Carboxylic acid derivatives leaving groups

Polar C=Y double bonds (Y = NR, O, S) with electrophilic carbon have been added to suifinic acids under formation of sulfones. As in the preceding section one must distinguish between carbonyl groups and their derivatives on the one hand, and carboxylic acids (possessing leaving groups at the electrophilic carbon) on the other. Aldehydes " of sufficient reactivity—especially mono-substituted glyoxals - —and their aryl or arylsulfonyl imines have been added to suifinic acids (in a reversible equilibrium) to yield a-hydroxy or a-amino sulfones the latter could also be obtained from the former in the presence of primary amines (equation 26). 

Conversion to a more facile, sulfur-derived, leaving group can be achieved by treatment with sodium thiosulfate or salts of thio and dithio acids (75,87). Under anhydrous conditions, boron tribromide converts the 3 -acetoxy group to a bromide whereas trimethyl silyl iodide gives good yields of the 3 -iodide (87,171,172). These 3 -halides are much more reactive, even when the carboxyl group is esterified, and can be displaced readily by cyano and by oxygen nucleophiles (127). 

Another factor which strongly affects the reactivity of these carboxylic acid derivatives is the leaving-group abihty of the substituents. The order is Cl > OAr > OR > NR2 > 0 so that not only does the ease of forming the tetrahedral intermediate decrease in the order Cl>0Ar>0R>NR2>0 , but the tendency for subsequent elimination to occur is also in the same order. Because the two factors work together, there are large differences in reactivity toward the nucleophiles. 

Correlations with o in carboxylic acid derivative reactions have been most successful for variations in the acyl portion, R in RCOX. Variation in the alkyl portion of esters, R in RCOOR, has not led to many good correlations, although use of relative rates of alkaline and acidic reactions, as in the defining relation, can generate linear correlations. The failure to achieve satisfactory correlations with cr for such substrates may be a consequence of the different steric effects of substituents in the acyl and alkyl locations. It has been shown that solvolysis rates of some acetates are related to the pA", of the leaving group, that is, of the parent alcohol. The pK of alcohols has been correlated with but this relationship... 

As a general rule, nucleophilic addition reactions are characteristic only of aldehydes and ketones, not of carboxylic acid derivatives. The reason for the difference is structural. As discussed previously in A Preview of Carbonyl Compounds and shown in Figure 19.14, the tetrahedral intermediate produced by addition of a nucleophile to a carboxylic acid derivative can eliminate a leaving group, leading to a net nucleophilic acyl substitution reaction. The tetrahedral intermediate... 

Figure 19.14 Carboxylic acid derivatives have an electronegative substituent Y = -Br, —Cl, -OR, -NR2 that can be expelled as a leaving group from the tetrahedral intermediate formed by nucleophilic addition. Aldehydes and ketones have no such leaving group and thus do not usually undergo this reaction.

Closely related to the carboxylic acids and nitriles discussed in the previous chapter are the carboxylic acid derivatives, compounds in which an acyl group is bonded to an electronegative atom or substituent that can net as a leaving group in a substitution reaction. Many kinds of acid derivatives are known, but we ll be concerned primarily with four of the more common ones acid halides, acid anhydrides, esters, and amides. Esters and amides are common in both laboratory and biological chemistry, while acid halides and acid anhydrides are used only in the laboratory. Thioesters and acyl phosphates are encountered primarily in biological chemistry. Note the structural similarity between acid anhydrides and acy) phosphates. 

The difference in behavior between aldehydes/ketones and carboxylic acic derivatives is a consequence of structure. Carboxylic acid derivatives have ai acyl carbon bonded to a group -Y that can leave as a stable anion. As soon a the tetrahedral intermediate is formed, the leaving group is expelled to general- a new carbonyl compound. Aldehydes and ketones have no such leaving grouj however, and therefore don t undergo substitution. 

A nucleophilic acyl substitution reaction involves the substitution of a nucleophile for a leaving group in a carboxylic acid derivative. Identify the leaving group (Cl- in the case of an acid chloride) and the nucleophile (an alcohol in this case), and replace one by the other. The product is isopropyl benzoate. 

Problem 21.6 The following structure represents a tetrahedral alkoxide ion intermediate formed by addition of a nucleophile to a carboxylic acid derivative. Identify the nucleophile, the leaving group, the starting acid derivative, and the ultimate product. 

Carboxylic acid derivative (Chapter 21 introduction) A compound in which an acyl group is bonded to an electronegative atom or substituent Y that can act as a leaving group in a substitution reaction, RCOY. 

In HO -catalyzed hydrolysis (specific base catalyzed hydrolysis), the tetrahedral intermediate is formed by the addition of a nucleophilic HO ion (Fig. 3.1, Pathway b). This reaction is irreversible for both esters and amides, since the carboxylate ion formed is deprotonated in basic solution and, hence, is not receptive to attack by the nucleophilic alcohol, phenol, or amine. The reactivity of the carboxylic acid derivative toward a particular nucleophile depends on a) the relative electron-donating or -withdrawing power of the substituents on the carbonyl group, and b) the relative ability of the -OR or -NR R" moiety to act as a leaving group. Thus, electronegative substituents accelerate hydrolysis, and esters are more readily hydrolyzed than amides. 

Much better leaving groups are encountered in carboxylic acid derivatives. Acyl halides possess... 

Table 7.2 Leaving groups and reactivity in carboxylic acid derivatives...

As one of the most reactive groups of carboxylic acid derivatives, acyl halides are very useful substrates for the preparation of the other classes of derivatives. For example, anhydrides may be synthesized by the reaction of carboxylic acid salts with an acyl halide. In this reaction, the carboxylate anion acts as the nucleophile, eventually displacing the halide leaving group. 

Section 6.1.2) second, RS is a better leaving group than RO (see Section 6.1.4), again because of size and the less localized electrons. Simple nucleophilic reactions with H2S parallel those with H2O, and those with RSH parallel those with ROH. This gives rise to carboxylic acid derivatives containing sulfur, such as thioacids and thioesters. 

Acyl halides and anhydrides are the most reactive class of carboxylic acid derivatives, and readily react with amines to give amides. It should be noted that in both cases the leaving group is a conjugate base that, upon protonation during the reaction, will become an... 

The initial reaction is effectively the same as with an aldehyde or ketone, in that hydride is transferred from the reducing agent, and that the tetrahedral anionic intermediate then complexes with the Lewis acid aluminium hydride. However, the typical reactivity of the carboxylic acid derivatives arises because of the presence of a leaving group. 

The Vcirious carboxylic acid derivatives vary in their reactivity (stability of the leaving group). Acid chlorides, for example, are more reactive than anhydrides (don t leave as easily). A summciry of the relative reactivities appears in Figure 12-32. 

The reactivity of carboxyhc acid derivatives depends on the basicity of the substituent attached to the acyl group. Therefore, the less basic the substituent, the more reactive is the derivative. In other words, strong bases make poor leaving groups. Carboxylic acid derivatives undergo a variety of reactions under both acidic and basic conditions, and almost aU involve the nucleophilic acyl substitution mechanism (see Section 5.5.5). 

Note that the reaction at the phosphorus atom is postulated to occur by an SN2 (no intermediate formed) rather than by an addition mechanism such as we encountered with carboxylic acid derivatives (Kirby and Warren, 1967). As we learned in Section 13.2, for attack at a saturated carbon atom, OH- is a better nucleophile than H20 by about a factor of 104 (Table 13.2). Toward phosphorus, which is a harder electrophilic center (see Box 13.1), however, the relative nucleophilicity increases dramatically. For triphenyl phosphate, for example, OH- is about 108 times stronger than H20 as a nucleophile (Barnard et al., 1961). Note that in the case of triphenyl phosphate, no substitution may occur at the carbon bound to the oxygen of the alcohol moiety, and therefore, neutral hydrolysis is much less important as compared to the other cases (see /NB values in Table 13.12). Consequently, the base-catalyzed reaction generally occurs at the phosphorus atom leading to the dissociation of the alcohol moiety that is the best leaving group (P-0 cleavage), as is illustrated by the reaction of parathion with OH ... 

Figure 3.23. Intramolecular electrophilic cleavage of carboxylic acid derivatives from polymeric supports. X leaving group Y NR, O.

Carboxylic acid derivative Nucleophile Tetrahedral intermediate Product Conjugate acid of leaving group... 

Such substitutions in saturated compounds can be carried out by a variety of strategics involving different nucleophiles and leaving groups, but the oxidation states remain the same. Acyl substitutions are analogous. For this reason carboxylic acid derivatives are treated as a common family of compounds. All have the same oxidation level and all can be converted from one to another by substitution reactions not requiring oxidation or reduction. 

Acid chlorides are the most reactive of the carboxylic acid derivatives because of the stability of the Cl leaving group. 

Many of these reactions an1 reversible, but equilibrium will prefer the more stable products. In other words, since a strong base makes a poor leaving group, the equilibrium will favor the formation of the compound whose leaving group is a stronger base. This explains the order of reactivity of carboxylic acid derivatives. 

A is correct. This question may require a little too much knowledge for the MCAT. It is more likely that a question like this will he associated with a passage that explains reactivity of carboxylic acid derivatives. To find the answer, we look at the strengths of the leaving groups ... 

The combination of addition and elimination reactions has the overall effect of substituting one nucleophile for another in this case, substituting an alcohol for water. The rate of these nucleophilic substitution reactions is determined by the ease with which the elimination step occurs. As a rule, the best leaving groups in nucleophilic substitutions reactions are weak bases. The most reactive of the carboxylic acid derivatives are the acyl chlorides because the leaving group is a chloride ion, which is a very weak base (ATb KT20). 

Figure 6.2 shows the standard mechanism of substitution reactions carried out on carboxylic acid derivatives in neutral or basic solutions. The tetrahedral intermediate—formed in the rate-determining step—can be converted to the substitution product via two different routes. The shorter route consists of a single step the leaving group X is eliminated with a rate constant Ad. In this way the substitution product is formed in a total of two steps. The longer route to the same substitution product is realized when the tetrahedral intermediate is proto-nated. To what extent this occurs depends, according to Equation 6.1, on the pH value and on the equilibrium constant Kcq defined in the middle of Figure 6.2 ...

All other carboxylic acid derivatives in Table 6.1, in which the leaving group is bound to the carboxyl carbon through an O atom, are increasingly better acylating agents than carboxylic acid alkyl esters (entry 3) in the order carboxylic acid phenyl ester (entry 4) < acyl isourea (entry 7) < mixed carboxylic acid/carbonic acid anhydride (entry 8) < carboxylic acid anhydride (entry 9) < mixed carboxylic acid anhydride (entry 10). 

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