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Home , Alkoxide, Carboxylate, Hydrolysis, Leaving group, Nitrile, Substitution reaction

21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1004

1004 CHAPTER 21 • THE OF CARBOXYLIC DERIVATIVES

substitution. Acyl substitution can be represented generally as follows, with E an elec- trophilic group and Y a nucleophilic group: = = O O S S R C X E Y R C Y E X (21.6) carboxylicL L acid+ L LanotherL + L derivative derivative

O an S R C X L L The term acyl substitution comes from the fact that substitution occurs at the carbonyl of an acyl group. In other words, an acyl group is transferred in Eq. 21.6 between an X and a Y group. The group X might be the Cl of an acid , the OR of an ,L and soL on; this group is substitutedL by another groupL Y. This is precisely theL same type of reac-

tion as esterification of carboxylic ( X L OH, E Y H OCH3; Sec. 20.8A). Acyl substitution reactions of carboxylic acidL derivatives= L areL the =majorL focus of this chapter. Although are not carbonyl compounds, the C'N bond behaves chemically much like a . For example, a typical reaction of nitriles is addition. Y

RNC ' E Y RN"C A E (21.7) L 3+ L L 2 L (Compare this reaction with addition to the carbonyl group of an or .) Although the resulting addition products are stable in some cases, in most situations they react further. Like and , carboxylic acid derivatives undergo certain reactions involving the a-carbon. The a-carbon reactions of all carbonyl compounds are grouped together in Chapter 22. The reactivity of at is discussed in Sec. 23.11D.

21.7 OF CARBOXYLIC ACID DERIVATIVES

All carboxylic acid derivatives have in common the fact that they undergo hydrolysis (a cleav- age reaction with ) to yield carboxylic acids.

A. Hydrolysis of Saponification of Esters One of the most important reactions of esters is the cleavage re- action with to yield a and an . The carboxylic acid itself is formed when a strong acid is subsequently added to the reaction mixture.

O OCH3 O O_ Na| O OH C C C # % # % # % " " " 20% NaOH HCl OH (21.8) _ 5–10 min + %NO2 %NO2 %NO2 methyl 3-nitrobenzoateCH3OH 3-nitrobenzoic acid + (90–96% yield) 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1005

21.7 HYDROLYSIS OF CARBOXYLIC ACID DERIVATIVES 1005

Ester hydrolysis in aqueous hydroxide is called saponification because it is used in the production of from fats (Sec. 21.12B). Despite its association with fatty-acid esters, the term saponification can be used to refer to the hydrolysis in of any carboxylic acid derivative. The mechanism of ester saponification involves the reaction of the nucleophilic hydroxide ion at the carbonyl carbon to give a tetrahedral addition intermediate from which an

ion is expelled. 1

1 1 1 O 1 O _ O S3 3 3 3 S3 3

R CO CH R" CO CH RCO H OCH (21.9a) 1 3 3 _ 3 LL1 LL1 LL1 + 3 1 OH "OH _ 1 3 1 tetrahedral3 addition intermediate

The alkoxide ion, after expulsion as a ( in Eq. 21.9a), reacts with the

acid to give the carboxylate salt and the alcohol.

1 1 1 O O 1 S3 3 S3 3 RCO H _ OCH3 RCO _ H OCH3 (21.9b) LLL1 + 3 1 LL1 3 + L 1 pKa 4.5 pKa 15 = = The equilibrium in this reaction lies far to the right because the carboxylic acid is a much stronger acid than . Le Chaˆtelier’s principle operates: The reaction in Eq. 21.9b removes the carboxylic acid from the equilibrium in Eq. 21.9a as its salt and thus drives the hydrolysis to completion. Hence, saponification is effectively irreversible. Although an excess of hydroxide ion is often used as a matter of convenience, many esters can be saponified with

just one equivalent of _OH. Saponification can also be carried out in an alcohol , even though an alcohol is one of the products of the reaction. If saponification were reversible, an alcohol could not be used as the solvent because the equilibrium would be driven toward start- ing materials.

Acid-Catalyzed Ester Hydrolysis Because esterification of an acid with an alcohol is a reversible reaction (Sec. 20.8A), esters can be hydrolyzed to carboxylic acids in aqueous so- lutions of strong acids. In most cases, this reaction is slow and must be carried out with an ex- cess of water, in which most esters are insoluble. Saponification, followed by acidification, is a much more convenient method for hydrolysis of most esters because it is faster, it is irre- versible, and it can be carried out not only in water but also in a variety of —even . As expected from the principle of microscopic reversibility (Sec. 4.9B), the mechanism of acid-catalyzed hydrolysis is the exact reverse of the mechanism of acid-catalyzed esterifica-

tion (Sec. 20.8A). The ester is first protonated by the acid catalyst:

1 H OH| 2 1

L 1 H H H

| 1 1 1 O 1 O O O % % % S3 3 S3 3 3 RCOCH3 R C OCH3 R "C OCH3 R "C A O|CH3 H2O LL1 LL1 LL| 1 L 1 + 1 (21.10a) 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1006

1006 CHAPTER 21 • THE CHEMISTRY OF CARBOXYLIC ACID DERIVATIVES

As in other acid-catalyzed reactions at the carbonyl group, protonation makes the carbonyl carbon more electrophilic by making the carbonyl a better acceptor of electrons. Water, acting as a , reacts at the carbonyl carbon and then loses a proton to give the tetra- hedral addition intermediate:

H O| OH OH S % 3 3 2 H2O 3 2 (21.10b) R C OCH3 R "C OCH3 2 3 R "C OCH3 H3O| LL LL LL + 2 OH2 | "OH "OH L 3 2 3 tetrahedral3 addition "H intermediate2

Protonation of the leaving oxygen converts it into a better leaving group. Loss of this group gives a protonated carboxylic acid, from which a proton is removed to give the carboxylic acid itself.

OH OH H H OH| 2 R "C OCH3 L R "C" OCH3 L L H2O2 LL 2 | ""OH 2 2 OH 2 2 OH OH| OH OH 3 22S3 3 OH 3 2 ||2 R "COH R COH R "COHA 3 2 R "COA H3O LLL| 2 LLL2 LL2 L 2 + 2 2 CH3OH2 2 (21.10c) + 2 Let’s summarize the2 important differences between acid-catalyzed ester hydrolysis and ester saponification. First, in acid-catalyzed hydrolysis, the carbonyl carbon can react with the STUDY GUIDE LINK 21.3 relatively weak nucleophile water because the carbonyl oxygen is protonated. In base, the car- Mechanism of Ester Hydrolysis bonyl oxygen is not protonated; hence, a much stronger base than water—namely, hydroxide ion—is required to react at the carbonyl carbon. Second, acid catalyzes ester hydrolysis, but base is not a catalyst because it is consumed by the reaction in Eq. 21.9b. Finally, acid-cat- alyzed ester hydrolysis is reversible, but saponification is irreversible, again because of the Further Exploration 21.2 ionization in Eq. 21.9b. Cleavage of Tertiary Ester hydrolysis and saponification are both examples of acyl substitution (Sec. 21.6). Esters and Carbonless Carbon Paper Specifically, the mechanisms of these reactions are classified as nucleophilic acyl substitu- tion mechanisms. In a nucleophilic acyl , the substituting group reacts as a nucleophile at the carbonyl carbon. As in the reactions of aldehydes and ketones (Fig. 19.8, p. 909), approach the carbonyl carbon from above or below the plane of the car- bonyl group (Fig. 21.5), first interacting with the p* (antibonding) molecular orbital of the carbonyl group. As the result of this reaction, a tetrahedral addition intermediate is formed. The leaving group is expelled from this intermediate, departing from above or below the plane

of the new carbonyl group. In saponification, the nucleophile is _OH, and in acid-catalyzed hydrolysis, the nucleophile is water; in both cases, the OR group of the ester is displaced. With the exception of the reactions of nitriles, most of Lthe reactions in the remainder of this chapter are nucleophilic acyl substitution reactions. They follow the same pattern as saponifi- cation, the only substantial difference being the identity of the nucleophiles and the leaving groups. 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1007

21.7 HYDROLYSIS OF CARBOXYLIC ACID DERIVATIVES 1007

sp2-hybridized sp3-hybridized sp2-hybridized

carbon carbon carbon

≈109Њ ..

1 .. ≈120Њ

..

O.. R O.. ≈120Њ R´O C 1 Nuc Nuc _ Nuc 3 tetrahedral R´O addition intermediate

Figure 21.5 The geometry of nucleophilic acyl substitution.The nucleophile (Nuc _) approaches the carbonyl 3 carbon above or below the carbonyl plane (gray) to form a tetrahedral intermediate.The leaving group (R O_) de- parts from above or below the plane of the newly formed carbonyl group (blue).The green arrows show the´ move- ment of the various groups.

Hydrolysis and Formation of Because lactones are cyclic esters, they un- dergo the reactions of esters, including saponification. Saponification converts a com- pletely into the carboxylate salt of the corresponding hydroxy acid.

O O

L L S L S

C C O_ H2C O H2C L (21.11) _OH L L + L H2C CH2 H2C CH2 OH L L L g-butyrolactone g-hydroxybutyrate

Upon acidification, the hydroxy acid forms. However, if a hydroxy acid is allowed to stand in acidic , it comes to equilibrium with the corresponding lactone. The formation of a lactone from a hydroxy acid is nothing more than an intramolecular esterification (an esterifi- cation within the same molecule) and, like esterification, the lactonization equilibrium is acid- catalyzed.

O O S acid S C OH catalyst O L H2O Keq ≈ 160 (21.12) + L OH

O S O S C OH acid L catalyst O H2O Keq 3.3 (21.13) + = L OH As the examples in Eqs. 21.12 and 21.13 illustrate, lactones containing five- and six-membered rings are favored at equilibrium over their corresponding hydroxy acids. Although lactones with ring sizes smaller than five or larger than six are well known, they are 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1008

1008 CHAPTER 21 • THE CHEMISTRY OF CARBOXYLIC ACID DERIVATIVES

less stable than their corresponding hydroxy acids. Consequently, the lactonization equilibria for these compounds favor instead the hydroxy acids. O S acid O C OH catalyst O (almost no lactone L @ H2O present at equilibrium) (21.14) VVOH +

B. Hydrolysis of Amides Amides can be hydrolyzed to carboxylic acids and or by heating them in acidic or basic solution. Ph O Ph O S S 55 wt % H2SO4 | (21.15) CH3CH2"CHC NH2 H2O heat, 2 h CH3CH2"CHC OH NH4 HSO_4 L + L + 2-phenylbutanamide 2-phenylbutanoic acid (88–90% yield)

In acid, protonation of the ammonia or product drives the hydrolysis equilibrium to completion. The amine can be isolated, if desired, by addition of base to the reaction mixture following hydrolysis, as in the following example.

protonated amine O S NHC CH3 |NH3 Cl_ NH2 LL " Br " Br " Br HCl, H O OH % 2 % _ % H2O Cl_ (21.16) + +

"CH3 "CH3 "CH3 (60–67% yield) CH3CO2H + The hydrolysis of amides in base is analogous to the saponification of esters. In base, the reaction is driven to completion by formation of the carboxylic .

O S NHC CH3 NH2 L NOL NO O " 2 " 2 30% KOH, heat S % % H CCO K CH OHրH O 3 _ | (21.17) 3 2 + LL

"OCH3 "OCH3 (95–97% yield) The conditions for both acid- and base-promoted hydrolysis are considerably more severe than the corresponding reactions of esters. That is, amides are considerably less reac- tive than esters. The relative reactivities of carboxylic acid derivatives are discussed in Sec. 21.7E. The mechanisms of amide hydrolysis are typical nucleophilic acyl substitution mecha- nisms; you are asked to explore this point in Problem 21.10. 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1009

21.7 HYDROLYSIS OF CARBOXYLIC ACID DERIVATIVES 1009

PROBLEMS 21.10 Show in detail curved-arrow the hydrolysis mechanism of N-methylbenzamide (a) in acidic solution; (b) in aqueous NaOH. Assume that each mechanism involves a tetrahedral addi- tion intermediate. 21.11 Give the structures of the hydrolysis products that result from each of the following reac- tions. Be sure to show the product in part (b). (a) O S NaOH (CH3)2CHC N H2O LL + (b)

NH + H2O, H3O , heat NaOH C O

C. Hydrolysis of Nitriles Nitriles are hydrolyzed to carboxylic acids and ammonia by heating them in strongly acidic or strongly basic solution. heat PhCH C ' N 2H OHSO PhCH CO H NH HSO (21.18) 2 2 2 4 3 h 2 2 |4 _4 L ++(57 wt %) L + phenylacetonitrile phenylacetic acid (78% yield)

O S ' C N CO_ K| CO2H heat L H3O % KOH H O % | % K 2 17 h | + + +

1-cyclohexenecarbonitrile NH3 1-cyclohexenecarboxylic acid + (79% yield) (21.19) Nitriles hydrolyze more slowly than esters and amides. Consequently, the conditions required for the hydrolysis of nitriles are more severe. The mechanism of hydrolysis in acidic solution involves, first, protonation of the ni-

trogen (Sec. 21.5): 1

RHC' N H OH||2 R CN' H O 2 (21.20a) L 3 L 1 L L + 3 This protonation makes the nitrile carbon much more electrophilic, just as protonation of a carbonyl oxygen makes a carbonyl carbon more electrophilic. A nucleophilic reaction of

water at the nitrile carbon and loss of a proton gives an intermediate called an imidic acid.

1

1 1

OH 1 2 HHO HO 1 3 |L OH 3 ' | A 2 A R CNHR"CNH 3 R "CNH H3O| (21.20b) L L L 2 L Lan imidic acidL + 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1010

1010 CHAPTER 21 • THE CHEMISTRY OF CARBOXYLIC ACID DERIVATIVES

An imidic acid is the nitrogen analog of an (Sec. 14.5A). That is, an imidic acid is to an amide as an enol is to a ketone.

OH O OH O S S R"C A NH RC NH2 R"C A CH2 RC CH3 imidicL acid LLamide L enol LLketone

Just as are converted spontaneously into aldehydes or ketones, an imidic acid is con-

verted under the reaction conditions into an amide:

1 1

OH O H O| H O

3 H OH| 2 3 L S3 L OH2 S3 3 A L A | RCN" H R" C NH2 R C NH2 3 2 R C NH2 H3O| L 2 L 2 L LL LL22+ 2 (21.20c) Because amide hydrolysis is faster than nitrile hydrolysis, the amide formed in Eq. 21.20c does not survive under the vigorous conditions of nitrile hydrolysis and is therefore hy- drolyzed to a carboxylic acid and ion, as discussed in Sec. 21.7B. Thus, the ultimate product of nitrile hydrolysis in acid is a carboxylic acid. Notice that nitriles behave mechanistically much like carbonyl compounds. Compare, for example, the mechanism of acid-promoted nitrile hydrolysis in Eqs. 21.20a and b with that for the acid-catalyzed hydration of an aldehyde or ketone (Sec. 19.7A). In both mechanisms, an electronegative is protonated (nitrogen of the C'N bond, or oxygen of the CAO bond), and water then reacts as a nucleophile at the carbon of the resulting cation. The parallel between nitrile and carbonyl chemistry is further illustrated by the hydrolysis of nitriles in base. The nitrile group, like a carbonyl group, reacts with basic nucleophiles and, as a result, the electronegative nitrogen assumes a negative charge. Proton transfer gives an imidic acid (which, like a carboxylic acid, ionizes in base).

H OH _ OH ' A 2 A 3 A RCN RCN_ L R C NH 2 RCNH H2O (21.21a) L 3 L 2 3 2 L 2 2 L 2 + 2 OH _ "OH "OH "O 2 3 2 _ 3 imidic3 acid ionized33 2 2 2 imidic2 acid

As in acid-promoted hydrolysis, the imidic acid reacts further to give the corresponding amide, which, in turn, hydrolyzes under the reaction conditions to the carboxylate salt of the corresponding carboxylic acid (Sec. 21.7B).

O _ O 3 2 3 3S3 H OH R" CA NH R C NH_ L 2 L 2 L L 2 2 2 O amide O 3S3 hydrolysis 3S3 R C NH2 _ OH RCO_ NH3 (21.21b) L L 2 + 3 2 L L 2 3 + 3 2 2 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1011

21.7 HYDROLYSIS OF CARBOXYLIC ACID DERIVATIVES 1011

D. Hydrolysis of Acid and Anhydrides Acid chlorides and anhydrides react rapidly with water, even in the absence of acids or bases.

O H CO2H room temperature, C

* few minutes % % *O H2O S (21.22) + C H CO H O % % 2 (94% yield)

Ph O Ph O S 1) Na2CO3/H2O S 2) H O CA CH C Cl H O 3 | CA CH C OH Cl (21.23) $ 2 0 C $ _ LL + ° LL + Ph) Ph) ( 95% yield) > However, the hydrolysis reactions of acid chlorides and anhydrides are almost never used for the preparation of carboxylic acids because these derivatives are themselves usually prepared from acids (Sec. 20.9). Rather, these reactions serve as reminders that if samples of acid chlo- rides and anhydrides are allowed to come into contact with moisture they will rapidly become contaminated with the corresponding carboxylic acids.

E. Mechanisms and Reactivity in Nucleophilic Acyl Substitution Reactions As we’ve seen, all carboxylic acid derivatives can be hydrolyzed to carboxylic acids; however, the conditions under which the different derivatives are hydrolyzed differ considerably. Hydrol- ysis reactions of amides and nitriles require heat as well as acid or base; hydrolysis reactions of esters require acid or base, but require heating only briefly, if at all; and hydrolysis reactions of acid chlorides and anhydrides occur rapidly at room temperature even in the absence of acid and base. These trends in reactivity, which are observed not only in hydrolysis but in all nucleophilic acyl substitution reactions, can be summarized as follows: Reactivities of carboxylic acid derivatives in nucleophilic acyl substitution reactions:

nitriles < amides < esters, acids << anhydrides < acid chlorides

increasing reactivity (21.24)

(The reactions of nitriles are additions, not substitutions, but are included for comparison.) The practical significance of this reactivity order is that selective reactions are possible. In other words, an ester can be hydrolyzed under conditions that will leave an amide in the same molecule unaffected; likewise, nucleophilic substitution reactions on an acid chloride can be carried out under conditions that will leave an ester group unaffected. Understanding the trends in relative reactivity requires, first, an understanding of the mecha- nisms by which nucleophilic acyl substitution reactions take place. (The reactivity of nitriles is considered later.) Let’s start with a reaction free-energy diagram for a generalized carbonyl sub- stitution reaction that occurs under neutral or basic conditions. Carbonyl substitution involves 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1012

1012 CHAPTER 21 • THE CHEMISTRY OF CARBOXYLIC ACID DERIVATIVES

the reaction of a nucleophile Nuc_with a carbonyl compound to form a tetrahedral addition in- termediate, which then breaks down3 with loss of a leaving group X_. 3 O O _ O 3S3 3 2 3 3S3 (21.25) RCX RX"C RCNuc _ X L L LL L L + 3 Nuc_ "Nuc 3 tetrahedral addition intermediate

In this generalized reaction, let’s imagine that reactants and products are of comparable stability and that the transition states for both formation and breakdown of the tetrahedral ad-

dition intermediates have the same energies. (The case in which Nuc_is identical to X_is the simplest example of such a case.) The reaction free-energy diagram for3 this case is shown3 in Fig. 21.6a.

O O worse S3 3 S3 3 leaving group R C X R C Nuc better L L L L leaving group Nuc _ X _ + 3 + 3

∆G°‡

∆G°‡ ∆G°‡ 1 STANDARD FREE ENERGY STANDARD

O _ carbonyl compound 3 3 is less stable R "C X carbonyl compound L L is more stable "Nuc (a) (b) (c) reaction coordinate

Figure 21.6 How the structure of a carbonyl compound affects the rates of its nucleophilic substitution reac- tions.In each case,the is the tetrahedral addition intermediate (see Eq.21.25).The transition state for the reaction of the nucleophile is shown at the same energy level in all three parts for reference. (a) A re- action free-energy diagram for a generalized reaction in which the reactants and products have the same stan- dard free energy, and the transition states for the two steps shown in Eq. 21.25 also have the same standard free energy. (b) When a carbonyl compound (for example, an amide) is stabilized by resonance and when it contains a poor leaving group, the rates of both formation and breakdown of the tetrahedral addition intermediate are de- creased, and nucleophilic substitution is slower. An increase in the stability of the carbonyl compound decreases the rate by increasing the free-energy difference between reactant and transition state. (c) When a carbonyl com- pound (for example, an acid chloride) is destabilized and when it contains an excellent leaving group, the rates of both formation and breakdown of the tetrahedral addition intermediate are increased,and nucleophilic substitu- tion is faster. 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1013

21.7 HYDROLYSIS OF CARBOXYLIC ACID DERIVATIVES 1013

Two major factors can alter this diagram and thus affect the rate of a carbonyl substitution reaction: 1. the stability of the carbonyl compound, and

2. the leaving-group ability of X_ 3 These two factors tend to track together. Let’s examine two extreme cases to understand the effect of these factors on reaction rate.

First, consider the reaction of a nucleophile (for example, _OH) with an amide. This situation is depicted in Fig. 21.6b. An amide is stabilized by the resonance interaction of the unshared electron pair of the nitrogen with the carbonyl group, as follows:

O O _ S2 3 3 2 3 RCNH2 R" CA NH| 2 (21.26) L L 2 L This stabilization increases the energy difference between the amide and the tetrahedral addi- tion intermediate, in which this resonance interaction is not present. The leaving group in this

case is the amide anion, _NH2, which is a poor leaving group because it is a very strong base; the pKa of its conjugate acid32 ( NH3) is about 32. The difficulty in expelling a very basic leav- ing group is reflected in a higher3 free-energy barrier for the second step, breakdown of the tetrahedral addition intermediate. As a result, the second step is rate-limiting. ‡ Remember that reactivity is governed by the standard free energy of activation DG , which is the difference in the standard free energies of the rate-limiting transition state and the° ‡ reactants (Sec. 4.8C). Also recall that reactions with larger DG are slower than reactions ‡ with smaller DG . For amide hydrolysis, the standard free energy° of activation is the differ- ence between the° standard free energy of the rate-limiting transition state—the transition state for breakdown of the tetrahedral intermediate—and that of the starting amide. As Fig. 21.6b ‡ shows, this is a much greater DG than in Fig. 21.6a. Hence, amide hydrolysis is a particu- larly slow reaction and therefore requires° harsh reaction conditions to proceed at a reasonable rate.

You may have noticed that the products of the reaction in Fig. 21.6b are less stable than the reactants. This is a direct reflection of the fact that the leaving group is much more basic than the nucleophile. Don’t forget that a subsequent and very rapid step of amide hydrolysis is not shown in this diagram— namely, ionization of the carboxylic acid product and protonation of the amide ion: O O O S L S L S L

R C N OH RCOH N RCO HN L L ___ L (21.27) L L 22+ 33L LL2 + 2 a carboxylateL LL2 ion3 + 2 an amide 2 2 an amide ion 2 an amine initial products of amide hydrolysis

It is this last, very favorable, equilibrium that drives base-promoted amide hydrolysis to completion.

Notice particularly the role of reactant stabilization in reducing the reaction rate. Recall that this is also an important factor in the relative reactivities of aldehydes and ketones (Sec. 19.7C). Notice also that the electron-donating ability—the Lewis basicity—of the amide ni- trogen is really at the heart of both the reactant-stabilization and the leaving-group effects. Its ability to donate electrons by resonance governs the reactant-stabilization effect, and its strong Brønsted basicity makes the nitrogen a poor leaving group. Amides in which this reso- nance interaction is absent are actually very reactive! (See the sidebar on pp. 1002–1003.) 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1014

1014 CHAPTER 21 • THE CHEMISTRY OF CARBOXYLIC ACID DERIVATIVES

The saponification of esters can be analyzed much like the base-promoted hydrolysis of amides. Esters are also stabilized by the resonance interaction between the carboxylate oxy- gen and the carbonyl group. This places a positive charge on the carboxylate oxygen:

O O _ S2 3 3 2 3 RCORЈ RC"A OR| Ј (21.28) L L 2 L Because oxygen is more electronegative2 than nitrogen, this resonance2 interaction is less im- portant in an ester than it is in an amide; hence, esters are stabilized less by resonance than amides are. Thus, the carbonyl stabilization effect in an ester is less pronounced than it is in an amide. Now consider the leaving group: an alkoxide ion is much less basic than an amide ion; hence, the increase in the energy barrier resulting from leaving group basicity is less pro- nounced in an ester as well. Esters, then, are more reactive than amides. Let’s now go to the other end of the reactivity spectrum: acid chlorides. This case is depicted in Fig. 21.6c. The resonance interaction between a unshared electron pair and the car- bonyl group is rather ineffective because it requires the overlap of a chlorine 3p orbital with a carbon 2p orbital. Because this overlap is very poor (Fig. 16.7, p. 771), acid chlorides are sta- bilized much less by resonance than esters or amides are. What’s more, the polar effect of the chlorine also destabilizes the carbonyl compound through an unfavorable interaction of the car- bon–chlorine bond dipole with the partial positive charge on the carbonyl carbon: d– O the partial positive charge on the carbonyl carbon d+S interacts unfavorably with the positive end of R C Cl the carbon–chlorine bond dipole

Acid chlorides, then, are destabilized relative to amides or esters, and this destabilization re- duces the standard free-energy difference between an acid chloride and its transition state. Now consider the leaving-group effect in the hydrolysis of an acid chloride. Because chlo- ride ion is a very , it is an excellent leaving group. Its leaving-group ability is re- flected in a decrease in the transition-state energy for the breakdown of the tetrahedral addi- tion intermediate. In fact, this transition-state energy is decreased so much that the first step—reaction with the nucleophile—becomes rate-limiting. The overall result implied by ‡ Fig. 21.6c is that acid chloride hydrolysis should have a much smaller DG than ester or amide hydrolysis. This means that acid chloride hydrolysis should be much faster° than amide or ester hydrolysis, as observed. The resonance stabilization of an anhydride is more important than that in an acid chloride (why?) but less important than that of an ester because of the repulsion between the positive charge on the carboxylate oxygen and the partial positive charge on the carbonyl carbon:

d– O O O _ O S2 3 SS3 2 3 RRC O C R "CCA O R (21.29) L LLL2 LLL2 d+ 2 repulsion between like charges

Hence, from the point of view of reactant stabilization, an anhydride should be more reactive than an ester, but less reactive than an acid chloride. The leaving group in an anhydride is a

carboxylate anion—the conjugate base of a carboxylic acid, which has a pKa typically in the 4–5 range. This leaving group is considerably more basic than a chloride ion, but considerably 21_BRCLoudon_pgs5-2.qxd 12/15/08 11:44 AM Page 1015

21.7 HYDROLYSIS OF CARBOXYLIC ACID DERIVATIVES 1015

less basic than an alkoxide ion. Hence, an analysis of leaving-group ability also places anhy- drides between acid chlorides and esters in reactivity, and this is what is observed. The following two important principles about nucleophilic carbonyl substitution have emerged from this discussion: 1. Stabilization of the carbonyl compound decreases reactivity; destabilization of the car- bonyl compound increases reactivity. 2. Higher basicity of the leaving group decreases reactivity; lower basicity increases reactivity. To summarize:

O S esters, R C X amides carboxylic acids anhydrides acid chlorides LL O (21.30)

X NH2 OR, OH OCR Cl = L L L LLL L increasing stabilization of the carbonyl compound

increasing leaving-group basicity

therefore increasing reactivity

Although this detailed analysis has been carried out for reactions that involve a negatively charged nucleophile, the same conclusions are obtained from an analysis of acid-catalyzed re- actions. What about nitriles? Reactions of nitriles in base are slower than those of other acid derivatives because nitrogen is less electronegative than oxygen and accepts additional elec- trons less readily. Reactions of nitriles in acid are slower because of their extremely low basic- ities. It is the protonated form of a nitrile that reacts with nucleophiles in acid solution, but so little of this form is present (Sec. 21.5) that the rate of the reaction is very small.

PROBLEMS 21.12 Use an analysis of resonance effects and leaving-group basicities to explain why acid-cat- alyzed hydrolysis of esters is faster than acid-catalyzed hydrolysis of amides. 21.13 Which should be faster: base-promoted hydrolysis of an acid fluoride or base-promoted hy- drolysis of an acid chloride? Explain your reasoning. 21.14 Complete the following reactions. (a) O S N ' C CH C OCH OH (1 equiv.) 2 3 _ H O/CH OH LLL + 2 3 (b) H O F CO CH –OH 3 | 2 3 H O LL + 2 (c) O S heat, H O H NC NH H O 3 | 2 2 2 H O LL + 2