0.2 Structure of Carboxylic Acid Derivatives Very effective resonance stabilization Amide resonance is a powerful stabilizing force and gives rise to a number of structural effects. Unlike the pyramidal arrangement of bonds in ammonia and amines, the bonds to nitrogen in amides lie in the same plane. The carbon-nitrogen bond has considerable double-bond character and, at 135 pm, is substantially shorter than the normal 147-pm carbon-nitrogen single-bond distance observed in amines The barrier to rotation about the carbon-nitrogen bond in amides is 75 to 85 kJ/mol (18-20 kcal/mol) R E=75-85 k/mol R er in ethane is only 12 I( kcal/mol) This is an unusually high rotational energy barrier for a single bond and indicates that the carbon-nitrogen bond has significant double-bond character, as the resonance picture PROBLEM 20.2 The 'H NMR spectrum of N, N-dimethylformamide shows a sep arate signal for each of the two methyl groups. Can you explain why? Electron release from nitrogen stabilizes the carbonyl group of amides and decreases the rate at which nucleophiles attack the carbonyl carbon. Nucleophilic reagents attack electrophilic sites in a molecule; if electrons are donated elec- trophilic site in a molecule by a substituent, then the tendency of that molecule to react with external nucleophiles is moderated An extreme example of carbonyl group stabilization is seen in carboxylate anions: O The negatively charged oxygen substituent is a powerful electron donor to the carbonyl group. Resonance in carboxylate anions is more effective than resonance in carboxylic acids, acyl chlorides, anhydrides, esters, and amides Table 20. 1 summarizes the stabilizing effects of substituents on carbonyl groups to which they are attached. In addition to a qualitative ranking, quantitative estimates of the relative rates of hydrolysis of the various classes of acyl derivatives are given. A weakly stabilized carboxy lic acid derivative reacts with water faster than does a more stabilized one toa. Most methods for their preparation convert one class of carboxylic acid derivative nother, and the order of carbonyl group stabilization given in Table 20. 1 bears directly on the means by which these transformations may be achieved. A reaction that converts one carboxylic acid derivative to another that lies below it in the table is practical;a reaction that converts it to one that lies above it in the table is not. This is another way f saying that one carboxylic acid derivative can be converted to another if the reaction Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Amide resonance is a powerful stabilizing force and gives rise to a number of structural effects. Unlike the pyramidal arrangement of bonds in ammonia and amines, the bonds to nitrogen in amides lie in the same plane. The carbon–nitrogen bond has considerable double-bond character and, at 135 pm, is substantially shorter than the normal 147-pm carbon–nitrogen single-bond distance observed in amines. The barrier to rotation about the carbon–nitrogen bond in amides is 75 to 85 kJ/mol (18–20 kcal/mol). This is an unusually high rotational energy barrier for a single bond and indicates that the carbon–nitrogen bond has significant double-bond character, as the resonance picture suggests. PROBLEM 20.2 The 1 H NMR spectrum of N,N-dimethylformamide shows a separate signal for each of the two methyl groups. Can you explain why? Electron release from nitrogen stabilizes the carbonyl group of amides and decreases the rate at which nucleophiles attack the carbonyl carbon. Nucleophilic reagents attack electrophilic sites in a molecule; if electrons are donated to an electrophilic site in a molecule by a substituent, then the tendency of that molecule to react with external nucleophiles is moderated. An extreme example of carbonyl group stabilization is seen in carboxylate anions: The negatively charged oxygen substituent is a powerful electron donor to the carbonyl group. Resonance in carboxylate anions is more effective than resonance in carboxylic acids, acyl chlorides, anhydrides, esters, and amides. Table 20.1 summarizes the stabilizing effects of substituents on carbonyl groups to which they are attached. In addition to a qualitative ranking, quantitative estimates of the relative rates of hydrolysis of the various classes of acyl derivatives are given. A weakly stabilized carboxylic acid derivative reacts with water faster than does a more stabilized one. Most methods for their preparation convert one class of carboxylic acid derivative to another, and the order of carbonyl group stabilization given in Table 20.1 bears directly on the means by which these transformations may be achieved. A reaction that converts one carboxylic acid derivative to another that lies below it in the table is practical; a reaction that converts it to one that lies above it in the table is not. This is another way of saying that one carboxylic acid derivative can be converted to another if the reaction R C O O R C O O Eact 75–85 kJ/mol (18–20 kcal/mol) C R R R O C N N R O R R R C O NR 2 R NR 2 C O Very effective resonance stabilization 20.2 Structure of Carboxylic Acid Derivatives 779 Recall that the rotational barrier in ethane is only 12 kJ/mol (3 kcal/mol). Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution TABLE 20.1 Relative Stability and Reactivity of Carboxylic Acid Derivatives Carboxylic acid Relative rate derivative Stabilization of hydrolysis* Acyl chloride Very small Anhydride RCOCR Sma Ester RCOR Moderate 1.0 Carboxylate anion RCO Very large *Rates are approximate and are relative to ester as standard substrate at pH 7. leads to a more stabilized carbonyl group. Numerous examples of reactions of this type ill be presented in the sections that follow. We begin with reactions of acyl chlorides 20.3 NUCLEOPHILIC SUBSTITUTION IN ACYL CHLORIDES Acyl chlorides are readily prepared from carboxylic acids by reaction with thionyl chlo- tions of acyl chlorides was ride (Section 12.7) RCCI SO,+ HCI with acyl chlorides in the RCOH SOCh presence of aluminum Carboxylic Sulfur Hyd chloride chloride (CH3)CHCOH 2-Methylpropanoic acid 2-Methylpropanoyl chloride(90%) On treatment with the appropriate nucleophile, an acyl chloride may be converted to an acid anhydride, an ester, an amide, or a carboxylic acid. Examples are presented in Table 20 PROBLEM 20.3 Apply the knowledge gained by studying Table 20.2 to help you predict the major organic product obtained by reaction of benzoyl chloride with each of the followin (a)Acetic acid (d)Methylamine, CH3NH2 (b )Benzoic acid (e)Dimethylamine, (CH3)2NH (eThanol (f) SAMPLE SoLUTIoN (a)As noted in Table 20.2, the reaction of an acyl chloride with a carboxylic acid yields an acid anhydride Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
leads to a more stabilized carbonyl group. Numerous examples of reactions of this type will be presented in the sections that follow. We begin with reactions of acyl chlorides. 20.3 NUCLEOPHILIC SUBSTITUTION IN ACYL CHLORIDES Acyl chlorides are readily prepared from carboxylic acids by reaction with thionyl chloride (Section 12.7). On treatment with the appropriate nucleophile, an acyl chloride may be converted to an acid anhydride, an ester, an amide, or a carboxylic acid. Examples are presented in Table 20.2. PROBLEM 20.3 Apply the knowledge gained by studying Table 20.2 to help you predict the major organic product obtained by reaction of benzoyl chloride with each of the following: (a) Acetic acid (d) Methylamine, CH3NH2 (b) Benzoic acid (e) Dimethylamine, (CH3)2NH (c) Ethanol (f) Water SAMPLE SOLUTION (a) As noted in Table 20.2, the reaction of an acyl chloride with a carboxylic acid yields an acid anhydride. Carboxylic acid RCOH O Acyl chloride RCCl O Thionyl chloride SOCl2 Sulfur dioxide SO2 Hydrogen chloride HCl 2-Methylpropanoic acid (CH3)2CHCOH O 2-Methylpropanoyl chloride (90%) (CH3)2CHCCl O SOCl2 heat 780 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution TABLE 20.1 Relative Stability and Reactivity of Carboxylic Acid Derivatives Relative rate of hydrolysis* 1011 107 1.0 102 Acyl chloride Anhydride Ester Amide Carboxylic acid derivative Carboxylate anion Stabilization Very small Small Moderate Large Very large RCCl O X RCOCR O X O X RCOR O X RCNR 2 O X RCO O X *Rates are approximate and are relative to ester as standard substrate at pH 7. One of the most useful reactions of acyl chlorides was presented in Section 12.7. Friedel–Crafts acylation of aromatic rings takes place when arenes are treated with acyl chlorides in the presence of aluminum chloride. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
20.3 Nucleophilic Substitution in Acyl Chlorides CHsCCI CH3COH - C6HsCOCCH Benzoyl chloride Acetic acid Acetic benzoic anhydride The product is a mixed anhydride. Acetic acid acts as a nucleophile and substi Ites for chloride on the benzoyl group TABLE 20.2 Conversion of Acyl Chlorides to Other Carboxylic Acid Derivatives Reaction(section) and comments General equation and specific example Reaction with carboxylic acids(Section 20.4)Acyl chlorides react with carboxylic acids to yield acid anhydrides. When this RCCI+ RCOH reaction is used for preparative purposes, Carbo a weak organic base such as pyridine is chloride normally added Pyridine is a catalyst for the reaction and also acts as a base to neutralize the hydrogen chloride that is CHa(CH))SCCl CH3 ( CH2)s COH pyridine, CH3(CH2)5 COC(CH2)SCH3 Heptanoyl Heptad chloride acid (78-83% aLcohols(Section 15.8)Acyl o with alcohols to form ction is typically carried out RCC|+R'OH—>RcoR!+HC of pyridine. Alcohol Ester chloride chloride CHsCCI +(CH3)3COH CHs COC(CH3)3 Benzoyl ert-B tert-B chloride Reaction omonia and amines sec tion 20.1 3)acyl chlorides react with mmonia and amines to form amides. A RCCI RNH HO →>RCNR2+H2O+C| base such as sodium hydroxide is normally Acyl Ammonia Hydroxide ter Chloride added to react with the hydrogen chlor- de produced C6HsCCI HN C6H5C—N Ben (87-91%) Hydrolysis(Section 20. 3) Acyl chlorides react with water to yield carboxylic acids. In base, the acid is converted to its carbox- RCCI H2O RCOH+ HCI ylate salt. The reaction has little prepara Wate Carboxylic Hydrogen tive value because the acyl chloride is nearly always prepared from the carboxyl- ic acid rather than vice versa CHsCH2CCI H20-C5HsCH2COH HCI Phenylacetyl Water Phenylac Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
The product is a mixed anhydride. Acetic acid acts as a nucleophile and substitutes for chloride on the benzoyl group. C6H5CCl O Benzoyl chloride C6H5COCCH3 O O Acetic benzoic anhydride CH3COH O Acetic acid 20.3 Nucleophilic Substitution in Acyl Chlorides 781 TABLE 20.2 Conversion of Acyl Chlorides to Other Carboxylic Acid Derivatives Reaction (section) and comments Reaction with carboxylic acids (Section 20.4) Acyl chlorides react with carboxylic acids to yield acid anhydrides. When this reaction is used for preparative purposes, a weak organic base such as pyridine is normally added. Pyridine is a catalyst for the reaction and also acts as a base to neutralize the hydrogen chloride that is formed. Reaction with alcohols (Section 15.8) Acyl chlorides react with alcohols to form esters. The reaction is typically carried out in the presence of pyridine. Reaction with ammonia and amines (Section 20.13) Acyl chlorides react with ammonia and amines to form amides. A base such as sodium hydroxide is normally added to react with the hydrogen chloride produced. Hydrolysis (Section 20.3) Acyl chlorides react with water to yield carboxylic acids. In base, the acid is converted to its carboxylate salt. The reaction has little preparative value because the acyl chloride is nearly always prepared from the carboxylic acid rather than vice versa. General equation and specific example Acyl chloride RCCl O X Carboxylic acid RCOH O X Acid anhydride RCOCR O X O X HCl Hydrogen chloride pyridine Heptanoyl chloride CH3(CH2)5CCl O X Heptanoic acid CH3(CH2)5COH O X Heptanoic anhydride (78–83%) CH3(CH2)5COC(CH2)5CH3 O X O X pyridine Benzoyl chloride C6H5CCl O X tert-Butyl alcohol (CH3)3COH tert-Butyl benzoate (80%) C6H5COC(CH3)3 O X Ester RCOR O X HCl Hydrogen chloride ROH Alcohol Acyl chloride RCCl O X Amide RCNR 2 O X Cl Chloride ion H2O Water R 2NH Ammonia or amine HO Hydroxide Acyl chloride RCCl O X Carboxylic acid RCOH O X HCl Hydrogen chloride H2O Water Acyl chloride RCCl O X NaOH H2O Benzoyl chloride C6H5CCl O X Piperidine HN N-Benzoylpiperidine (87–91%) C6H5C±N O X Phenylacetyl chloride C6H5CH2CCl O X Water H2O Phenylacetic acid C6H5CH2COH O X Hydrogen chloride HCl Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution First stage: Formation of the tetrahedral intermediate by nucleophilic addition of Acyl chloride Tetrahedral intermediate Second stage: Dissociation of the tetrahedral intermediate by dehydrohalogenation R Tetrahedral Water Carboxylic FIGURE 20. 3 Hydrolysis of acyl chloride proceeds by way of a tetrahedral intermediate. For- mation of the tetrahedral intermediate is rate-determini The mechanisms of all the reactions cited in Table 20.2 are similar to the mecha- nism of hydrolysis of an acyl chloride outlined in Figure 20.3. They differ with respect to the nucleophile that attacks the carbonyl group In the first stage of the mechanism, water undergoes nucleophilic addition to the carbonyl group to form a tetrahedral intermediate. This stage of the process is analogous to the hydration of aldehydes and ketones discussed in Section 17.6. The tetrahedral intermediate has three potential leaving groups on carbon: two hydroxyl groups and a chlorine. In the second stage of the reaction, the tetrahedral inter mediate dissociates, Loss of chloride from the tetrahedral intermediate is faster than loss of hydroxide; chloride is less basic than hydroxide and is a better leaving group. The tetrahedral intermediate dissociates because this dissociation restores the resonance- tabilized carbonyl group PROBLEM 20.4 Write the structure of the tetrahedral intermediate formed each of the reactions given in Problem 20. 3. Using curved arrows, show how each tetrahedral intermediate dissociates to the appropriate products SAMPLE SOLUTION (a)The tetrahedral intermediate arises by nucleophilic addi- tion of acetic acid to benzoyl chloride C6HsCCI CH3COH C6HsCOCCH3 Benzoyl Acetic acid Tetrahedral intermediate Loss of a proton and of chloride ion from the tetrahedral intermediate yields the mixed anhydride Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
The mechanisms of all the reactions cited in Table 20.2 are similar to the mechanism of hydrolysis of an acyl chloride outlined in Figure 20.3. They differ with respect to the nucleophile that attacks the carbonyl group. In the first stage of the mechanism, water undergoes nucleophilic addition to the carbonyl group to form a tetrahedral intermediate. This stage of the process is analogous to the hydration of aldehydes and ketones discussed in Section 17.6. The tetrahedral intermediate has three potential leaving groups on carbon: two hydroxyl groups and a chlorine. In the second stage of the reaction, the tetrahedral intermediate dissociates. Loss of chloride from the tetrahedral intermediate is faster than loss of hydroxide; chloride is less basic than hydroxide and is a better leaving group. The tetrahedral intermediate dissociates because this dissociation restores the resonancestabilized carbonyl group. PROBLEM 20.4 Write the structure of the tetrahedral intermediate formed in each of the reactions given in Problem 20.3. Using curved arrows, show how each tetrahedral intermediate dissociates to the appropriate products. SAMPLE SOLUTION (a) The tetrahedral intermediate arises by nucleophilic addition of acetic acid to benzoyl chloride. Loss of a proton and of chloride ion from the tetrahedral intermediate yields the mixed anhydride. C6H5CCl O Benzoyl chloride C6H5COCCH3 HO Cl O Tetrahedral intermediate CH3COH O Acetic acid 782 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution O H H Water C R C R O slow O O H H fast H O C R O H Acyl chloride Tetrahedral intermediate First stage: Formation of the tetrahedral intermediate by nucleophilic addition of water to the carbonyl group Second stage: Dissociation of the tetrahedral intermediate by dehydrohalogenation H O C R O Cl Tetrahedral intermediate H O H H Water fast C R O H O H H Carboxylic acid Hydronium ion O H Cl Chloride ion Cl Cl Cl FIGURE 20.3 Hydrolysis of acyl chloride proceeds by way of a tetrahedral intermediate. Formation of the tetrahedral intermediate is rate-determining. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
0. 4 Preparation of Carboxylic Acid Anhydrides CHsCOCCH3-> CHsCOCCH3 HCI Acetic benzoic Hydrogen chloride Nucleophilic substitution in acyl chlorides is much faster than in alkyl chlorides CCI -CH,CI Benzoyl chloride Benzyl chloride Relative rate of hydrolysis 1.000 (80%o ethanol-20% water; 25.C) The sp2-hybridized carbon of an acyl chloride is less sterically hindered than the sp' hybridized carbon of an alkyl chloride, making an acyl chloride more open toward nucle- ophilic attack. Also, unlike the Sn2 transition state or a carbocation intermediate in an SNI reaction, the tetrahedral intermediate in nucleophilic acyl substitution has a stable arrangement of bonds and can be formed via a lower energy transition state 20.4 PREPARATION OF CARBOXYLIC ACID ANHYDRIDES After acyl halides, acid anhydrides are the most reactive carboxylic acid derivatives Three of them, acetic anhydride, phthalic anhydride, and maleic anhydride, are indus- trial chemicals and are encountered far more often than others. Phthalic anhydride and maleic anhydride have their anhydride function incorporated into a ring and are referred to as cyclic anhydrides Acetic Phthalic Maleic anhydride 00 species of beetle. RCCI RCoh+ ) RCOCR′+ Cl This procedure is applicable to the preparation of both symmetrical anhydrides(r and R the same)and mixed anhydrides(R and r different) Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Nucleophilic substitution in acyl chlorides is much faster than in alkyl chlorides. The sp2 -hybridized carbon of an acyl chloride is less sterically hindered than the sp3 - hybridized carbon of an alkyl chloride, making an acyl chloride more open toward nucleophilic attack. Also, unlike the SN2 transition state or a carbocation intermediate in an SN1 reaction, the tetrahedral intermediate in nucleophilic acyl substitution has a stable arrangement of bonds and can be formed via a lower energy transition state. 20.4 PREPARATION OF CARBOXYLIC ACID ANHYDRIDES After acyl halides, acid anhydrides are the most reactive carboxylic acid derivatives. Three of them, acetic anhydride, phthalic anhydride, and maleic anhydride, are industrial chemicals and are encountered far more often than others. Phthalic anhydride and maleic anhydride have their anhydride function incorporated into a ring and are referred to as cyclic anhydrides. The customary method for the laboratory synthesis of acid anhydrides is the reaction of acyl chlorides with carboxylic acids (Table 20.2). This procedure is applicable to the preparation of both symmetrical anhydrides (R and R the same) and mixed anhydrides (R and R different). Cl RCCl O Acyl chloride O RCOH Carboxylic acid N Pyridine O O RCOCR Carboxylic acid anhydride N H Pyridinium chloride Acetic anhydride CH3COCCH3 O O O O O Phthalic anhydride O O O Maleic anhydride CCl O Benzoyl chloride Relative rate of hydrolysis 1,000 (80% ethanol–20% water; 25°C) CH2Cl Benzyl chloride 1 HCl Hydrogen chloride C6H5COCCH3 O O Acetic benzoic anhydride C6H5COCCH3 H O Cl O Tetrahedral intermediate 20.4 Preparation of Carboxylic Acid Anhydrides 783 Acid anhydrides rarely occur naturally. One example is the putative aphrodisiac cantharidin, obtained from a species of beetle. O CH3 O CH3 O O Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website