Spectroscopy of Carboxylic Acids and Nitriles Infrared Spectroscopy Carboxylic acids have two characteristic IR absorptions that make the –CO 2 H group easily identifiable. The O–H bond of the carboxyl group gives rise to a very broad absorption over the range 2500 to 3300 cm –1 . The C═O bond shows an absorption between 1710 and 1760 cm –1 . The exact position of C═O absorption depends both on the structure of the molecule and on whether the acid is free (monomeric) or hydrogen-bonded (dimeric). Free carboxyl groups absorb at 1760 cm –1 , but the more commonly encountered dimeric carboxyl groups absorb in a broad band centered around 1710 cm –1 . As with other carbonyl-containing functional groups, conjugation with an alkene or benzene ring lowers the frequency of the C═O stretch by 20 to 30 cm –1 . Both the broad O–H absorption and the C═O absorption at 1710 cm –1 (dimeric) are identified in the IR spectrum of butanoic acid shown in . IR spectrum of butanoic acid, CH 3 CH 2 CH 2 CO 2 H. Nitriles show an intense and easily recognizable C≡N bond absorption near 2250 cm –1 for saturated compounds and 2230 cm –1 for aromatic and conjugated molecules. Few other functional groups absorb in this region, so IR spectroscopy is highly diagnostic for nitriles. Problems Nuclear Magnetic Resonance Spectroscopy Carboxyl carbon atoms absorb in the range 165 to 185 δ in the 13 C NMR spectrum, with aromatic and α , β -unsaturated acids near the upfield end of the range (∼165 δ ) and saturated aliphatic acids near the downfield end (∼185 δ ). Nitrile carbons absorb in the range 115 to 130 δ . In the 1 H NMR spectrum, the acidic –CO 2 H proton normally absorbs as a singlet near 12 δ . The chemical shift of the carboxyl proton is concentration and solvent dependent, as these variables can change the extent of hydrogen-bonding in the sample. In some cases, the carboxyl-proton resonance is broadened to the point of being nearly undetectable. Traces of water in the sample can exacerbate the situation. As with alcohols ( ), the –CO 2 H proton can be replaced by deuterium when D 2 O is added to the sample tube, causing the absorption to disappear from the NMR spectrum. shows the 1 H NMR spectrum of phenylacetic acid. Note that the –CO 2 H absorption occurs at 12.0 δ . Proton NMR spectrum of phenylacetic acid, C 6 H 5 CH 2 CO 2 H. Problems Vitamin C The word vitamin, despite its common usage, is actually an imprecise term. Generally speaking, a vitamin is an organic substance that a given organism requires in small amounts to live and grow but is unable to synthesize and must obtain in its diet. Thus, to be considered a vitamin, only a small amount of the substance is needed—anywhere from a few micrograms to 100 mg or so per day. Dietary substances needed in larger amounts, such as some amino acids and unsaturated fats, are not considered vitamins. In addition to the hazards of weather, participants in early polar expeditions often suffered from scurvy, caused by a dietary vitamin C deficiency. (credit: “Shackleton’s expedition to the Antarctic last moments of the Endurance” by Underwood & Underwood/Wikimedia Commons, Public Domain) Furthermore, different organisms need different vitamins. More than 4000 species of mammals can synthesize ascorbic acid in their bodies, for instance, but humans are not among them. Ascorbic acid is therefore a human vitamin—what we all know as vitamin C—and must be provided by our diet. Small amounts of more than a dozen other substances are similarly required by humans: retinol (vitamin A), thiamine (vitamin B 1 ), and tocopherol (vitamin E), for instance. Vitamin C is surely the best known of all human vitamins. It was the first to be discovered (1912), the first to be isolated (1928), the first to be structurally characterized (1933), and the first to be synthesized in the laboratory (1933). Over 121,000 tons of vitamin C is synthesized worldwide each year, more than the total amount of all other vitamins combined. In addition to its use as a supplement, vitamin C is used as a food preservative, a “flour improver” in bakeries, and an animal-food additive. Vitamin C is perhaps most well-known for its antiscorbutic properties, meaning that it prevents the onset of scurvy, a bleeding disease affecting those with a deficiency of fresh vegetables and citrus fruits in their diet. Sailors in the Age of Exploration were particularly susceptible to scurvy, and the death toll was high. The Portuguese explorer Vasco da Gama lost more than half his crew to scurvy during his two-year voyage around the Cape of Good Hope in 1497–1499. More recently, large doses of vitamin C have been claimed to prevent the common cold, cure infertility, delay the onset of symptoms in acquired immunodeficiency syndrome (AIDS), and inhibit the development of gastric and cervical cancers. None of these claims have been backed by medical evidence, however. In the largest study yet of the effect of vitamin C on the common cold, a meta-analysis of more than 100 separate trials covering 40,000 people found no difference in the incidence of colds between those who took supplemental vitamin C regularly and those who did not. When taken during a cold, however, vitamin C does appear to decrease the cold’s duration by perhaps a day. The industrial preparation of vitamin C involves an unusual blend of biological and laboratory organic chemistry, beginning with glucose and following the five-step route shown in . Glucose, a pentahydroxy aldehyde, is first reduced to sorbitol, which is then oxidized by the microorganism Acetobacter suboxydans. No chemical reagent is known that is selective enough to oxidize only one of the six alcohol groups in sorbitol, so an enzymatic reaction is used. Treatment with acetone and an acid catalyst then converts four of the other hydroxyl groups into acetal linkages, and the remaining hydroxyl group is chemically oxidized to a carboxylic acid by reaction with aqueous NaOCl (household bleach). Hydrolysis with acid then removes the two acetal groups and causes an internal ester-forming reaction to give ascorbic acid. Each of the five steps has a yield better than 90%. The industrial synthesis of ascorbic acid from glucose. carboxyl group carboxylation carboxylic acid, RCO 2 H Henderson–Hasselbalch equation nitrile Summary Carboxylic acids are among the most useful building blocks for synthesizing other molecules, both in nature and in the laboratory. Thus, an understanding of their properties and reactions is fundamental to understanding biological chemistry. In this chapter, we’ve looked both at acids and at their close relatives, nitriles ( RC≡N ) . Carboxylic acids are named systematically by replacing the terminal - e of the corresponding alkane name with - oic acid. Like aldehydes and ketones, the carbonyl carbon atom is sp 2 -hybridized; like alcohols, carboxylic acids are associated through hydrogen-bonding and therefore have high boiling points. The distinguishing characteristic of carboxylic acids is their acidity. Although weaker than mineral acids such as HCl, carboxylic acids dissociate much more readily than alcohols because the resultant carboxylate ions are stabilized by resonance between two equivalent forms. Most carboxylic acids have p K a values near 5, but the exact p K a of a given acid depends on structure. Carboxylic acids substituted by electron-withdrawing groups are more acidic (have a lower p K a ) because their carboxylate ions are stabilized. Carboxylic acids substituted by electron-donating groups are less acidic (have a higher p K a ) because their carboxylate ions are destabilized. The extent of dissociation of a carboxylic acid in a buffered solution of a given pH can be calculated with the Henderson–Hasselbalch equation. Inside living cells, where the physiological pH = 7.3, carboxylic acids are entirely dissociated and exist as their carboxylate anions. Methods of synthesis for carboxylic acids include ( 1 ) oxidation of alkylbenzenes, ( 2 ) oxidation of primary alcohols or aldehydes, ( 3 ) reaction of Grignard reagents with CO 2 (carboxylation) , and ( 4 ) hydrolysis of nitriles. General reactions of carboxylic acids include ( 1 ) loss of the acidic proton, ( 2 ) nucleophilic acyl substitution at the carbonyl group, ( 3 ) substitution on the α carbon, and ( 4 ) reduction. Nitriles are similar in some respects to carboxylic acids and are prepared either by S N 2 reaction of an alkyl halide with cyanide ion or by dehydration of an amide. Nitriles undergo nucleophilic addition to the polar C≡N bond in the same way that carbonyl compounds do. The most important reactions of nitriles are their hydrolysis to carboxylic acids, reduction to primary amines, and reaction with Grignard reagents to yield ketones. Carboxylic acids and nitriles are easily distinguished spectroscopically. Acids show a characteristic IR absorption at 2500 to 3300 cm –1 due to the O−H bond and another at 1710 to 1760 cm –1 due to the C═O bond; nitriles have an absorption at 2250 cm –1 . Acids also show 13 C NMR absorptions at 165 to 185 δ and 1 H NMR absorptions near 12 δ . Nitriles have a 13 C NMR absorption in the range 115 to 130 δ . Summary of Reactions Preparation of carboxylic acids ( ) Carboxylation of Grignard reagents Hydrolysis of nitriles Preparation of nitriles ( ) S N 2 reaction of alkyl halides Dehydration of amides Reactions of nitriles ( ) Hydrolysis to yield carboxylic acids Reduction to yield primary amines Reaction with Grignard reagents to yield ketones Additional Problems Visualizing Chemistry Mechanism Problems Naming Carboxylic Acids and Nitriles Acidity of Carboxylic Acids Reactions of Carboxylic Acids and Nitriles Spectroscopy General Problems

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Why This Chapter? The lives of rock climbers depend on their ropes, typically made of a nylon polymer prepared by a nucleophilic acyl substitution reaction. (credit: modification of work “110823-A-NR754-001” by USASOC News Service/Flickr, CC BY 2.0) Carboxylic acid derivatives are among the most widely occurring of all molecules, both in laboratory chemistry and in biological pathways. Thus, a study of them and their primary reaction—nucleophilic acyl substitution—is fundamental to understanding organic chemistry. We’ll begin this chapter by first learning about carboxylic acid derivatives, and we’ll then explore the chemistry of acyl substitution reactions. Closely related to the carboxylic acids and nitriles discussed in the previous chapter are the carboxylic acid derivatives , compounds in which an acyl group is bonded to an electronegative atom or substituent that can act as a leaving group in the nucleophilic acyl substitution reaction that we saw briefly in the Preview of Carbonyl Chemistry : Many kinds of acid derivatives are known, but we’ll be concerned primarily with four of the most common ones: acid halides , acid anhydrides , esters , and amides . Acid halides and acid anhydrides are used only in the laboratory, while esters and amides are common in both laboratory and biological chemistry. In addition, carboxylic acid derivatives called thioesters and acyl phosphates are encountered primarily in biological chemistry. Note the structural similarity between acid anhydrides and acyl phosphates.

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Naming Carboxylic Acid Derivatives Acid Halides, RCOX Acid halides are named by identifying first the acyl group and then the halide. As described in and shown in , the acyl group name is derived from the carboxylic acid name by replacing the - ic acid or - oic acid ending with - oyl, or the - carboxylic acid ending with - carbonyl. To keep things interesting, however, IUPAC recognizes eight exceptions for which a - yl rather than an - oyl ending is used: formic (formyl), acetic (acetyl), propionic (propionyl), butyric (butyryl), oxalic (oxalyl), malonic (malonyl), succinic (succinyl), and glutaric (glutaryl). Acid Anhydrides, RCO 2 COR ′ Symmetrical anhydrides of unsubstituted monocarboxylic acids and cyclic anhydrides of dicarboxylic acids are named by replacing the word acid with anhydride. Unsymmetrical anhydrides—those prepared from two different carboxylic acids—are named by listing the two acids alphabetically and then adding anhydride. Esters, RCO 2 R ′ Esters are named by first identifying the alkyl group attached to oxygen and then the carboxylic acid, with the - ic acid ending replaced by - ate. Amides, RCONH 2 Amides with an unsubstituted –NH 2 group are named by replacing the - oic acid or - ic acid ending with - amide, or by replacing the - carboxylic acid ending with - carboxamide. If the nitrogen atom is further substituted, the compound is named by first identifying the substituent groups and then the parent amide. The substituents are preceded by the letter N to identify them as being directly attached to nitrogen. Thioesters, RCOSR ′ Thioesters are named like the corresponding esters. If the related ester has a common name, the prefix thio - is added to the name of the carboxylate: acetate becomes thioacetate, for instance. If the related ester has a systematic name, the - oate or - carboxylate ending is replaced by - thioate or - carbothioate: butanoate becomes butanethioate and cyclohexanecarboxylate becomes cyclohexanecarbothioate, for instance. Acyl Phosphates, RCO 2 PO 3 2– and RCO 2 PO 3 R ′ – Acyl phosphates are named by citing the acyl group and adding the word phosphate. If an alkyl group is attached to one of the phosphate oxygens, it is identified after the name of the acyl group. In biological chemistry, acyl adenosyl phosphates are particularly common. A summary of nomenclature rules for carboxylic acid derivatives is given in . Nomenclature of Carboxylic Acid Derivatives Functional group Structure Name ending Carboxylic acid -ic acid (-carboxylic acid) Acid halide -oyl halide (-carbonyl halide) Acid anhydride anhydride Amide -amide (-carboxamide) Ester -oate (-carboxylate) Thioester -thioate (-carbothioate) Acyl phosphate -oyl phosphate Problems

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Nucleophilic Acyl Substitution Reactions The addition of a nucleophile to a polar C═O bond is the key step in three of the four major carbonyl-group reactions. We saw in the chapter on Aldehydes and Ketones: Nucleophilic Addition Reactions that when a nucleophile adds to an aldehyde or ketone, the initially formed tetrahedral intermediate can be protonated to yield an alcohol. When a nucleophile adds to a carboxylic acid derivative, however, a different reaction path is taken. The initially formed tetrahedral intermediate eliminates one of the two substituents originally bonded to the carbonyl carbon, leading to a net nucleophilic acyl substitution reaction ( ). The general mechanisms of nucleophilic addition and nucleophilic acyl substitution reactions. Both reactions begin with addition of a nucleophile to a polar C═O bond to give a tetrahedral, alkoxide ion intermediate. (a) The intermediate formed from an aldehyde or ketone is protonated to give an alcohol, but (b) the intermediate formed from a carboxylic acid derivative expels a leaving group to give a new carbonyl compound. The difference in behavior between aldehydes/ketones and carboxylic acid derivatives is a consequence of structure. Carboxylic acid derivatives have an acyl carbon bonded to a group –Y that can act as a leaving group, often as a stable anion. As soon as the tetrahedral intermediate is formed, the leaving group is expelled to generate a new carbonyl compound. Aldehydes and ketones, however, have no such leaving group, however, and therefore don’t undergo substitution. The net effect of the addition/elimination sequence is a substitution of the nucleophile for the –Y group that was originally bonded to the acyl carbon. Thus, the overall reaction is superficially similar to the kind of nucleophilic substitution that occurs during an S N 2 reaction ( ), but the mechanisms of the two reactions are completely different. An S N 2 reaction occurs in a single step by backside displacement of the leaving group, while a nucleophilic acyl substitution takes place in two steps and involves a tetrahedral intermediate. Problems Relative Reactivity of Carboxylic Acid Derivatives Both the initial addition step and the subsequent elimination step can affect the overall rate of a nucleophilic acyl substitution reaction, but the addition is usually the rate-limiting step. Thus, any factor that makes the carbonyl group more reactive toward nucleophiles favors the substitution process. Steric and electronic factors are both important in determining reactivity. Sterically, we find within a series of similar acid derivatives that unhindered, accessible carbonyl groups react with nucleophiles more readily than do sterically hindered carbonyl groups. The reactivity order is Electronically, we find that strongly polarized acyl compounds react more readily than less polar ones. Thus, acid chlorides are the most reactive because the electronegative chlorine atom withdraws electrons from the carbonyl carbon, whereas amides are the least reactive. Although subtle, electrostatic potential maps of various carboxylic acid derivatives indicate these differences by the relative blueness on the C═O carbons. Acyl phosphates are hard to place on this scale because they are not often used in the laboratory, but in biological systems they appear to be somewhat more reactive than thioesters. The way in which various substituents affect the polarization of a carbonyl group is similar to the way they affect the reactivity of an aromatic ring toward electrophilic substitution ( ). A chlorine substituent, for example, inductively withdraws electrons from an acyl group in the same way that it withdraws electrons from and thus deactivates an aromatic ring. Similarly, amino, methoxyl, and methylthio substituents donate electrons to acyl groups by resonance in the same way that they donate electrons to, and thus activate, aromatic rings. As a consequence of these reactivity differences, it’s usually possible to convert a more reactive acid derivative into a less reactive one. Acid chlorides, for instance, can be directly converted into anhydrides, thioesters, esters, and amides, but amides can’t be directly converted into esters, thioesters, anhydrides, or acid chlorides. Remembering the reactivity order is therefore a way to keep track of a large number of reactions ( ). Another consequence, as noted previously, is that only acyl phosphates, thioesters, esters, and amides are commonly found in nature. Acid halides and acid anhydrides react so rapidly with water that they can’t exist for long in living organisms. Interconversions of carboxylic acid derivatives. A more reactive acid derivative can be converted into a less reactive one, but not vice versa. In studying the chemistry of carboxylic acid derivatives in the next few sections, we’ll be concerned largely with the reactions of just a few nucleophiles and will see that the same kinds of reactions tend to reoccur ( ). Reaction Yield • Hydrolysis Reaction with water to yield a carboxylic acid • Alcoholysis Reaction with an alcohol to yield an ester • Aminolysis Reaction with ammonia or an amine to yield an amide • Reduction Reaction with a hydride reducing agent to yield an aldehyde or an alcohol • Grignard reaction Reaction with an organometallic reagent to yield a ketone or an alcohol Some general reactions of carboxylic acid derivatives. Predicting the Product of a Nucleophilic Acyl Substitution Reaction Predict the product of the following nucleophilic acyl substitution reaction of benzoyl chloride with 2-propanol: Strategy A nucleophilic acyl substitution reaction involves the substitution of a nucleophile for a leaving group in a carboxylic acid derivative. Identify the leaving group (Cl – in the case of an acid chloride) and the nucleophile (an alcohol in this case), and replace one by the other. The product is isopropyl benzoate. Solution Problems

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Reactions of Carboxylic Acids The direct nucleophilic acyl substitution of a carboxylic acid is difficult because –OH is a poor leaving group ( ). Thus, it’s usually necessary to enhance the reactivity of the acid, either by using a strong acid catalyst to protonate the carboxyl and make it a better acceptor or by converting the –OH into a better leaving group. Under the right circumstances, however, acid chlorides, anhydrides, esters, and amides can all be prepared from carboxylic acids by nucleophilic acyl substitution reactions. Conversion of Carboxylic Acids into Acid Chlorides In the laboratory, carboxylic acids are converted into acid chlorides by treatment with thionyl chloride, SOCl 2 . This reaction occurs by a nucleophilic acyl substitution pathway in which the carboxylic acid is first converted into an acyl chlorosulfite intermediate, thereby replacing the –OH of the acid with a much better leaving group. The chlorosulfite then reacts with a nucleophilic chloride ion. You might recall from that an analogous chlorosulfite is involved in the reaction of an alcohol with SOCl 2 to yield an alkyl chloride. Conversion of Carboxylic Acids into Acid Anhydrides Acid anhydrides can be derived from two molecules of carboxylic acid by heating to remove 1 equivalent of water. Because of the high temperatures needed, however, only acetic anhydride is commonly prepared this way. Conversion of Carboxylic Acids into Esters Perhaps the most useful reaction of carboxylic acids is their conversion into esters. There are many methods for accomplishing this, including the S N 2 reaction of a carboxylate anion with a primary alkyl halide that we saw in . Esters can also be synthesized by an acid-catalyzed nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol, a process called the Fischer esterification reaction . Unfortunately, the need for an excess of a liquid alcohol as solvent effectively limits the method to the synthesis of methyl, ethyl, propyl, and butyl esters. The mechanism of the Fischer esterification reaction is shown in . Carboxylic acids are not reactive enough to undergo nucleophilic addition directly, but their reactivity is greatly enhanced in the presence of a strong acid such as HCl or H 2 SO 4 . The mineral acid protonates the carbonyl-group oxygen atom, thereby giving the carboxylic acid a positive charge and rendering it much more reactive toward nucleophiles. Subsequent loss of water from the tetrahedral intermediate yields the ester product. MECHANISM Mechanism of Fischer esterification. The reaction is an acid-catalyzed, nucleophilic acyl substitution of a carboxylic acid. The net effect of Fischer esterification is substitution of an –OH group by –OR′. All steps are reversible, and the reaction typically has an equilibrium constant close to 1. Thus, the reaction can be driven in either direction by the choice of reaction conditions. Ester formation is favored when a large excess of alcohol is used as solvent, but carboxylic acid formation is favored when a large excess of water is present. Evidence in support of the mechanism shown in comes from isotope-labeling experiments. When 18 O-labeled methanol reacts with benzoic acid, the methyl benzoate produced is found to be 18 O-labeled whereas the water produced is unlabeled. Thus, it is the C–OH bond of the carboxylic acid that is broken during the reaction rather than the CO–H bond and the RO–H bond of the alcohol that is broken rather than the R–OH bond. Synthesizing an Ester from an Acid How might you prepare the following ester using a Fischer esterification reaction? Strategy Begin by identifying the two parts of the ester. The acyl part comes from the carboxylic acid and the –OR part comes from the alcohol. In this case, the target molecule is propyl o -bromobenzoate, so it can be prepared by treating o -bromobenzoic acid with 1-propanol. Solution Problems Conversion of Carboxylic Acids into Amides Amides are difficult to prepare by direct reaction of carboxylic acids with amines because amines are bases that convert acidic carboxyl groups into their unreactive carboxylate anions. Thus, the –OH must be replaced by a better, nonacidic leaving group to carry out a nucleophilic acyl substitution. In practice, amides are often prepared by activating the carboxylic acid with a carbodiimide ( R–N═C═N–R ), followed by addition of the amine. Dicyclohexylcarbodiimide (DCC) and 1-ethyl-3-(3-dimethylaminopropylcarbodiimide (EDEC) are commonly used. As shown in , the acid first adds to a C═N double bond of DCC, and nucleophilic acyl substitution by amine then ensues. Alternatively, and depending on the reaction solvent, the reactive acyl intermediate might also react with a second equivalent of carboxylate ion to generate an acid anhydride that then reacts with the amine. The product from either pathway is the same. MECHANISM Mechanism of amide formation by reaction of a carboxylic acid and an amine with dicyclohexylcarbodiimide (DCC). We’ll see in Section 26.7 that this carbodiimide method of amide formation is the key step in the laboratory synthesis of small proteins, or peptides . For instance, when one amino acid with its NH 2 rendered unreactive and a second amino acid with its –CO 2 H rendered unreactive are treated with carbodiimide, a dipeptide is formed. Conversion of Carboxylic Acids into Alcohols We said in that carboxylic acids are reduced by LiAlH 4 to give primary alcohols, but we deferred a discussion of the reaction mechanism at that time. In fact, the reduction is a nucleophilic acyl substitution reaction in which –H replaces –OH to give an aldehyde that is further reduced by nucleophilic addition to produce a primary alcohol. The aldehyde intermediate is much more reactive than the starting acid, so it reacts instantly and is not isolated. Because hydride ion is a base as well as a nucleophile, the actual nucleophilic acyl substitution step takes place on the carboxylate ion rather than on the free carboxylic acid and gives a high-energy dianion intermediate. In this intermediate, the two oxygens are complexed to a Lewis acidic aluminum species. Thus, the reaction is relatively difficult, and acid reductions require higher temperatures and extended reaction times. Alternatively, borane in tetrahydrofuran (BH 3 /THF) is a useful reagent for reducing carboxylic acids to primary alcohols. Reaction of an acid with BH 3 /THF occurs rapidly at room temperature, and the procedure is often preferred to reduction with LiAlH 4 because of its relative ease and safety. Borane reacts with carboxylic acids faster than with any other functional group, thereby allowing selective transformations such as that on p -nitrophenylacetic acid. If the reduction of p -nitrophenylacetic acid were done with LiAlH 4 , both the nitro and carboxyl groups would be reduced. Biological Conversions of Carboxylic Acids The direct conversion of a carboxylic acid to an acyl derivative by nucleophilic acyl substitution does not occur in biological chemistry. As in the laboratory, the acid must first be activated by converting the –OH into a better leaving group. This activation is often accomplished in living organisms by reaction of the acid with adenosine triphosphate (ATP) to give an acyl adenosyl phosphate, or acyl adenylate, a mixed anhydride combining a carboxylic acid and adenosine monophosphate (AMP, also known as adenylic acid). In the biosynthesis of fats, for example, a long-chain carboxylic acid reacts with ATP to give an acyl adenylate, followed by subsequent nucleophilic acyl substitution of a thiol group in coenzyme A to give the corresponding acyl CoA ( ). MECHANISM In fatty-acid biosynthesis, a carboxylic acid is activated by reaction with ATP to give an acyl adenylate, which undergoes nucleophilic acyl substitution with the –SH group on coenzyme A. (ATP = adenosine triphosphate; AMP = adenosine monophosphate.) Note that the first step in —reaction of the carboxylate with ATP to give an acyl adenylate—is itself a nucleophilic acyl substitution on phosphorus. The carboxylate first adds to a P═O double bond, giving a five-coordinate phosphorus intermediate that expels diphosphate ion as a leaving group.

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Chemistry of Acid Halides Preparation of Acid Halides Acid chlorides are prepared from carboxylic acids by reaction with thionyl chloride (SOCl 2 ), as we saw in the previous section. Similar reaction of a carboxylic acid with phosphorus tribromide (PBr 3 ) yields the acid bromide. Reactions of Acid Halides Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by –OH to yield an acid, by –OCOR to yield an anhydride, by –OR to yield an ester, by –NH 2 to yield an amide, or by R′ to yield a ketone. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we’ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. Conversion of Acid Halides into Carboxylic Acids: Hydrolysis Acid chlorides react with water to yield carboxylic acids. This hydrolysis reaction is a typical nucleophilic acyl substitution process and is initiated by attack of water on the acid chloride carbonyl group. The tetrahedral intermediate undergoes elimination of Cl – and loss of H + to give the product carboxylic acid plus HCl. Because HCl is formed during hydrolysis, the reaction is often carried out in the presence of a base such as pyridine or NaOH to remove the HCl and prevent it from causing side reactions. Conversion of Acid Halides into Anhydrides Nucleophilic acyl substitution reaction of an acid chloride with a carboxylate anion gives an acid anhydride. Both symmetrical and unsymmetrical acid anhydrides can be prepared. Conversion of Acid Halides into Esters: Alcoholysis Acid chlorides react with alcohols to yield esters in a process analogous to their reaction with water to yield acids. In fact, this reaction is probably the most common method for preparing esters in the laboratory. As with hydrolysis, alcoholysis reactions are usually carried out in the presence of pyridine or NaOH to react with the HCl formed. The reaction of an alcohol with an acid chloride is strongly affected by steric hindrance. Bulky groups on either partner slow down the reaction considerably, resulting in a reactivity order among alcohols of primary > secondary > tertiary. As a result, it’s often possible to selectively esterify an unhindered alcohol in the presence of a more hindered one. This can be important in complex syntheses in which it’s sometimes necessary to distinguish between similar functional groups. For example, Conversion of Acid Halides into Amides: Aminolysis Acid chlorides react rapidly with ammonia and amines to give amides. As with the acid chloride-plus-alcohol method for preparing esters, this reaction of acid chlorides with amines is the most commonly used laboratory method for preparing amides. Both monosubstituted and disubstituted amines can be used, but not trisubstituted amines (R 3 N). Because HCl is formed during the reaction, two equivalents of the amine must be used. One equivalent reacts with the acid chloride, and one equivalent reacts with the HCl by-product to form an ammonium chloride salt. If, however, the amine component is valuable, amide synthesis is often carried out using one equivalent of the amine plus one equivalent of an inexpensive base such as NaOH. For example, the sedative trimetozine is prepared commercially by reaction of 3,4,5-trimethoxybenzoyl chloride with the amine morpholine in the presence of one equivalent of NaOH. Synthesizing an Amide from an Acid Chloride How might you prepare N -methylpropanamide by reaction of an acid chloride with an amine? Strategy As its name implies, N -methylpropanamide can be made by reaction of methylamine with the acid chloride of propanoic acid. Solution Conversion of Acid Chlorides into Alcohols: Reduction and Grignard Reaction Acid chlorides are reduced by LiAlH 4 to yield primary alcohols. The reaction is of little practical value, however, because the parent carboxylic acids are generally more readily available and can themselves be reduced by LiAlH 4 to yield alcohols. Reduction occurs via a typical nucleophilic acyl substitution mechanism in which a hydride ion (H : – ) adds to the carbonyl group, yielding a tetrahedral intermediate that expels Cl – . The net effect is a substitution of –Cl by –H to yield an aldehyde, which is then further reduced by LiAlH 4 in a second step to yield the primary alcohol. Grignard reagents react with acid chlorides to yield tertiary alcohols with two identical substituents. The mechanism of the reaction is similar to that of LiAlH 4 reduction. The first equivalent of Grignard reagent adds to the acid chloride, loss of Cl – from the tetrahedral intermediate yields a ketone, and a second equivalent of Grignard reagent immediately adds to the ketone to produce an alcohol. Conversion of Acid Chlorides into Ketones: Diorganocopper Reaction The ketone intermediate formed in the reaction of an acid chloride with a Grignard reagent can’t usually be isolated because addition of the second equivalent of organomagnesium reagent occurs too rapidly. A ketone can, however, be isolated from the reaction of an acid chloride with a lithium diorganocopper (Gilman) reagent, Li + R′ 2 Cu – . The reaction occurs by initial nucleophilic acyl substitution on the acid chloride by the diorganocopper anion to yield an acyl diorganocopper intermediate, followed by loss of R′Cu and formation of the ketone. The reaction is generally carried out at –78 °C in ether solution, and yields are often excellent. For example, manicone, a substance secreted by male ants to coordinate ant pairing and mating, has been synthesized by reaction of lithium diethylcopper with ( E )-2,4-dimethyl-2-hexenoyl chloride. Note that the diorganocopper reaction occurs only with acid chlorides. Carboxylic acids, esters, acid anhydrides, and amides do not react with lithium diorganocopper reagents.

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Chemistry of Acid Anhydrides Preparation of Acid Anhydrides Acid anhydrides are typically prepared by nucleophilic acyl substitution reaction of an acid chloride with a carboxylate anion, as we saw in the previous section. Both symmetrical and unsymmetrical acid anhydrides can be prepared in this way. Reactions of Acid Anhydrides The chemistry of acid anhydrides is similar to that of acid chlorides, although anhydrides react more slowly. Thus, acid anhydrides react with water to form acids, with alcohols to form esters, with amines to form amides, and with LiAlH 4 to form primary alcohols. Only the ester- and amide-forming reactions are commonly used, however. Conversion of Acid Anhydrides into Esters Acetic anhydride is often used to prepare acetate esters from alcohols. For example, aspirin (acetylsalicylic acid) is prepared commercially by the acetylation of o -hydroxybenzoic acid (salicylic acid) with acetic anhydride. Conversion of Acid Anhydrides into Amides Acetic anhydride is also commonly used to prepare N -substituted acetamides from amines. For example, acetaminophen, a drug used in over-the-counter analgesics such as Tylenol, is prepared by reaction of p -hydroxyaniline with acetic anhydride. Only the more nucleophilic –NH 2 group reacts rather than the less nucleophilic –OH group. Notice in both of the previous reactions that only “half” of the anhydride molecule is used, while the other half acts as the leaving group during the nucleophilic acyl substitution step and produces acetate ion as a by-product. Thus, anhydrides are inefficient, and acid chlorides are normally preferred for introducing acyl substituents other than acetyl groups. Problems

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Chemistry of Esters Esters are among the most widespread of all naturally occurring compounds. Many simple esters are pleasant-smelling liquids that are responsible for the fragrant odors of fruits and flowers. For example, methyl butanoate is found in pineapple oil, and isopentyl acetate is a constituent of banana oil. The ester linkage is also present in animal fats and in many biologically important molecules. The chemical industry uses esters for a variety of purposes. Ethyl acetate, for instance, is a commonly used solvent, and dialkyl phthalates are used as plasticizers to keep polymers from becoming brittle. You may be aware that there is current concern about the possible toxicity of phthalates at high concentrations, although a recent assessment by the U.S. Food and Drug Administration found the risk to be minimal for most people, with the possible exception of male infants. Preparation of Esters Esters are usually prepared from carboxylic acids by the methods already discussed. Thus, carboxylic acids are converted directly into esters by S N 2 reaction of a carboxylate ion with a primary alkyl halide or by Fischer esterification of a carboxylic acid with an alcohol in the presence of a mineral acid catalyst. In addition, acid chlorides are converted into esters by treatment with an alcohol in the presence of base ( ). Reactions of Esters Esters undergo the same kinds of reactions that we’ve seen for other carboxylic acid derivatives, but they are less reactive toward nucleophiles than either acid chlorides or anhydrides. All their reactions are applicable to both acyclic and cyclic esters, called lactones . Conversion of Esters into Carboxylic Acids: Hydrolysis An ester is hydrolyzed, either by aqueous base or aqueous acid, to yield a carboxylic acid plus an alcohol. Ester hydrolysis in basic solution is called saponification , after the Latin word sapo, meaning “soap.” We’ll see in Section 27.2 that soap is in fact made by boiling animal fat with aqueous base to hydrolyze the ester linkages. As shown in , ester hydrolysis occurs through a typical nucleophilic acyl substitution pathway in which hydroxide ion is the nucleophile that adds to the ester carbonyl group to give a tetrahedral intermediate. Loss of alkoxide ion then gives a carboxylic acid, which is deprotonated to give the carboxylate ion. Addition of aqueous HCl, in a separate step after the saponification is complete, protonates the carboxylate ion and gives the carboxylic acid. MECHANISM Mechanism of base-induced ester hydrolysis (saponification) . The mechanism shown in is supported by isotope-labeling studies. When ethyl propanoate labeled with 18 O in the ether-like oxygen is hydrolyzed in aqueous NaOH, the 18 O label shows up exclusively in the ethanol product. None of the label remains with the propanoic acid, indicating that saponification occurs by cleavage of the C–OR′ bond rather than the CO–R′ bond. Acid-catalyzed ester hydrolysis can occur by more than one mechanism, depending on the structure of the ester. The usual pathway, however, is just the reverse of a Fischer esterification reaction ( ). As shown in , the ester is first activated toward nucleophilic attack by protonation of the carboxyl oxygen atom, and nucleophilic addition of water then occurs. Transfer of a proton and elimination of alcohol yields the carboxylic acid. Because this hydrolysis reaction is the reverse of a Fischer esterification reaction, is the reverse of . MECHANISM Mechanism of acid-catalyzed ester hydrolysis. The forward reaction is a hydrolysis; the back-reaction is a Fischer esterification and is thus the reverse of . Ester hydrolysis is common in biological chemistry, particularly in the digestion of dietary fats and oils. We’ll save a complete discussion of the mechanistic details of fat hydrolysis until Section 29.2 but will note for now that the reaction is catalyzed by various lipase enzymes and involves two sequential nucleophilic acyl substitution reactions. The first is a transesterification reaction in which an alcohol group on the lipase adds to an ester linkage in the fat molecule to give a tetrahedral intermediate that expels alcohol and forms an acyl enzyme intermediate. The second is an addition of water to the acyl enzyme, followed by expulsion of the enzyme to give a hydrolyzed acid and a regenerated enzyme. Conversion of Esters into Amides: Aminolysis Esters react with ammonia and amines to yield amides. The reaction is not often used, however, because it’s usually easier to prepare an amide by starting with an acid chloride ( ). Conversion of Esters into Alcohols: Reduction Esters are easily reduced by treatment with LiAlH 4 to yield primary alcohols ( ). The mechanism of ester reduction is similar to that of acid chloride reduction in that a hydride ion first adds to the carbonyl group, followed by elimination of alkoxide ion to yield an aldehyde. Further reduction of the aldehyde gives the primary alcohol. The aldehyde intermediate can be isolated if 1 equivalent of diisobutylaluminum hydride (DIBAH, or DIBAL-H) is used as the reducing agent instead of LiAlH 4 . The reaction has to be carried out at –78 °C to avoid further reduction to the alcohol. Such partial reductions of carboxylic acid derivatives to aldehydes also occur in numerous biological pathways, although the substrate is either a thioester or acyl phosphate rather than an ester. Conversion of Esters into Alcohols: Grignard Reaction Esters react with 2 equivalents of a Grignard reagent to yield a tertiary alcohol in which two of the substituents are identical ( ). The reaction occurs by the usual nucleophilic substitution mechanism to give an intermediate ketone, which reacts further with the Grignard reagent to yield a tertiary alcohol.

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Chemistry of Amides Amides, like esters, are abundant in all living organisms. Proteins, nucleic acids, and many pharmaceutical agents have amide functional groups. The reason for this abundance of amides is that they are stable in the aqueous conditions found in living organisms. Amides are the least reactive of the common acid derivatives and undergo relatively few nucleophilic acyl substitution reactions. Preparation of Amides Amides are usually prepared by reaction of an amine with an acid chloride ( ). Ammonia, monosubstituted amines, and disubstituted amines all undergo the reaction. Reactions of Amides Conversion of Amides into Carboxylic Acids: Hydrolysis Amides undergo hydrolysis to yield carboxylic acids plus ammonia or an amine upon heating in either aqueous acid or aqueous base. The conditions required for amide hydrolysis are more extreme than those required for the hydrolysis of acid chlorides or esters, but the mechanisms are similar. Acidic hydrolysis reaction occurs by nucleophilic addition of water to the protonated amide, followed by transfer of a proton from oxygen to nitrogen to make the nitrogen a better leaving group, and subsequent elimination. The steps are reversible, with the equilibrium shifted toward product by protonation of NH 3 in the final step. Basic hydrolysis occurs by nucleophilic addition of OH – to the amide carbonyl group, followed by elimination of amide ion ( – NH 2 ) and subsequent deprotonation of the initially formed carboxylic acid by ammonia. The steps are reversible, with the equilibrium shifted toward product by the final deprotonation of the carboxylic acid. Basic hydrolysis is substantially more difficult than the analogous acid-catalyzed reaction because amide ion is a very poor leaving group, making the elimination step difficult. Amide hydrolysis is common in biological chemistry. Just as the hydrolysis of esters is the initial step in the digestion of dietary fats, the hydrolysis of amides is the initial step in the digestion of dietary proteins. The reaction is catalyzed by protease enzymes and occurs by a mechanism almost identical to what we just saw for fat hydrolysis. That is, an initial nucleophilic acyl substitution of an alcohol group in the enzyme on an amide linkage in the protein gives an acyl enzyme intermediate, which then undergoes hydrolysis. Conversion of Amides into Amines: Reduction Like other carboxylic acid derivatives, amides can be reduced by LiAlH 4 . The product of the reduction, however, is an amine rather than an alcohol. The net effect of an amide reduction is thus the conversion of the amide carbonyl group into a methylene group ( C = O ⟶ CH 2 ). This kind of reaction is specific to amides and does not occur with other carboxylic acid derivatives. Amide reduction occurs by nucleophilic addition of hydride ion to the amide carbonyl group, followed by expulsion of the oxygen atom as an aluminate anion leaving group to give an iminium ion intermediate. The intermediate iminium ion is further reduced by LiAlH 4 to yield the amine. The reaction is effective with both acyclic and cyclic amides, or lactams , and is a good method for preparing cyclic amines. Synthesizing an Amine from an Amide How could you prepare N -ethylaniline by reduction of an amide with LiAlH 4 ? Strategy Reduction of an amide with LiAlH 4 yields an amine. To find the starting material for synthesis of N -ethylaniline, look for a CH 2 position next to the nitrogen atom and replace that CH 2 by C═O . In this case, the amide is N -phenylacetamide. Solution Problems

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Chemistry of Thioesters and Acyl Phosphates: Biological Carboxylic Acid Derivatives As mentioned in the chapter introduction, the substrate for a nucleophilic acyl substitution reaction in living organisms is generally either a thioester (RCOSR′) or an acyl phosphate (RCO 2 PO 3 2– or RCO 2 PO 3 R′ – ). Neither is as reactive as an acid chloride or acid anhydride, yet both are stable enough to exist in living organisms while still reactive enough to undergo acyl substitution. Acyl CoA’s, such as acetyl CoA, are the most common thioesters in nature. Coenzyme A, abbreviated CoA, is a thiol formed by a phosphoric anhydride linkage ( O═P–O–P═O ) between phosphopantetheine and adenosine 3′,5′-bisphosphate. (The prefix bis - means “two” and indicates that adenosine 3′,5′-bisphosphate has two phosphate groups, one on C3′ and one on C5′.) Reaction of coenzyme A with an acyl phosphate or acyl adenylate gives acyl CoA ( ). As we saw in ( ), formation of the acyl adenylate occurs by reaction of a carboxylic acid with ATP and is itself a nucleophilic acyl substitution reaction that takes place on phosphorus. Formation of the thioester acetyl CoA by nucleophilic acyl substitution reaction of coenzyme A (CoA) with acetyl adenylate. Once formed, an acyl CoA is a substrate for further nucleophilic acyl substitution reactions. For example, N -acetylglucosamine, a component of cartilage and other connective tissues, is synthesized by an aminolysis reaction between glucosamine and acetyl CoA. Another example of a nucleophilic acyl substitution reaction on a thioester—this one a substitution by hydride ion to effect the partial reduction of a thioester to an aldehyde—occurs in the biosynthesis of mevaldehyde, an intermediate in terpenoid synthesis, which we’ll discuss in some detail in Section 27.5 . In this reaction, (3 S )-3-hydroxy-3-methylglutaryl CoA is reduced by hydride donation from NADPH. Problems

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Polyamides and Polyesters: Step-Growth Polymers When an amine reacts with an acid chloride, an amide is formed. What would happen, though, if a diamine and a diacid chloride were allowed to react? Each partner would form two amide bonds, linking more and more molecules together until a giant polyamide resulted. In the same way, reaction of a diol with a diacid would lead to a polyester. There are two main classes of synthetic polymers: chain-growth polymers and step-growth polymers. The polyethylene and other alkene and diene polymers that we saw in and are called chain-growth polymers because they are produced in chain-reaction processes. An initiator adds to a C═C bond to give a reactive intermediate, which adds to a second alkene molecule to produce a new intermediate, which adds to a third molecule, and so on. By contrast, polyamides and polyesters are step-growth polymers because each bond in the polymer is formed independently in a discrete step, often the nucleophilic acyl substitution reaction of a carboxylic acid derivative. Some commercially important step-growth polymers are shown in . Some Common Step-Growth Polymers and Their Uses Monomers Structure Polymer Uses Nylon 66 Fibers, clothing, tire cord Dacron, Mylar, Terylene Fibers, clothing, films, tire cord Nylon 6, Perlon Fibers, castings Lexan, polycarbonate Equipment housing, molded articles Polyurethane, Spandex Fibers, coatings, foams Polyamides (Nylons) The best known step-growth polymers are the polyamides, or nylons, first prepared in 1930 by Wallace Carothers at the DuPont Company by heating a diamine with a diacid. For instance, nylon 66 is prepared by reaction of adipic acid (hexanedioic acid) with hexamethylenediamine (1,6-hexanediamine) at 280 °C. The designation “66” indicates the number of carbon atoms in the diamine (the first 6) and the diacid (the second 6). Nylons are used both in engineering applications and in making fibers. A combination of high impact strength and abrasion resistance makes nylon an excellent metal substitute for bearings and gears. As fiber, nylon is used in a variety of applications, from clothing to tire cord to ropes. Polyesters The most generally useful polyester is made by reaction between dimethyl terephthalate (dimethyl 1,4-benzenedicarboxylate) and ethylene glycol (1,2-ethanediol). The product is used under the trade name Dacron to make clothing fiber or tire cord and under the name Mylar to make recording tape. The tensile strength of poly(ethylene terephthalate) film is nearly equal to that of steel. Lexan, a polycarbonate prepared from diphenyl carbonate and bisphenol A, is another commercially valuable polyester. Lexan has an unusually high impact strength, making it valuable for use in bicycle helmets and laptop cases. Sutures and Biodegradable Polymers Because plastics are too often thrown away rather than recycled, much work has been carried out on developing biodegradable polymers, which can be broken down rapidly in landfills by soil microorganisms. Among the most common biodegradable polymers are poly(glycolic acid) (PGA), poly(lactic acid) (PLA), and poly(hydroxybutyrate) (PHB). All are polyesters and are therefore susceptible to hydrolysis of their ester links. Copolymers of PGA with PLA have found a particularly wide range of uses. A 90/10 copolymer of poly(glycolic acid) with poly(lactic acid) is used to make absorbable sutures, for instance. The sutures are entirely hydrolyzed and absorbed by the body within 90 days after surgery. In Europe, interest has centered particularly on poly(hydroxybutyrate), which can be made into films for packaging as well as into molded items. The polymer degrades within four weeks in landfills, both by ester hydrolysis and by an E1cB elimination reaction of the oxygen atom β to the carbonyl group. The use of poly(hydroxybutyrate) is limited at present by its cost—about four times that of polypropylene. Problems

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Spectroscopy of Carboxylic Acid Derivatives Infrared Spectroscopy All carbonyl-containing compounds have intense IR absorptions in the range 1650 to 1850 cm –1 . As shown in the exact position of the absorption provides information about the specific kind of carbonyl group. For comparison, the IR absorptions of aldehydes, ketones, and carboxylic acids are included in the table, along with values for carboxylic acid derivatives. Infrared Absorptions of Some Carbonyl Compounds Carbonyl type Example Absorption (cm –1 ) Saturated acid chloride Acetyl chloride 1810 Aromatic acid chloride Benzoyl chloride 1770 Saturated acid anhydride Acetic anhydride 1820, 1760 Saturated ester Ethyl acetate 1735 Aromatic ester Ethyl benzoate 1720 Saturated amide Acetamide 1690 Aromatic amide Benzamide 1675 N -Substituted amide N -Methylacetamide 1680 N , N -Disubstituted amide N , N -Dimethylacetamide 1650 Saturated aldehyde Acetaldehyde 1730 Saturated ketone Acetone 1715 Saturated carboxylic acid Acetic acid 1710 Acid chlorides are easily detected by their characteristic absorption near 1810 cm –1 . Acid anhydrides can be identified by a pair of absorptions in the carbonyl region, one at 1820 cm –1 and another at 1760 cm –1 . Note that each of these functional groups has a strong electron-withdrawing group attached to the carbonyl. The inductive withdrawal of electron density shortens the C=O bond, thereby raising its stretching frequency. Esters are detected by their absorption at 1735 cm –1 , a position somewhat higher than that for either aldehydes or ketones. Amides, by contrast, absorb near the low-wavenumber end of the carbonyl region, with the degree of substitution on nitrogen affecting the exact position of the IR band. That is, for amides, the delocalization of electron density (resonance) from nitrogen into the carbonyl lengthens the C=O bond and lowers its stretching frequency. Problems Nuclear Magnetic Resonance Spectroscopy Hydrogens on the carbon next to a carbonyl group are slightly deshielded and absorb near 2 δ in the 1 H NMR spectrum, although the exact identity of the carbonyl group can’t be determined. shows the 1 H NMR spectrum of ethyl acetate. 1 H NMR spectrum of ethyl acetate. Although 13 C NMR is useful for determining the presence or absence of a carbonyl group in a molecule, the identity of the carbonyl group is difficult to determine. Aldehydes and ketones absorb near 200 δ, while the carbonyl carbon atoms of various acid derivatives absorb in the range 160 to 180 δ ( ). 13 C NMR Absorptions of Some Carbonyl Compounds Compound Absorption ( δ ) Acetic acid 177.3 Ethyl acetate 170.7 Acetyl chloride 170.3 Acetamide 172.6 Acetic anhydride 166.9 Acetone 205.6 Acetaldehyde 201.0 β -Lactam Antibiotics You should never underestimate the value of hard work and logical thinking, but it’s also true that blind luck often plays a role in most real scientific breakthroughs. What has been called “the supreme example of luck in all scientific history” occurred in the late summer of 1928, when the Scottish bacteriologist Alexander Fleming went on vacation, leaving in his lab a culture plate recently inoculated with the bacterium Staphylococcus aureus . While Fleming was away, an extraordinary chain of events occurred. First, a nine-day cold spell lowered the laboratory temperature to a point where the Staphylococcus in the culture plate could not grow. During this time, spores from a colony of the mold Penicillium notatum, being grown in a lab on the floor below, wafted up into Fleming’s lab and landed in the culture plate. The temperature then rose, and both Staphylococcus and Penicillium began to grow. On returning from vacation, Fleming discarded the plate into a tray of antiseptic, intending to sterilize it. Evidently, though, the plate did not sink deeply enough into the antiseptic, because when Fleming happened to glance at it a few days later, what he saw changed the course of history. He noticed that the growing Penicillium mold appeared to dissolve the colonies of staphylococci. Fleming realized that the Penicillium mold must be producing a chemical that killed the Staphylococcus bacteria, and he spent several years trying to isolate the substance. Finally, in 1939, the Australian pathologist Howard Florey and the German refugee Ernst Chain managed to isolate the active substance, called penicillin. The dramatic ability of penicillin to cure infections in mice was soon demonstrated, and successful tests in humans followed shortly thereafter. By 1943, penicillin was being produced on a large scale for military use in World War II, and by 1944 it was being used on civilians. Fleming, Florey, and Chain shared the 1945 Nobel Prize in Physiology or Medicine. Now called benzylpenicillin, or penicillin G, the substance first discovered by Fleming is but one member of a large class of so-called β -lactam antibiotics , compounds with a four-membered lactam (cyclic amide) ring. The four-membered lactam ring is fused to a five-membered, sulfur-containing ring, and the carbon atom next to the lactam carbonyl group is bonded to an acylamino substituent, RCONH–. This acylamino side chain can be varied in the laboratory to provide many hundreds of penicillin analogs with different biological activity profiles. Ampicillin, for instance, has an α -aminophenylacetamido substituent [PhCH(NH 2 )CONH–]. Closely related to the penicillins are the cephalosporins , a group of β -lactam antibiotics that contain an unsaturated, six-membered, sulfur-containing ring. Cephalexin, marketed under the trade name Keflex, is an example. Cephalosporins generally have much greater antibacterial activity than penicillins, particularly against resistant strains of bacteria. The biological activity of penicillins and cephalosporins is due to the presence of the strained β -lactam ring, which reacts with and deactivates the transpeptidase enzyme needed to synthesize and repair bacterial cell walls. With the wall either incomplete or weakened, the bacterial cell ruptures and dies. acid anhydride acid halide acyl phosphate amide carboxylic acid derivative chain-growth polymer ester Fischer esterification reaction lactam lactone nucleophilic acyl substitution reaction saponification step-growth polymer thioester Summary Carboxylic acid derivatives —compounds in which the –OH group of a carboxylic acid has been replaced by another substituent—are among the most widely occurring of all molecules and are involved in almost all biological pathways. In this chapter, we covered the chemistry necessary for understanding them and thus also necessary for understanding living organisms. Acid halides, acid anhydrides, esters, and amides are the most common such derivatives in the laboratory; thioesters and acyl phosphates are common in biological molecules. The chemistry of carboxylic acid derivatives is dominated by the nucleophilic acyl substitution reaction . Mechanistically, these substitutions take place by addition of a nucleophile to the polar carbonyl group of the acid derivative to give a tetrahedral intermediate, followed by expulsion of a leaving group. The reactivity of an acid derivative toward substitution depends both on the steric environment near the carbonyl group and on the electronic nature of the substituent, Y. The reactivity order is acid halide > acid anhydride > thioester > ester > amide. The most common reactions of carboxylic acid derivatives are substitution by water to yield an acid (hydrolysis), by an alcohol to yield an ester (alcoholysis), by an amine to yield an amide (aminolysis), by hydride ion to yield an alcohol (reduction), and by an organomagnesium halide to yield an alcohol (Grignard reaction). Step-growth polymers , such as polyamides and polyesters, are prepared by reactions between difunctional molecules. Polyamides (nylons) are formed by reaction between a diacid and a diamine; polyesters are formed from a diacid and a diol. IR spectroscopy is a valuable tool for the structural analysis of acid derivatives. Acid chlorides, anhydrides, esters, and amides all show characteristic IR absorptions that can be used to identify these functional groups. Summary of Reactions Reactions of carboxylic acids ( ) Conversion into acid chlorides Conversion into esters Conversion into amides Reduction to yield primary alcohols Reactions of acid chlorides ( ) Hydrolysis to yield acids Reaction with carboxylates to yield anhydrides Alcoholysis to yield esters Aminolysis to yield amides Reduction to yield primary alcohols Grignard reaction to yield tertiary alcohols Diorganocopper reaction to yield ketones Reactions of acid anhydrides ( ) Hydrolysis to yield acids Alcoholysis to yield esters Aminolysis to yield amides Reactions of esters ( ) Hydrolysis to yield acids Reduction to yield primary alcohols Partial reduction to yield aldehydes Grignard reaction to yield tertiary alcohols Reactions of amides ( ) Hydrolysis to yield acids Reduction to yield amines Additional Problems Visualizing Chemistry Mechanism Problems Naming Carboxylic Acid Derivatives Nucleophilic Acyl Substitution Reactions Step-Growth Polymers Spectroscopy General Problems

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Why This Chapter? Tear gas is a controversial riot-control device used by some military and police forces. It is a simple chloroketone made by a carbonyl α -substitution reaction. (credit: modification of work “Tear Gas in CWB Hennessy Road View” by The Stand News/Wikimedia Commons, Public Domain) As with nucleophilic additions and nucleophilic acyl substitutions, many laboratory schemes, pharmaceutical syntheses, and biochemical pathways make frequent use of carbonyl α -substitution reactions. Their great value comes from the fact that they constitute one of the few general methods for forming carbon–carbon bonds, thereby making it possible to build larger molecules from smaller precursors. In this chapter, we’ll see how and why these reactions occur. We said in the Preview of Carbonyl Chemistry that much of the chemistry of carbonyl compounds can be explained by just four fundamental reaction types: nucleophilic additions, nucleophilic acyl substitutions, α substitutions, and carbonyl condensations. Having studied the first two of these reactions in the past three chapters, let’s now look in more detail at the third major carbonyl-group process—the α -substitution reaction . Alpha-substitution reactions occur at the position next to the carbonyl group—the α position —and involve the substitution of an α hydrogen atom by an electrophile, E, through either an enol or enolate ion intermediate. Let’s begin by learning more about these two species.

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Keto–Enol Tautomerism A carbonyl compound with a hydrogen atom on its α carbon is in equilibrium with its corresponding enol isomer ( ). This spontaneous interconversion between two isomers, usually with the change in position of a hydrogen, is called tautomerism, from the Greek tauto, meaning “the same,” and meros, meaning “part.” The individual keto and enol isomers are called tautomers . Note the difference between tautomers and resonance forms. Tautomers are constitutional isomers—different compounds with different structures—while resonance forms are different representations of a single compound. Tautomers have their atoms arranged differently, while resonance forms differ only in the position of their π and nonbonding electrons. Most monocarbonyl compounds exist almost entirely in their keto form at equilibrium, and it’s usually difficult to isolate the pure enol. Cyclohexanone, for example, contains only about 0.0001% of its enol tautomer at room temperature. The percentage of enol tautomer is even lower for carboxylic acids, esters, and amides. The enol can only predominate when stabilized by conjugation or intramolecular hydrogen bonding. Thus, 2,4-pentanedione is about 76% enol tautomer. Although enols are scarce at equilibrium, they are nevertheless responsible for much of the chemistry of carbonyl compounds because they are so reactive. Keto–enol tautomerism of carbonyl compounds is catalyzed by both acids and bases. Acid catalysis occurs by protonation of the carbonyl oxygen atom to give an intermediate cation that loses H + from its α carbon to yield a neutral enol ( a). This proton loss from the cation intermediate is similar to what occurs during an E1 reaction when a carbocation loses H + to form an alkene ( ). Base-catalyzed enol formation occurs because the presence of a carbonyl group makes the hydrogens on the α carbon weakly acidic. Thus, a carbonyl compound can act as an acid and donate one of its α hydrogens to a sufficiently strong base. The resultant resonance-stabilized anion, an enolate ion , is then protonated to yield a neutral compound. If protonation of the enolate ion takes place on the α carbon, the keto tautomer is regenerated and no net change occurs. If, however, protonation takes place on the oxygen atom, an enol tautomer is formed ( b). MECHANISM Mechanism of enol formation under both acid-catalyzed and base-catalyzed conditions. (a) Acid catalysis involves ( 1 ) initial protonation of the carbonyl oxygen followed by ( 2 ) removal of H + from the α position. (b) Base catalysis involves ( 1 ) initial deprotonation of the α position to give an enolate ion, followed by ( 2 ) reprotonation on oxygen. Note that only the hydrogens on the α position of carbonyl compounds are acidic. Hydrogens at β, γ, δ, and so on, aren’t acidic and can’t be removed by base because the resulting anions can’t be resonance-stabilized by the carbonyl group. Problems

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Reactivity of Enols: α -Substitution Reactions What kind of chemistry do enols have? Because their double bonds are electron-rich, enols behave as nucleophiles and react with electrophiles in much the same way that alkenes do. But because of resonance-electron donation of a lone pair of electrons on the neighboring oxygen, enols are more electron-rich and correspondingly more reactive than alkenes. Notice in the following electrostatic potential map of ethenol ( H 2 C ═ CHOH ) how there is a substantial electron density (yellow-red) on the α carbon. When an alkene reacts with an electrophile, E + , initial addition gives an intermediate cation and subsequent reaction with a nucleophile, such as a halide ion, yields an addition product ( ). When an enol reacts with an electrophile, however, only the initial addition step is the same ( ). Instead of reacting with a nucleophile to give an addition product, the intermediate cation loses the –OH proton to give an α -substituted carbonyl compound. MECHANISM General mechanism of a carbonyl α -substitution reaction. In step 3, the initially formed cation loses H + to regenerate a carbonyl compound.

Reactivity of Enols:α-Substitution Reactions

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Alpha Halogenation of Aldehydes and Ketones A particularly common α -substitution reaction in the laboratory is the halogenation of aldehydes and ketones at their α positions by reaction with Cl 2 , Br 2 , or I 2 in acidic solution. Bromine in acetic acid solvent is often used. Remarkably, ketone halogenation also occurs in biological systems, particularly in marine alga, where dibromoacetaldehyde, bromoacetone, 1,1,1-tribromoacetone, and other related compounds have been found. This form of halogenation is a typical α -substitution reaction that proceeds by acid-catalyzed formation of an enol intermediate, as shown in . MECHANISM Mechanism of the acid-catalyzed bromination of acetone. Evidence for the mechanism shown in includes the observation that acid-catalyzed halogenations show second-order kinetics and follow the rate law Reaction rate = k [Ketone ] [ H + ] In other words, the rate of halogenation depends only on the concentrations of ketone and acid and is independent of halogen concentration. Since halogen is not involved in the rate-limiting step, chlorination, bromination, and iodination of a given substrate all occur at the same rate. Furthermore, if an aldehyde or ketone is treated with D 3 O + , the acidic α hydrogens are replaced by deuterium. For a given ketone, the rate of deuterium exchange is identical to the rate of halogenation, implying that a common intermediate—presumably the enol—is involved in both processes. α -Bromo ketones are useful in the laboratory because they can be dehydrobrominated by base treatment to yield α , β -unsaturated ketones. For example, 2-methylcyclohexanone gives 2-bromo-2-methylcyclohexanone on halogenation, and the α -bromo ketone gives 2-methyl-2-cyclohexenone when heated in pyridine. The reaction takes place by an E2 elimination pathway ( ) and is a good method for introducing a C═C bond into a molecule. Note that bromination of 2-methylcyclohexanone occurs primarily on the more highly substituted α position because the more highly substituted enol is favored over the less highly substituted one ( ). Problems

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Alpha Bromination of Carboxylic Acids The α bromination of carbonyl compounds by Br 2 in acetic acid is limited to aldehydes and ketones because acids, esters, and amides don’t enolize to a sufficient extent. Carboxylic acids, however, can be α brominated by a mixture of Br 2 and PBr 3 in the Hell–Volhard–Zelinskii (HVZ) reaction. The Hell–Volhard–Zelinskii reaction is a bit more complex than it looks and actually involves α substitution of an acid bromide enol rather than a carboxylic acid enol. The process begins by reaction of the carboxylic acid with PBr 3 to form an acid bromide plus HBr ( ). The HBr then catalyzes enolization of the acid bromide, and the resultant enol reacts with Br 2 in an α -substitution reaction to give an α -bromo acid bromide. Addition of water hydrolyzes the acid bromide in a nucleophilic acyl substitution reaction and yields the α -bromo carboxylic acid product. Problems

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Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation As noted in , a hydrogen on the α position of a carbonyl compound is weakly acidic and can be removed by a strong base to yield an enolate ion. In comparing acetone (p K a = 19.3) with ethane (p K a ≈ 60), for instance, the presence of a neighboring carbonyl group increases the acidity of the ketone over the alkane by a factor of 10 40 . Proton abstraction from a carbonyl compound occurs when the α C–H bond is oriented roughly parallel to the p orbitals of the carbonyl group. The α carbon atom of the enolate ion is sp 2 -hybridized and has a p orbital that overlaps the neighboring carbonyl p orbitals. Thus, the negative charge is shared by the electronegative oxygen atom, and the enolate ion is stabilized by resonance ( ). Mechanism of enolate-ion formation by abstraction of an α proton from a carbonyl compound. The enolate ion is stabilized by resonance, and the negative charge (red) is shared by the oxygen and the α carbon atom, as indicated in the electrostatic potential map. Because carbonyl compounds are only weakly acidic, a strong base is needed for the formation of an enolate-ion. If an alkoxide ion, such as sodium ethoxide, is used as base, deprotonation of acetone only takes place to the extent of about 0.1% because acetone is a weaker acid than ethanol (p K a = 16). If, however, a more powerful base is used, then a carbonyl compound is completely converted into its enolate ion. In practice, the strong base lithium diisopropylamide [LiN( i -C 3 H 7 ) 2 ; abbreviated LDA] is commonly used for making enolate ions. As the lithium salt of the weak acid diisopropylamine, p K a = 36, LDA can readily deprotonate most carbonyl compounds. It is easily prepared by reaction of butyllithium with diisopropylamine and is soluble in organic solvents because of its two alkyl groups. Many types of carbonyl compounds, including aldehydes, ketones, esters, thioesters, acids, and amides, can be converted into enolate ions by reaction with LDA. lists the approximate p K a values of different types of carbonyl compounds and shows how these values compare to other acidic substances we’ve seen. Note that nitriles, too, are acidic and can be converted into enolate-like anions. Acidity Constants for Some Organic Compounds Functional group Example p K a Carboxylic acid 5 1,3-Diketone 9 3-Keto ester 11 1,3-Diester 13 Alcohol CH 3 O H 16 Acid chloride 16 Aldehyde 17 Ketone 19 Thioester 21 Ester 25 Nitrile C H 3 C ≡ N 25 N , N -Dialkylamide 30 Dialkylamine H N( i -C 3 H 7 ) 2 36 When a hydrogen atom is flanked by two carbonyl groups, its acidity is enhanced further. thus shows that 1,3-diketones ( β -diketones), 3-oxo esters ( β -keto esters), and 1,3-diesters (malonic esters) are more acidic than water. The enolate ions derived from these β -dicarbonyl compounds are stabilized by sharing the negative charge of the two neighboring carbonyl oxygens. The enolate ion of 2,4-pentanedione, for instance, has three resonance forms. Similar resonance forms can be drawn for other doubly stabilized enolate ions. Identifying the Acidic Hydrogens in a Compound Identify the most acidic hydrogens in each of the following compounds, and rank the compounds in order of increasing acidity: Strategy Hydrogens on carbon next to a carbonyl group are acidic. In general, a β -dicarbonyl compound is most acidic, a ketone or aldehyde is next most acidic, and a carboxylic acid derivative is least acidic. Remember that alcohols, phenols, and carboxylic acids are also acidic because of their –OH hydrogens. Solution The acidity order is ( a ) > ( c ) > ( b ). Acidic hydrogens are shown in red. Problems

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Reactivity of Enolate Ions Enolate ions are more useful than enols for two reasons. First, pure enols can’t normally be isolated but are instead generated only as short-lived intermediates in low concentration. By contrast, stable solutions of pure enolate ions are easily prepared from most carbonyl compounds by reaction with a strong base. Second, enolate ions are more reactive than enols and undergo many reactions that enols don’t. Whereas enols are neutral, enolate ions are negatively charged, making them much better nucleophiles. Because they are resonance hybrids of two nonequivalent forms, enolate ions can be looked at either as vinylic alkoxides ( C═C− O − ) or as α -keto carbanions ( − C−C═O ). Thus, enolate ions can react with electrophiles either on oxygen or on carbon. Reaction on oxygen yields an enol derivative, while reaction on carbon yields an α -substituted carbonyl compound ( ). Both kinds of reactivity are known, but reaction on carbon is more common. The electrostatic potential map of acetone enolate ion shows how the negative charge is delocalized over both the oxygen and the α carbon. As a result, two modes of reaction of an enolate ion with an electrophile E + are possible. Reaction on carbon to yield an α -substituted carbonyl product is more common. As an example of enolate ion reactivity, aldehydes and ketones undergo base-promoted α halogenation. Even relatively weak bases such as hydroxide ion are effective for halogenation because it’s not necessary to convert the ketone completely into its enolate ion. As soon as a small amount of enolate is generated, halogen reacts with it immediately, removing it from the reaction and driving the equilibrium toward further enolate ion formation. Base-promoted halogenation of aldehydes and ketones is seldom used in practice because it’s difficult to stop the reaction at the monosubstituted product. An α -halogenated ketone is generally more acidic than the starting, unsubstituted ketone because of the electron-withdrawing inductive effect of the halogen atom. Thus, the monohalogenated products are themselves rapidly turned into enolate ions and further halogenated. If excess base and halogen are used, a methyl ketone is triply halogenated and then cleaved by base in the haloform reaction. The products are a carboxylic acid plus a so-called haloform (chloroform, CHCl 3 ; bromoform, CHBr 3 ; or iodoform, CHI 3 ). Note that the second step of the reaction is a nucleophilic acyl substitution of – CX 3 by – OH. That is, a halogen-stabilized carbanion acts as a leaving group. Problems

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Alkylation of Enolate Ions Perhaps the most useful reaction of enolate ions is their alkylation by treatment with an alkyl halide, thereby forming a new C−C bond and joining two smaller pieces into one larger molecule. Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic alkyl halide in an S N 2 reaction and displaces the leaving group by backside attack. Alkylation reactions are subject to the same constraints that affect all S N 2 reactions ( ). Thus, the leaving group X in the alkylating agent R−X can be chloride, bromide, or iodide. The alkyl group R should be primary or methyl, and preferably should be allylic or benzylic. Secondary halides react poorly, and tertiary halides don’t react at all because a competing E2 elimination of HX occurs instead. Vinylic and aryl halides are also unreactive because a backside approach is sterically prevented. The Malonic Ester Synthesis One of the oldest and best known carbonyl alkylation reactions is the malonic ester synthesis , a method for preparing a carboxylic acid from an alkyl halide while lengthening the carbon chain by two atoms. Diethyl propanedioate, commonly called diethyl malonate, or malonic ester, is relatively acidic (p K a = 13) because its α hydrogens are flanked by two carbonyl groups. Thus, malonic ester is easily converted into its enolate ion by reaction with sodium ethoxide in ethanol. The enolate ion, in turn, is a good nucleophile that reacts rapidly with an alkyl halide to give an α -substituted malonic ester. Note in the following examples that the abbreviation “Et” is used for an ethyl group, –CH 2 CH 3 . The product of a malonic ester alkylation has one acidic α hydrogen remaining, so the alkylation process can be repeated to yield a dialkylated malonic ester. On heating with aqueous hydrochloric acid, the alkylated (or dialkylated) malonic ester undergoes hydrolysis of its two ester groups followed by decarboxylation (loss of CO 2 ) to yield a substituted monocarboxylic acid. Decarboxylation is not a general reaction of carboxylic acids. Rather, it is unique to compounds that have a second carbonyl group two atoms away from the –CO 2 H. That is, only substituted malonic acids and β -keto acids undergo loss of CO 2 on heating. The decarboxylation reaction occurs by a cyclic mechanism and involves initial formation of an enol, thereby accounting for the need to have a second carbonyl group appropriately positioned. As noted previously, the overall effect of malonic ester synthesis is to convert an alkyl halide into a carboxylic acid while lengthening the carbon chain by two atoms (RX → RCH 2 CO 2 H). A malonic ester synthesis can also be used to prepare cyclo alkanecarboxylic acids. For example, when 1,4-dibromobutane is treated with diethyl malonate in the presence of two equivalents of sodium ethoxide base, the second alkylation step occurs intramolecularly to yield a cyclic product. Hydrolysis and decarboxylation then give cyclopentanecarboxylic acid. Three-, four-, five-, and six-membered rings can be prepared in this way, but yields decrease for larger ring sizes. Using Malonic Ester Synthesis to Prepare a Carboxylic Acid How would you prepare heptanoic acid using a malonic ester synthesis? Strategy A malonic ester synthesis converts an alkyl halide into a carboxylic acid having two more carbons. Thus, a seven-carbon acid chain must be derived from the five-carbon alkyl halide 1-bromopentane. Solution Problems The Acetoacetic Ester Synthesis Just as the malonic ester synthesis converts an alkyl halide into a carboxylic acid, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone having three more carbons. Ethyl 3-oxobutanoate, commonly called ethyl acetoacetate, or acetoacetic ester, is much like malonic ester in that its α hydrogens are flanked by two carbonyl groups. It is therefore readily converted into its enolate ion, which can be alkylated by reaction with an alkyl halide. A second alkylation can also be carried out if desired, since acetoacetic ester has two acidic α hydrogens. On heating with aqueous HCl, the alkylated (or dialkylated) acetoacetic ester is hydrolyzed to a β -keto acid, which then undergoes decarboxylation to yield a ketone product. The decarboxylation occurs in the same way as in the malonic ester synthesis and involves a ketone enol as the initial product. The three-step sequence of ( 1 ) enolate ion formation, ( 2 ) alkylation, and ( 3 ) hydrolysis/decarboxylation is applicable to all β -keto esters with acidic α hydrogens, not just to acetoacetic ester itself. For example, cyclic β -keto esters, such as ethyl 2-oxocyclohexanecarboxylate, can be alkylated and decarboxylated to give 2-substituted cyclohexanones. Using Acetoacetic Ester Synthesis to Prepare a Ketone How would you prepare 2-pentanone by an acetoacetic ester synthesis? Strategy An acetoacetic ester synthesis yields a methyl ketone by adding three carbons to an alkyl halide. Thus, the acetoacetic ester synthesis of 2-pentanone must involve reaction of bromoethane. Solution Problems Direct Alkylation of Ketones, Esters, and Nitriles Both the malonic ester synthesis and the acetoacetic ester synthesis are easy to carry out because they involve relatively acidic dicarbonyl compounds. As a result, sodium ethoxide in ethanol can be used to prepare the necessary enolate ions. Alternatively, however, it’s also possible in many cases to directly alkylate the α position of mono carbonyl compounds. A strong, sterically hindered base such as LDA is needed so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used. Ketones, esters, and nitriles can all be alkylated using LDA or related dialkylamide bases in tetrahydrofuran (THF). Aldehydes, however, rarely give high yields of pure products because their enolate ions undergo carbonyl condensation reactions instead of alkylation. (We’ll study this condensation reaction in the next chapter.) Some specific examples of alkylation reactions are shown. Note in the ketone example that alkylation of 2-methylcyclohexanone leads to a mixture of products because both possible enolate ions are formed. In general, the major product in such cases occurs by alkylation at the less hindered, more accessible position. Thus, alkylation of 2-methylcyclohexanone occurs primarily at C6 (secondary) rather than C2 (tertiary). Using an Alkylation Reaction to Prepare a Substituted Ester How might you use an alkylation reaction to prepare ethyl 1-methylcyclohexanecarboxylate? Strategy An alkylation reaction is used to introduce a methyl or primary alkyl group onto the α position of a ketone, ester, or nitrile by S N 2 reaction of an enolate ion with an alkyl halide. Thus, we need to look at the target molecule and identify any methyl or primary alkyl groups attached to an α carbon. In the present instance, the target has an α methyl group, which might be introduced by alkylation of an ester enolate ion with iodomethane. Solution Problems Biological Alkylations Alkylations are rare but not unknown in biological chemistry. One example occurs during biosynthesis of the antibiotic indolmycin from indolylpyruvate when a base abstracts an acidic hydrogen from an α position and the resultant enolate ion carries out an S N 2 alkylation reaction on the methyl group of S -adenosylmethionine (SAM; ). Although it’s convenient to speak of “enolate ion” intermediates in biological pathways, it’s unlikely that they exist for long in an aqueous cellular environment. Rather, proton removal and alkylation probably occur at essentially the same time ( ). The biosynthesis of indolmycin from indolylpyruvate occurs through a pathway that includes an alkylation reaction of a short-lived enolate ion intermediate. Barbiturates The use of herbal remedies to treat illness and disease goes back thousands of years, but the medical use of chemicals prepared in the laboratory has a much shorter history. Barbiturates, a large class of drugs with a wide variety of uses, constitute one of the earliest successes of medicinal chemistry. The synthesis and medical use of barbiturates goes back to 1904 when Bayer, a German chemical company, first marketed a compound called barbital, trade named Veronal, as a treatment for insomnia. Since that time, more than 2500 different barbiturate analogs have been synthesized by drug companies, more than 50 have been used medicinally, and about a dozen are still in use as anesthetics, anticonvulsants, sedatives, and anxiolytics. Different barbiturates come in a multitude of colors, giving rise to similarly colorful street names when the drugs are abused. (credit: “Medications” by freestocks.org/Flickr, Public Domain) The synthesis of barbiturates is relatively simple and relies on reactions that are now familiar: enolate alkylations and nucleophilic acyl substitutions. Starting with diethyl malonate, alkylation of the corresponding enolate ion with simple alkyl halides provides a wealth of different disubstituted malonic esters. Reaction with urea, ( H 2 N ) 2 C ═ O , then gives the product barbiturates by a twofold nucleophilic acyl substitution reaction of the ester groups with the –NH 2 groups of urea ( ). Amobarbital (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal) are typical examples. The synthesis of barbiturates relies on malonic ester alkylations and nucleophilic acyl substitution reactions. More than 2500 different barbiturates have been synthesized over the past 100 years. In addition to their prescribed medical uses, many barbiturates have also found widespread illegal use as street drugs. Each barbiturate often comes as a tablet of regulated size, shape, and color. Although still used today, most barbiturates have been replaced by safer, more potent alternatives with markedly different structures. acetoacetic ester synthesis α -substitution reaction decarboxylation enol enolate ion malonic ester synthesis tautomer Summary The α -substitution reaction of a carbonyl compound through either an enol or enolate ion intermediate is one of the four fundamental reaction types in carbonyl-group chemistry. Carbonyl compounds are in an equilibrium with their enols, a process called keto–enol tautomerism. Although enol tautomers are normally present to only a small extent at equilibrium and can’t usually be isolated in pure form, they nevertheless contain a highly nucleophilic double bond and react with electrophiles in an α -substitution reaction . An example is the α halogenation of ketones on treatment with Cl 2 , Br 2 , or I 2 in acid solution. Alpha bromination of carboxylic acids can be similarly accomplished by the Hell–Volhard–Zelinskii (HVZ) reaction, in which an acid is treated with Br 2 and PBr 3 . The α -halogenated products can then undergo base-induced E2 elimination to yield α , β -unsaturated carbonyl compounds. Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most useful reaction of enolate ions is their S N 2 alkylation with alkyl halides. The Malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms (RX → RCH 2 CO 2 H). Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone with the addition of three carbon atoms (RX → RCH 2 COCH 3 ). In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. Summary of Reactions Aldehyde/ketone halogenation ( ) Hell–Volhard–Zelinskii bromination of acids ( ) Dehydrobromination of α -bromo ketones ( ) Haloform reaction ( ) Alkylation of enolate ions ( ) Malonic ester synthesis Acetoacetic ester synthesis Direct alkylation of ketones Direct alkylation of esters Direct alkylation of nitriles Additional Problems Visualizing Chemistry Mechanism Problems Acidity of Carbonyl Compounds α -Substitution Reactions General Problems

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Why This Chapter? Many of the molecules needed by all growing organisms are biosynthesized using carbonyl condensation reactions . (credit: modification of work “Newborn Sea Lion” by Steven Bedard/Flickr, CC BY 2.0) We’ll see later in this chapter and again in Chapter 29 that carbonyl condensation reactions occur in a large number of metabolic pathways. In fact, almost all classes of biomolecules—carbohydrates, lipids, proteins, nucleic acids, and many others—are biosynthesized through pathways that involve carbonyl condensation reactions. As with the α -substitution reaction discussed in the previous chapter, the great value of carbonyl condensations is that they are one of the few general methods for forming carbon–carbon bonds, thereby making it possible to build larger molecules from smaller precursors. In this chapter, we’ll see how and why these reactions occur. We’ve now studied three of the four general kinds of carbonyl-group reactions and have seen two general kinds of behavior. In nucleophilic addition and nucleophilic acyl substitution reactions, a carbonyl compound behaves as an electrophile when an electron-rich reagent adds to it. In α -substitution reactions, however, a carbonyl compound behaves as a nucleophile when it is converted into its enol or enolate ion. In the carbonyl condensation reactions that we’ll study in this chapter, the carbonyl compound behaves both as an electrophile and as a nucleophile.

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Carbonyl Condensations: The Aldol Reaction Carbonyl condensation reactions take place between two carbonyl partners and involve a combination of nucleophilic addition and α -substitution steps. One partner is converted into an enolate-ion nucleophile and adds to the electrophilic carbonyl group of the second partner. In so doing, the nucleophilic partner undergoes an α -substitution reaction and the electrophilic partner undergoes a nucleophilic addition. The general mechanism of the process is shown in . MECHANISM The general mechanism of a carbonyl condensation reaction . One partner becomes a nucleophilic donor and adds to the second partner as an electrophilic acceptor. After protonation, the final product is a β -hydroxy carbonyl compound. Aldehydes and ketones with an α hydrogen atom undergo a base-catalyzed carbonyl condensation reaction called the aldol reaction . For example, treatment of acetaldehyde with a base such as sodium ethoxide or sodium hydroxide in a protic solvent leads to rapid and reversible formation of 3-hydroxybutanal, known commonly as aldol ( ald ehyde + alcoh ol ), hence the general name of the reaction. The exact position of the aldol equilibrium depends both on reaction conditions and on substrate structure. The equilibrium generally favors the condensation product in the case of aldehydes with no α substituent (RCH 2 CHO) but favors the reactant for disubstituted aldehydes (R 2 CHCHO) and for most ketones. Steric factors are probably responsible for these trends, since increased substitution near the reaction site increases steric congestion in the aldol product. Predicting the Product of an Aldol Reaction What is the structure of the aldol product from propanal? Strategy An aldol reaction combines two molecules of reactant by forming a bond between the α carbon of one partner and the carbonyl carbon of the second partner. The product is a β -hydroxy aldehyde or ketone, meaning that the two oxygen atoms in the product have a 1,3 relationship. Solution Problems

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Carbonyl Condensations versus Alpha Substitutions Two of the four general carbonyl-group reactions—carbonyl condensations and α substitutions—take place under basic conditions and involve enolate-ion intermediates. Because the experimental conditions for the two reactions are similar, how can we predict which will occur in a given case? When we generate an enolate ion with the intention of carrying out an α alkylation, how can we be sure that a carbonyl condensation reaction won’t occur instead? There is no simple answer to this question, but the exact experimental conditions usually have much to do with the result. Alpha-substitution reactions require a full equivalent of strong base and are normally carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at a low temperature. An electrophile is then added rapidly to ensure that the reactive enolate ion is quenched quickly. In a ketone alkylation reaction, for instance, we might use 1 equivalent of lithium diisopropylamide (LDA) in tetrahydrofuran solution at –78 °C. Rapid and complete generation of the ketone enolate ion would occur, and no unreacted ketone would remain, meaning that no condensation reaction could take place. We would then immediately add an alkyl halide to complete the alkylation reaction. On the other hand, carbonyl condensation reactions require only a catalytic amount of a relatively weak base, rather than a full equivalent, so that a small amount of enolate ion is generated in the presence of unreacted carbonyl compound. Once a condensation occurs, the basic catalyst is regenerated. To carry out an aldol reaction on propanal, for instance, we might dissolve the aldehyde in methanol, add 0.05 equivalent of sodium methoxide, and then warm the mixture to give the aldol product.

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Dehydration of Aldol Products: Synthesis of Enones When heated under either acidic or basic conditions, the β -hydroxy aldehydes or ketones formed in aldol reactions can be dehydrated to yield α , β -unsaturated products, or conjugated enones (ene + ketone). In fact, it’s this loss of water that gives the carbonyl condensation reaction its name, because water condenses out when an enone product forms. Most alcohols are resistant to dehydration by base ( ) because hydroxide ion is a poor leaving group, but aldol products dehydrate easily because of their carbonyl group. Under basic conditions, an acidic α hydrogen is removed, yielding an enolate ion that expels the nearby – OH leaving group in an E1cB reaction ( ). Under acidic conditions, an enol is formed, the –OH group is protonated, and water is expelled in an E1 or E2 reaction. The reaction conditions needed for aldol dehydration are often only a bit more vigorous (slightly higher temperature, for instance) than the conditions needed for the aldol formation itself. As a result, conjugated enones are usually obtained directly from aldol reactions without isolating the intermediate β -hydroxy carbonyl compounds. Conjugated enones are more stable than nonconjugated enones for the same reason that conjugated dienes are more stable than nonconjugated dienes ( ). Interaction between the π electrons of the C═C bond and the π electrons of the C═O group leads to a molecular-orbital description for a conjugated enone with an interaction of the π electrons over all four atomic centers ( ). The π bonding molecular orbitals of a conjugated enone (propenal) and a conjugated diene (1,3-butadiene) are similar in shape and are spread over the entire π system . The real value of aldol dehydration is that removal of water from the reaction mixture can be used to drive the aldol equilibrium toward the product. Even though the initial aldol step itself may be unfavorable, as it usually is for ketones, the subsequent dehydration step nevertheless allows many aldol condensations to be carried out in good yield. Cyclohexanone, for example, gives cyclohexylidenecyclohexanone in 92% yield, even though the initial equilibrium is unfavorable. Predicting the Product of an Aldol Reaction What is the structure of the enone obtained from aldol condensation of acetaldehyde? Strategy In the aldol reaction, H 2 O is eliminated and a double bond is formed by removing two hydrogens from the acidic α position of one partner and the carbonyl oxygen from the second partner. The product is thus an α , β -unsaturated aldehyde or ketone. Solution Problems

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Using Aldol Reactions in Synthesis The aldol reaction yields either a β -hydroxy aldehyde/ketone or an α , β -unsaturated aldehyde/ketone, depending on the experimental conditions. By learning how to work backward, it’s possible to predict when the aldol reaction might be useful in synthesis. Whenever the target molecule contains either a β -hydroxy aldehyde/ketone or a conjugated enone functional group, it might come from an aldol reaction. We can extend this kind of reasoning even further by imagining that subsequent transformations might be carried out on the aldol products. For example, a saturated ketone might be prepared by catalytic hydrogenation of the enone product. A good example can be found in the industrial preparation of 2-ethyl-1-hexanol, an alcohol used in the synthesis of plasticizers for polymers. Although 2-ethyl-1-hexanol bears little resemblance to an aldol product at first glance, it is in fact prepared commercially from butanal by an aldol reaction. Working backward, we can reason that 2-ethyl-1-hexanol might come from 2-ethylhexanal by a reduction. 2-Ethylhexanal, in turn, might be prepared by catalytic reduction of 2-ethyl-2-hexenal, which is the aldol condensation product of butanal. The reactions that follow show the sequence in reverse order. Problems

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Mixed Aldol Reactions Until now, we’ve considered only symmetrical aldol reactions, in which the two carbonyl components have been the same. What would happen, though, if an aldol reaction were carried out between two different carbonyl partners? In general, a mixed aldol reaction between two similar aldehyde or ketone partners leads to a mixture of four possible products. For example, base treatment of a mixture of acetaldehyde and propanal gives a complex product mixture containing two “symmetrical” aldol products and two “mixed” aldol products. Clearly, such a reaction is of no practical value. On the other hand, mixed aldol reactions can lead cleanly to a single product if either of two conditions is met: If one of the carbonyl partners contains no α hydrogens (and thus can’t form an enolate ion to become a donor), but does contain an unhindered carbonyl group (and so is a good acceptor of nucleophiles), then a mixed aldol reaction is likely to be successful. This is the case, for instance, when either benzaldehyde or formaldehyde is used as one of the carbonyl partners. Neither benzaldehyde nor formaldehyde can form an enolate ion to add to another partner, yet both compounds have an unhindered carbonyl group. The ketone 2-methylcyclohexanone, for instance, gives the mixed aldol product on reaction with benzaldehyde. If one of the carbonyl partners is much more acidic than the other, and is thus transformed into its enolate ion in preference to the other, then a mixed aldol reaction is likely to be successful. Ethyl acetoacetate, for instance, is completely converted into its enolate ion in preference to enolate ion formation from monocarbonyl partners. Thus, aldol condensations of monoketones with ethyl acetoacetate occur preferentially to give the mixed product. The situation can be summarized by saying that a mixed aldol reaction leads to a mixture of products unless one of the partners either has no α hydrogens but is a good electrophilic acceptor (such as benzaldehyde) or is an unusually acidic nucleophilic donor (such as ethyl acetoacetate). Problems

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