Intramolecular Aldol Reactions The aldol reactions we’ve seen thus far have all been intermolecular , meaning that they have taken place between two different molecules. When certain di carbonyl compounds are treated with base, however, an intramolecular aldol reaction can occur, leading to the formation of a cyclic product. For example, base treatment of a 1,4-diketone such as 2,5-hexanedione yields a cyclopentenone product, and base treatment of a 1,5-diketone such as 2,6-heptanedione yields a cyclohexenone. The mechanism of intramolecular aldol reactions is similar to that of intermolecular reactions. The only difference is that both the nucleophilic carbonyl anion donor and the electrophilic carbonyl acceptor are now in the same molecule. One complication, however, is that intramolecular aldol reactions might lead to a mixture of products, depending on which enolate ion is formed. For example, 2,5-hexanedione might yield either the five-membered-ring product 3-methyl-2-cyclopentenone or the three-membered-ring product (2-methylcyclopropenyl) ethanone ( ). In practice, though, only the cyclopentenone is formed. Intramolecular aldol reaction of 2,5-hexanedione yields 3-methyl-2-cyclopentenone rather than the alternative cyclopropene . The selectivity observed in the intramolecular aldol reaction of 2,5-hexanedione is due to the fact that all steps in the mechanism are reversible, so an equilibrium is reached. Thus, the relatively strain-free cyclopentenone product is considerably more stable than the highly strained cyclopropene alternative. For similar reasons, intramolecular aldol reactions of 1,5-diketones lead only to cyclohexenone products rather than to the more strained acylcyclobutenes. Problems

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The Claisen Condensation Reaction Esters, like aldehydes and ketones, are weakly acidic. When an ester with an α hydrogen is treated with 1 equivalent of a base such as sodium ethoxide, a reversible carbonyl condensation reaction occurs to yield a β -keto ester. For instance, ethyl acetate yields ethyl acetoacetate on base treatment. This reaction between two ester molecules is known as the Claisen condensation reaction . (We’ll use ethyl esters, abbreviated “Et,” for consistency, but other esters will also work.) The mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule ( ). The only difference between the aldol condensation of an aldehyde or ketone and the Claisen condensation of an ester involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is protonated to give an alcohol product—exactly the behavior previously seen for aldehydes and ketones ( ). The tetrahedral intermediate in the Claisen reaction, however, expels an alkoxide leaving group to yield an acyl substitution product—as previously seen for esters ( ). MECHANISM Mechanism of the Claisen condensation reaction . If the starting ester has more than one acidic α hydrogen, the product β -keto ester has a highly acidic, doubly activated hydrogen atom that can be abstracted by base. This deprotonation of the product requires the use of a full equivalent of base rather than a catalytic amount. Furthermore, the deprotonation serves to drive the equilibrium completely to the product side so that high yields are usually obtained in Claisen condensations. Predicting the Product of a Claisen Condensation Reaction What product would you obtain from Claisen condensation of ethyl propanoate? Strategy The Claisen condensation of an ester results in loss of one molecule of alcohol and formation of a product in which an acyl group of one reactant bonds to the α carbon of the second reactant. The product is a β -keto ester. Solution Problems

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Mixed Claisen Condensations The mixed Claisen condensation of two different esters is similar to the mixed aldol condensation of two different aldehydes or ketones ( ). Mixed Claisen reactions are successful only when one of the two ester components has no α hydrogens and thus can’t form an enolate ion. For example, ethyl benzoate and ethyl formate can’t form enolate ions and thus can’t serve as donors. They can, however, act as the electrophilic acceptor components in reactions with other ester anions to give mixed β -keto ester products. Mixed Claisen-like reactions can also be carried out between an ester and a ketone, resulting in the synthesis of a β -diketone. The reaction works best when the ester component has no α hydrogens and thus can’t act as the nucleophilic donor. For example, ethyl formate gives high yields in mixed Claisen condensations with ketones. Predicting the Product of a Mixed Claisen Condensation Reaction Diethyl oxalate, (CO 2 Et) 2 , often gives high yields in mixed Claisen reactions. What product would you expect to obtain from a mixed Claisen reaction of ethyl acetate with diethyl oxalate? Strategy A mixed Claisen reaction is effective when only one of the two partners has an acidic α hydrogen atom. In the present case, ethyl acetate can be converted into its enolate ion, but diethyl oxalate cannot. Thus, ethyl acetate acts as the donor and diethyl oxalate as the acceptor. Solution Problems

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Intramolecular Claisen Condensations: The Dieckmann Cyclization Intramolecular Claisen condensations can be carried out with diesters, just as intramolecular aldol condensations can be carried out with diketones ( ). Called the Dieckmann cyclization , this reaction works best on 1,6-diesters and 1,7-diesters. Intramolecular Claisen cyclization of a 1,6-diester gives a five-membered cyclic β -keto ester, and cyclization of a 1,7-diester gives a six-membered cyclic β -keto ester. The mechanism of the Dieckmann cyclization, shown in , is the same as that of the Claisen condensation. One of the two ester groups is converted into an enolate ion, which carries out a nucleophilic acyl substitution on the second ester group at the other end of the molecule. A cyclic β -keto ester product results. MECHANISM Mechanism of the Dieckmann cyclization of a 1,7-diester to yield a cyclic β -keto ester product . The cyclic β -keto ester produced in a Dieckmann cyclization can be further alkylated and decarboxylated by a series of reactions analogous to those used in the acetoacetic ester synthesis ( ). Alkylation and subsequent decarboxylation of ethyl 2-oxocyclohexanecarboxylate, for instance, yields a 2-alkylcyclohexanone. The overall sequence of ( 1 ) Dieckmann cyclization, ( 2 ) β -keto ester alkylation, and ( 3 ) decarboxylation is a powerful method for preparing 2-substituted cyclopentanones and cyclohexanones. Problems

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Conjugate Carbonyl Additions: The Michael Reaction We saw in that certain nucleophiles, such as amines, react with α , β -unsaturated aldehydes and ketones to give a conjugate addition product, rather than a direct addition product. Exactly the same kind of conjugate addition can occur when a nucleophilic enolate ion reacts with an α , β -unsaturated carbonyl compound—a process known as the Michael reaction after Arthur Michael at Tufts College and Harvard University. The best Michael reactions are those that take place when a particularly stable enolate ion, such as that derived from a β -keto ester or other 1,3-dicarbonyl compound, adds to an unhindered α , β -unsaturated ketone. For example, ethyl acetoacetate reacts with 3-buten-2-one in the presence of sodium ethoxide to yield the conjugate addition product. Michael reactions take place by addition of a nucleophilic enolate ion donor to the β carbon of an α , β -unsaturated carbonyl acceptor, according to the mechanism shown in . MECHANISM Mechanism of the Michael reaction between a β -keto ester and an α , β -unsaturated ketone . The reaction is a conjugate addition of an enolate ion to the unsaturated carbonyl compound. The Michael reaction occurs with a variety of α , β -unsaturated carbonyl compounds, not just conjugated ketones. Unsaturated aldehydes, esters, thioesters, nitriles, amides, and nitro compounds can all act as the electrophilic acceptor component in Michael reactions ( ). Similarly, a variety of different donors can be used, including β -diketones, β -keto esters, malonic esters, β -keto nitriles, and nitro compounds. Some Michael Acceptors and Michael Donors Michael acceptors Michael donors Propenal β -Diketone 3-Buten-2-one β -Keto ester Ethyl propenoate Diethyl malonate Propenamide β -Keto nitrile Propenenitrile Nitro compound Nitroethylene Using the Michael Reaction How might you obtain the following compound using a Michael reaction? Strategy A Michael reaction involves the conjugate addition of a stable enolate ion donor to an α , β -unsaturated carbonyl acceptor, yielding a 1,5-dicarbonyl product. Usually, the stable enolate ion is derived from a β -diketone, β -keto ester, malonic ester, or similar compound. The C–C bond formed in the conjugate addition step is the one between the α carbon of the acidic donor and the β carbon of the unsaturated acceptor. Solution Problems

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Carbonyl Condensations with Enamines: The Stork Enamine Reaction In addition to enolate ions, other kinds of carbon nucleophiles also add to α , β -unsaturated acceptors in Michael-like reactions. Among the most important and useful of such nucleophiles, particularly in biological chemistry, are enamines, which are readily prepared by reaction between a ketone and a secondary amine ( ). For example: As the following resonance structures indicate, enamines are electronically similar to enolate ions. Overlap of the nitrogen lone-pair orbital with the double-bond p orbitals leads to an increase in electron density on the α carbon atom, making that carbon nucleophilic. An electrostatic potential map of N,N -dimethylaminoethylene shows this shift of electron density (red) toward the α position. Enamines behave in much the same way as enolate ions and enter into many of the same kinds of reactions. In the Stork enamine reaction , named for its discoverer, Gilbert Stork of Columbia University, for example, an enamine adds to an α , β -unsaturated carbonyl acceptor in a Michael-like process. The initial product is then hydrolyzed by aqueous acid to yield a 1,5-dicarbonyl compound. The overall reaction is thus a three-step sequence of ( 1 ) enamine formation from a ketone, ( 2 ) Michael addition to an α , β -unsaturated carbonyl compound, and ( 3 ) enamine hydrolysis back to a ketone. The net effect of the Stork enamine reaction is the Michael addition of a ketone to an α , β -unsaturated carbonyl compound. For example, cyclohexanone reacts with the cyclic amine pyrrolidine to yield an enamine; further reaction with an enone such as 3-buten-2-one yields a Michael adduct; and aqueous hydrolysis completes the sequence to give a 1,5-diketone ( ). The Stork enamine reaction between cyclohexanone and 3-buten-2-one . ( 1 ) Cyclohexanone is first converted into an enamine, ( 2 ) the enamine adds to the α , β -unsaturated ketone in a Michael reaction, and ( 3 ) the conjugate addition product is hydrolyzed to yield a 1,5-diketone. The enamine–Michael reaction has two advantages over the enolate-ion–Michael reaction that makes it particularly useful in biological pathways. First, an enamine is neutral, easily prepared, and easily handled, while an enolate ion is charged, sometimes difficult to prepare, and must be handled carefully. Second, an enamine from a mono ketone can be used in the Michael addition, whereas only enolate ions from β -dicarbonyl compounds can be used. Using the Stork Enamine Reaction How might you use an enamine reaction to prepare the following compound? Strategy The overall result of an enamine reaction is the Michael addition of a ketone as donor to an α , β -unsaturated carbonyl compound as acceptor, yielding a 1,5-dicarbonyl product. The C–C bond formed in the Michael addition step is the one between the α carbon of the ketone donor and the β carbon of the unsaturated acceptor. Solution Problems

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The Robinson Annulation Reaction Carbonyl condensation reactions are perhaps the most versatile methods available for synthesizing complex molecules. By putting a few fundamental reactions together in the proper sequence, some remarkably useful transformations can be carried out. One such example is the Robinson annulation reaction for the synthesis of polycyclic molecules. The word annulation derives from the Latin annulus, meaning “ring,” so an annulation reaction is one that builds a new ring onto a molecule. Named after Robert Robinson, a British chemist and 1947 Nobel Prize winner, the Robinson annulation is a two-step process that combines a Michael reaction with an intramolecular aldol reaction. It takes place between a nucleophilic donor, such as a β -keto ester; an enamine, or a β -diketone; and an α , β -unsaturated ketone acceptor, such as 3-buten-2-one. The product is a substituted 2-cyclohexenone. The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a β -keto ester or β -diketone effects a conjugate addition to an α , β -unsaturated ketone, yielding a 1,5-diketone. But as we saw in , 1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. One example of this occurs during a synthesis of the steroid hormone estrone ( ). Synthesis of the steroid hormone estrone using a Robinson annulation reaction . The nucleophilic donor is a β -diketone. In this example, the β -diketone 2-methyl-1,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted α , β -unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. Problems

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Some Biological Carbonyl Condensation Reactions Biological Aldol Reactions Aldol reactions occur in many biological pathways but are particularly common in carbohydrate metabolism, where enzymes called aldolases catalyze the addition of a ketone enolate ion to an aldehyde. Aldolases occur in all organisms and are of two types. Type I aldolases occur primarily in animals and higher plants; type II aldolases occur primarily in fungi and bacteria. Both types catalyze the same kind of reaction, but type I aldolases operate through an enamine while type II aldolases require a metal ion (usually Zn 2+ ) as a Lewis acid and operate through an enolate ion. An example of an aldolase-catalyzed reaction occurs in glucose biosynthesis when dihydroxyacetone phosphate reacts with glyceraldehyde 3-phosphate to give fructose 1,6-bisphosphate. In animals and higher plants, dihydroxyacetone phosphate is first converted into an enamine by reaction with the –NH 2 group on a lysine amino acid in the enzyme. The enamine then adds to glyceraldehyde 3-phosphate, and the iminium ion that results is hydrolyzed. In bacteria and fungi, the aldol reaction occurs directly, with the ketone carbonyl group of glyceraldehyde 3-phosphate complexed to a Zn 2+ ion to make it a better acceptor. Note that the aldolase-catalyzed reactions are mixed aldol reactions, which take place between two different partners, as opposed to the symmetrical aldol reactions between identical partners usually carried out in the laboratory. Mixed aldol reactions often give mixtures of products in the laboratory but are successful in living systems because of the selectivity of the enzyme catalysts. Biological Claisen Condensations Claisen condensations, like aldol reactions, also occur in a large number of biological pathways. In fatty-acid biosynthesis, for instance, an enolate ion generated by decarboxylation ( ) of malonyl ACP adds to the carbonyl group of another acyl group bonded through a thioester linkage to a synthase enzyme. The tetrahedral intermediate that results then expels the synthase, giving acetoacetyl ACP. (The abbreviation ACP stands for acyl carrier protein, which forms thioester bonds to acyl groups.) Mixed Claisen condensations also occur frequently in living organisms, particularly in the pathway for fatty-acid biosynthesis that we’ll discuss in Section 29.4 . Butyryl synthase, for instance, reacts with malonyl ACP in a mixed Claisen condensation to give 3-ketohexanoyl ACP. A Prologue to Metabolism Biochemistry is carbonyl chemistry. Almost all metabolic pathways used by living organisms involve one or more of the four fundamental carbonyl-group reactions we’ve seen in the chapters on Aldehydes and Ketones: Nucleophilic Addition Reactions through Carbonyl Condensation Reactions . The digestion and metabolic breakdown of all the major classes of food molecules—fats, carbohydrates, and proteins—take place by nucleophilic addition reactions, nucleophilic acyl substitutions, α substitutions, and carbonyl condensations. Similarly, hormones and other crucial biological molecules are built up from smaller precursors by these same carbonyl-group reactions. You are what you eat. Food molecules are metabolized by pathways that involve the four major carbonyl-group reactions . (credit: “Spring” by Giuseppe Arcimboldo, Louvre Museum/Wikimedia Commons, Public Domain) Take glycolysis, for example, the metabolic pathway by which organisms convert glucose to pyruvate as the first step in extracting energy from carbohydrates. Glycolysis is a ten-step process that begins with isomerization of glucose from its cyclic hemiacetal form to its open-chain aldehyde form—the reverse of a nucleophilic addition reaction. The aldehyde then undergoes tautomerization to yield an enol, which undergoes yet another tautomerization to give the ketone fructose. Fructose, a β -hydroxy ketone, is then cleaved by a retro-aldol reaction into two three-carbon molecules—one ketone and one aldehyde. Further carbonyl-group reactions then occur until pyruvate is formed. These few examples are only an introduction; we’ll look at several of the major metabolic pathways in more detail in Chapter 29. The bottom line, however, is that you haven’t seen the end of carbonyl-group chemistry if you have any interest in biological or medical fields. A solid grasp of carbonyl-group reactions is crucial to an understanding of biochemistry. aldol reaction carbonyl condensation reaction Claisen condensation reaction Dieckmann cyclization Michael reaction Robinson annulation reaction Stork enamine reaction Summary In this chapter, we’ve discussed the fourth and last of the common carbonyl-group reactions—the carbonyl condensation. A carbonyl condensation reaction takes place between two carbonyl partners and involves both nucleophilic addition and α -substitution processes. One carbonyl partner is converted by base into a nucleophilic enolate ion, which then adds to the electrophilic carbonyl group of the second partner. The first partner thus undergoes an α substitution, while the second undergoes a nucleophilic addition. The aldol reaction is a carbonyl condensation that occurs between two aldehyde or ketone molecules. Aldol reactions are reversible, leading first to β -hydroxy aldehydes/ketones and then to α , β -unsaturated products after dehydration. Mixed aldol condensations between two different aldehydes or ketones generally give a mixture of all four possible products. A mixed reaction can be successful, however, if one of the two partners is an unusually good donor (ethyl acetoacetate, for instance) or if it can act only as an acceptor (formaldehyde and benzaldehyde, for instance). Intramolecular aldol condensations of 1,4- and 1,5-diketones are also successful and provide a good way to make five- and six-membered rings. The Claisen condensation reaction is a carbonyl condensation that occurs between two ester components and gives a β -keto ester product. Mixed Claisen condensations between two different esters are successful only when one of the two partners has no acidic α hydrogens (ethyl benzoate and ethyl formate, for instance) and thus can function only as the acceptor partner. Intramolecular Claisen condensations, called Dieckmann cyclization reactions , yield five- and six-membered cyclic β -keto esters starting from 1,6- and 1,7-diesters. The conjugate addition of a carbon nucleophile to an α , β -unsaturated acceptor is known as the Michael reaction . The best Michael reactions take place between relatively acidic donors ( β -keto esters or β -diketones) and unhindered α , β -unsaturated acceptors. Enamines, prepared by reaction of a ketone with a disubstituted amine, are also good Michael donors in the Stork enamine reaction. Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson annulation reaction , which leads to the formation of a substituted cyclohexenone. Treatment of a β -diketone or β -keto ester with an α , β -unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. Summary of Reactions Aldol reaction ( ) Mixed aldol reaction ( ) Intramolecular aldol reaction ( ) Dehydration of aldol products ( ) Claisen condensation reaction ( ) Mixed Claisen condensation reaction ( ) Intramolecular Claisen condensation (Dieckmann cyclization; ) Michael reaction ( ) Carbonyl condensations with enamines (Stork enamine reaction; ) Additional Problems Visualizing Chemistry Mechanism Problems Aldol Reactions Claisen Condensations Michael and Enamine Reactions General Problems

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Why This Chapter? The characteristic and unmistakable odor of fish is due to a mixture of simple alkylamines . (credit: modification of work “Pike Place” by Sharat Ganapati/Flickr, CC BY 2.0) By the end of this chapter, we will have seen all the common functional groups. Of those groups, carbonyl compounds and amines are the most abundant and have the richest chemistry. In addition to proteins and nucleic acids, the majority of pharmaceutical agents contain amine functional groups, and many of the common coenzymes necessary for biological catalysis are amines. Amines are organic derivatives of ammonia in the same way that alcohols and ethers are organic derivatives of water. Like ammonia, amines contain a nitrogen atom with a lone pair of electrons, making amines both basic and nucleophilic. We’ll soon see, in fact, that most of the chemistry of amines depends on the presence of this lone pair of electrons. Amines occur widely in all living organisms. Trimethylamine, for instance, occurs in animal tissues and is partially responsible for the distinctive odor of fish; nicotine is found in tobacco; and cocaine is a stimulant found in the leaves of the South American coca bush. In addition, amino acids are the building blocks from which all proteins are made, and cyclic amine bases are constituents of nucleic acids.

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Naming Amines Amines can be either alkyl-substituted ( alkylamines ) or aryl-substituted ( arylamines ). Although much of the chemistry of the two classes is similar, there are also substantial differences. Amines are classified as primary (RNH 2 ) , secondary (R 2 NH) , or tertiary (R 3 N) , depending on the number of organic substituents attached to nitrogen. Thus, methylamine (CH 3 NH 2 ) is a primary amine, dimethylamine [(CH 3 ) 2 NH] is a secondary amine, and trimethylamine [(CH 3 ) 3 N] is a tertiary amine. Note that this usage of the terms primary, secondary, and tertiary differs from our previous usage. When we speak of a tertiary alcohol or alkyl halide, we refer to the degree of substitution at the alkyl carbon atom, but when we speak of a tertiary amine, we refer to the degree of substitution at the nitrogen atom. Compounds containing a nitrogen atom with four attached groups also exist, but the nitrogen atom must carry a formal positive charge. Such compounds are called quaternary ammonium salts . Primary amines are named in the IUPAC system in several ways. For simple amines, the suffix - amine is added to the name of the alkyl substituent. You might also recall from the chapter on Benzene and Aromaticity that the aromatic phenylamine, H 2 N–C 6 H 5 , has the common name aniline. Alternatively, the suffix - amine can be used in place of the final - e in the name of the parent compound. Amines with more than one functional group are named by considering the −NH 2 as an amino substituent on the parent molecule. Symmetrical secondary and tertiary amines are named by adding the prefix di - or tri - to the alkyl group. Unsymmetrically substituted secondary and tertiary amines are referred to as N -substituted primary amines. The largest alkyl group takes the parent name, and the other alkyl groups are considered N -substituents on the parent ( N because they’re attached to nitrogen). Heterocyclic amines —compounds in which the nitrogen atom occurs as part of a ring—are also common, and each different heterocyclic ring system has its own parent name. The heterocyclic nitrogen atom is always numbered as position 1. Problems

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Structure and Properties of Amines The bonding in alkylamines is similar to the bonding in ammonia. The nitrogen atom is sp 3 -hybridized, with its three substituents occupying three corners of a regular tetrahedron and the lone pair of electrons occupying the fourth corner. As you might expect, the C–N–C bond angles are close to the 109° tetrahedral value. For trimethylamine, the C–N–C bond angle is 108° and the C–N bond length is 147 pm. One consequence of tetrahedral geometry is that an amine with three different substituents on nitrogen is chiral, as we saw in . Unlike chiral carbon compounds, however, chiral amines can’t usually be resolved because the two enantiomeric forms rapidly interconvert by a pyramidal inversion , much as an alkyl halide inverts in an S N 2 reaction. Pyramidal inversion occurs by a momentary rehybridization of the nitrogen atom to planar, sp 2 geometry, followed by rehybridization of the planar intermediate to tetrahedral, sp 3 geometry ( ). The barrier to inversion is about 25 kJ/mol (6 kcal/mol), an amount only twice as large as the barrier to rotation about a C–C single bond. Pyramidal inversion rapidly interconverts the two mirror-image (enantiomeric) forms of an amine . Alkylamines have a variety of applications in the chemical industry as starting materials for the preparation of insecticides and pharmaceuticals. Labetalol, for instance, a so-called β -blocker used for the treatment of high blood pressure, is prepared by S N 2 reaction of an epoxide with a primary amine. The substance marketed for drug use is a mixture of all four possible stereoisomers, but the biological activity results primarily from the ( R , R ) isomer. Like alcohols, amines with fewer than five carbon atoms are generally water-soluble. Also like alcohols, primary and secondary amines form hydrogen bonds and are highly associated. As a result, amines have higher boiling points than alkanes of similar molecular weight. Diethylamine (MW = 73 amu) boils at 56.3 °C, for instance, while pentane (MW = 72 amu) boils at 36.1 °C. Hydrogen bonding in amines . One other characteristic of amines is their odor. Low-molecular-weight amines such as trimethylamine have a distinctive fishlike aroma, while diamines such as cadaverine (1,5-pentanediamine) and putrescine (1,4-butanediamine) have the appalling odors you might expect from their common names. Both of these diamines arise from the decomposition of decaying tissue.

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Basicity of Amines The chemistry of amines is dominated by the lone pair of electrons on nitrogen, which makes amines both basic and nucleophilic. They react with acids to form acid–base salts, and they react with electrophiles in many of the polar reactions seen in past chapters. Note in the following electrostatic potential map of trimethylamine how the negative (red) region corresponds to the lone pair of electrons on nitrogen. Amines are much stronger bases than alcohols and ethers, their oxygen-containing analogs. When an amine is dissolved in water, an equilibrium is established in which water acts as an acid and transfers a proton to the amine. Just as the acid strength of a carboxylic acid can be measured by defining an acidity constant K a ( ), the base strength of an amine can be measured by defining an analogous basicity constant K b . The larger the value of K b and the smaller the value of p K b , the more favorable the proton-transfer equilibrium and the stronger the base. For the reaction RNH 2 + H 2 O ⇄ RNH 3 + + OH – K b = [RNH 3 + ] [OH – ] [RNH 2 ] p K b = –log K b In practice, K b values are not often used. Instead, the most convenient way to measure the basicity of an amine (RNH 2 ) is to look at the acidity of the corresponding ammonium ion (RNH 3 + ). For the reaction RNH 3 + + H 2 O ⇄ RNH 2 + H 3 O + K a = [RNH 2 ] [H 3 O + ] [RNH 3 + ] so K a ⋅ K b = [RNH 2 ] [H 3 O + ] [RNH 3 + ] [RNH 3 + ] [OH – ] [RNH 2 ] = [H 3 O + ] [OH – ] = K w = 1 .00 × 10 –14 Thus K a = K w K b and K b = K w K a and p K a + p K b = 14 These equations say that the K b of an amine multiplied by the K a of the corresponding ammonium ion is equal to K w , the ion-product constant for water (1.00 × 10 –1 4 ). Thus, if we know K a for an ammonium ion, we also know K b for the corresponding amine base because K b = K w / K a . The more acidic the ammonium ion, the less tightly the proton is held and the weaker the corresponding base. That is, a weaker base has an ammonium ion with a smaller p K a and a stronger base has an ammonium ion with a larger p K a . Base Strength p K a size Weaker base Smaller p K a for ammonium ion Stronger base Larger p K a for ammonium ion lists p K a values of the ammonium ions from a variety of amines and indicates that there is a substantial range of amine basicities. Most simple alkylamines are similar in their base strength, with p K a ’s for their ammonium ions in the narrow range 10 to 11. Arylamines, however, are considerably less basic than alkylamines, as are the heterocyclic amines pyridine and pyrrole. Basicity of Some Common Amines Name Structure p K a of ammonium ion Ammonia NH 3 9.26 Primary alkylamine Methylamine CH 3 NH 2 10.64 Ethylamine CH 3 CH 2 NH 2 10.75 Secondary alkylamine Diethylamine (CH 3 CH 2 ) 2 NH 10.98 Pyrrolidine 11.27 Tertiary alkylamine Triethylamine (CH 3 CH 2 ) 3 N 10.76 Arylamine Aniline 4.63 Heterocyclic amine Pyridine 5.25 Pyrimidine 1.3 Pyrrole 0.4 Imidazole 6.95 In contrast with amines, amides (RCONH 2 ) are nonbasic. Amides aren’t protonated by aqueous acids, and they are poor nucleophiles. The main reason for this difference in basicity between amines and amides is that an amide is stabilized by delocalization of the nitrogen lone-pair electrons through orbital overlap with the carbonyl group. In resonance terms, amides are more stable and less reactive than amines because they are hybrids of two resonance forms. This amide resonance stabilization is lost when the nitrogen atom is protonated, so protonation is disfavored. The following electrostatic potential maps clearly show a reduced electron density on the amide nitrogen. To purify amines, it’s often possible to take advantage of their basicity. For example, if a mixture of a basic amine and a neutral compound such as a ketone or alcohol is dissolved in an organic solvent and aqueous acid is added, the basic amine dissolves in the water layer as its protonated salt, while the neutral compound remains in the organic solvent layer. Separation of the water layer and neutralization of the ammonium ion by addition of NaOH then provides the pure amine ( ). Separation and purification of an amine component from a mixture by extraction of its ammonium salt into water . In addition to their behavior as bases, primary and secondary amines can also act as very weak acids because an N–H proton can be removed by a sufficiently strong base. We’ve seen, for example, how diisopropylamine (p K a ≈ 36) reacts with butyllithium to yield lithium diisopropylamide (LDA; ). Dialkylamine anions like LDA are very strong bases that are often used in laboratory organic chemistry for the generation of enolate ions from carbonyl compounds ( ). They are not, however, encountered in biological chemistry. Problems

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Basicity of Arylamines As noted previously, arylamines are generally less basic than alkylamines. Anilinium ion has p K a = 4.63, for instance, whereas methylammonium ion has p K a = 10.64. Arylamines are less basic than alkylamines because the nitrogen lone-pair electrons are delocalized by interaction with the aromatic ring’s π electron system and are less available for bonding to H + . In resonance terms, arylamines are stabilized relative to alkylamines because of their five resonance forms. Much of the resonance stabilization is lost on protonation, however, so the energy difference between protonated and nonprotonated forms is higher for arylamines than it is for alkylamines. As a result, arylamines are less basic. illustrates this difference. Arylamines have a larger positive ∆ G ° for protonation and are therefore less basic than alkylamines, primarily because of resonance stabilization of the ground state . Electrostatic potential maps show that lone-pair electron density is delocalized in the amine but the charge is localized in the corresponding ammonium ion. Substituted arylamines can be either more basic or less basic than aniline, depending on the substituent. Electron-donating substituents, such as –CH 3 , –NH 2 , and –OCH 3 , which increase the reactivity of an aromatic ring toward electrophilic substitution ( ), also increase the basicity of the corresponding arylamine. Electron-withdrawing substituents, such as –Cl, –NO 2 , and –CN, which decrease ring reactivity toward electrophilic substitution, also decrease arylamine basicity. considers only p -substituted anilines, but similar trends are observed for ortho and meta derivatives. Base Strength of Some p -Substituted Anilines Substituent, Y p K a –NH 2 6.15 Activating groups –OCH 3 5.34 –CH 3 5.08 –H 4.63 –Cl 3.98 Deactivating groups –Br 3.86 –CN 1.74 –NO 2 1.00 Problems

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Biological Amines and the Henderson–Hasselbalch Equation We saw in that the extent of dissociation of a carboxylic acid HA in an aqueous solution buffered to a given pH can be calculated with the Henderson–Hasselbalch equation. Furthermore, we concluded that at the physiological pH of 7.3 inside living cells, carboxylic acids are almost entirely dissociated into their carboxylate anions, RCO 2 – . Henderson–Hasselbalch equation: pH = p K a + log [A – ] [HA] so log [A – ] [HA] = pH – p K a What about amine bases? In what form do they exist at physiological pH? As the amine (A – = RNH 2 ), or as the ammonium ion (HA = RNH 3 + )? Let’s take a 0.0010 M solution of methylamine at pH = 7.3, for example. According to , the p K a of methylammonium ion is 10.64, so from the Henderson–Hasselbalch equation, we have l og [RNH 2 ] [RNH 3 + ] = pH – p K a = 7 .3 – 10 .64 = –3 .34 [RNH 2 ] [RNH 3 + ] = antilog(–3 .34) = 4 .6 × 10 –4 so [RNH 2 ] = (4 .6 × 10 –4 )[RNH 3 + ] In addition, we know that [RNH 2 ] + [RNH 3 + ] = 0 .0010 M Solving the two simultaneous equations gives [RNH 3 + ] = 0.0010 M and [RNH 2 ] = 5 × 10 –7 M. In other words, at a physiological pH of 7.3, essentially 100% of the methylamine in a 0.0010 M solution exists in its protonated form as methylammonium ion. The same is true of other amine bases, so we always write cellular amines in their protonated form and amino acids in their ammonium carboxylate form to reflect their structures at physiological pH. Problems

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Synthesis of Amines Reduction of Nitriles, Amides, and Nitro Compounds We’ve already seen in and how amines can be prepared by reduction of nitriles and amides with LiAlH 4 . The two-step sequence of S N 2 displacement with CN – followed by reduction thus converts an alkyl halide into a primary alkylamine having an additional carbon atom. Amide reduction converts carboxylic acids and their derivatives into amines with the same number of carbon atoms. Arylamines are usually prepared by nitration of an aromatic starting material, followed by reduction of the nitro group ( ). The reduction step can be carried out in many different ways, depending on the circumstances. Catalytic hydrogenation over platinum works well but is often incompatible with the presence elsewhere in the molecule of other reducible groups, such as C=C bonds or carbonyl groups. Iron, zinc, tin, and tin(II) chloride (SnCl 2 ) are also effective when used in acidic aqueous solution. Tin(II) chloride is particularly mild and is often used when other reducible functional groups are present. Problems S N 2 Reactions of Alkyl Halides Ammonia and other amines are good nucleophiles in S N 2 reactions. As a result, the simplest method of alkylamine synthesis is by S N 2 alkylation of ammonia or an alkylamine with an alkyl halide. If ammonia is used, a primary amine results; if a primary amine is used, a secondary amine results; and so on. Even tertiary amines react rapidly with alkyl halides to yield quaternary ammonium salts, R 4 N + X – . Unfortunately, these reactions don’t stop cleanly after a single alkylation has occurred. Because ammonia and primary amines have similar reactivity, the initially formed monoalkylated substance often undergoes further reaction to yield a mixture of products. Even secondary and tertiary amines undergo further alkylation, although to a lesser extent. For example, treatment of 1-bromooctane with a twofold excess of ammonia leads to a mixture containing only 45% octylamine. A nearly equal amount of dioctylamine is produced by double alkylation, along with smaller amounts of trioctylamine and tetraoctylammonium bromide. A better method for preparing primary amines is to use azide ion, N 3 – , rather than ammonia, as the nucleophile for S N 2 reaction with a primary or secondary alkyl halide. The product is an alkyl azide, which is not nucleophilic, so overalkylation can’t occur. Subsequent reduction of the alkyl azide with LiAlH 4 then leads to the desired primary amine. Although this method works well, low-molecular-weight alkyl azides are explosive and must be handled carefully. Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis , which uses a phthalimide alkylation. An imide ( O=C–N–C=O ) is similar to a β -keto ester in that the acidic N–H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to acetoacetic ester synthesis ( ). Basic hydrolysis of the N -alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide ( ). Problems Reductive Amination of Aldehydes and Ketones Amines can be synthesized in a single step by treatment of an aldehyde or ketone with ammonia or an amine in the presence of a reducing agent, a process called reductive amination . For example, amphetamine, a central nervous system stimulant, is prepared commercially by reductive amination of phenyl-2-propanone with ammonia using hydrogen gas over a nickel catalyst as the reducing agent. In the laboratory, either NaBH 4 or the related NaBH(OAc) 3 is commonly used (OAc = acetate). Reductive amination takes place by the pathway shown in . An imine intermediate is first formed by a nucleophilic addition reaction ( ), and the C═N bond of the imine is then reduced to the amine, much as the C═O bond of a ketone can be reduced to an alcohol. MECHANISM Mechanism for reductive amination of a ketone to yield an amine . Details of the imine-forming step are shown in . Ammonia, primary amines, and secondary amines can all be used in the reductive amination reaction, yielding primary, secondary, and tertiary amines, respectively. Reductive aminations also occur in various biological pathways. In the biosynthesis of the amino acid proline, for instance, glutamate 5-semialdehyde undergoes internal imine formation to give 1-pyrrolinium 5-carboxylate, which is then reduced by nucleophilic addition of hydride ion to the C═N bond. Reduced nicotinamide adenine dinucleotide, NADH, acts as the biological reducing agent. Using a Reductive Amination Reaction How might you prepare N -methyl-2-phenylethylamine using a reductive amination reaction? Strategy Look at the target molecule, and identify the groups attached to nitrogen. One of the groups must be derived from the aldehyde or ketone component, and the other must be derived from the amine component. In the case of N -methyl-2-phenylethylamine, two combinations can lead to the product: phenylacetaldehyde plus methylamine or formaldehyde plus 2-phenylethylamine. It’s usually better to choose the combination with the simpler amine component—methylamine in this case—and to use an excess of that amine as reactant. Solution Problems Hofmann and Curtius Rearrangements Carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement and the Curtius rearrangement . Although the Hofmann rearrangement involves a primary amide and the Curtius rearrangement involves an acyl azide, both proceed through similar mechanisms. Hofmann rearrangement occurs when a primary amide, RCONH 2 , is treated with Br 2 and base ( ). The overall mechanism is lengthy, but most of the individual steps have been encountered before. Thus, the bromination of an amide in steps 1 and 2 is analogous to the base-promoted bromination of a ketone enolate ion ( ), and the rearrangement of the bromoamide anion in step 4 is analogous to a carbocation rearrangement ( ). Nucleophilic addition of water to the isocyanate carbonyl group in step 5 is a typical carbonyl-group process ( ), as is the final decarboxylation step 6 ( ). MECHANISM Mechanism of the Hofmann rearrangement of an amide to an amine . Each step is analogous to a reaction studied previously. Despite its mechanistic complexity, the Hofmann rearrangement often gives high yields of both arylamines and alkylamines. For example, the appetite-suppressant drug phentermine is prepared commercially by Hofmann rearrangement of a primary amide. Commonly known by the name Fen-Phen, the combination of phentermine with another appetite-suppressant, fenfluramine, is suspected of causing heart damage. The Curtius rearrangement, like the Hofmann rearrangement, involves migration of an –R group from the C═O carbon atom to the neighboring nitrogen with simultaneous loss of a leaving group. The reaction takes place on heating an acyl azide that is itself prepared by nucleophilic acyl substitution of an acid chloride. Also like the Hofmann rearrangement, the Curtius rearrangement is often used commercially. The antidepressant drug tranylcypromine, for instance, is made by Curtius rearrangement of 2-phenylcyclopropanecarbonyl chloride. Using the Hofmann and Curtius Rearrangements How would you prepare o -methylbenzylamine from a carboxylic acid, using both Hofmann and Curtius rearrangements? Strategy Both Hofmann and Curtius rearrangements convert a carboxylic acid derivative—either an amide (Hofmann) or an acid chloride (Curtius)—into a primary amine with loss of one carbon, RCOY → RNH 2 . Both reactions begin with the same carboxylic acid, which can be identified by replacing the –NH 2 group of the amine product by a –CO 2 H group. In the present instance, o -methylphenylacetic acid is needed. Solution Problems

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Reactions of Amines Alkylation and Acylation We’ve already studied the two most general reactions of amines—alkylation and acylation. As we saw earlier in this chapter, primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to control and often give mixtures of products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution reaction with an acid chloride or an acid anhydride to yield an amide ( and ). Note that overacylation of the nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the starting amine. Hofmann Elimination Reaction Like alcohols, amines can be converted into alkenes by an elimination reaction. But because an amide ion, NH 2 – , is such a poor leaving group, it must first be converted into a better leaving group. In the Hofmann elimination reaction , an amine is completely methylated by reaction with an excess amount of iodomethane to produce the corresponding quaternary ammonium salt. This salt then undergoes elimination to give an alkene on heating with a base, typically silver oxide, Ag 2 O. For example, 1-methylpentylamine is converted into 1-hexene. Silver oxide acts by exchanging iodide ion for hydroxide ion in the quaternary salt, thus providing the base necessary for elimination. The actual elimination step is an E2 reaction ( ) in which hydroxide ion removes a proton while the positively charged nitrogen atom leaves. Unlike what happens in other E2 reactions, the major product of Hofmann elimination is the less highly substituted alkene rather than the more highly substituted one, as shown by the reaction of (1-methylbutyl)trimethylammonium hydroxide to give 1-pentene rather than the alternative 2-pentene. The reason for this non-Zaitsev result is probably steric. Because of the large size of the trialkylamine leaving group, the base must abstract a hydrogen from the more accessible, least hindered position. The Hofmann elimination reaction is not often currently used in the laboratory, but analogous biological eliminations occur frequently, although usually with protonated ammonium ions rather than quaternary ammonium salts. In the biosynthesis of nucleic acids, for instance, a substance called adenylosuccinate undergoes an elimination of a positively charged nitrogen to give fumarate plus adenosine monophosphate. Predicting the Product of a Hofmann Elimination What product would you expect from Hofmann elimination of the following amine? Strategy The Hofmann elimination is an E2 reaction that converts an amine into an alkene and occurs with non-Zaitsev regiochemistry to form the less highly substituted double bond. To predict the product, look at the reactant and identify the positions from which elimination might occur (the positions two carbons away from nitrogen). Then, carry out an elimination using the most accessible hydrogen. In the present instance, there are three possible positions from which elimination might occur—one primary, one secondary, and one tertiary. The primary position is the most accessible and leads to the least highly substituted alkene, ethylene. Solution Problems

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Reactions of Arylamines Electrophilic Aromatic Substitutions An amino group is strongly activating and ortho- and para-directing in electrophilic aromatic substitution reactions ( ). This high reactivity of amino-substituted benzenes can be a drawback at times because it’s often difficult to prevent polysubstitution. Reaction of aniline with Br 2 , for instance, takes place rapidly and yields the 2,4,6-tribrominated product. The amino group is so strongly activating that it’s not possible to stop at the monobromo stage. Another drawback to the use of amino-substituted benzenes in electrophilic aromatic substitution reactions is that Friedel–Crafts reactions are not successful ( ). The amino group forms an acid–base complex with the AlCl 3 catalyst, which prevents further reaction. Both drawbacks can be overcome, however, by carrying out electrophilic aromatic substitution reactions on the corresponding amide rather than on the free amine. As we saw in , treatment of an amine with acetic anhydride yields the corresponding acetyl amide, or acetamide. Although still activating and ortho-, para-directing, amido substituents ( R–N–C=O ) are less strongly activating and less basic than amino groups because their nitrogen lone-pair electrons are delocalized by the neighboring carbonyl group. As a result, bromination of an N -arylamide occurs cleanly to give a monobromo product, and hydrolysis of the amide with aqueous base then gives the free amine. For example, p -toluidine (4-methylaniline) can be acetylated, brominated, and hydrolyzed to yield 2-bromo-4-methylaniline. None of the 2,6-dibrominated product is obtained. Friedel–Crafts alkylations and acylations of N -arylamides also proceed normally. For example, benzoylation of acetanilide ( N -acetylaniline) under Friedel–Crafts conditions gives 4-aminobenzophenone in 80% yield after hydrolysis. Moderating the reactivity of an amino-substituted benzene by forming an amide is a useful trick that allows many kinds of electrophilic aromatic substitutions to be carried out that would otherwise be impossible. One example is the preparation of the sulfa drugs, such as sulfanilamide. Sulfa drugs were among the first pharmaceutical agents to be used clinically against bacterial infection. Although they have largely been replaced today by safer and more powerful antibiotics, sulfa drugs are credited with saving the lives of thousands of wounded during World War II and are still prescribed for urinary tract infections. They are prepared by chlorosulfonation of acetanilide, followed by reaction of p -( N -acetylamino)benzenesulfonyl chloride with ammonia or some other amine to give a sulfonamide. Hydrolysis of the amide then yields the sulfa drug. Note that hydrolysis of the amide can be carried out in the presence of the sulfonamide group because sulfonamides hydrolyze very slowly. Problems Diazonium Salts: The Sandmeyer Reaction Primary arylamines react with nitrous acid, HNO 2 , to yield stable arenediazonium salts , Ar– N + ≡N X − , a process called a diazotization reaction. Alkylamines also react with nitrous acid, but the corresponding alkanediazonium products are so reactive they can’t be isolated. Instead, they lose nitrogen instantly to yield carbocations. The analogous loss of N 2 from an arenediazonium ion to yield an aryl cation is disfavored by the instability of the cation. Arenediazonium salts are useful because the diazonio group ( –N≡N ) can be replaced by a nucleophile in a substitution reaction. Many different nucleophiles—halide, hydride, cyanide, and hydroxide among others—react with arenediazonium salts, yielding many different kinds of substituted benzenes. The overall sequence of ( 1 ) nitration, ( 2 ) reduction, ( 3 ) diazotization, and ( 4 ) nucleophilic substitution is perhaps the single most versatile method of aromatic substitution. Aryl chlorides and bromides are prepared by reaction of an arenediazonium salt with the corresponding copper(I) halide, CuX, a process called the Sandmeyer reaction . Aryl iodides can be prepared by direct reaction with NaI without using a copper(I) salt. Yields generally fall between 60% and 80%. Similar treatment of an arenediazonium salt with CuCN yields the nitrile ArCN, which can then be further converted into other functional groups such as carboxyl. For example, Sandmeyer reaction of o -methylbenzenediazonium bisulfate with CuCN yields o -methylbenzonitrile, which can be hydrolyzed to give o -methylbenzoic acid. This product can’t be prepared from o -xylene by the usual side-chain oxidation route because both methyl groups would be oxidized. The diazonio group can also be replaced by –OH to yield a phenol and by –H to yield an arene. A phenol is prepared by reaction of the arenediazonium salt with copper(I) oxide in an aqueous solution of copper(II) nitrate, a reaction that is especially useful because few other general methods exist for introducing an –OH group onto an aromatic ring. Reduction of a diazonium salt to give an arene occurs on treatment with hypophosphorous acid, H 3 PO 2 . This reaction is used primarily when there is a need for temporarily introducing an amino substituent onto a ring to take advantage of its directing effect. Suppose, for instance, that you needed to make 3,5-dibromotoluene. This product can’t be made by direct bromination of toluene because reaction would occur at positions 2 and 4. Starting with p -methylaniline ( p -toluidine), however, dibromination occurs ortho to the strongly directing amino substituent, and diazotization followed by treatment with H 3 PO 2 to remove the amino group yields the desired product. Mechanistically, these diazonio replacement reactions occur through radical rather than polar pathways. In the presence of a copper(I) compound, for instance, it’s thought that the arenediazonium ion is first converted to an aryl radical plus copper(II), followed by subsequent reaction to give product plus regenerated copper(I) catalyst. Using Diazonium Replacement Reactions How would you prepare m -hydroxyacetophenone from benzene, using a diazonium replacement reaction in your scheme? Strategy As always, organic syntheses are planned by working retrosynthetically from the final product, one step at a time. First, identify the functional groups in the product and recall how those groups can be synthesized. m -Hydroxyacetophenone has an –OH group and a –COCH 3 group in a meta relationship on a benzene ring. A hydroxyl group is generally introduced onto an aromatic ring by a four-step sequence of nitration, reduction, diazotization, and diazonio replacement. An acetyl group is introduced by a Friedel–Crafts acylation reaction. Next, ask yourself what an immediate precursor of the target might be. Since an acetyl group is a meta director while a hydroxyl group is an ortho and para director, acetophenone might be a precursor of m -hydroxyacetophenone. Benzene, in turn, is a precursor of acetophenone. Solution Problems Diazonium Coupling Reactions Arenediazonium salts undergo a coupling reaction with activated aromatic rings such as phenols and arylamines to yield brightly colored azo compounds, Ar–N=N–A r ′ . Diazonium coupling reactions are typical electrophilic aromatic substitutions in which the positively charged diazonium ion is the electrophile that reacts with the electron-rich ring of a phenol or arylamine. Reaction usually occurs at the para position. Azo-coupled products are widely used as dyes for textiles because their extended conjugated π electron system causes them to absorb in the visible region of the electromagnetic spectrum ( ). p -(Dimethylamino)-azobenzene, for instance, is a bright yellow compound that was at one time used as a coloring agent in margarine. Problems

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Heterocyclic Amines As noted in in connection with a discussion of aromaticity, a cyclic organic compound that contains atoms of two or more elements in its ring is a called a heterocycle. Heterocyclic amines are particularly common, and many have important biological properties. Pyridoxal phosphate, a coenzyme; sildenafil (Viagra), a well-known pharmaceutical; and heme, the oxygen carrier in blood, are a few examples. Most heterocycles have the same chemistry as their open-chain counterparts. Lactones and acyclic esters behave similarly, lactams and acyclic amides behave similarly, and cyclic and acyclic ethers behave similarly. In certain cases, however, particularly when the ring is unsaturated, heterocycles have unique and interesting properties. Pyrrole and Imidazole Pyrrole, the simplest five-membered unsaturated heterocyclic amine, is obtained commercially by treatment of furan with ammonia over an alumina catalyst at 400 °C. Furan, the oxygen-containing analog of pyrrole, is obtained by acid-catalyzed dehydration of the five-carbon sugars found in oat hulls and corncobs. Although pyrrole appears to be both an amine and a conjugated diene, its chemical properties are not consistent with either of these structural features. Unlike most other amines, pyrrole is not basic—the p K a of the pyrrolinium ion is 0.4; unlike most other conjugated dienes, pyrrole undergoes electrophilic substitution reactions rather than additions. The reason for both of these properties, as noted in , is that pyrrole has six π electrons and is aromatic. Each of the four carbons contributes one π electron, and the sp 2 -hybridized nitrogen contributes two more from its lone pair. Because the nitrogen lone pair is a part of the aromatic sextet, protonation on nitrogen would destroy the aromaticity of the ring. The nitrogen atom in pyrrole is therefore less electron-rich, less basic, and less nucleophilic than the nitrogen in an aliphatic amine. By the same token, the carbon atoms of pyrrole are more electron-rich and more nucleophilic than typical double-bond carbons. The pyrrole ring is therefore reactive toward electrophiles in the same way as enamines ( ). Electrostatic potential maps show how the pyrrole nitrogen is electron-poor (less red) compared with the nitrogen in its saturated counterpart pyrrolidine, while the pyrrole carbon atoms are electron-rich (more red) compared with the carbons in 1,3-cyclopentadiene. The chemistry of pyrrole is similar to that of activated benzene rings. In general, however, the heterocycles are more reactive toward electrophiles than benzene rings, and low temperatures are often necessary to control the reactions. Halogenation, nitration, sulfonation, and Friedel–Crafts acylation can all be accomplished. For example: Electrophilic substitutions normally occur at C2, the position next to the nitrogen, because reaction at this position leads to a more stable intermediate cation having three resonance forms, whereas reaction at C3 gives a less stable cation with only two resonance forms ( ). Electrophilic nitration of pyrrole. The intermediate produced by reaction at C2 is more stable than that produced by reaction at C3. Other common five-membered heterocyclic amines include imidazole and thiazole. Imidazole, a constituent of the amino acid histidine, has two nitrogens, only one of which is basic. Thiazole, the five-membered ring system on which the structure of thiamin (vitamin B 1 ) is based, also contains a basic nitrogen that is alkylated in thiamin to form a quaternary ammonium ion. Problems Pyridine and Pyrimidine Pyridine is the nitrogen-containing heterocyclic analog of benzene. Like benzene, pyridine is a flat, aromatic molecule, with bond angles of 120° and C–C bond lengths of 139 pm, intermediate between typical single and double bonds. The five carbon atoms and the sp 2 -hybridized nitrogen atom each contribute one π electron to the aromatic sextet, and the lone-pair electrons occupy an sp 2 orbital in the plane of the ring ( ). As shown previously in , pyridine (p K a = 5.25) is a stronger base than pyrrole but a weaker base than the alkylamines. The diminished basicity of pyridine compared with that of alkylamines is due to the fact that the lone-pair electrons on the pyridine nitrogen are in an sp 2 orbital, while those on an alkylamine nitrogen are in an sp 3 orbital. Because s orbitals have their maximum electron density at the nucleus but p orbitals have a node at the nucleus, electrons in an orbital with more s character are held more closely to the positively charged nucleus and are less available for bonding. As a result, the sp 2 -hybridized nitrogen atom (33% s character) in pyridine is less basic than the sp 3 -hybridized nitrogen in an alkylamine (25% s character). Unlike benzene, pyridine undergoes electrophilic aromatic substitution reactions with difficulty. Halogenation can be carried out under drastic conditions, but nitration occurs in very low yield, and Friedel–Crafts reactions are not successful. Reactions usually give the 3-substituted product. The low reactivity of pyridine toward electrophilic aromatic substitution is caused by a combination of factors. One is that acid–base complexation between the basic ring’s nitrogen atom and the incoming electrophile places a positive charge on the ring, thereby deactivating it. Equally important is that the electron density of the ring is decreased by the electron-withdrawing inductive effect of the electronegative nitrogen atom. Thus, pyridine has a substantial dipole moment ( μ = 2.26 D), with the ring carbons acting as the positive end of the dipole. Reaction of an electrophile with the positively polarized carbon atoms is therefore difficult. In addition to pyridine, the six-membered diamine pyrimidine is also found commonly in biological molecules, particularly as a constituent of nucleic acids. With a p K a of 1.3, pyrimidine is substantially less basic than pyridine because of the inductive effect of the second nitrogen. Problems Polycyclic Heterocycles As we saw in , quinoline, isoquinoline, indole, and purine are common polycyclic heterocycles. The first three contain both a benzene ring and a heterocyclic aromatic ring, while purine contains two heterocyclic rings joined together. All four ring systems occur commonly in nature, and many compounds with these rings have pronounced physiological activity. The quinoline alkaloid quinine, for instance, is widely used as an antimalarial drug; tryptophan is a common amino acid; and the purine adenine is a constituent of nucleic acids. The chemistry of these polycyclic heterocycles is just what you might expect from a knowledge of the simpler heterocycles pyridine and pyrrole. Quinoline and isoquinoline both have basic, pyridine-like nitrogen atoms, and both undergo electrophilic substitutions. As with pyridine, both quinoline and isoquinoline are less reactive toward electrophilic substitution than benzene because of the electronegative nitrogen atom that withdraws electrons from the ring. Reaction occurs on the benzene ring rather than on the nitrogen-containing pyridine ring, and a mixture of substitution products is obtained. Indole has a nonbasic, pyrrole-like nitrogen and undergoes electrophilic substitution more easily than benzene. Substitution occurs at C3 of the electron-rich pyrrole ring rather than on the benzene ring. Purine has three basic, pyridine-like nitrogens with lone-pair electrons in sp 2 orbitals in the plane of the ring. The remaining purine nitrogen is nonbasic and pyrrole-like, with its lone-pair electrons as part of the aromatic π electron system. Problems

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Spectroscopy of Amines Infrared Spectroscopy Primary and secondary amines can be identified by a characteristic N–H stretching absorption in the 3300 to 3500 cm –1 range of the IR spectrum. Alcohols also absorb in this range ( ), but amine absorption bands are generally sharper and less intense than hydroxyl bands. Primary amines show a pair of bands at about 3350 and 3450 cm –1 from the symmetric and asymmetric stretching modes, and secondary amines show a single band at 3350 cm –1 . Tertiary amines have no absorption in this region because they have no N–H bonds. recalls the IR spectrum of cyclohexylamine from . IR spectrum of cyclohexylamine. Nuclear Magnetic Resonance Spectroscopy Amines are difficult to identify solely by 1 H NMR spectroscopy because N–H hydrogens tend to appear as broad signals without clear-cut coupling to neighboring C–H hydrogens. As with O–H absorptions ( ), amine N–H absorptions can appear over a wide range and are best identified by adding a small amount of D 2 O to the sample. Exchange of N–D for N–H occurs, and the N–H signal disappears from the NMR spectrum. Hydrogens on the carbon next to nitrogen are deshielded because of the electron-withdrawing effect of the nitrogen, and they therefore absorb further downfield than alkane hydrogens. N -Methyl groups are particularly distinctive because they absorb as a sharp three-proton singlet at 2.2 to 2.6 δ . This N -methyl resonance at 2.42 δ is easily seen in the 1 H NMR spectrum of N -methylcyclohexylamine ( ). Proton NMR spectrum of N -methylcyclohexylamine. Carbons next to amine nitrogens are slightly deshielded in the 13 C NMR spectrum and absorb about 20 ppm downfield from where they would absorb in an alkane of similar structure. In N -methylcyclohexylamine, for example, the ring carbon to which nitrogen is attached absorbs at a position 24 ppm downfield from any other ring carbon. Problems Mass Spectrometry The nitrogen rule of mass spectrometry says that a compound with an odd number of nitrogen atoms has an odd-numbered molecular weight. Thus, the presence of nitrogen in a molecule is detected simply by observing its mass spectrum. An odd-numbered molecular ion usually means that the unknown compound has one or three nitrogen atoms, and an even-numbered molecular ion usually means that a compound has either zero or two nitrogen atoms. The logic behind the rule derives from the fact that nitrogen is trivalent, thus requiring an odd number of hydrogen atoms. For example, morphine has the formula C 17 H 19 NO 3 and a molecular weight of 285 amu. Alkylamines undergo a characteristic α cleavage in the mass spectrometer, similar to the cleavage observed for alcohols ( ). C–C bond nearest the nitrogen atom is broken, yielding an alkyl radical and a resonance-stabilized, nitrogen-containing cation. As an example, the mass spectrum of N -ethylpropylamine shown in has peaks at m / z = 58 and m / z = 72, corresponding to the two possible modes of α cleavage. Mass spectrum of N -ethylpropylamine. The two possible modes of α cleavage lead to the observed fragment ions at m / z = 58 and m / z = 72. Green Chemistry II: Ionic Liquids Liquids made of ions? Usually when we think of ionic compounds, we think of high-melting solids: sodium chloride, magnesium sulfate, lithium carbonate, and so forth. But yes, there are also ionic compounds that are liquid at room temperature, and they are gaining importance as reaction solvents, particularly for use in green chemistry processes (see the Chapter 11 Chemistry Matters ). More than 1500 ionic liquids are known, and about 500 are available commercially. Ionic liquids have been studied for nearly a century; the first to be discovered was ethylammonium nitrate, CH 3 CH 2 NH 3 + NO 3 – , with a melting point of 12 °C. More generally, however, the ionic liquids in use today are salts in which the cation is unsymmetrical and in which one or both of the ions are bulky so that the charges are dispersed over a large volume. Both factors minimize the crystal lattice energy and disfavor formation of the solid. Typical cations are quaternary ammonium ions from heterocyclic amines, either 1,3-dialkylimidazolium ions, N -alkylpyridinium ions, or ring-substituted N -alkylpyridinium ions. Anions are just as varied as the cations. Hexafluorophosphate, tetrafluoroborate, alkyl sulfates, trifluoromethanesulfonates (triflates), and halides are some anion possibilities. Ionic liquids have several important features that make them attractive for use, both as solvents in green chemistry and as specialty chemicals in such applications as paint additives and refrigerants: They dissolve both polar and nonpolar organic compounds, giving high solute concentrations and thereby minimizing the amount of solvent needed. They can be optimized for specific reactions by varying cation and anion structures. They are nonflammable. They are thermally stable. They have negligible vapor pressures and do not evaporate. They are generally recoverable and can be reused many times. As an example of their use in organic chemistry, the analgesic drug pravadoline has been synthesized in two steps using 1-butyl-3-methylimidazolium hexafluorophosphate, abbreviated [bmim][PF 6 ], as the solvent for both steps. The first step is a base-induced S N 2 reaction of 2-methylindole with a primary alkyl halide, and the second is a Friedel–Crafts acylation. Both steps take place with 95% yield, and the ionic solvent is recovered simply by washing the reaction mixture, first with toluene and then with water. The first commercial process using an ionic liquid catalyst was introduced by PetroChina in 2008, when they opened a plant producing 65,000 tons per year of alkylate gasoline from isobutane. The aluminum-based ionic liquid catalyst replaced the sulfuric acid and hydrofluoric acid catalysts that had previously been used. alkylamine amine arylamine azo compound ( R–N=N–R ′ ) Curtius rearrangement Gabriel amine synthesis heterocyclic amine Hofmann elimination reaction Hofmann rearrangement imide ( O=C–N–C=O ) primary amine (RNH 2 ) quaternary ammonium salt reductive amination Sandmeyer reaction secondary amine (R 2 NH) tertiary amine (R 3 N) Summary We’ve now seen all the common functional groups that occur in organic and biological chemistry. Of those groups, amines are among the most abundant and have among the richest chemistry. In addition to proteins and nucleic acids, the majority of pharmaceutical agents contain amine functional groups and many of the common coenzymes necessary for biological reactions are amines. Amines are organic derivatives of ammonia. They are named in the IUPAC system either by adding the suffix - amine to the name of the alkyl substituent or by considering the amino group as a substituent on a more complex parent molecule. The chemistry of amines is dominated by the lone-pair electrons on nitrogen, which makes amines both basic and nucleophilic. The basicity of arylamines is generally lower than that of alkylamines because the nitrogen lone-pair electrons are delocalized by interaction with the aromatic π system. Electron-withdrawing substituents on the aromatic ring further weaken the basicity of a substituted aniline, while electron-donating substituents increase basicity. Alkylamines are sufficiently basic that they exist almost entirely in their protonated form at the physiological pH of 7.3. Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic π system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. Arylamines are prepared by nitration of an aromatic ring followed by reduction. Alkylamines are prepared by S N 2 reaction of ammonia or an amine with an alkyl halide or by the Gabriel amine synthesis . Amines can also be prepared by a number of reductive methods, including LiAlH 4 reduction of amides, nitriles, and azides. Also important is the reductive amination reaction in which a ketone or an aldehyde is treated with an amine in the presence of a reducing agent such as NaBH 4 . In addition, amines result from Hofmann and Curtius rearrangements of carboxylic acid derivatives. Both methods involve migration of the –R group bonded to the carbonyl carbon and yield a product that has one less carbon atom than the starting material. Many of the reactions of amines are familiar from past chapters. Thus, amines react with alkyl halides in S N 2 reactions and with acid chlorides in nucleophilic acyl substitution reactions. Amines also undergo E2 elimination to yield alkenes if they are first quaternized by treatment with iodomethane and then heated with silver oxide, a process called the Hofmann elimination . Arylamines are converted by diazotization with nitrous acid into arenediazonium salts , ArN 2 + X – . The diazonio group can then be replaced by many other substituents by the Sandmeyer reaction to give a wide variety of substituted aromatic compounds. Aryl chlorides, bromides, iodides, and nitriles can be prepared from arenediazonium salts, as can arenes and phenols. In addition to their reactivity toward substitution reactions, diazonium salts undergo coupling with phenols and arylamines to give brightly colored azo compounds . Summary of Reactions Synthesis of amines ( ) Reduction of nitriles Reduction of amides Reduction of nitrobenzenes S N 2 Alkylation of alkyl halides Gabriel amine synthesis Reduction of azides Reductive amination of aldehydes/ketones Hofmann rearrangement of amides Curtius rearrangement of acyl azides Reactions of amines Alkylation with alkyl halides; see reaction 1(d) Hofmann elimination ( ) Diazotization ( ) Reactions of arenediazonium salts ( ) Nucleophilic substitutions Diazonium coupling Additional Problems Visualizing Chemistry Mechanism Problems Naming Amines Amine Basicity Synthesis of Amines Reactions of Amines Spectroscopy General Problems

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Why This Chapter? Produced by honeybees from the nectar of flowers, honey is primarily a mixture of the two simple sugars fructose and glucose. (credit: modification of work “Apis mellifera” by Thomas Bresson/Flickr, CC BY 2.0) We’ve now seen all the common functional groups and reaction types that occur in organic and biological chemistry. In this and the next four chapters, we’ll focus on the major classes of biological molecules, beginning with a look at the structures and primary biological functions of carbohydrates. Then, in Chapter 29, we’ll return to the subject to see how carbohydrates are both synthesized and degraded in organisms. Carbohydrates occur in every living organism. The sugar and starch in food, and the cellulose in wood, paper, and cotton are nearly pure carbohydrates. Modified carbohydrates form part of the coating around living cells, other carbohydrates are part of the nucleic acids that carry our genetic information, and still others are used as medicines. The word carbohydrate derives historically from the fact that glucose, the first simple carbohydrate to be obtained in pure form, has the molecular formula C 6 H 12 O 6 and was originally thought to be a “hydrate of carbon, C 6 (H 2 O) 6 .” This view was soon abandoned, but the name persisted. Today, the term carbohydrate is used to refer loosely to the broad class of polyhydroxylated aldehydes and ketones commonly called sugars. Glucose, also known as dextrose in medical work, is the most familiar example. Carbohydrates are synthesized by green plants during photosynthesis, a complex process in which sunlight provides the energy to convert CO 2 and H 2 O into glucose plus oxygen. Many molecules of glucose are then chemically linked for storage by the plant in the form of either cellulose or starch. It has been estimated that more than 50% of the dry weight of the earth’s biomass—all plants and animals—consists of glucose polymers. When eaten and metabolized, carbohydrates then provide animals with a source of readily available energy. Thus, carbohydrates act as the chemical intermediaries by which solar energy is stored and used to support life. Because humans and most other mammals lack the enzymes needed for digestion of cellulose, they require starch as their dietary source of carbohydrates. Grazing animals such as cows, however, have microorganisms in their first stomach that are able to digest cellulose. The energy stored in cellulose is thus moved up the biological food chain when these ruminant animals eat grass and are themselves used for food.

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Classification of Carbohydrates Carbohydrates are generally classified as either simple or complex. Simple sugars , or monosaccharides , are carbohydrates like glucose and fructose that can’t be converted into smaller sugars by hydrolysis. Complex carbohydrates are made of two or more simple sugars linked together by acetal bonds ( ). Sucrose (table sugar), for instance, consists of one glucose linked to one fructose. Similarly, cellulose is made up of several thousand glucose units linked together. Enzyme-catalyzed hydrolysis of a complex carbohydrate breaks it down into its constituent monosaccharides. Monosaccharides are further classified as either aldoses or ketoses . The - ose suffix designates a carbohydrate, and the prefixes aldo - and keto - identify the kind of carbonyl group in the molecule, whether aldehyde or ketone. The number of carbon atoms in the monosaccharide is indicated by the appropriate numerical prefix tri -, tetr -, pent -, hex -, and so forth, in the name. Putting it all together, glucose is an aldohexose, a six-carbon aldehyde sugar; fructose is a ketohexose, a six-carbon keto sugar; ribose is an aldopentose, a five-carbon aldehyde sugar; and sedoheptulose is a ketoheptose, a seven-carbon keto sugar. Most of the common simple sugars are either pentoses or hexoses. Problems

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Representing Carbohydrate Stereochemistry: Fischer Projections Because most carbohydrates have numerous chirality centers, it was recognized long ago that a quick method for representing their stereochemistry was needed. In 1891, the German chemist Emil Fischer suggested a method based on the projection of a tetrahedral carbon atom onto a flat surface. These Fischer projections were soon adopted and are still a common means of representing stereochemistry at chirality centers in carbohydrate chemistry. A tetrahedral carbon atom is represented in a Fischer projection by two crossed lines. The horizontal lines represent bonds coming out of the page, and the vertical lines represent bonds going into the page. For example, ( R )-glyceraldehyde, the simplest monosaccharide, can be drawn as in . A Fischer projection of ( R )-glyceraldehyde. Because a given chiral molecule can be drawn in many ways, it’s sometimes necessary to compare two projections to see if they represent the same or different enantiomers. To test for identity, Fischer projections can be moved around on the paper, but only two kinds of motions are allowed; moving a Fischer projection in any other way inverts its meaning. A Fischer projection can be rotated on the page by 180°, but not by 90° or 270°. Only a 180° rotation maintains the Fischer convention by keeping the same substituent groups going into and coming out of the plane. In the following Fischer projection of ( R )-glyceraldehyde, for instance, the –H and –OH groups come out of the plane both before and after a 180° rotation. A 90° rotation breaks the Fischer convention by exchanging the groups that go into the plane with those that come out. In the following Fischer projections of ( R )-glyceraldehyde, the –H and –OH groups originally come out of the plane but go into the plane after a 90° rotation. As a result, the rotated projection represents ( S )-glyceraldehyde. A Fischer projection can also have one group held steady while the other three rotate in either a clockwise or a counterclockwise direction. The effect is simply to rotate around a single bond, which does not change the stereochemistry. R , S stereochemical designations ( ) can be assigned to the chirality center in a Fischer projection by following three steps, as shown in Worked Example 25.1. STEP 1 Rank the four substituents in the usual way ( ). STEP 2 Place the group of lowest ranking, usually H, at the top of the Fischer projection by using one of the allowed motions. This means that the lowest-ranked group is oriented back, away from the viewer, as required for assigning configuration. STEP 3 Determine the direction of rotation 1 → 2 → 3 of the remaining three groups, and assign R or S configuration. Carbohydrates with more than one chirality center are shown in Fischer projections by stacking the centers on top of one another, with the carbonyl carbon at or near the top. Glucose, for example, has four chirality centers stacked on top of one another in a Fischer projection. Such representations don’t, however, give an accurate picture of the molecule’s true three-dimensional conformation, which is curled around on itself like a bracelet. Assigning R or S Configuration to a Fischer Projection Assign R or S configuration to the following Fischer projection of alanine: Strategy Follow the steps in the text. ( 1 ) Rank the four substituents on the chiral carbon. ( 2 ) Manipulate the Fischer projection to place the group of lowest ranking at the top by carrying out one of the allowed motions. ( 3 ) Determine the direction 1 → 2 → 3 of the remaining three groups. Solution The rankings of the groups are ( 1 ) –NH 2 , ( 2 ) –CO 2 H, ( 3 ) –CH 3 , and ( 4 ) –H. To bring the group of lowest ranking (–H) to the top, we might want to hold the –CH 3 group steady while rotating the other three groups counterclockwise. Going from first- to second- to third-highest ranking requires a counterclockwise turn, corresponding to S stereochemistry. Problems

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D , L Sugars Glyceraldehyde, the simplest aldose, has only one chirality center and thus has two enantiomeric (nonidentical mirror-image) forms. Only the dextrorotatory enantiomer occurs naturally, however. That is, a sample of naturally occurring glyceraldehyde placed in a polarimeter rotates plane-polarized light in a clockwise direction, denoted (+). Since (+)-glyceraldehyde has been found to have an R configuration at C2, it can be represented by a Fischer projection as shown previously in . For historical reasons dating back long before the adoption of the R,S system, ( R )-(+)-glyceraldehyde is also referred to as D -glyceraldehyde ( D for dextrorotatory). The other enantiomer, ( S )-(–)-glyceraldehyde, is known as L -glyceraldehyde ( L for levorotatory). Because of the way that monosaccharides are biosynthesized in nature, glucose, fructose, and most other naturally occurring monosaccharides all have the same R stereochemical configuration as D -glyceraldehyde at the chirality center farthest from the carbonyl group. In Fischer projections, therefore, most naturally occurring sugars have the hydroxyl group at the bottom chirality center pointing to the right ( ). Such compounds are referred to as D sugars . Some naturally occurring D sugars. The –OH group at the chirality center farthest from the carbonyl group has the same configuration as ( R )-(+)-glyceraldehyde and points toward the right in Fischer projections. In contrast with D sugars, L sugars have an S configuration at the lowest chirality center, with the bottom –OH group pointing to the left in Fischer projections. Thus, an L sugar is the mirror image (enantiomer) of the corresponding D sugar and has the opposite configuration from the D sugar at all chirality centers. Note that the D and L notations have no relation to the direction in which a given sugar rotates plane-polarized light. A D sugar can be either dextrorotatory or levorotatory. The prefix D indicates only that the –OH group at the lowest chirality center has R stereochemistry and points to the right when the molecule is drawn in a standard Fischer projection. Note also that the D , L system of carbohydrate nomenclature describes the configuration at only one chirality center and says nothing about the configuration of other chirality centers that may be present. Problems

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Configurations of the Aldoses An aldotetrose is a four-carbon sugar with two chirality centers. Thus, there are 2 2 = 4 possible stereoisomeric aldotetroses, or two D , L pairs of enantiomers named erythrose and threose. Aldopentoses have three chirality centers and a total of 2 3 = 8 possible stereoisomers, or four D , L pairs of enantiomers. These four pairs are called ribose, arabinose, xylose, and lyxose. All except lyxose occur widely in nature. D -Ribose is an important constituent of RNA (ribonucleic acid), L -arabinose is found in many plants, and D -xylose is found in wood. Aldohexoses have four chirality centers and a total of 2 4 = 16 possible stereoisomers, or eight D , L pairs of enantiomers. The names of the eight are allose, altrose, glucose, mannose, gulose, idose, galactose, and talose. Only D -glucose, from starch and cellulose, and D -galactose, from gums and fruit pectins, are widely distributed in nature. D -mannose and D -talose also occur naturally but in lesser abundance. Fischer projections of the four-, five-, and six-carbon D aldoses are shown in . Starting with D -glyceraldehyde, we can imagine constructing the two D aldotetroses by inserting a new chirality center just below the aldehyde carbon. Each of the two D aldotetroses then leads to two D aldopentoses (four total), and each of the four D aldopentoses leads to two D aldohexoses (eight total). In addition, each of the D aldoses in has an L enantiomer, which is not shown. Configurations of D aldoses. The structures are arranged from left to right so that the –OH groups on C2 alternate right/left (R/L) across each series. Similarly, the –OH groups at C3 alternate two right/two left (2R/2L), the –OH groups at C4 alternate 4R/4L, and the –OH groups at C5 are to the right in all eight (8R). Each D aldose has a corresponding L enantiomer that is not shown. Louis Fieser of Harvard University long ago suggested a simple procedure for remembering the names and structures of the eight D aldohexoses: STEP 1 Set up eight Fischer projections with the –CHO group on top and the –CH 2 OH group at the bottom. STEP 2 At C5, place all eight –OH groups to the right ( D series). STEP 3 At C4, alternate four –OH groups to the right and four to the left. STEP 4 At C3, alternate two –OH groups to the right, two to the left. STEP 5 At C2, alternate –OH groups right, left, right, left. STEP 6 Name the eight isomers using the mnemonic “ All alt ruists gl adly ma ke gu m i n gal lon ta nks.” The structures of the four D aldopentoses can be generated in a similar way and named by the mnemonic suggested by a Cornell University undergraduate: “ RIB s ARe eXtra Lean.” Drawing a Fischer Projection Draw a Fischer projection of L -fructose. Strategy Because L -fructose is the enantiomer of D -fructose, simply look at the structure of D -fructose and reverse the configuration at each chirality center. Solution Drawing a Fischer Projection of a Molecular Model Draw the following aldotetrose as a Fischer projection, and identify it as a D sugar or an L sugar: Strategy The Fischer projection of a monosaccharide is drawn vertically, with the carbonyl group at or near the top and the –CH 2 OH group at the bottom. The interior –H and –OH are drawn to the sides, pointing out of the page toward the viewer. Solution Problems

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Cyclic Structures of Monosaccharides: Anomers We said in that aldehydes and ketones undergo a rapid and reversible nucleophilic addition reaction with alcohols to form hemiacetals. If the carbonyl and the hydroxyl group are in the same molecule, an intramolecular nucleophilic addition can take place, leading to the formation of a cyclic hemiacetal. Five- and six-membered cyclic hemiacetals are relatively strain-free and particularly stable, and many carbohydrates therefore exist in an equilibrium between open-chain and cyclic forms. Glucose, for instance, exists in aqueous solution primarily in the six-membered pyranose form resulting from intramolecular nucleophilic addition of the –OH group at C5 to the C1 carbonyl group ( ). The name pyranose is derived from pyran, the name of the unsaturated six-membered cyclic ether. Like cyclohexane rings ( ), pyranose rings have a chairlike geometry with axial and equatorial substituents. By convention, the rings are usually drawn by placing the hemiacetal oxygen atom at the right rear, as shown in . Note that an –OH group on the right in a Fischer projection is on the bottom face of the pyranose ring, and an –OH group on the left in a Fischer projection is on the top face of the ring. For D sugars, the terminal –CH 2 OH group is on the top of the ring, whereas for L sugars, the –CH 2 OH group is on the bottom. When an open-chain monosaccharide cyclizes to a pyranose form, a new chirality center is generated at the former carbonyl carbon and two diastereomers, called anomers , are produced. The hemiacetal carbon atom is referred to as the anomeric center . For example, glucose cyclizes reversibly in aqueous solution to a 37 : 63 mixture of two anomers ( ). The compound with its newly generated –OH group at C1 cis to the –OH at the lowest chirality center in a Fischer projection is called the α anomer ; its full name is α - D -glucopyranose. The compound with its newly generated –OH group trans to the –OH at the lowest chirality center is called the β anomer ; its full name is β - D -glucopyranose. Note that in β - D -glucopyranose, all the substituents on the ring are equatorial. Thus, β - D -glucopyranose is the least sterically crowded and most stable of the eight D aldohexoses. Glucose in its cyclic pyranose forms. As explained in the text, two anomers are formed by cyclization of glucose. The molecule whose newly formed –OH group at C1 is cis to the oxygen atom on the lowest chirality center (C5) in a Fischer projection is the α anomer. The molecule whose newly formed –OH group is trans to the oxygen atom on the lowest chirality center in a Fischer projection is the β anomer. Some monosaccharides also exist in a five-membered cyclic hemiacetal form called a furanose . D -Fructose, for instance, exists in water solution as 68% β -pyranose, 2.7% α -pyranose, 0.5% open-chain, 22.4% β -furanose, and 6.2% α -furanose. The pyranose form results from addition of the –OH at C6 to the carbonyl group, while the furanose form results from addition of the –OH at C5 to the carbonyl group ( ). Pyranose and furanose forms of fructose in aqueous solution. The two pyranose anomers result from addition of the C6 –OH group to the C2 carbonyl; the two furanose anomers result from addition of the C5 –OH group to the C2 carbonyl. Both anomers of D -glucopyranose can be crystallized and purified. Pure α - D -glucopyranose has a melting point of 146 °C and a specific rotation [ α ] D = +112.2; pure β - D -glucopyranose has a melting point of 148 to 155 °C and a specific rotation [ α ] D = +18.7. When a sample of either pure anomer is dissolved in water, however, its optical rotation slowly changes until it reaches a constant value of +52.6. That is, the specific rotation of the α -anomer solution decreases from +112.2 to +52.6, and the specific rotation of the β -anomer solution increases from +18.7 to +52.6. Called mutarotation , this change in optical rotation is due to the slow interconversion of the pure anomers to give the same 37 : 63 equilibrium mixture. Mutarotation occurs by a reversible ring-opening of each anomer to the open-chain aldehyde, followed by reclosure. Although the equilibration is slow at neutral pH, it is catalyzed by both acid and base. Drawing the Chair Conformation of an Aldohexose D -Mannose differs from D -glucose in its stereochemistry at C2. Draw D -mannose in its chairlike pyranose form. Strategy First draw a Fischer projection of D -mannose. Then lay it on its side, and curl it around so that the –CHO group (C1) is on the right front and the –CH 2 OH group (C6) is toward the left rear. Now, connect the –OH at C5 to the C1 carbonyl group to form the pyranose ring. In drawing the chair form, raise the leftmost carbon (C4) up and drop the rightmost carbon (C1) down. Solution Drawing the Chair Conformation of a Pyranose Draw β - L -glucopyranose in its more stable chair conformation. Strategy It’s probably easiest to begin by drawing the chair conformation of β - D -glucopyranose. Then draw its mirror-image L enantiomer by changing the stereochemistry at every position on the ring, and carry out a ring-flip to give the more stable chair conformation. Note that the –CH 2 OH group is on the bottom face of the ring in the L enantiomer, as is the anomeric –OH. Solution Problems

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