you can read books in other subjects.You must write things as you go along.There is a real connection between the hand and the brain in this business,it seems.When you come to the description of a reaction,especial- ly where the text tells you that it is an important reaction,by all means take the time to draw out the steps yourself.It is not enough to read the text and look at the draw- ings;it is not sufficient to highlight.Neither of these procedures is reading with a pencil.Highlighting does not reinforce the way working out the steps of the syn- thesis or chemical reaction at hand does.You might even make a collection of file cards labeled "Reaction descriptions"on which you force yourself to write out the steps of the reaction.Another set of file cards should be used to keep track of the various ways to make molecules.At first,these cards will be few in number,and sparsely filled,but as we reach the middle of the course there will be an explosion in the number of synthetic methods available.This subject can sneak up on you,and keeping a catalog will help you to stay on top of this part of the subject.We will try to help you to work in this interactive way by interrupting the text with problems, with solutions that follow immediately when we think it is time to stop,take stock, and reinforce a point before going on.These problems are important.You can read right by them of course,or read the answer without stopping to do the problem,but to do so will be to cheat yourself and make it harder to learn the subject.Doing these in-chapter problems is a part of reading with a pencil and should be very helpful in getting the material under control.There is no more important point to be made than this one.Ignore it at your peril! Don't Memorize.In the old days,courses in organic chemistry rewarded people who could memorize.Indeed,the notorious dependence of medical school admis- sion committees on the grade in organic chemistry may have stemmed from the need to memorize in medical school.If you could show that you could do it in organic, you could be relied upon to be able to memorize that the shin bone was connected to the foot bone,or whatever.Nowadays,memorization is the road to disaster;there is just too much material.Those who teach this subject have come to see an all too
be able to co-opt Nature’s methods, deliberately modified in specific ways, to retain the specificity but change the resulting products. This is one frontier of synthetic chemistry. The social consequences of this work are surely enormous. We are soon going to be able to tinker in a controlled way with much of Nature’s machinery. How does humankind control itself? How does it avoid doing bad things with this power? Those questions are not easy, but there is no hiding from them. We are soon going to be faced with the most difficult social questions of human history, and how we deal with them will determine the quality of the lives of us and our children. That’s one big reason that education in science is so important today. It is not that we will need more scientists; rather it is that we must have a scientifically educated population in order to deal sensibly with the knowledge and powers that are to come. So, this book is not specifically aimed at the dedicated chemist-to-be. That person can use this book, but so can anyone who will need to have an appreciation of organic chemistry in his or her future—and that’s nearly everyone these days. How to Study Organic Chemistry Work with a Pencil. We were taught very early that “Organic chemistry must be read with a pencil.” Truer words were never spoken. You can’t read this book, or any chemistry book, in the way you can read books in other subjects. You must write things as you go along. There is a real connection between the hand and the brain in this business, it seems. When you come to the description of a reaction, especially where the text tells you that it is an important reaction, by all means take the time to draw out the steps yourself. It is not enough to read the text and look at the drawings; it is not sufficient to highlight. Neither of these procedures is reading with a pencil. Highlighting does not reinforce the way working out the steps of the synthesis or chemical reaction at hand does. You might even make a collection of file cards labeled “Reaction descriptions” on which you force yourself to write out the steps of the reaction. Another set of file cards should be used to keep track of the various ways to make molecules. At first, these cards will be few in number, and sparsely filled, but as we reach the middle of the course there will be an explosion in the number of synthetic methods available.This subject can sneak up on you, and keeping a catalog will help you to stay on top of this part of the subject. We will try to help you to work in this interactive way by interrupting the text with problems, with solutions that follow immediately when we think it is time to stop, take stock, and reinforce a point before going on. These problems are important. You can read right by them of course, or read the answer without stopping to do the problem, but to do so will be to cheat yourself and make it harder to learn the subject. Doing these in-chapter problems is a part of reading with a pencil and should be very helpful in getting the material under control. There is no more important point to be made than this one. Ignore it at your peril! Don’t Memorize. In the old days, courses in organic chemistry rewarded people who could memorize. Indeed, the notorious dependence of medical school admission committees on the grade in organic chemistry may have stemmed from the need to memorize in medical school. If you could show that you could do it in organic, you could be relied upon to be able to memorize that the shin bone was connected to the foot bone, or whatever. Nowadays, memorization is the road to disaster; there is just too much material. Those who teach this subject have come to see an all too INTRODUCTION xxxvii
xxxviii INTRODUCTION familiar pattern.There is a group of people who do very well early and then crash sometime around the middle of the first semester.These folks didn't suddenly become stupid or lazy;they were relying on memorization and simply ran out of memory. Success these days requires generalization,understanding of principles that unify seemingly disparate reactions or collections of data.Medical schools still regard the grade in organic as important,but it is no longer because they look for people who can memorize.Medicine,too,has outgrown the old days.Now medical schools seek people who have shown that they can understand a complex subject,people who can generalize. Work in Groups.Many studies have shown that an effective way to learn is to work in small groups.Form a group of your roommates or friends,and solve prob- lems for each other.Assign each person one or two problems to be solved for the group.Afterward,work through the solution found in the chapter or Study Guide. You will find that the exercise of explaining the problem to others will be enormous- ly useful.You will learn much more from "your"problems than from the problems solved by others.When Mait teaches organic chemistry at Princeton,and now at NYU,he increasingly replaces lecture with small-group problem solving. Work the Problems.As noted above,becoming good at organic chemistry is an interactive process;you can't just read the material and hope to become expert. Expertise in organic chemistry requires experience,a commodity that by definition you are very low on at the start of your study.Doing the problems is vital to gain- ing the necessary experience.Resist the temptation to look at the answer before you have tried to do the problem.Disaster awaits you if you succumb to this tempta- tion,for you cannot learn effectively that way and there will be no answers available on the examinations until it is too late.That is not to say that you must be able to solve all the problems straight away.There are problems of all difficulty levels in each chapter,and some of them are very challenging indeed.Even though the problem is hard or very hard,give it a try.When you are truly stuck,that is the time to gath- er a group to work on it.Only as a last resort should you take a peek at the Study Guide.There you will find not just a bare bones answer,but,often,advice on how to do the problem as well.Giving hard problems is risky,because there is the poten- tial for discouraging people.Please don't worry if some problems,especially hard ones,do not come easily or do not come at all.Each of us in this business has favorite problems that we still can't solve.Some of these form the basis of our research efforts, and may not yield,even to determined efforts,for years.A lot of the pleasure in organic chemistry is working challenging problems,and it would not be fair to deprive you of such fun. Use All the Resources Available to You.You are not alone.Moreover,every- one will have difficulty at one time or another.The important thing is to get help when you need it.Of course the details will differ at each college or university but there are very likely to be extensive systems set up to help you.Professors have office hours,there are probably teaching assistants with office hours,and there will likely be help,review,or question sessions at various times.Professors are there to help you, and they will not be upset if you show enough interest to ask questions about a sub- ject they love."Dumb questions"do not exist!You are not expected to be an instant genius in this subject,and many students are too shy to ask perfectly reasonable ques- tions.Don't be one of those people!
familiar pattern. There is a group of people who do very well early and then crash sometime around the middle of the first semester.These folks didn’t suddenly become stupid or lazy; they were relying on memorization and simply ran out of memory. Success these days requires generalization, understanding of principles that unify seemingly disparate reactions or collections of data. Medical schools still regard the grade in organic as important, but it is no longer because they look for people who can memorize. Medicine, too, has outgrown the old days. Now medical schools seek people who have shown that they can understand a complex subject, people who can generalize. Work in Groups. Many studies have shown that an effective way to learn is to work in small groups. Form a group of your roommates or friends, and solve problems for each other. Assign each person one or two problems to be solved for the group. Afterward, work through the solution found in the chapter or Study Guide. You will find that the exercise of explaining the problem to others will be enormously useful. You will learn much more from “your” problems than from the problems solved by others. When Mait teaches organic chemistry at Princeton, and now at NYU, he increasingly replaces lecture with small-group problem solving. Work the Problems. As noted above, becoming good at organic chemistry is an interactive process; you can’t just read the material and hope to become expert. Expertise in organic chemistry requires experience, a commodity that by definition you are very low on at the start of your study. Doing the problems is vital to gaining the necessary experience. Resist the temptation to look at the answer before you have tried to do the problem. Disaster awaits you if you succumb to this temptation, for you cannot learn effectively that way and there will be no answers available on the examinations until it is too late. That is not to say that you must be able to solve all the problems straight away.There are problems of all difficulty levels in each chapter, and some of them are very challenging indeed. Even though the problem is hard or very hard, give it a try. When you are truly stuck, that is the time to gather a group to work on it. Only as a last resort should you take a peek at the Study Guide. There you will find not just a bare bones answer, but, often, advice on how to do the problem as well. Giving hard problems is risky, because there is the potential for discouraging people. Please don’t worry if some problems, especially hard ones, do not come easily or do not come at all. Each of us in this business has favorite problems that we still can’t solve. Some of these form the basis of our research efforts, and may not yield, even to determined efforts, for years. A lot of the pleasure in organic chemistry is working challenging problems, and it would not be fair to deprive you of such fun. Use All the Resources Available to You. You are not alone. Moreover, everyone will have difficulty at one time or another. The important thing is to get help when you need it. Of course the details will differ at each college or university but there are very likely to be extensive systems set up to help you. Professors have office hours, there are probably teaching assistants with office hours, and there will likely be help, review, or question sessions at various times. Professors are there to help you, and they will not be upset if you show enough interest to ask questions about a subject they love. “Dumb questions” do not exist! You are not expected to be an instant genius in this subject, and many students are too shy to ask perfectly reasonable questions. Don’t be one of those people! xxxviii INTRODUCTION