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19.19 Summary 807 Mass Spectrometry: A prominent peak in the mass spectra of most carboxylic acid derivatives corresponds to an acylium ion derived by cleavage of the bond to the carbonyl group: O R C R C O X X Amides, however, tend to cleave in the opposite direction to produce a nitrogen-stabilized acylium ion: O R R [O C C NR2 O C NR2] NR2 19.19 Summary Section 19.1 This chapter concerns the preparation and reactions of acyl chlorides, acid anhydrides, esters, amides, and nitriles. These compounds are generally classified as carboxylic acid derivatives, and their nomenclature is based on that of carboxylic acids. Section 19.2 O X RCCl O O X X RCOCR O X RCOR O X RCNR2 RCPN Acyl chloride Acid anhydride Ester Amide Nitrile The structure and reactivity of carboxylic acid derivatives depend on how well the atom bonded to the carbonyl group donates electrons to it. O O C R X R C X Electron-pair donation stabilizes the carbonyl group and makes it less reactive toward nucleophilic acyl substitution. Most reactive O X RCCl Least reactive O O O X X X RCOCR RCOR Least stabilized carbonyl group O X RCNR2 Most stabilized carbonyl group Nitrogen is a better electron-pair donor than oxygen, and amides have a more stabilized carbonyl group than esters and anhydrides. Chlorine is the poorest electron-pair donor, and acyl chlorides have the least stabilized carbonyl group and are the most reactive. Section 19.3 The characteristic reaction of acyl chlorides, acid anhydrides, esters, and amides is nucleophilic acyl substitution. In the most common mechanism, addition of a nucleophilic reagent :Nu ⎯ H to the carbonyl group leads to a tetrahedral intermediate that dissociates to give the product of substitution: RC O OH O X Nu H RC X RC Nu HX Nu Carboxylic acid derivative car02745_ch19_770-819.indd 807 Nucleophile Tetrahedral intermediate Product of nucleophilic acyl substitution Conjugate acid of leaving group 10/2/12 12:46 PM 808 Chapter 19 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Section 19.4 Acyl chlorides are converted to acid anhydrides, esters, and amides by nucleophilic acyl substitution. O O O O RCCl RCOH Acyl chloride RCOCR Carboxylic acid Acid anhydride O ROH Acyl chloride RCOR Alcohol HCl Ester O Hydrogen chloride O RCNR2 R2NH2 Cl RCCl 2R2NH Acyl chloride Hydrogen chloride O RCCl HCl Amine Amide Ammonium chloride salt Examples of each of these reactions may be found in Table 19.1. Section 19.5 Acid anhydrides are less reactive toward nucleophilic acyl substitution than acyl chlorides, but are useful reagents for preparing esters and amides. O O O RCOCR ROH Acid anhydride RCOR RCOH Alcohol Ester O O Acid anhydride Carboxylic acid O O RCOCR 2R2NH O RCNR2 R2NH2 Amine Amide OCR Ammonium carboxylate salt Table 19.2 presents examples of these reactions. Section 19.6 Esters occur naturally or are prepared from alcohols by Fischer esterification or by acylation with acyl chlorides or acid anhydrides (see Table 19.3). Esters are polar and have higher boiling points than alkanes of comparable size and shape. Esters don’t form hydrogen bonds to other ester molecules so have lower boiling points than analogous alcohols. They can form hydrogen bonds to water and so are comparable to alcohols in their solubility in water. Section 19.7 Esters give amides on reaction with ammonia and amines and are cleaved to a carboxylic acid and an alcohol on hydrolysis (see Table 19.4). Section 19.8 Ester hydrolysis can be catalyzed by acids and its mechanism (see Mechanism 19.2) is the reverse of the mechanism for Fischer esterification. The reaction proceeds via a tetrahedral intermediate. OH R C OR OH Section 19.9 car02745_ch19_770-819.indd 808 Tetrahedral intermediate in ester hydrolysis Ester hydrolysis in basic solution is called saponification and proceeds through the same tetrahedral intermediate (see Mechanism 19.3) as in acid-catalyzed hydrolysis. Unlike acid-catalyzed hydrolysis, saponification is irreversible because the carboxylic acid is deprotonated under the reaction conditions. 10/2/12 12:46 PM 19.19 Summary O 809 O HO RCO Hydroxide ion Carboxylate ion RCOR Ester ROH Alcohol Section 19.10 Esters react with amines to give amides. O O RCOR R2NH Ester Section 19.11 RCNR2 ROH Amine Amide Alcohol Esters react with two equivalents of a Grignard or organolithium reagent to form tertiary alcohols. O X RCOCH3 OH 2RMgX 1. diethyl ether 2. H3O RC R R Methyl ester Grignard reagent Tertiary alcohol Lithium aluminum hydride reduces esters to alcohols. Two alcohols are formed; the acyl group is reduced to the primary alcohol. O Section 19.12 RCOR RCH2OH Ester Primary alcohol ROH Alcohol Amides having at least one N ⎯ H unit can form intermolecular hydrogen bonds with other amide molecules. Compounds of this type have higher melting and boiling points than comparable compounds in which N ⎯ H bonds are absent. Amides are normally prepared by the reaction of amines with acyl chlorides, anhydrides, or esters. Section 19.13 Like ester hydrolysis, amide hydrolysis can be achieved in either aqueous acid or aqueous base. The process is irreversible in both media. In base, the carboxylic acid is converted to the carboxylate anion; in acid, the amine is protonated to an ammonium ion: O H3O O Carboxylic acid RCNR2 H2O Amide RCOH Ammonium ion O Water HO RCO R2NH Carboxylate ion R2NH2 Amine Section 19.14 Lactams are cyclic amides. Section 19.15 Nitriles are prepared by nucleophilic substitution (SN2) of alkyl halides with cyanide ion, by converting aldehydes or ketones to cyanohydrins (see Table 19.6), or by dehydration of amides. Section 19.16 The hydrolysis of nitriles to carboxylic acids is irreversible in both acidic and basic solution. O RC car02745_ch19_770-819.indd 809 N Nitrile H3O, heat RCOH or 1. H2O, HO, heat Carboxylic acid 2. H3O 10/2/12 12:46 PM 810 Chapter 19 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Section 19.17 Nitriles are useful starting materials for the preparation of ketones by reaction with Grignard reagents. O RC N Nitrile RMgX Grignard reagent 1. diethyl ether 2. H3O, heat RCR Ketone Section 19.18 Acyl chlorides, anhydrides, esters, and amides all show a strong band for C= O stretching in the infrared. The range extends from about 1820 cm−1 (acyl chlorides) to 1690 cm–1 (amides). Their 13C NMR spectra are characterized by a peak near δ 180 for the carbonyl carbon. 1H NMR spectroscopy is useful for distinguishing between the groups R and R′ in esters (RCO2R′). The protons on the carbon bonded to O in R′ appear at lower field (less shielded) than those on the carbon bonded to C= O. Problems 19.27 Write a structural formula for each of the following compounds: (a) m-Chlorobenzoyl chloride (b) Trifluoroacetic anhydride (c) cis-1,2-Cyclopropanedicarboxylic anhydride (d) Ethyl cycloheptanecarboxylate (e) 1-Phenylethyl acetate (f) (g) (h) (i) 2-Phenylethyl acetate p-Ethylbenzamide N-Ethylbenzamide 2-Methylhexanenitrile 19.28 Give an acceptable IUPAC name for each of the following compounds: O O (a) CH3CHCH2CCl (e) Cl H3C O H3C O O (f) (CH3)2CHCH2CH2CqN (b) CH3COCH2 O O (g) (CH3)2CHCH2CH2CNH2 (c) CH3OCCH2 O (h) (CH3)2CHCH2CH2CNHCH3 O O (d) ClCH2CH2COCCH2CH2Cl O (i) (CH3)2CHCH2CH2CN(CH3)2 19.29 Write a structural formula for the principal organic product or products of each of the following reactions: (a) Propanoyl chloride and sodium propanoate (b) Butanoyl chloride and benzyl alcohol (c) p-Chlorobenzoyl chloride and ammonia (d) (e) (f) and water O O O O O O and aqueous sodium hydroxide to give C4H4Na2O4 O O O and aqueous ammonia to give C4H10N2O3 (g) Methyl benzoate and excess phenylmagnesium bromide, then H3O+ car02745_ch19_770-819.indd 810 10/2/12 12:46 PM