CHAPTER 20 CARBoXYLIC ACID DERIVATIVES: NUCLEOPHILIO ACYL SUBSTITUTION his chapter differs from preceding ones in that it deals with several related classes of compounds rather than just one. Included are 1. Acyl chlorides, RCCI 2. Carboxylic acid anhydrides, RCOCR 3. Esters of carboxvlic acids rcor 4. Carboxamides, RCNH,. RCNHR and RCNR,2 These classes of compounds are classified as carboxylic acid derivatives. All may converted to carboxylic acids by hydrolysis RCX+H2O—RCOH+ HX Carboxylic acid Water Carboxylic Conjugate acid derivative of leaving group Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
CHAPTER 20 CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL SUBSTITUTION This chapter differs from preceding ones in that it deals with several related classes of compounds rather than just one. Included are 1. Acyl chlorides, 2. Carboxylic acid anhydrides, 3. Esters of carboxylic acids, 4. Carboxamides, , , and These classes of compounds are classified as carboxylic acid derivatives. All may be converted to carboxylic acids by hydrolysis. RCX O X Carboxylic acid derivative H2O Water HX Conjugate acid of leaving group Carboxylic acid RCOH O X RCNR 2 O X RCNHR O X RCNH2 O X RCOR O X RCOCR O X O X RCCl O X 774 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
20.1 Nomenclature of Carboxylic Acid Derivatives The hydrolysis of a carboxylic acid derivative is but one example of a nucleophilic acyl substitution. Nucleophilic acyl substitutions connect the various classes of car- boxylic acid derivatives, with a reaction of one class often serving as preparation of another. These reactions provide the basis for a large number of functional group trans- formations both in synthetic organic chemistry and in biological chemist Also included in this chapter is a discussion of the chemistry of nitriles, compounds of the type rC=N. Nitriles may be hydrolyzed to carboxylic acids or to amides and so, are indirectly related to the other functional groups presented here. 20.1 NOMENCLATURE OF CARBOXYLIC ACID DERIVATIVES with the exception of nitriles (RCEn, all carboxylic acid derivatives consist of an acyl group(RC-)attached to an electronegative atom. Acyl groups are named by replacing the-ic acid ending of the corresponding carboxylic acid by -yl. Acy! halides are named by placing the name of the appropriate halide after that of the acyl group CHaCO CH,=CHCH,CCI Acetyl chloride p-Fluorobenzoyl bromide Although acyl fluorides, bromides, and iodides are all known classes of organic com- pounds, they are encountered far less frequently than are acyl chlorides. Acyl chlorides will be the only acyl halides discussed in this chapter In naming carboxylic acid anhydrides in which both acyl groups are the same, we simply specify the acyl group and add the word"anhydride. "When the acyl groups are different, they are cited in alphabetical order. O CH3COCCH3 C6HSCOCC6H ChS COC(CH2)5CH Acetic anhydride Benzoic anhydride The alkyl group and the acyl group of an ester are specified independently. Esters are named as alkyl alkanoates. The alkyl group Rof RCoR'is cited first, followed by the acyl portion RC-. The acyl portion is named by substituting the suffix -ate for the ending of the corresponding acid. CH3COCH2CH3 CH3CH, COCH3 -CoCH,CHCI Ethyl acetate Methyl propanoate 2-Chloroethyl benzoate Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
The hydrolysis of a carboxylic acid derivative is but one example of a nucleophilic acyl substitution. Nucleophilic acyl substitutions connect the various classes of carboxylic acid derivatives, with a reaction of one class often serving as preparation of another. These reactions provide the basis for a large number of functional group transformations both in synthetic organic chemistry and in biological chemistry. Also included in this chapter is a discussion of the chemistry of nitriles, compounds of the type RCPN. Nitriles may be hydrolyzed to carboxylic acids or to amides and, so, are indirectly related to the other functional groups presented here. 20.1 NOMENCLATURE OF CARBOXYLIC ACID DERIVATIVES With the exception of nitriles (RCPN), all carboxylic acid derivatives consist of an acyl group attached to an electronegative atom. Acyl groups are named by replacing the -ic acid ending of the corresponding carboxylic acid by -yl. Acyl halides are named by placing the name of the appropriate halide after that of the acyl group. Although acyl fluorides, bromides, and iodides are all known classes of organic compounds, they are encountered far less frequently than are acyl chlorides. Acyl chlorides will be the only acyl halides discussed in this chapter. In naming carboxylic acid anhydrides in which both acyl groups are the same, we simply specify the acyl group and add the word “anhydride.” When the acyl groups are different, they are cited in alphabetical order. The alkyl group and the acyl group of an ester are specified independently. Esters are named as alkyl alkanoates. The alkyl group R of is cited first, followed by the acyl portion . The acyl portion is named by substituting the suffix -ate for the -ic ending of the corresponding acid. CH3COCH2CH3 O Ethyl acetate CH3CH2COCH3 O Methyl propanoate COCH2CH2Cl O 2-Chloroethyl benzoate RC± O X RCOR O X CH3COCCH3 O X O X Acetic anhydride C6H5COCC6H5 O X O X Benzoic anhydride C6H5COC(CH2)5CH3 O X O X Benzoic heptanoic anhydride F CBr O p-Fluorobenzoyl bromide CHCH2CCl O CH2 3-Butenoyl chloride CH3CCl O Acetyl chloride (RC±) O X 20.1 Nomenclature of Carboxylic Acid Derivatives 775 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Aryl esters, that is, compounds of the type RCOAr, are named in an analogous way The names of amides of the type RCNH2 are derived from carboxylic acids by replacing the suffix -oic acid or -ic acid by -amide O CH3CNH, C6H5C ( CH3)2CHCH,CNH Benzamide 3-Methylbutanamide We name compounds of the type RCNHR and RCNr2 as N-alkyl- and N, N-dialkyl substituted derivatives of a parent amide O O CH3CNHCH C,HSCN(CH, CH3) CH3 CH, CH, CNCH(CH3)2 H3 N-Methylacetamide N, N-Diethylbenzamide N-lsopropyl-N-methyl- Substitutive iupac names for nitriles add the suffix -nitrile to the name of the parent hydrocarbon chain that includes the carbon of the cyano group. Nitriles may also be named by replacing the -ic acid or-oic acid ending of the corresponding carboxylic acid with -nitrile. Alternatively, they are sometimes given functional class IUPAC names as alkyl cyanides C6H5C≡N CH3CHCH3 Ethanenitrile Benzonitrile 2-Methylpropaneni (acetonitrile) (isopropyl cyanic PROBLEM 20.1 Write a structural formula for each of the following compounds: (a)2-Phenylbutanoyl bromide (e)2-Phenylbutanamide (b)2-Phenylbutanoic anhydride (f)N-Ethyl-2-phenylbutanamide (c) Butyl 2-F SAMPLE SOLUTION (a)A 2-phenylbutanoyl group is a four-carbon acyl unit that bears a phenyl substituent at C-2. When the name of an acyl group is followed by the name of a halide, it designates an acyl halide CH3CH2 CHCBr 2-Phenylbutanoyl bromide Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Aryl esters, that is, compounds of the type , are named in an analogous way. The names of amides of the type are derived from carboxylic acids by replacing the suffix -oic acid or -ic acid by -amide. We name compounds of the type and as N-alkyl- and N,N-dialkylsubstituted derivatives of a parent amide. Substitutive IUPAC names for nitriles add the suffix -nitrile to the name of the parent hydrocarbon chain that includes the carbon of the cyano group. Nitriles may also be named by replacing the -ic acid or -oic acid ending of the corresponding carboxylic acid with -onitrile. Alternatively, they are sometimes given functional class IUPAC names as alkyl cyanides. PROBLEM 20.1 Write a structural formula for each of the following compounds: (a) 2-Phenylbutanoyl bromide (e) 2-Phenylbutanamide (b) 2-Phenylbutanoic anhydride (f) N-Ethyl-2-phenylbutanamide (c) Butyl 2-phenylbutanoate (g) 2-Phenylbutanenitrile (d) 2-Phenylbutyl butanoate SAMPLE SOLUTION (a) A 2-phenylbutanoyl group is a four-carbon acyl unit that bears a phenyl substituent at C-2. When the name of an acyl group is followed by the name of a halide, it designates an acyl halide. CH3CH2CHCBr C6H5 O 2-Phenylbutanoyl bromide Ethanenitrile (acetonitrile) CH3C N Benzonitrile C6H5C N 2-Methylpropanenitrile (isopropyl cyanide) CH3CHCH3 C N N-Methylacetamide CH3CNHCH3 O N,N-Diethylbenzamide C6H5CN(CH2CH3)2 O N-Isopropyl-N-methylbutanamide CH3CH2CH2CNCH(CH3)2 O CH3 RCNR 2 O X RCNHR O X CH3CNH2 O X Acetamide C6H5CNH2 O X Benzamide (CH3)2CHCH2CNH2 O X 3-Methylbutanamide RCNH2 O X RCOAr O X 776 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
0.2 Structure of Carboxylic Acid Derivatives 20.2 STRUCTURE OF CARBOXYLIC ACID DERIVATIVES Figure 20. 1 shows the structures and electrostatic potentials of the various derivatives of acetic acid-acetyl chloride, acetic anhydride, ethyl acetate, acetamide, and acetonitrile Like the other carbonyl-containing compounds that weve studied, acyl chlorides, anhy drides, esters, and amides all have a planar arrangement of bonds to the carbonyl group An important structural feature of acyl chlorides, anhydrides, esters, and amides is that the atom attached to the acyl group bears an unshared pair of electrons that can interact with the carbonyl TT system, as shown in Figure 20.2 This electron delocalization can be represented in resonance terms by contributions from the following resonance structures →R Electron release from the substituent stabilizes the carbonyl group and decreases its elec- trophilic character. The extent of this electron delocalization depends on the electron 00 CHaCOCCI CHaCSCHCH Acetyl chloride Acetic anhydride Ethyl thioacetate FIGURE 20.1 The structures and electrostatic of va CH,CH CH3 CNH2 rivatives of acetic acid. thes Ethyl acetate Acetonitnle Learning By Modeling. Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
20.2 STRUCTURE OF CARBOXYLIC ACID DERIVATIVES Figure 20.1 shows the structures and electrostatic potentials of the various derivatives of acetic acid–acetyl chloride, acetic anhydride, ethyl acetate, acetamide, and acetonitrile. Like the other carbonyl-containing compounds that we’ve studied, acyl chlorides, anhydrides, esters, and amides all have a planar arrangement of bonds to the carbonyl group. An important structural feature of acyl chlorides, anhydrides, esters, and amides is that the atom attached to the acyl group bears an unshared pair of electrons that can interact with the carbonyl system, as shown in Figure 20.2. This electron delocalization can be represented in resonance terms by contributions from the following resonance structures: Electron release from the substituent stabilizes the carbonyl group and decreases its electrophilic character. The extent of this electron delocalization depends on the electronR X C O R X C O R X C O 20.2 Structure of Carboxylic Acid Derivatives 777 CH3CCl CH3COCCH3 CH3CSCH2CH3 CH3COCH2CH3 CH3CNH2 O O O O O O O O O O O O CH3CPN Acetyl chloride Acetic anhydride Ethyl thioacetate Ethyl acetate Acetamide Acetonitrile FIGURE 20.1 The structures and electrostatic potential maps of various derivatives of acetic acid. These models may be viewed on Learning By Modeling. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution FIGURE 20.2 The three o bonds originating at X=Cl; acyl chloride X=OCR: acid anhydride planar. The p orbital of the arbonyl carbon, its oxyger nd the atom by which X= OR: ester group x is attached to the acyl group overlap to form an extended T syster through which the elec trons are delocalized donating properties of the substituent X. Generally, the less electronegative X is, the bet- ter it donates electrons to the carbonyl group and the greater its stabilizing effect Resonance stabilization in acyl chlorides is not nearly as pronounced as in other derivatives of carboxylic acids Weak resonance stabilization Because the carbon-chlorine bond is so long--typically on the order of 180 pm for acyl chlorides--overlap between the 3p orbitals of chlorine and the T orbital of the carbonyl group is poor. Consequently, there is little delocalization of the electron pairs of chlo- rine into the T system. The carbonyl group of an acyl chloride feels the normal electron- withdrawing inductive effect of a chlorine substituent without a significant compensat ing electron-releasing effect due to lone-pair donation by chlorine. This makes the carbonyl carbon of an acyl chloride more susceptible to attack by nucleophiles than that of other carboxylic acid derivatives Acid anhydrides are better stabilized by electron delocalization than are acyl chlo- rides. The lone-pair electrons of oxygen are delocalized more effectively into the car bonyl group Resonance involves both carbonyl groups of an acid anhydride The carbonyl group of an ester is stabilized more than is that of an anhydride Since both acyl groups of an anhydride compete for the oxygen lone pair, each carbonyl is stabilized less than the single carbonyl group of an ester. is more effective th Ester Acid anhydride Esters are stabilized by resonance to about the same extent as carboxylic acids bu h as amides. Nitrogen is less electronegative than oxygen and is a better electron-pair donor Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
donating properties of the substituent X. Generally, the less electronegative X is, the better it donates electrons to the carbonyl group and the greater its stabilizing effect. Resonance stabilization in acyl chlorides is not nearly as pronounced as in other derivatives of carboxylic acids: Because the carbon–chlorine bond is so long—typically on the order of 180 pm for acyl chlorides—overlap between the 3p orbitals of chlorine and the orbital of the carbonyl group is poor. Consequently, there is little delocalization of the electron pairs of chlorine into the system. The carbonyl group of an acyl chloride feels the normal electronwithdrawing inductive effect of a chlorine substituent without a significant compensating electron-releasing effect due to lone-pair donation by chlorine. This makes the carbonyl carbon of an acyl chloride more susceptible to attack by nucleophiles than that of other carboxylic acid derivatives. Acid anhydrides are better stabilized by electron delocalization than are acyl chlorides. The lone-pair electrons of oxygen are delocalized more effectively into the carbonyl group. Resonance involves both carbonyl groups of an acid anhydride. The carbonyl group of an ester is stabilized more than is that of an anhydride. Since both acyl groups of an anhydride compete for the oxygen lone pair, each carbonyl is stabilized less than the single carbonyl group of an ester. Esters are stabilized by resonance to about the same extent as carboxylic acids but not as much as amides. Nitrogen is less electronegative than oxygen and is a better electron-pair donor. is more effective than Ester R OR C O R C C R O O O Acid anhydride C C R R O O O R C C R O O O R C O C R O O R C O Cl R Cl C O Weak resonance stabilization 778 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution O C X X OH; carboxylic acid X Cl; acyl chloride X OCR; acid anhydride X O X OR; ester X NR2; amide FIGURE 20.2 The three bonds originating at the carbonyl carbon are coplanar. The p orbital of the carbonyl carbon, its oxygen, and the atom by which group X is attached to the acyl group overlap to form an extended system through which the electrons are delocalized. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website