CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution PROBLEM 20.5 Benzoic anhydride has been prepared in excellent yield by dding one molar equivalent of water to two molar equivalents of benzoyl chlo- ride. How do you suppose this reaction takes place? Cyclic anhydrides in which the ring is five- or six-membered are sometimes pre- pared by heating the corresponding dicarboxylic acids in an inert solvent: H HO, C CO,H Maleic acid (89%) 20.5 REACTIONS OF CARBOXYLIC ACID ANHYDRIDES Nucleophilic acyl substitution in acid anhydrides involves cleavage of a bond between oxygen and one of the carbonyl groups. One acyl group is transferred to an attacking nucleophile; the other retains its single bond to oxygen and becomes the acyl group of a carboxylic acid OCR+ HY HOCR Bond cleavage Nucleophile Product of occurs here in an acid anhydride One reaction of this type, Friedel-Crafts acylation(Section 12.7), is already familiar to us. RCOCR Arh RCAr RCOH Acid Arene Ketone Carboxylic hydride 00 CHaCOCCH,+ OCH3 OCH CHCO,H Acetic acetophenone Acetic (70-80%) An acyl cation is an intermediate in Friedel-Crafts acylation reactions PROBLEM206 Write a structural formula for the acyl cation intermediate he preceding reaction. Conversions of acid anhydrides to other carboxylic acid derivatives are illustrated in Table 20.3. Since a more highly stabilized carbonyl group must result in order for nucleophilic acyl substitution to be effective, acid anhydrides are readily converted to carboxylic acids, esters, and amides but not to acyl chlorides Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
PROBLEM 20.5 Benzoic anhydride has been prepared in excellent yield by adding one molar equivalent of water to two molar equivalents of benzoyl chloride. How do you suppose this reaction takes place? Cyclic anhydrides in which the ring is five- or six-membered are sometimes prepared by heating the corresponding dicarboxylic acids in an inert solvent: 20.5 REACTIONS OF CARBOXYLIC ACID ANHYDRIDES Nucleophilic acyl substitution in acid anhydrides involves cleavage of a bond between oxygen and one of the carbonyl groups. One acyl group is transferred to an attacking nucleophile; the other retains its single bond to oxygen and becomes the acyl group of a carboxylic acid. One reaction of this type, Friedel–Crafts acylation (Section 12.7), is already familiar to us. An acyl cation is an intermediate in Friedel–Crafts acylation reactions. PROBLEM 20.6 Write a structural formula for the acyl cation intermediate in the preceding reaction. Conversions of acid anhydrides to other carboxylic acid derivatives are illustrated in Table 20.3. Since a more highly stabilized carbonyl group must result in order for nucleophilic acyl substitution to be effective, acid anhydrides are readily converted to carboxylic acids, esters, and amides but not to acyl chlorides. RCOCR O O Acid anhydride ArH Arene RCAr O Ketone RCOH O Carboxylic acid AlCl3 AlCl3 CH3COCCH3 O O Acetic anhydride OCH3 F o-Fluoroanisole CH3C OCH3 F O 3-Fluoro-4-methoxyacetophenone (70–80%) CH3CO2H Acetic acid Bond cleavage occurs here in an acid anhydride. RC O OCR O HY Nucleophile RC O Y Product of nucleophilic acyl substitution HOCR O Carboxylic acid tetrachloroethane 130°C H C HO2C CO2H H C Maleic acid O O O Maleic anhydride (89%) H2O Water 784 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
20.5 Reactions of Carboxylic Acid Anhydrides TABLE 20.3 Conversion of Acid Anhydrides to Other Carboxylic Acid Derivatives Reaction(section) and General equation and specific example Reaction with alcohols( Section 15.8)Acid anhydrides react with alcohols to form esters. the RCOCR R'OH reaction may be carried out in Alcohol the presence of pyridine or it may be catalyzed by acids. In the example shown, only one becomes incorporated into the CH3COCCH3 +HOCHCH,CH.H2So acetyl group of acetic anhydride CH3COCHCH2 CH3 ester: the other becomes the CH acetyl group of an acetic acid molecule Acetic sec-Butyl sec-Butyl acetate(60%) Reaction with ammon amines(Section 20. 13) anhydrides react wi RCOCR 2RNH-RCNR2 RCO H2NR and amines to form amides Ammoniu Two molar equivalents of amine anhydride carboxylate are required. In the example own,only one acetyl group of acetic anhydride becomes incor- porated into the amide; the CH3COCCH3 H2N CH(CH3)2—>CH3CNH一 CH(CHa)2 ther becomes the acetyl group of the amine salt of acetic acid Acetic p-lsopropylaniline Isopropylacetanilide (98%) Hydrolysis ( Section 20.5) Acid anhydrides react with water to yield two carboxylic acid func- R+H2O- 2RCOH dicarboxylic acids 0+H20 COH PROBLEM 20.7 Apply the knowledge gained by studying Table 20.3 to he predict the major organic product of each of the following reactions elp you (a)Benzoic anhydride+ methanol (b)Acetic anhydride ammonia(2 mol)- (c)Phthalic anhydride +(CH3)2NH (2 mol) (d) Phthalic anhydride sodium hydroxide(2 mol) Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
PROBLEM 20.7 Apply the knowledge gained by studying Table 20.3 to help you predict the major organic product of each of the following reactions: (a) (b) Acetic anhydride ammonia (2 mol) ±£ (c) Phthalic anhydride (CH3)2NH (2 mol) ±£ (d) Phthalic anhydride sodium hydroxide (2 mol) ±£ H Benzoic anhydride methanol 20.5 Reactions of Carboxylic Acid Anhydrides 785 TABLE 20.3 Conversion of Acid Anhydrides to Other Carboxylic Acid Derivatives Reaction (section) and comments Reaction with alcohols (Section 15.8) Acid anhydrides react with alcohols to form esters. The reaction may be carried out in the presence of pyridine or it may be catalyzed by acids. In the example shown, only one acetyl group of acetic anhydride becomes incorporated into the ester; the other becomes the acetyl group of an acetic acid molecule. Reaction with ammonia and amines (Section 20.13) Acid anhydrides react with ammonia and amines to form amides. Two molar equivalents of amine are required. In the example shown, only one acetyl group of acetic anhydride becomes incorporated into the amide; the other becomes the acetyl group of the amine salt of acetic acid. Hydrolysis (Section 20.5) Acid anhydrides react with water to yield two carboxylic acid functions. Cyclic anhydrides yield dicarboxylic acids. General equation and specific example H2SO4 Acetic anhydride CH3COCCH3 O X O X sec-Butyl alcohol HOCHCH2CH3 CH3 W sec-Butyl acetate (60%) CH3COCHCH2CH3 CH3 O X W Carboxylic acid RCOH O X Acid anhydride RCOCR O X O X Ester RCOR O X ROH Alcohol Ammonium carboxylate salt RCO O X H2NR 2 Acid anhydride RCOCR O X O X Amide RCNR 2 O X 2R 2NH Amine Acid anhydride RCOCR O X O X Carboxylic acid 2RCOH O X H2O Water Acetic anhydride CH3COCCH3 O X O X H2N CH(CH3)2 p-Isopropylaniline p-Isopropylacetanilide (98%) CH3CNH O X CH(CH3)2 Phthalic anhydride O O O Water H2O Phthalic acid COH O X COH X O Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution SAMPLE SOLUTION (a) Nucleophilic acyl substitution by an alcohol on an acid anhydride yields an este CHsCOCC6Hs CH3OH-) CHs COCH3 CsHsCOH Methanol Methyl benzoate Benzoic acid anhydride The first example in Table 20.3 introduces a new aspect of nucleophilic acyl sub- stitution that applies not only to acid anhydrides but also to acyl chlorides, esters, and amides. Nucleophilic acyl substitutions can be catalyzed by acids We can see how an acid catalyst increases the rate of nucleophilic acyl substitu- tion by considering the hydrolysis of an acid anhydride. Formation of the tetrahedral intermediate is rate-determining and is the step that is accelerated by the catalyst. The acid anhydride is activated toward nucleophilic addition by protonation of one of its car bonyl groups: Cocr +Ht RCOCR Proton Protonated form anhydride acid anhydrid The protonated form of the acid anhydride is present to only a very small extent, but it is quite electrophilic. Water(and other nucleophiles) add to a protonated carbonyl group much faster than they do to a neutral one. Thus, the rate-determining nucleophilic addi- tion of water to form a tetrahedral intermediate takes place more rapidly in the presence id than in its ab C=OH H,O-C-OH HO-C-OH C=0 Water Protonated form of Tetrahedral intermediate Acids also catalyze the dissociation of the tetrahedral intermediate. Protonation of its car- bonyl oxygen permits the leaving group to depart as a neutral carboxylic acid molecule, which is a less basic leaving group than a carboxylate anion R H H+ oton intermed cid molecules Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
SAMPLE SOLUTION (a) Nucleophilic acyl substitution by an alcohol on an acid anhydride yields an ester. The first example in Table 20.3 introduces a new aspect of nucleophilic acyl substitution that applies not only to acid anhydrides but also to acyl chlorides, esters, and amides. Nucleophilic acyl substitutions can be catalyzed by acids. We can see how an acid catalyst increases the rate of nucleophilic acyl substitution by considering the hydrolysis of an acid anhydride. Formation of the tetrahedral intermediate is rate-determining and is the step that is accelerated by the catalyst. The acid anhydride is activated toward nucleophilic addition by protonation of one of its carbonyl groups: The protonated form of the acid anhydride is present to only a very small extent, but it is quite electrophilic. Water (and other nucleophiles) add to a protonated carbonyl group much faster than they do to a neutral one. Thus, the rate-determining nucleophilic addition of water to form a tetrahedral intermediate takes place more rapidly in the presence of an acid than in its absence. Acids also catalyze the dissociation of the tetrahedral intermediate. Protonation of its carbonyl oxygen permits the leaving group to depart as a neutral carboxylic acid molecule, which is a less basic leaving group than a carboxylate anion. fast fast HO R C OH O C R O Tetrahedral intermediate HO H R C O O C R OH H H Proton 2RC O OH Two carboxylic acid molecules ratedetermining step fast, H H2O Water C R C R OH O O Protonated form of an acid anhydride H2O R C OH O C R O HO R C OH O C R O Tetrahedral intermediate RCOCR O O Acid anhydride RCOCR HO O Protonated form of acid anhydride H Proton fast C6H5COCC6H5 O O Benzoic anhydride C6H5COCH3 O Methyl benzoate C6H5COH O Benzoic acid CH3OH Methanol H 786 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
20.6 Sources of esters This pattern of increased reactivity resulting from carbonyl group prote been seen before in nucleophilic additions to aldehydes and ketones(Section 17.6)and in the mechanism of the acid-catalyzed esterification of carboxylic acids(Section 19. 14) Many biological reactions involve nucleophilic acyl substitution and are catalyzed by enzymes that act by donating a proton to the carbonyl oxygen, the leaving group, or both PROBLEM 20.8 Write the each of the reactions given it tetrahedral intermediate diss in Problem of the tetrahedral intermediate formed in m 20.7. Using curved arrows, show how each to the appropriate products SAMPLE SOLUTION (a)The reaction given is the acid-catalyzed esterification of ethano by benzoic anhydride. The first step is the activation of the anhydride toward nucleophilic addition by protonation CsH5COCC6H5 H F CHscOCCsH roton Protonated form of benzoic anhydride The tetrahedral intermediate is formed by nucleophilic addition of methanol to the protonated carbonyl group CsHs C6H5 CHO: r CH30-C-OH 3O oH+ Methanol Protonated form Tetrahedral intermediate CsH ChS H CH3O-C-OH H* F CH30-CYO CsHs COCH3 C6HsCOH + H+ C6H5 Tetrahed Proton Benzoic Proton termed Acid anhydrides are more stable and less reactive than acyl chlorides. Acetyl chlo- ride, for example, undergoes hydrolysis about 100,000 times more rapidly than acetic anhydride at25°C 20.6 SOURCES OF ESTERS Many esters occur naturally. Those of low molecular weight are fairly volatile, and many have pleasing odors. Esters often form a significant fraction of the fragrant oil of fruits and flowers. The aroma of oranges, for example, contains 30 different esters along with 10 carboxylic acids, 34 alcohols, 34 aldehydes and ketones, and 36 hydrocarbons Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
This pattern of increased reactivity resulting from carbonyl group protonation has been seen before in nucleophilic additions to aldehydes and ketones (Section 17.6) and in the mechanism of the acid-catalyzed esterification of carboxylic acids (Section 19.14). Many biological reactions involve nucleophilic acyl substitution and are catalyzed by enzymes that act by donating a proton to the carbonyl oxygen, the leaving group, or both. PROBLEM 20.8 Write the structure of the tetrahedral intermediate formed in each of the reactions given in Problem 20.7. Using curved arrows, show how each tetrahedral intermediate dissociates to the appropriate products. SAMPLE SOLUTION (a) The reaction given is the acid-catalyzed esterification of methanol by benzoic anhydride. The first step is the activation of the anhydride toward nucleophilic addition by protonation. The tetrahedral intermediate is formed by nucleophilic addition of methanol to the protonated carbonyl group. Acid anhydrides are more stable and less reactive than acyl chlorides. Acetyl chloride, for example, undergoes hydrolysis about 100,000 times more rapidly than acetic anhydride at 25°C. 20.6 SOURCES OF ESTERS Many esters occur naturally. Those of low molecular weight are fairly volatile, and many have pleasing odors. Esters often form a significant fraction of the fragrant oil of fruits and flowers. The aroma of oranges, for example, contains 30 different esters along with 10 carboxylic acids, 34 alcohols, 34 aldehydes and ketones, and 36 hydrocarbons. Protonated form of benzoic anhydride H Benzoic anhydride Proton C6H5COCC6H5 O O C6H5COCC6H5 HO O 20.6 Sources of Esters 787 CH3O H Methanol C6H5 O C C C6H5 OH O Protonated form of benzoic anhydride CH3O C H C6H5 OH O C C6H5 O Tetrahedral intermediate CH3O C C6H5 OH O C C6H5 O H Tetrahedral intermediate CH3O C C6H5 OH O C C6H5 O Proton H Proton H CH3O C H C6H5 O O C C6H5 OH Methyl benzoate C6H5COCH3 O Benzoic acid C6H5COH O Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution COCH3 CH3COCH, CH,CH(CH3)2 H 3-Methylbutyl acetate is 3-Methylbutyl acetate Methyl salicylat more commonly known as (contributes to characteristic (principal component of oil odor of bananas) of wintergreen) Among the chemicals used by insects to communicate with one another, esters CH2(CH2)6CH3 COCH,CH H O Ethyl cinna (Z)-5-Tetradecen-4-olide glide is a cyclic ester. Recall one of the constituents of (sex pheromone of female the sex pheromone of the apanese beetle) esters are called lactones and male oriental fruit moth) hat the suffix -glide is char acteristic of IUPAC names for Esters of glycerol, called glycerol triesters, triacylglycerols, or triglyceride oundant natural products. The most important group of glycerol triesters includes those in which each acyl group is unbranched and has 14 or more carbon atoms CH3(CH2)16CO OC(CH2)16CH ar model of Tristearin, a trioctadecanoyl ester of glycerol found in many animal and vegetable fats Fats and oils are naturally occurring mixtures of glycerol triesters. Fats are mixtures that are solids at room temperature; oils are liquids. The long-chain carboxylic acids obtained from fats and oils by hydrolysis are known as fatty acids. The chief methods used to prepare esters in the laboratory have all been descrit earlier and are summarized in Table 20. 4. 20.7 PHYSICAL PROPERTIES OF ESTERS Esters are moderately polar, with dipole moments in the 1.5 to 2.0-D range ipole-dipole attractive forces give esters higher boiling points than hydrocarbons of milar shape and molecular weight. Because they lack hydroxyl groups, however, ester molecules cannot form hydrogen bonds to each other; consequently, esters have lower boiling points than alcohols of comparable molecular weight Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Among the chemicals used by insects to communicate with one another, esters occur frequently. Esters of glycerol, called glycerol triesters, triacylglycerols, or triglycerides, are abundant natural products. The most important group of glycerol triesters includes those in which each acyl group is unbranched and has 14 or more carbon atoms. Fats and oils are naturally occurring mixtures of glycerol triesters. Fats are mixtures that are solids at room temperature; oils are liquids. The long-chain carboxylic acids obtained from fats and oils by hydrolysis are known as fatty acids. The chief methods used to prepare esters in the laboratory have all been described earlier, and are summarized in Table 20.4. 20.7 PHYSICAL PROPERTIES OF ESTERS Esters are moderately polar, with dipole moments in the 1.5 to 2.0-D range. Dipole–dipole attractive forces give esters higher boiling points than hydrocarbons of similar shape and molecular weight. Because they lack hydroxyl groups, however, ester molecules cannot form hydrogen bonds to each other; consequently, esters have lower boiling points than alcohols of comparable molecular weight. CH3(CH2)16CO OC(CH2)16CH3 OC(CH2)16CH3 O O O Tristearin, a trioctadecanoyl ester of glycerol found in many animal and vegetable fats COCH2CH3 H H O Ethyl cinnamate (one of the constituents of the sex pheromone of the male oriental fruit moth) H CH2(CH2)6CH3 H O O (Z)-5-Tetradecen-4-olide (sex pheromone of female Japanese beetle) CH3COCH2CH2CH(CH3)2 O 3-Methylbutyl acetate (contributes to characteristic odor of bananas) COCH3 OH O Methyl salicylate (principal component of oil of wintergreen) 788 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution 3-Methylbutyl acetate is more commonly known as isoamyl acetate. Notice that (Z)-5-tetradecen- 4-olide is a cyclic ester. Recall from Section 19.15 that cyclic esters are called lactones and that the suffix -olide is characteristic of IUPAC names for lactones. A molecular model of tristearin is shown in Figure 26.2. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website