Some Conclusions about Biological Chemistry As promised in the chapter introduction, the past few sections have been a fast-paced tour of a large number of reactions. Following it all undoubtedly required a lot of work and a lot of page-turning to look at earlier sections. After examining the various metabolic pathways, perhaps the main conclusion about biological chemistry is the remarkable similarity between the mechanisms of biological reactions and the mechanisms of laboratory reactions. If you were to look at the steps of vitamin B 12 biosynthesis, you would see the same kinds of reactions we’ve been seeing throughout the text—nucleophilic substitutions, eliminations, aldol reactions, nucleophilic acyl substitutions, and so forth. There are, of course, some complexities, but the fundamental mechanisms of organic chemistry remain the same, whether in the laboratory with smaller molecules or in organisms with larger molecules. So what is there to be learned from studying metabolism? One good answer is given in the following Chemistry Matters , which relates the story of how knowledge of a biosynthetic pathway led to the design of new drugs that have saved millions of lives. Statin Drugs Coronary heart disease—the buildup of cholesterol-containing plaques on the walls of heart arteries—is the leading cause of death for people older than 20 in industrialized countries. It’s estimated that up to one-third of women and one-half of men will develop the disease at some point in their lives. The onset of coronary heart disease is directly correlated with blood cholesterol levels (see the Chapter 27 Chemistry Matters ), and the first step in disease prevention is to lower those levels. It turns out that only about 25% of your blood cholesterol comes from what you eat; the remaining 75%—about 1 gram each day—is biosynthesized in your liver from dietary fats and carbohydrates. Thus, any effective plan for lowering your cholesterol level means limiting the amount that your body makes, which is where a detailed chemical knowledge of cholesterol biosynthesis comes in. The buildup of cholesterol deposits inside arteries can cause coronary heart disease, a leading cause of death for adults in industrialized nations. We saw in and that all steroids, including cholesterol, are biosynthesized from the triterpenoid lanosterol, which in turn comes from acetyl CoA through isopentenyl diphosphate. If you knew all the mechanisms for all the chemical steps in cholesterol biosynthesis, you might be able to devise a drug that would block one of those steps, thereby short-circuiting the biosynthetic process and controlling the amount of cholesterol produced. But we do know those mechanisms! Look back at the pathway for the biosynthesis of isopentenyl diphosphate from acetyl CoA, shown in . It turns out that the rate-limiting step in the pathway is the reduction of 3-hydroxy-3-methylglutaryl CoA (abbreviated HMG-CoA) to mevalonate, brought about by the enzyme HMG-CoA reductase. If that enzyme could be stopped from functioning, cholesterol biosynthesis would also be stopped. To find a drug that blocks HMG-CoA reductase, chemists did two simultaneous experiments on a large number of potential drug candidates isolated from soil microbes. In one experiment, the drug candidate and mevalonate were added to liver extract; in the second experiment, only the drug candidate was added without mevalonate. If cholesterol was produced only in the presence of added mevalonate but not in the absence of mevalonate, the drug candidate must have blocked the enzyme for mevalonate synthesis. The drugs that block HMG-CoA reductase, and thus control cholesterol synthesis in the body, are called statins . In just the 10-year period following their introduction in 1994, the death rate from coronary heart disease decreased by 33% in the United States. Like many drugs, statins don’t come without risks and have some serious side effects that people considering their use should be aware of, but approaching 30 years later, they remain among the most widely prescribed drugs in the world, with estimated annual sales of $14 billion. Atorvastatin (Lipitor), simvastatin (Zocor), rosuvastatin (Crestor), pravastatin (Pravachol), and lovastatin (Mevacor) are some examples. An X-ray crystal structure of the active site in the HMG-CoA reductase enzyme is shown in the accompanying graphic, along with a molecule of atorvastatin (purple) that is tightly bound in the active site and stops the enzyme from functioning. A good understanding of organic chemistry certainly paid off in this instance. anabolism β -oxidation pathway catabolism citric acid cycle deamination gluconeogenesis glycolysis metabolism Schiff base transamination Summary Metabolism is the sum of all chemical reactions in the body. Reactions that break down large molecules into smaller fragments are called catabolism , and those that build up large molecules from small pieces are called anabolism . Although the details of specific biochemical pathways are sometimes complex, all the reactions that occur follow the normal rules of organic chemical reactivity. The catabolism of fats begins with digestion, in which ester bonds are hydrolyzed to give glycerol and fatty acids. The fatty acids are degraded in the four-step β -oxidation pathway by removal of two carbons at a time, yielding acetyl CoA. Catabolism of carbohydrates begins with the hydrolysis of glycoside bonds to give glucose, which is degraded in the ten-step glycolysis pathway. Pyruvate, the initial product of glycolysis, is then converted into acetyl CoA. Acetyl CoA next enters the eight-step citric acid cycle , where it is further degraded into CO 2 . The cycle is a closed loop of reactions in which the product of the final step (oxaloacetate) is a reactant in the first step. Catabolism of proteins is more complex than that of fats or carbohydrates because each of the 20 different amino acids is degraded by its own unique pathway. In general, though, the amino nitrogen atoms are removed and the substances that remain are converted into compounds that enter the citric acid cycle. Most amino acids lose their nitrogen atom by transamination , a reaction in which the –NH 2 group of the amino acid trades places with the keto group of an α -keto acid such as α -ketoglutarate. The products are a new α -keto acid and glutamate. The energy released in catabolic pathways is used in the electron-transport chain to make molecules of adenosine triphosphate, ATP. ATP, the final result of food catabolism, couples to and drives many otherwise unfavorable reactions. Biomolecules are synthesized as well as degraded, but the pathways for anabolism and catabolism are not the exact reverse of one another. Fatty acids are biosynthesized from acetate by an 8-step pathway, and carbohydrates are made from pyruvate by the 11-step gluconeogenesis pathway. Additional Problems Visualizing Chemistry Mechanism Problems Enzymes and Coenzymes Metabolism General Problems

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Why This Chapter? It may look easy, but these sunbathers are working hard to carry out a pericyclic reaction . (credit: modification of work “Tanning” by Meraj Chhaya/Flickr, CC BY 2.0). Broad outlines of both polar and radical reactions have been in place for more than a century, but our understanding of pericyclic reactions has emerged more recently. Prior to the mid-1960s, in fact, they were even occasionally referred to as “no-mechanism reactions.” They occur largely in the laboratory rather than in biological processes, but a knowledge of them is necessary, both for completeness in studying organic chemistry and in understanding biological pathways where they do occur. Most organic reactions take place by polar mechanisms, in which a nucleophile donates two electrons to an electrophile in forming a new bond. Other reactions take place by radical mechanisms, in which each of two reactants donates one electron in forming a new bond. Both kinds of reactions occur frequently in the laboratory and in living organisms. Less common, however, is the third major class of organic reactions— pericyclic reactions. A pericyclic reaction is one that occurs by a concerted process through a cyclic transition state. A concerted reaction is one in which all bonding changes occur simultaneously; no intermediates are involved. Rather than try to expand this definition now, we’ll begin by briefly reviewing some of the ideas of molecular orbital theory introduced in the chapters on Structure and Bonding and Conjugated Compounds and Ultraviolet Spectroscopy and then looking individually at the three main classes of pericyclic reactions: electrocyclic reactions, cycloadditions, and sigmatropic rearrangements.

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Molecular Orbitals of Conjugated Pi Systems A conjugated polyene, as we saw in , is one with alternating double and single bonds. According to molecular orbital (MO) theory, the p orbitals on the sp 2 -hybridized carbons of a conjugated polyene interact to form a set of π molecular orbitals whose energies depend on the number of nodes they have between nuclei. Molecular orbitals with fewer nodes are lower in energy than isolated p atomic orbitals and are bonding MOs; molecular orbitals with more nodes are higher in energy than isolated p orbitals and are antibonding MOs. Pi molecular orbitals of ethylene and 1,3-butadiene are shown in . Pi molecular orbitals of (a) ethylene and (b) 1,3-butadiene. A similar sort of molecular orbital description can be derived for any conjugated π electron system. 1,3,5-Hexatriene, for example, has three double bonds and six π MOs, as shown in . In the ground state, only the three bonding orbitals, ψ 1 , ψ 2 , and ψ 3 , are filled. On irradiation with ultraviolet light, however, an electron is promoted from the highest-energy filled orbital ( ψ 3 ) to the lowest-energy unfilled orbital ( ψ 4 *) to give an excited state ( ), in which ψ 3 and ψ 4 * are each half-filled. (An asterisk denotes an antibonding orbital.) What do molecular orbitals and their nodes have to do with pericyclic reactions? The answer is, everything . According to a series of rules formulated in the mid-1960s by R. B. Woodward and Roald Hoffmann at Harvard University, a pericyclic reaction can take place only if the symmetries of the reactant MOs are the same as the symmetries of the product MOs. In other words, the lobes of reactant MOs must be of the correct algebraic sign for bonding to occur in the transition state leading to product. If the symmetries of reactant and product orbitals match up, or correlate , the reaction is said to be symmetry-allowed . If the symmetries of reactant and product orbitals don’t correlate, the reaction is symmetry-disallowed . Symmetry-allowed reactions often occur under relatively mild conditions, but symmetry-disallowed reactions can’t occur by concerted paths. They either take place by nonconcerted, higher-energy pathways, or they don’t take place at all. The six π molecular orbitals of 1,3,5-hexatriene. In the ground state, the three bonding MOs, ψ 1 , ψ 2 , and ψ 3 , are filled. In the excited state, ψ 3 and ψ 4 * are both half-filled. The Woodward–Hoffmann rules for pericyclic reactions require an analysis of all reactant and product molecular orbitals, but Kenichi Fukui at Kyoto Imperial University in Japan introduced a simplified version. Hoffman and Fukui shared a Nobel Prize for their work, and Woodward would have joined them (for his second Nobel Prize) had he not passed away before the award was made. According to Fukui’s simplified version, we need to consider only two molecular orbitals, called the frontier orbitals . These frontier orbitals are the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) . In ground-state 1,3,5-hexatriene, for example, ψ 3 is the HOMO and ψ 4 * is the LUMO ( ). In excited-state 1,3,5-hexatriene, however, ψ 4 * is the HOMO and ψ 5 * is the LUMO. Problems

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Electrocyclic Reactions The best way to understand how orbital symmetry affects pericyclic reactions is to look at some examples. Let’s look first at a group of polyene rearrangements called electrocyclic reactions . An electrocyclic reaction is a pericyclic process that involves the cyclization of a conjugated acyclic polyene. One π bond is broken, the other π bonds change position, a new σ bond is formed, and a cyclic compound results. For example, a conjugated triene can be converted into a cyclohexadiene, and a conjugated diene can be converted into a cyclobutene. Pericyclic reactions are reversible, and the position of the equilibrium depends on the specific case. In general, the triene ⇄ cyclohexadiene equilibrium favors the cyclic product, whereas the diene ⇄ cyclobutene equilibrium favors the less strained open-chain product. The most striking feature of electrocyclic reactions is their stereochemistry. For example, (2 E ,4 Z ,6 E )-2,4,6-octatriene yields only cis -5,6-dimethyl-1,3-cyclohexadiene when heated, and (2 E ,4 Z ,6 Z )-2,4,6-octatriene yields only trans -5,6-dimethyl-1,3-cyclohexadiene. Remarkably, however, the stereochemical results change completely when the reactions are carried out under what are called photochemical , rather than thermal , conditions. Irradiation of (2 E ,4 Z ,6 E )-2,4,6-octatriene with ultraviolet light (denoted hν) yields trans -5,6-dimethyl-1,3-cyclohexadiene ( ). Electrocyclic interconversions of 2,4,6-octatriene isomers and 5,6-dimethyl-1,3-cyclohexadiene isomers. A similar result is obtained for the thermal electrocyclic ring-opening of 3,4-dimethylcyclobutene. The trans isomer yields only (2 E ,4 E )-2,4-hexadiene when heated, and the cis isomer yields only (2 E ,4 Z )-2,4-hexadiene. On UV irradiation, however, the results are opposite. Cyclization of the 2 E ,4 E isomer under photochemical conditions yields cis product ( ). Electrocyclic interconversions of 2,4-hexadiene isomers and 3,4-dimethylcyclobutene isomers. To account for these results, we need to look at the two outermost lobes of the polyene MOs—the lobes that interact when cyclization occurs. There are two possibilities: lobes of like sign can be either on the same side of the molecule or on opposite sides. For a bond to form, the outermost π lobes must rotate so that favorable bonding interaction is achieved—a positive lobe with a positive lobe or a negative lobe with a negative lobe. If two lobes of like sign are on the same side of the molecule, the two orbitals must rotate in opposite directions—one clockwise and one counterclockwise. This kind of motion is referred to as disrotatory . Conversely, if lobes of like sign are on opposite sides of the molecule, both orbitals must rotate in the same direction, either both clockwise or both counterclockwise. This kind of motion is called conrotatory .

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Stereochemistry of Thermal Electrocyclic Reactions How can we predict whether conrotatory or disrotatory motion will occur in a given case? According to frontier orbital theory, the stereochemistry of an electrocyclic reaction is determined by the symmetry of the polyene HOMO. The electrons in the HOMO are the highest-energy, most loosely held electrons and are therefore most easily moved during reaction. For thermal reactions, the ground-state electron configuration is used to identify the HOMO; for photochemical reactions , the excited-state electron configuration is used. Let’s look again at the thermal ring-closure of conjugated trienes. According to , the HOMO of a conjugated triene in its ground state has lobes of like sign on the same side of the molecule, a symmetry that predicts disrotatory ring-closure. This disrotatory cyclization is precisely what is observed in the thermal cyclization of 2,4,6-octatriene. The 2 E ,4 Z ,6 E isomer yields cis product; the 2 E ,4 Z ,6 Z isomer yields trans product ( ). Thermal cyclizations of 2,4,6-octatrienes occur by disrotatory ring-closures. In the same way, the ground-state HOMO of conjugated dienes ( ) has a symmetry that predicts conrotatory ring-closure. In practice, however, the conjugated diene reaction can be observed only in the reverse direction (cyclobutene → diene) because of the position of the equilibrium. We therefore find that the 3,4-dimethylcyclobutene ring opens in a conrotatory fashion. cis -3,4-Dimethylcyclobutene yields (2 E ,4 Z )-2,4-hexadiene, and trans -3,4-dimethylcyclobutene yields (2 E ,4 E )-2,4-hexadiene by conrotatory opening ( ). Thermal ring-openings of cis - and trans -dimethylcyclobutene occur by conrotatory paths. Note that a conjugated diene and a conjugated triene react with opposite stereochemistry. The diene opens and closes by a conrotatory path, whereas the triene opens and closes by a disrotatory path. This is due to the different symmetries of the diene and triene HOMOs. It turns out that there is an alternating relationship between the number of electron pairs (double bonds) undergoing bond reorganization and the stereochemistry of ring-opening or -closure. Polyenes with an even number of electron pairs undergo thermal electrocyclic reactions in a conrotatory sense, whereas polyenes with an odd number of electron pairs undergo the same reactions in a disrotatory sense. Problems

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Photochemical Electrocyclic Reactions We noted previously that photochemical electrocyclic reactions take a different stereochemical course than their thermal counterparts, and we can now explain this difference. Ultraviolet irradiation of a polyene causes an excitation of one electron from the ground-state HOMO to the ground-state LUMO, thus changing their symmetries. But because electronic excitation changes the symmetries of HOMO and LUMO, it also changes the reaction stereochemistry. (2 E ,4 E )-2,4-Hexadiene, for instance, undergoes photochemical cyclization by a disrotatory path, whereas the thermal reaction is conrotatory. Similarly, (2 E ,4 Z ,6 E )-2,4,6-octatriene undergoes photochemical cyclization by a conrotatory path, whereas the thermal reaction is disrotatory ( ). Photochemical cyclizations of conjugated dienes and trienes. The two processes occur with different stereochemistry because of their different orbital symmetries. Thermal and photochemical electrocyclic reactions always take place with opposite stereochemistry because the symmetries of the frontier orbitals are always different. gives some simple rules that make it possible to predict the stereochemistry of electrocyclic reactions. Stereochemical Rules for Electrocyclic Reactions Electron pairs (double bonds) Thermal reaction Photochemical reaction Even number Conrotatory Disrotatory Odd number Disrotatory Conrotatory Problems

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Cycloaddition Reactions A cycloaddition reaction is one in which two unsaturated molecules add to one another to yield a cyclic product. As with electrocyclic reactions, cycloadditions are governed by the orbital symmetry of the reactants. Symmetry-allowed processes often take place readily, but symmetry-disallowed processes take place with difficulty, if at all, and then only by nonconcerted pathways. Let’s look at two examples to see how they differ. As we saw in , the Diels–Alder cycloaddition reaction is a pericyclic process that takes place between a diene (four π electrons) and a dienophile (two π electrons) to yield a cyclohexene product. Many thousands of Diels–Alder reactions are known. They often take place easily at room temperature or slightly above, and they are stereospecific with respect to substituents. For example, room-temperature reaction between 1,3-butadiene and diethyl maleate (cis) exclusively yields the cis-disubstituted cyclohexene product. A similar reaction between 1,3-butadiene and diethyl fumarate (trans) exclusively yields the trans-disubstituted product. In contrast to the [4 + 2]- π -electron Diels–Alder reaction, the [2 + 2]- π -electron cycloaddition between two alkenes does not occur thermally. The [2 + 2] cycloaddition takes place only on irradiation, yielding cyclobutane products. For a successful cycloaddition, the terminal π lobes of the two reactants must have the correct symmetry for bonding to occur. This can happen in either of two ways, called suprafacial and antarafacial . Suprafacial cycloadditions take place when a bonding interaction occurs between lobes on the same face of one reactant and lobes on the same face of the other reactant. Antarafacial cycloadditions take place when a bonding interaction occurs between lobes on the same face of one reactant and lobes on opposite faces of the other reactant ( ). (a) Suprafacial cycloaddition occurs when there is bonding between lobes on the same face of one reactant and lobes on the same face of the other reactant. (b) Antarafacial cycloaddition occurs when there is bonding between lobes on the same face of one reactant and lobes on opposite faces of the other, which requires a twist in one π system . Note that both suprafacial and antarafacial cycloadditions are symmetry-allowed. Geometric constraints often make antarafacial reactions difficult, however, because there must be a twisting of the π orbital system in one of the reactants. Thus, suprafacial cycloadditions are much more common for small π systems.

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Stereochemistry of Cycloadditions How can we predict whether a given cycloaddition reaction will occur with suprafacial or with antarafacial geometry? According to frontier orbital theory, a cycloaddition reaction takes place when a bonding interaction occurs between the HOMO of one reactant and the LUMO of the other. An intuitive explanation of this rule is to imagine that one reactant donates electrons to the other. As with electrocyclic reactions, it’s the electrons in the HOMO of the first reactant that are least tightly held and most likely to be donated. Of course when the second reactant accepts those electrons, they must go into a vacant, unoccupied orbital—the LUMO. For a [4 + 2] cycloaddition (Diels–Alder reaction), let’s arbitrarily select the diene LUMO and the alkene HOMO. The symmetries of the two ground-state orbitals are such that bonding of the terminal lobes can occur with suprafacial geometry ( ), so the Diels–Alder reaction takes place readily under thermal conditions. Note that, as with electrocyclic reactions, we need be concerned only with the terminal lobes. For purposes of prediction, interactions among the interior lobes need not be considered. Interaction of diene LUMO and alkene HOMO in a suprafacial [4 + 2] cycloaddition reaction (Diels–Alder reaction). In contrast with the thermal [4 + 2] Diels–Alder reaction, the [2 + 2] cycloaddition of two alkenes to yield a cyclobutane can only occur photochemically. The explanation for this follows from orbital-symmetry arguments. Looking at the ground-state HOMO of one alkene and the LUMO of the second alkene, it’s apparent that a thermal [2 + 2] cycloaddition must take place by an antarafacial pathway ( a). Geometric constraints make the antarafacial transition state difficult, however, and so concerted thermal [2 + 2] cycloadditions are not observed. In contrast with the thermal process, photochemical [2 + 2] cycloadditions are observed. Irradiation of an alkene with UV light excites an electron from ψ 1 , the ground-state HOMO, to ψ 2 *, which becomes the excited-state HOMO. Interaction between the excited-state HOMO of one alkene and the LUMO of the second alkene allows a photochemical [2 + 2] cycloaddition reaction to occur by a suprafacial pathway ( b). (a) Interaction of a ground-state HOMO and a ground-state LUMO in a potential [2 + 2] cycloaddition does not occur thermally because the antarafacial geometry is too strained. (b) Interaction of an excited-state HOMO and a ground-state LUMO in a photochemical [2 + 2] cycloaddition reaction is less strained, however, and occurs with suprafacial geometry . The photochemical [2 + 2] cycloaddition reaction occurs smoothly, particularly with α , β -unsaturated carbonyl compounds, and represents one of the best methods known for synthesizing cyclobutane rings. For example: Thermal and photochemical cycloaddition reactions always take place with opposite stereochemistry. As with electrocyclic reactions, we can categorize cycloadditions according to the total number of electron pairs (double bonds) involved in the rearrangement. Thus, a thermal [4 + 2] Diels–Alder reaction between a diene and a dienophile involves an odd number (three) of electron pairs and takes place by a suprafacial pathway. A thermal [2 + 2] reaction between two alkenes involves an even number (two) of electron pairs and must take place by an antarafacial pathway. For photochemical cyclizations, these selectivities are reversed. These general rules are given in . Stereochemical Rules for Cycloaddition Reactions Electron pairs (double bonds) Thermal reaction Photochemical reaction Even number Antarafacial Suprafacial Odd number Suprafacial Antarafacial Problems

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Sigmatropic Rearrangements A sigmatropic rearrangement , the third general kind of pericyclic reaction, is a process in which a σ -bonded substituent atom or group migrates across a π electron system from one position to another. A σ bond is broken in the reactant, the π bonds move, and a new σ bond is formed in the product. The σ -bonded group can be either at the end or in the middle of the π system, as the following [1,5] and [3,3] rearrangements illustrate: The notations [1,5] and [3,3] describe the kind of rearrangement that is occurring. The numbers refer to the two groups connected by the σ bond in the reactant and designate the positions in those groups to which migration occurs. For example, in the [1,5] sigmatropic rearrangement of a 1,3-diene, the two groups connected by the σ bond are a hydrogen atom and a pentadienyl group. Migration occurs to position 1 of the H group (the only possibility) and to position 5 of the pentadienyl group. In the [3,3] rearrangement of an allylic vinylic ether, the two groups connected by the σ bond are an allylic group and the vinylic ether. Migration occurs to position 3 of the allylic group and also to position 3 of the vinylic ether. Like electrocyclic reactions and cycloadditions, sigmatropic rearrangements are controlled by orbital symmetries. There are two possible modes of reaction: migration of a group across the same face of the π system is suprafacial, and migration of a group from one face of the π system to the other face is antarafacial ( ). Suprafacial and antarafacial sigmatropic rearrangements. Both suprafacial and antarafacial sigmatropic rearrangements are symmetry-allowed, but suprafacial rearrangements are often easier for geometric reasons. The rules for sigmatropic rearrangements are identical to those for cycloaddition reactions ( ). Stereochemical Rules for Sigmatropic Rearrangements Electron pairs (double bonds) Thermal reaction Photochemical reaction Even number Antarafacial Suprafacial Odd number Suprafacial Antarafacial Problems

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Some Examples of Sigmatropic Rearrangements Because a [1,5] sigmatropic rearrangement involves three electron pairs (two π bonds and one σ bond), the orbital-symmetry rules in predict a suprafacial reaction. In fact, the [1,5] suprafacial shift of a hydrogen atom across two double bonds of a π system is a commonly observed sigmatropic rearrangements. For example, 5-methyl-1,3-cyclopentadiene rapidly rearranges at room temperature to yield a mixture of 1-methyl-, 2-methyl-, and 5-methyl-isomers. As another example, heating 5,5,5-trideuterio-(3 Z )-1,3-pentadiene causes scrambling of deuterium between positions 1 and 5. Both these [1,5] hydrogen shifts occur by a symmetry-allowed suprafacial pathway, as illustrated in . In contrast with these thermal [1, 5 ] sigmatropic hydrogen shifts, however, thermal [1, 3 ] hydrogen shifts are unknown. If they were to occur, they would have to proceed by a strained antarafacial reaction pathway. An orbital view of a suprafacial [1,5] hydrogen shift. Two other important sigmatropic reactions are the Claisen rearrangement of either an allyl aryl ether ( H 2 C ═ CHCH 2 ─ O ─ Ar ) or an allyl vinyl ( H 2 C ═ CHCH 2 ─ O ─ CH ═ CH 2 ) ether, and the Cope rearrangement of a 1,5 hexadiene to an isomeric 1,5-diene. These two rearrangements, along with the Diels–Alder reaction, are among the most generally useful pericyclic reactions for organic synthesis. Thousands of examples of all three are known. Like the Diels–Alder reaction discussed in and , the Claisen rearrangement takes place in a single step through a pericyclic mechanism in which a reorganization of bonding electrons occurs in a six-membered, cyclic transition state. The 6-allyl-2,4-cyclohexadienone intermediate then isomerizes to o -allylphenol ( ). Mechanism of Claisen rearrangement. C─O bond-breaking and C─C bond-making occur simultaneously. Evidence for this mechanism comes from the observation that the rearrangement takes place with transposition of the allyl group. That is, allyl phenyl ether containing a 14 C label on the allyl ether carbon atom yields o -allylphenol in which the label is on the terminal vinylic carbon (green in ). Problems The Cope rearrangement that converts a 1,5-diene to an isomeric 1,5-diene is somewhat limited but a modification called the Oxy Cope Rearrangement is wider in scope. As shown in the following example, a 1-5 diene with an –OH next to the double bond can be converted into an oxy-anion by reaction with a strong base such as potassium hydride (KH). A Cope rearrangement then occurs, and reaction with aqueous acid gives an enol that tautomerizes to an aldehyde. Although biological examples of pericyclic reactions are relatively rare, a much-studied example occurs in bacteria during biosynthesis of the essential amino acid phenylalanine. Phenylalanine arises from the precursor chorismate through a Claisen rearrangement to prephenate, followed by decarboxylation to phenylpyruvate and reductive amination ( ). You might note that the reductive amination of phenylpyruvate is the exact reverse of the transamination process shown in , by which amino acids are deaminated. In addition, the reductive amination of ketones is a standard method for preparing amines in the laboratory, as we saw in . Suprafacial [3,3] (a) Cope and (b) Claisen rearrangements. Pathway for the bacterial biosynthesis of phenylalanine from chorismate, involving a Claisen rearrangement. Problems

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A Summary of Rules for Pericyclic Reactions How can you keep straight all the rules about pericyclic reactions? The summary in , , and can be distilled into a mnemonic phrase that provides an easy way to predict the stereochemical outcome of any pericyclic reaction: The Electrons Circle Around ( TECA ) T hermal reactions with an E ven number of electron pairs are C onrotatory or A ntarafacial. A change either from thermal to photochemical or from an even to an odd number of electron pairs changes the outcome from conrotatory/antarafacial to disrotatory/suprafacial. A change from both thermal and even to photochemical and odd causes no change because two negatives make a positive. These selection rules are summarized in ; knowing them gives you the ability to predict the stereochemistry of literally thousands of pericyclic reactions. Stereochemical Rules for Pericyclic Reactions Electronic state Electron pairs Stereochemistry Ground state (thermal) Even number Odd number Antara–con Supra–dis Excited state (photochemical) Even number Odd number Supra–dis Antara–con Problems Vitamin D, the Sunshine Vitamin Vitamin D, discovered in 1918, is a general name for two related compounds, cholecalciferol (vitamin D 3 ) and ergocalciferol (vitamin D 2 ). Both are derived from steroids ( ) and differ only in the nature of the hydrocarbon side chain attached to the five-membered ring. Cholecalciferol comes primarily from dairy products and fish; ergocalciferol comes from some vegetables. Here are the sunbathers, again, with their chemical work complete. (credit: “Tanning” by Meraj Chhaya/Flickr, CC BY 2.0) The function of vitamin D in the body is to control the calcification of bones by increasing intestinal absorption of calcium. When sufficient vitamin D is present, approximately 30% of ingested calcium is absorbed, but in the absence of vitamin D, calcium absorption falls to about 10%. A deficiency of vitamin D thus leads to poor bone growth and to the diseases rickets in children and osteoporosis in adults. Actually, neither vitamin D 2 nor D 3 is present in foods. Rather, foods contain the precursor molecules 7-dehydrocholesterol and ergosterol. In the presence of sunlight, both precursors are converted in the outer, epidermal layer of skin to the active vitamins, hence the nickname for vitamin D, the “sunshine vitamin.” Pericyclic reactions are unusual in living organisms, and the photochemical synthesis of vitamin D is one of only a few well-studied examples. The reaction takes place in two steps, an electrocyclic ring-opening of a cyclohexadiene to yield an open-chain hexatriene, followed by a sigmatropic [1,7] H shift to yield an isomeric hexatriene. Only the initial electrocyclic ring-opening requires irradiation by so-called UVB light of 295 to 300 nm wavelength. The subsequent sigmatropic [1,7] H shift occurs spontaneously by a thermal isomerization. Following synthesis under the skin, further metabolic processing of cholecalciferol and ergocalciferol in the liver and kidney introduces two additional –OH groups to give the active forms of the vitamin, calcitriol and ergocalcitriol. antarafacial conrotatory cycloaddition reaction disrotatory electrocyclic reaction frontier orbitals highest occupied molecular orbital (HOMO) lowest unoccupied molecular orbital (LUMO) pericyclic reaction photochemical reaction sigmatropic rearrangement suprafacial symmetry-allowed symmetry-disallowed Summary A pericyclic reaction takes place in a single step through a cyclic transition state without intermediates. There are three major classes of pericyclic processes: electrocyclic reactions, cycloaddition reactions, and sigmatropic rearrangements. The stereochemistry of these reactions is controlled by the symmetry of the orbitals involved in bond reorganization. Electrocyclic reactions involve the cyclization of conjugated acyclic polyenes. For example, 1,3,5-hexatriene cyclizes to 1,3-cyclohexadiene on heating. Electrocyclic reactions can occur by either conrotatory or disrotatory pathways, depending on the symmetry of the terminal lobes of the π system. Conrotatory cyclization requires that both lobes rotate in the same direction, whereas disrotatory cyclization requires that the lobes rotate in opposite directions. The reaction course in a specific case can be found by looking at the symmetry of the highest occupied molecular orbital (HOMO) . Cycloaddition reactions are those in which two unsaturated molecules add together to yield a cyclic product. For example, Diels–Alder reaction between a diene (four π electrons) and a dienophile (two π electrons) yields a cyclohexene. Cycloadditions can take place either by suprafacial or antarafacial pathways. Suprafacial cycloaddition involves interaction between lobes on the same face of one component and on the same face of the second component. Antarafacial cycloaddition involves interaction between lobes on the same face of one component and on opposite faces of the other component. The reaction course in a specific case can be found by looking at the symmetry of the HOMO of one component and the lowest unoccupied molecular orbital (LUMO) of the other. Sigmatropic rearrangements involve the migration of a σ -bonded group across a π electron system. For example, Claisen rearrangement of an allylic vinylic ether yields an unsaturated carbonyl compound, and Cope rearrangement of a 1,5-hexadiene yields an isomeric 1,5-hexadiene. Sigmatropic rearrangements can occur with either suprafacial or antarafacial stereochemistry; the selection rules for a given case are the same as those for cycloaddition reactions. The stereochemistry of any pericyclic reaction can be predicted by counting the total number of electron pairs (bonds) involved in bond reorganization and then applying the mnemonic “ T he E lectrons C ircle A round.” That is, thermal (ground-state) reactions involving an even number of electron pairs occur with either conrotatory or antarafacial stereochemistry. Exactly the opposite rules apply to photochemical (excited-state) reactions. Additional Problems Visualizing Chemistry Mechanism Problems Electrocyclic Reactions Cycloaddition Reactions Sigmatropic Rearrangements General Problems

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Why This Chapter? If you ride a bike, wear your helmet! Most bike helmets are made of two different polymers, a hard polycarbonate shell and an inner layer of polystyrene . (credit: modification of work “View from the top” by Gene Bisbee/Flickr, CC BY 2.0) Our treatment of polymers has thus far been dispersed over several chapters, but it’s also important to take a comprehensive view. In the present chapter, we’ll look further at how polymers are made, and we’ll see how polymer structure correlates with physical properties. No course in organic chemistry would be complete without a look at polymers. Polymers are a fundamental part of the modern world, used in everything from coffee cups to cars to clothing. In medicine, too, their importance is growing, with uses as diverse as cardiac pacemakers, artificial heart valves, and biodegradable sutures. We’ve seen on several occasions in previous chapters that a polymer , whether synthetic or biological, is a large molecule built up by repetitive bonding of many smaller units, or monomers . Polyethylene, for instance, is a synthetic polymer made from ethylene ( ), nylon is a synthetic polyamide made from a diacid and a diamine ( ), and proteins are biological polyamides made from amino acids. Note that polymers are often drawn by indicating their repeating unit in parentheses. The repeating unit in polystyrene, for example, comes from the monomer styrene.

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Chain-Growth Polymers Synthetic polymers are classified by their method of synthesis as either chain-growth or step-growth . These categories are somewhat imprecise but nevertheless provide a useful distinction. Chain-growth polymers are produced by chain-reaction polymerization in which an initiator adds to the carbon–carbon double bond of an unsaturated substrate (a vinyl monomer ) to yield a reactive intermediate. This intermediate reacts with a second molecule of monomer to yield a new intermediate, which reacts with a third monomer unit, and so on. The initiator can be a radical, an acid, or a base. Historically, as we saw in , radical polymerization was the most common method because it can be carried out with practically any vinyl monomer. Acid-catalyzed (cationic) polymerization, by contrast, is effective only with vinyl monomers that contain an electron-donating group (EDG) capable of stabilizing the chain-carrying carbocation intermediate. Propene (2-methylpropylene) is a good example of a monomer that polymerizes rapidly under cationic conditions. The reaction is carried out commercially at –80 °C, using BF 3 and a small amount of water to generate BF 3 OH – H + catalyst. The product is used in the manufacture of truck and bicycle inner tubes. Vinyl monomers with electron-withdrawing groups (EWG) can be polymerized by basic (anionic) catalysts. The chain-carrying step is a conjugate nucleophilic addition of an anion to the unsaturated monomer ( ). Acrylonitrile ( H 2 C ═ CHCN ), methyl methacrylate [ H 2 C ═ C ( CH 3 ) CO 2 CH 3 ], and styrene ( H 2 C ═ CHC 6 H 5 ) can all be polymerized anionically. The polystyrene used in foam coffee cups, for example, is prepared by anionic polymerization of styrene using butyllithium as catalyst. An interesting example of anionic polymerization accounts for the remarkable properties of “super glue,” one drop of which can support up to 2000 lb. Super glue is simply a solution of pure methyl α -cyanoacrylate, which has two electron-withdrawing groups that make anionic addition particularly easy. Trace amounts of water or bases on the surface of an object are sufficient to initiate polymerization of the cyanoacrylate and bind articles together. Skin is a good source of the necessary basic initiators, and many people have found their fingers stuck together after inadvertently touching super glue. So good is super glue at binding tissues that related cyanoacrylate esters such as Dermabond are often used in place of sutures to close wounds. Problems

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Stereochemistry of Polymerization: Ziegler–Natta Catalysts Although we didn’t point it out when discussing chain-growth polymers in , the polymerization of a substituted vinyl monomer can lead to a polymer with numerous chirality centers in its chain. Propylene, for example, might polymerize with any of the three stereochemical outcomes shown in . A polymer with all methyl groups on the same side of the zigzag backbone is called isotactic , one in which the methyl groups alternate regularly on opposite sides of the backbone is called syndiotactic , and one with its methyl groups randomly oriented is called atactic . Isotactic, syndiotactic, and atactic forms of polypropylene. The three different stereochemical forms of polypropylene all have somewhat different properties, and all can be made by using the right polymerization catalyst. Propylene polymerization using radical initiators does not work well, but polymerization using Ziegler–Natta catalysts allows preparation of isotactic, syndiotactic, and atactic polypropylene. Ziegler–Natta catalysts —there are many different formulations—are organometallic transition-metal complexes prepared by treatment of an alkylaluminum with a titanium compound. Triethylaluminum with titanium tetrachloride is a typical preparation. ( CH 3 CH 2 ) 3 Al + TiCl 4 → A Ziegler–Natta catalyst Following their introduction in 1953, Ziegler–Natta catalysts revolutionized the field of polymer chemistry because of two advantages: first, the resultant polymers are linear, with practically no chain branching, and second, they are stereochemically controllable. Isotactic, syndiotactic, and atactic forms can all be produced, depending on the catalyst system used. The active form of a Ziegler–Natta catalyst is an alkyltitanium intermediate with a vacant coordination site on the metal. Coordination of alkene monomer to the titanium occurs, and the coordinated alkene then inserts into the carbon–titanium bond to extend the alkyl chain. A new coordination site opens up during the insertion step, so the process repeats indefinitely. The linear polyethylene produced by the Ziegler–Natta process, called high-density polyethylene, is a highly crystalline polymer with 4000 to 7000 ethylene units per chain and molecular weights in the range 100,000 to 200,000 amu. High-density polyethylene has greater strength and heat resistance than the branched product of radical-induced polymerization, called low-density polyethylene, and is used to produce plastic squeeze bottles and molded housewares. Polyethylenes of even higher molecular weights are produced for specialty applications. So-called high-molecular-weight (HMW) polyethylene contains 10,000 to 18,000 monomer units per chain and molecular weights in the range of 300,000–500,000. It is used for underground pipes and large containers. Ultrahigh-molecular-weight (UHMW) polyethylene contains more than 100,000 monomer units per chain and has molecular weights ranging from 3,000,000 to 6,000,000 amu. It is used in bearings, conveyor belts, and bulletproof vests, among other applications requiring exceptional wear resistance. Problems

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Copolymers Up to this point we’ve discussed only homopolymers —polymers that are made up of identical repeating units. In practice, however, copolymers are more important commercially. Copolymers are obtained when two or more different monomers are allowed to polymerize together. For example, copolymerization of vinyl chloride with vinylidene chloride (1,1-dichloroethylene) in a 1 : 4 ratio leads to the polymer Saran. Copolymerization of monomer mixtures often leads to materials with properties quite different from those of either corresponding homopolymer, giving the polymer chemist a vast flexibility for devising new materials. lists some common copolymers and their commercial applications. Some Common Copolymers and Their Uses Monomers Structures Trade name Uses Vinyl chloride Vinylidene chloride Saran Fibers, food packaging Styrene 1,3-Butadiene SBR (styrene–butadiene rubber) Tires, rubber articles Hexafluoropropene Vinylidene fluoride Viton Gaskets, seals Acrylonitrile 1,3-Butadiene Nitrile rubber Adhesives, hoses Isobutylene Isoprene Butyl rubber Inner tubes Acrylonitrile 1,3-Butadiene Styrene ABS (monomer initials) Pipes, high-impact applications Several different types of copolymers can be defined, depending on the distribution of monomer units in the chain. If monomer A is copolymerized with monomer B, for instance, the resultant product might have a random distribution of the two units throughout the chain, or it might have an alternating distribution. The exact distribution of monomer units depends on the initial proportions of the two reactant monomers and their relative reactivities. In practice, neither perfectly random nor perfectly alternating copolymers are usually found. Most copolymers have many random imperfections. Two other forms of copolymers that can be prepared under certain conditions are called block copolymers and graft copolymers . Block copolymers are those in which different blocks of identical monomer units alternate with each other; graft copolymers are those in which homopolymer branches of one monomer unit are “grafted” onto a homopolymer chain of another monomer unit. Block copolymers are prepared by initiating the polymerization of one monomer as if growing a homopolymer chain and then adding an excess of the second monomer to the still-active reaction mix. Graft copolymers are made by gamma irradiation of a completed homopolymer chain in the presence of the second monomer. The high-energy irradiation knocks hydrogen atoms off the homopolymer chain at random points, thus generating new radical sites that can initiate polymerization of the added monomer. Problems

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Step-Growth Polymers Step-growth polymers are produced by reactions in which each bond in the polymer is formed stepwise, independently of the other bonds. Like the polyamides (nylons) and polyesters that we saw in , most step-growth polymers are produced by reaction between two difunctional reactants. The polymer Nylon 66, for instance, is made by reaction between the six-carbon adipic acid and the six-carbon hexamethylenediamine (1,6-hexanediamine). Alternatively, a single reactant with two different functional groups can polymerize. Nylon 6 is made by polymerization of the six-carbon caprolactam. The reaction is initiated by adding a small amount of water, which hydrolyzes some caprolactam to 6-aminohexanoic acid. Nucleophilic addition of the amino group to caprolactam then propagates the polymerization. Polycarbonates Polycarbonates are like polyesters, but their carbonyl group is linked to two –OR groups, [ O ═ C ( OR ) 2 ]. Lexan, for instance, is a polycarbonate prepared from diphenyl carbonate and a diphenol called bisphenol A. Lexan has unusually high impact strength, making it valuable for use in machinery housings, telephones, bicycle safety helmets, and bulletproof glass. Polyurethanes A urethane is a carbonyl-containing functional group in which the carbonyl carbon is bonded to both an –OR group and an –NR 2 group. As such, a urethane is halfway between a carbonate and a urea. A urethane is typically prepared by nucleophilic addition reaction of an alcohol with an isocyanate ( R ─ N ═ C ═ O ), so a polyurethane is prepared by reaction of a diol with a diisocyanate. The diol is usually a low-molecular-weight polymer (MW ≈ 1000 amu) with hydroxyl end-groups; the diisocyanate is often toluene-2,4-diisocyanate. Several different kinds of polyurethanes can be produced, depending on the nature of the polymeric alcohol used. One major use of polyurethane is in the stretchable spandex fibers used for bathing suits and athletic gear. These polyurethanes have a fairly low degree of cross-linking so that the resultant polymer is soft and elastic. A second major use of polyurethanes is in the foams used for insulation. Foaming occurs when a small amount of water is added during polymerization, giving a carbamic acid intermediate that spontaneously loses bubbles of CO 2 . Polyurethane foams are generally made using a poly alcohol rather than a diol as the monomer so that the polymer has a high amount of three-dimensional cross-linking. The result is a rigid but very light foam suitable for use as thermal insulation in building construction and portable ice chests. Problems

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Olefin Metathesis Polymerization Perhaps the most important advance in polymer synthesis in recent years has been the development of olefin metathesis polymerization by Yves Chauvin of the Institut Français du Pétrole, Robert H. Grubbs of CalTech, and Richard R.Schrock of MIT who shared the 2005 Nobel Prize in Chemistry for their work. At its simplest, an olefin metathesis reaction is two olefins (alkenes) exchanging substituents on their double bonds. Olefin metathesis catalysts, such as the Grubbs catalyst now in common use, contain a carbon–metal double bond (usually to ruthenium, Ru) and have the general structure M═ CH ─ R . They function by reacting reversibly with an alkene to form a four-membered, metal-containing intermediate called a metallacycle , which immediately opens to give a different catalyst and a different alkene. The mechanism is shown in . Mechanism of the olefin metathesis reaction. The process is initiated by a two-step sequence that involves ( 1 ) reaction of the catalyst and olefin 1 to give a four-membered metallacycle intermediate, followed by ( 2 ) ring-opening to give a different form of catalyst that contains part of olefin 1. ( 3 ) Reaction of this new catalyst with olefin 2 gives another metallacycle intermediate, ( 4 ) which opens to give metathesis product and another form of catalyst. ( 5 , 6 ) The repeating ring-forming and ring-opening steps then continue. There are several methods for implementing the olefin metathesis reaction to prepare polymers. One method, called ring-opening metathesis polymerization , or ROMP , involves the use of a moderately strained cycloalkene, such as cyclopentene. The strain of the ring favors ring-opening, thereby driving formation of the open-chain product. The polymer that results has double bonds spaced regularly along the chain, allowing for either hydrogenation or further functionalization if desired. A second method of using olefin metathesis to prepare polymers is by acyclic diene metathesis , or ADMET . As the name suggests, ADMET involves olefin metathesis of an open-chain substrate with two double bonds at the ends of a long chain, such as 1,8-nonadiene. As the reaction proceeds, the gaseous ethylene by-product escapes, thereby driving the equilibrium toward polymer product. So efficient is this reaction that polymers with molecular weights as high as 80,000 amu have been prepared. The ROMP and ADMET procedures are particularly valuable because the metathesis reaction is compatible with the presence in the olefin monomer of many different functional groups. In addition, the double bonds in the polymers provide still more flexibility for further manipulations. Among the commercial polymers produced by olefin metathesis are Vestenamer, used in the manufacture of tires and other molded rubber objects, and Norsorex, used in the automobile industry as a sealing material. Problems

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Intramolecular Olefin Metathesis The olefin metathesis reaction has been used primarily as an intermolecular process for polymer synthesis, but it is also finding increased usage in complex organic synthesis as an intramolecular process in what is called ring-closing metathesis (RCM). The optimum catalyst is an Ru(II) complex, and cyclic alkenes with up to 30 atoms in ring size are easily produced.

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Polymer Structure and Physical Properties Polymers aren’t really that different from other organic molecules. They’re much larger, of course, but their chemistry is similar to that of analogous small molecules. Thus, the alkane chains of polyethylene undergo radical-initiated halogenation, the aromatic rings of polystyrene undergo typical electrophilic aromatic substitution reactions, and the amide linkages of nylon are hydrolyzed by aqueous base. The major difference between small and large organic molecules is in their physical properties. For instance, their large size means that polymers experience substantially greater van der Waals forces than do small molecules ( ). But because van der Waals forces operate only at close distances, they are strongest in polymers like high-density polyethylene, in which chains can pack together closely in a regular way. Many polymers, in fact, have regions that are essentially crystalline. These regions, called crystallites , consist of highly ordered portions in which the zigzag polymer chains are held together by van der Waals forces ( ). Crystallites in linear polyethylene. The long polymer chains are arranged in parallel lines in the crystallite regions. As you might expect, polymer crystallinity is strongly affected by the steric requirements of substituent groups on the chains. Linear polyethylene is highly crystalline, but poly(methyl methacrylate) is noncrystalline because the chains can’t pack closely together in a regular way. Polymers with a high degree of crystallinity are generally hard and durable. When heated, the crystalline regions melt at the melt transition temperature, T m , to give an amorphous material. Noncrystalline, amorphous polymers like poly(methyl methacrylate), sold under the trade name Plexiglas, have little or no long-range ordering among chains but can nevertheless be very hard at room temperature. When heated, the hard amorphous polymer becomes soft and flexible at a point called the glass transition temperature, T g . Much of the art in polymer synthesis lies in finding methods for controlling the degree of crystallinity and the glass transition temperature, thereby imparting useful properties to the polymer. In general, polymers can be divided into four major categories, depending on their physical behavior: thermoplastics, fibers, elastomers, and thermosetting resins . Thermoplastics are the polymers most people think of when the word plastic is mentioned. These polymers have a high glass transition temperature and are therefore hard at room temperature but become soft and viscous when heated. As a result, they can be molded into toys, beads, telephone housings, or any of a thousand other items. Because thermoplastics have little or no cross-linking, the individual chains can slip past one another in the melt. Some thermoplastic polymers, such as poly(methyl methacrylate) and polystyrene, are amorphous and noncrystalline; others, such as polyethylene and nylon, are partially crystalline. Among the better-known thermoplastics is poly(ethylene terephthalate), or PET, used for making plastic soft-drink bottles. Plasticizers —small organic molecules that act as lubricants between chains—are usually added to thermoplastics to keep them from becoming brittle at room temperature. An example is poly(vinyl chloride), which is brittle when pure but becomes supple and pliable when a plasticizer is added. In fact, most drip bags used in hospitals to deliver intravenous saline solutions are made of poly(vinyl chloride), although replacements such as polypropylene are appearing. Dialkyl phthalates such as di(2-ethylhexyl) phthalate (generally called dioctyl phthalate) are commonly used as plasticizers, although questions about their safety have been raised. The U.S. Food and Drug Administration (FDA) has advised the use of alternative materials in compromised patients and infants but has found no evidence of toxicity for healthy individuals. In addition, children’s toys that contain phthalates have been banned in the United States. Fibers are thin threads produced by extruding a molten polymer through small holes in a die, or spinneret. The fibers are then cooled and drawn out, which orients the crystallite regions along the axis of the fiber and adds considerable tensile strength . Nylon, Dacron, and polyethylene all have the semicrystalline structure necessary for being drawn into oriented fibers. Oriented crystallite regions in a polymer fiber. Elastomers are amorphous polymers that have the ability to stretch out and spring back to their original shapes. These polymers must have low glass transition temperatures and a small amount of cross-linking to prevent the chains from slipping over one another. In addition, the chains must have an irregular shape to prevent crystallite formation. When stretched, the randomly coiled chains straighten out and orient along the direction of the pull. Van der Waals forces are too weak and too few to maintain this orientation, however, and the elastomer therefore reverts to its random coiled state when the stretching force is released ( ). Unstretched and stretched forms of an elastomer. Natural rubber ( ) is the most common example of an elastomer. Rubber has the long chains and occasional cross-links needed for elasticity, but its irregular geometry prevents close packing of the chains into crystallites. Gutta-percha, by contrast, is highly crystalline and is not an elastomer ( ). (a) Natural rubber is elastic and noncrystalline because of its cis double-bond geometry, but (b) gutta-percha is nonelastic and crystalline because its geometry allows for better packing together of chains. Thermosetting resins are polymers that become highly cross-linked and solidify into a hard, insoluble mass when heated. Bakelite, a thermosetting resin first produced in 1907, has been in commercial use longer than any other synthetic polymer. It is widely used for molded parts, adhesives, coatings, and even high-temperature applications such as missile nose cones. Chemically, Bakelite is a phenolic resin , produced by reaction of phenol and formaldehyde. On heating, water is eliminated, many cross-links form, and the polymer sets into a rocklike mass. The cross-linking in Bakelite and other thermosetting resins is three-dimensional and is so extensive that we can’t really speak of polymer “chains.” A piece of Bakelite is essentially one large molecule. Problems Degradable Polymers The high chemical stability of many polymers is both a blessing and a curse. Heat resistance, wear resistance, and long life are valuable characteristics of clothing fibers, bicycle helmets, underground pipes, food wrappers, and many other items. Yet when these items outlive their usefulness, disposal becomes a problem. What happens to the plastics that end up here? (credit: modification of work “King of the trash hill” by Alan Levine/Flickr, CC BY 2.0) Recycling of unwanted polymers is the best solution, and six types of plastics in common use are frequently stamped with identifying codes assigned by the Society of the Plastics Industry . After being sorted by type, the items to be recycled are shredded into small chips, washed, dried, and melted for reuse. Soft-drink bottles, for instance, are made from recycled poly(ethylene terephthalate), trash bags are made from recycled low-density polyethylene, and garden furniture is made from recycled polypropylene and mixed plastics. Recyclable Plastics Polymer Recycling code Use Poly(ethylene terephthalate) 1—PET Soft-drink bottles High-density polyethylene 2—HDPE Bottles Poly(vinyl chloride) 3—V Floor mats Low-density polyethylene 4—LDPE Grocery bags Polypropylene 5—PP Furniture Polystyrene 6—PS Molded articles Mixed plastics 7 Benches, plastic lumber Frequently, however, plastics are simply thrown away rather than recycled, and much work has therefore been carried out on developing biodegradable polymers, which can be broken down by soil microorganisms. Among the most common biodegradable polymers are polyglycolic acid (PGA), polylactic acid (PLA), and polyhydroxybutyrate (PHB). All are polyesters and are therefore susceptible to hydrolysis of their ester links. Copolymers of PGA with PLA have found a particularly wide range of uses. A 90/10 copolymer of polyglycolic acid with polylactic acid is used to make absorbable sutures that are degraded and absorbed by the body within 90 days after surgery. Biodegradation is important, but even better than the breakdown of a small group of specialized polymers would be the development of a generalized method of breakdown that could be used on any polymer, including even hydrocarbon polymers such as polyethylene and polypropylene. Such a method has recently been reported by chemists at the University of Delaware, using hydrogen at 200 °C and 2 atm pressure in the presence of an organozirconium catalyst to turn polyethylene into simple hydrocarbons. The method uses a large amount of hydrogen at present, but it is an impressive start. atactic polymer block copolymer chain-growth polymer copolymer crystallite elastomer fiber glass transition temperature ( T g ) graft copolymer homopolymer isotactic polymer melt transition temperature ( T m ) monomer olefin metathesis polymerization plasticizer polycarbonate polymer polyurethane syndiotactic polymer thermoplastic thermosetting resin urethane Ziegler–Natta catalyst Summary Synthetic polymers can be classified as either chain-growth or step-growth. Chain-growth polymers are prepared by chain-reaction polymerization of vinyl monomers in the presence of a radical, an anion, or a cation initiator. Radical polymerization is sometimes used, but alkenes such as 2-methylpropene that have electron-donating substituents on the double bond polymerize easily by a cationic route through carbocation intermediates. Similarly, monomers such as methyl α -cyanoacrylate that have electron-withdrawing substituents on the double bond polymerize by an anionic, conjugate addition pathway. Copolymerization of two monomers gives a product with properties different from those of either homopolymer. Graft copolymers and block copolymers are two examples. Alkene polymerization can be carried out in a controlled manner using a Ziegler–Natta catalyst . Ziegler–Natta polymerization minimizes the amount of chain branching in the polymer and leads to stereoregular chains—either isotactic (substituents on the same side of the chain) or syndiotactic (substituents on alternate sides of the chain), rather than atactic (substituents randomly disposed). Step-growth polymers, the second major class of polymers, are prepared by reactions between difunctional molecules, with individual bonds in the polymer formed independently of one another. Polycarbonates are formed from a diester and a diol, and polyurethanes are formed from a diisocyanate and a diol. The chemistry of synthetic polymers is similar to the chemistry of small molecules with the same functional groups, but the physical properties of polymers are greatly affected by size. Polymers can be classified by physical property into four groups: thermoplastics , fibers , elastomers , and thermosetting resins . The properties of each group can be accounted for by the structure, the degree of crystallinity, and the amount of cross-linking they contain. Additional Problems Visualizing Chemistry Mechanism Problems General Problems

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Nomenclature of Polyfunctional Organic Compounds With more than 40 million organic compounds now known and thousands more being created daily, naming them all is a real problem. Part of the problem is due to the sheer complexity of organic structures, but part is also due to the fact that chemical names have more than one purpose. For the Chemical Abstracts Service (CAS), which catalogs and indexes the worldwide chemical literature, each compound must have only one correct name. It would be chaos if half the entries for CH 3 Br were indexed under “M” for methyl bromide and half under “B” for bromomethane. Furthermore, a CAS name must be strictly systematic so that it can be assigned and interpreted by computers; common names are not allowed. People, however, have different requirements than computers. For people—which is to say students and professional chemists in their spoken and written communications—it’s best that a chemical name be pronounceable and as easy as possible to assign and interpret. Furthermore, it’s convenient if names follow historical precedents, even if that means a particularly well-known compound might have more than one name. People can readily understand that bromomethane and methyl bromide both refer to CH 3 Br. As noted in the text, chemists overwhelmingly use the nomenclature system devised and maintained by the International Union of Pure and Applied Chemistry, or IUPAC. Rules for naming monofunctional compounds were given throughout the text as each new functional group was introduced, and a list of where these rules can be found is given in . Nomenclature Rules for Functional Groups Functional group Text section Acid anhydrides 21-1 Acid halides 21-1 Acyl phosphates 21-1 Alcohols 17-1 Aldehydes 19-1 Alkanes 3-4 Alkenes 7-3 Alkyl halides 10-1 Alkynes 9-1 Amides 21-1 Amines 24-1 Aromatic compounds 15-1 Carboxylic acids 20-1 Cycloalkanes 4-1 Esters 21-1 Ethers 18-1 Ketones 19-1 Nitriles 20-1 Phenols 17-1 Sulfides 18-7 Thiols 18-7 Thioesters 21-1 Naming a monofunctional compound is reasonably straightforward, but even experienced chemists often encounter problems when faced with naming a complex polyfunctional compound. Take the following compound, for instance. It has three functional groups, ester, ketone, and C ═ C , but how should it be named? As an ester with an - oate ending, a ketone with an - one ending, or an alkene with an - ene ending? It’s actually named methyl 3-(2-oxo-6-cyclohexenyl)propanoate. The name of a polyfunctional organic molecule has four parts—suffix, parent, prefixes, and locants—which must be identified and expressed in the proper order and format. Let’s look at each of the four. Name Part 1. The Suffix: Functional-Group Precedence Although a polyfunctional organic molecule might contain several different functional groups, we must choose just one suffix for nomenclature purposes. It’s not correct to use two suffixes. Thus, keto ester 1 must be named either as a ketone with an - one suffix or as an ester with an - oate suffix, but it can’t be named as an - onoate. Similarly, amino alcohol 2 must be named either as an alcohol (- ol ) or as an amine (- amine ), but it can’t be named as an - olamine or - aminol. The only exception to the rule requiring a single suffix is when naming compounds that have double or triple bonds. Thus, the unsaturated acid H 2 C ═ CHCH 2 CO 2 H is 3-butenoic acid, and the acetylenic alcohol HC ≡ CCH 2 CH 2 CH 2 OH is 5-pentyn-1-ol. How do we choose which suffix to use? Functional groups are divided into two classes, principal groups and subordinate groups , as shown in . Principal groups can be cited either as prefixes or as suffixes, while subordinate groups are cited only as prefixes. Within the principal groups, an order of priority has been established: the proper suffix for a given compound is determined by choosing the principal group of highest priority. For example, indicates that keto ester 1 should be named as an ester rather than as a ketone because an ester functional group is higher in priority than a ketone. Similarly, amino alcohol 2 should be named as an alcohol rather than as an amine. Thus, the name for 1 is methyl 4-oxopentanoate and the name for 2 is 5-amino-2-pentanol. Further examples are shown: Classification of Functional Groups a Functional group Name as suffix Name as prefix a Principal groups are listed in order of decreasing priority; subordinate groups have no priority order. Principal groups Carboxylic acids -oic acid carboxy -carboxylic acid Acid anhydrides -oic anhydride — -carboxylic anhydride Esters -oate alkoxycarbonyl -carboxylate Thioesters -thioate alkylthiocarbonyl -carbothioate Acid halides -oyl halide halocarbonyl -carbonyl halide Amides -amide carbamoyl -carboxamide Nitriles -nitrile cyano -carbonitrile Aldehydes -al oxo -carbaldehyde Ketones -one oxo Alcohols -ol hydroxy Phenols -ol hydroxy Thiols -thiol mercapto Amines -amine amino Imines -imine imino Ethers ether alkoxy Sulfides sulfide alkylthio Disulfides disulfide — Alkenes -ene — Alkynes -yne — Alkanes -ane — Subordinate groups Azides — azido Halides — halo Nitro compounds — nitro Name Part 2. The Parent: Selecting the Main Chain or Ring The parent, or base, name of a polyfunctional organic compound is usually easy to identify. If the principal group of highest priority is part of an open chain, the parent name is that of the longest chain containing the largest number of principal groups. For example, compounds 6 and 7 are isomeric aldehydo amides, which must be named as amides rather than as aldehydes according to . The longest chain in compound 6 has six carbons, and the substance is named 5-methyl-6-oxohexanamide. Compound 7 also has a chain of six carbons, but the longest chain that contains both principal functional groups has only four carbons. Thus, compound 7 is named 4-oxo-3-propylbutanamide. If the highest-priority principal group is attached to a ring, the parent name is that of the ring system. Compounds 8 and 9 , for instance, are isomeric keto nitriles and must both be named as nitriles according to . Substance 8 is named as a benzonitrile because the −CN functional group is a substituent on the aromatic ring, but substance 9 is named as an acetonitrile because the −CN functional group is on an open chain. Thus, their names are 2-acetyl-(4-bromomethyl)benzonitrile (8) and (2-acetyl-4-bromophenyl)acetonitrile (9) . As further examples, compounds 10 and 11 are both keto acids and must be named as acids, but the parent name in 10 is that of a ring system (cyclohexanecarboxylic acid) and the parent name in 11 is that of an open chain (propanoic acid). Thus, their names are trans -2-(3-oxopropyl)cyclohexanecarboxylic acid (10) and 3-(2-oxocyclohexyl)propanoic acid (11) . Name Parts 3 and 4. The Prefixes and Locants With the parent name and the suffix established, the next step is to identify and give numbers, or locants, to all substituents on the parent chain or ring. The substituents include all alkyl groups and all functional groups other than the one cited in the suffix. For example, compound 12 contains three different functional groups (carboxyl, keto, and double bond). Because the carboxyl group is highest in priority and the longest chain containing the functional groups has seven carbons, compound 12 is a heptenoic acid. In addition, the parent chain has a keto (oxo) substituent and three methyl groups. Numbering from the end nearer the highest-priority functional group gives the name ( E )-2,5,5-trimethyl-4-oxo-2-heptenoic acid. Look back at some of the other compounds we’ve named to see other examples of how prefixes and locants are assigned. Writing the Name With the name parts established, the entire name can be written out. Several additional rules apply: Order of prefixes. When the substituents have been identified, the parent chain has been numbered, and the proper multipliers such as di - and tri - have been assigned, the name is written with the substituents listed in alphabetical, rather than numerical, order. Multipliers such as di - and tri - are not used for alphabetization, but the italicized prefixes iso - and sec - are used. Use of hyphens; single- and multiple-word names. The general rule is to determine whether the parent is itself an element or compound. If it is, then the name is written as a single word; if it isn’t, then the name is written as multiple words. Methylbenzene is written as one word, for instance, because the parent—benzene—is a compound. Diethyl ether, however, is written as two words because the parent—ether—is a class name rather than a compound name. Some further examples follow: Parentheses. Parentheses are used to denote complex substituents when ambiguity would otherwise arise. For example, chloromethylbenzene has two substituents on a benzene ring, but (chloromethyl)benzene has only one complex substituent. Note that the expression in parentheses is not set off by hyphens from the rest of the name. Additional Reading Further explanations of the rules of organic nomenclature can be found online at ACD Labs (accessed May 2023) and in the following references: “A Guide to IUPAC Nomenclature of Organic Compounds,” CRC Press, Boca Raton, FL, 1993. “Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H,” International Union of Pure and Applied Chemistry, Pergamon Press, Oxford, 1979.

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Acidity Constants for Some Organic Compounds Compound p K a CH 3 SO 3 H −1.8 CH(NO 2 ) 3 0.1 0.3 CCl 3 CO 2 H 0.5 CF 3 CO 2 H 0.5 CBr 3 CO 2 H 0.7 HO 2 CC ≡ CCO 2 H 1.2; 2.5 HO 2 CCO 2 H 1.2; 3.7 CHCl 2 CO 2 H 1.3 CH 2 (NO 2 )CO 2 H 1.3 HC ≡ CCO 2 H 1.9 (Z) HO 2 CCH ═ CHCO 2 H 1.9; 6.3 2.4 CH 3 COCO 2 H 2.4 NCCH 2 CO 2 H 2.5 CH 3 C ≡ CCO 2 H 2.6 CH 2 FCO 2 H 2.7 CH 2 ClCO 2 H 2.8 HO 2 CCH 2 CO 2 H 2.8; 5.6 CH 2 BrCO 2 H 2.9 3.0 3.0 CH 2 ICO 2 H 3.2 CHOCO 2 H 3.2 3.4 3.5 HSCH 2 CO 2 H 3.5; 10.2 CH 2 (NO 2 ) 2 3.6 CH 3 OCH 2 CO 2 H 3.6 CH 3 COCH 2 CO 2 H 3.6 HOCH 2 CO 2 H 3.7 HCO 2 H 3.7 3.8 4.0 CH 2 BrCH 2 CO 2 H 4.0 4.1 4.2 H 2 C ═ CHCO 2 H 4.2 HO 2 CCH 2 CH 2 CO 2 H 4.2; 5.7 HO 2 CCH 2 CH 2 CH 2 CO 2 H 4.3; 5.4 4.5 H 2 C ═ C(CH 3 )CO 2 H 4.7 CH 3 CO 2 H 4.8 CH 3 CH 2 CO 2 H 4.8 (CH 3 ) 3 CCO 2 H 5.0 CH 3 COCH 2 NO 2 5.1 5.3 O 2 NCH 2 CO 2 CH 3 5.8 5.8 6.2 6.6 HCO 3 H 7.1 7.2 (CH 3 ) 2 CHNO 2 7.7 7.8 CH 3 CO 3 H 8.2 8.5 CH 3 CH 2 NO 2 8.5 8.7 CH 3 COCH 2 COCH 3 9.0 9.3; 11.1 9.3; 12.6 9.4 9.9; 11.5 9.9 CH 3 COCH 2 SOCH 3 10.0 10.3 CH 3 NO 2 10.3 CH 3 SH 10.3 CH 3 COCH 2 CO 2 CH 3 10.6 CH 3 COCHO 11.0 CH 2 (CN) 2 11.2 CCl 3 CH 2 OH 12.2 Glucose 12.3 (CH 3 ) 2 C ═ NOH 12.4 CH 2 (CO 2 CH 3 ) 2 12.9 CHCl 2 CH 2 OH 12.9 CH 2 (OH) 2 13.3 HOCH 2 CH(OH)CH 2 OH 14.1 CH 2 ClCH 2 OH 14.3 15.0 15.4 CH 3 OH 15.5 H 2 C ═ CHCH 2 OH 15.5 CH 3 CH 2 OH 16.0 CH 3 CH 2 CH 2 OH 16.1 CH 3 COCH 2 Br 16.1 16.7 CH 3 CHO 17 (CH 3 ) 2 CHCHO 17 (CH 3 ) 2 CHOH 17.1 (CH 3 ) 3 COH 18.0 CH 3 COCH 3 19.3 23 CH 3 CO 2 CH 2 CH 3 25 HC ≡ CH 25 CH 3 CN 25 CH 3 SO 2 CH 3 28 (C 6 H 5 ) 3 CH 32 (C 6 H 5 ) 2 CH 2 34 CH 3 SOCH 3 35 NH 3 36 CH 3 CH 2 NH 2 36 (CH 3 CH 2 ) 2 NH 40 41 43 H 2 C ═ CH 2 44 CH 4 ∼60 An acidity list covering more than 5000 organic compounds has been published: E.P. Serjeant and B. Dempsey (eds.), “Ionization Constants of Organic Acids in Aqueous Solution,” IUPAC Chemical Data Series No. 23, Pergamon Press, Oxford, 1979.

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