Carboxylic acid derivatives addition-elimination

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... 

The addition of a nucleophile to a polar C=0 bond is the key step in thre< of the four major carbonyl-group reactions. We saw in Chapter 19 that when. nucleophile adds to an aldehyde or ketone, the initially formed tetrahedra intermediate either can be protonated to yield an alcohol or can eliminate th< carbonyl oxygen, leading to a new C=Nu bond. When a nucleophile adds to carboxylic acid derivative, however, a different reaction course is followed. Tin initially formed tetrahedral intermediate eliminates one of the two substituent originally bonded to the carbonyl carbon, leading to a net nucleophilic acy substitution reaction (Figure 21.1. ... 

Before discussmg the mechanism of cleavage of carboxylic acid esters and amides by hydrolases, some chemical principles are worth recalling. The chemical hydrolysis of carboxylic acid derivatives can be catalyzed by acid or base, and, in both cases, the mechanisms involve addition-elimination via a tetrahedral intermediate. A general scheme of ester and amide hydrolysis is presented in Fig. 3. / the chemical mechanisms of ester hydrolysis will be... 

The nucleophilic addition of a trifluoromethyl anion or its equivalent to an activated carboxylic acid derivative is another potential method for the synthesis of trifluoromethyl ketones (Scheme 8). Due to the well-known instability of the trifluoromethyl anion, the organometallic approach (Section 15.1.4.3.3) is often difficult to utilize. However, a trifluoromethyl anion equivalent, (trifluoromethyl)trimethylsilane (CF3TMS), was developed in 1984 by Ruppert and co-workers.[30] This reagent, known as Ruppert s reagent, is stable and does not undergo fluoride elimination like other equivalent trifluoromethyl anions. An obvious limitation to this method is that it is only useful for the synthesis of a-amino trifluoromethyl ketones unless other fluoroalkyl analogues of Ruppert s reagent are developed. 

Addition/Elimination Reactions of Carboxylic Acid Derivatives... 

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). 

Addition-Elimination of Carboxylic Acid Derivatives Summary... 

Figure 4.50 The flowchart for addition-elimination on carboxylic acid derivatives.

The cleavage of organic compounds from nucleophile-labile resins usually relies on the addition-elimination chemistry at the carbonyl group of the carboxylic acid derivative (i.e. an ester or thioester) that mediates the linkage between the assembled compound and the linker-resin. The overall reaction is a nucleophilic substitution that involves the release into the solution of the compound of interest with the attacking nucleophile generally incorporated. The linker-resin generally acts... 

Let us now examine how substituent effects in reactants influence the rates of nucleophilic additions to carbonyl groups. The most common mechanism for substitution reactions at carbon centers is by an addition-elimination mechanism. The adduct formed by the nucleophilic addition step is tetrahedral and has sp hybridization. This adduct may be the product (as in hydride reduction) or an intermediate (as in nucleophilic substitution). For carboxylic acid derivatives, all of the steps can be reversible, but often one direction will be strongly favored by product stability. The addition step can be acid-catalyzed or base-catalyzed or can occur without specific catalysis. In protic solvents, proton transfer reactions can be an integral part of the mechanism. Solvent molecules, the nucleophile, and the carbonyl compound can interact in a concerted addition reaction that includes proton transfer. The overall rate of reaction depends on the reactivity of the nucleophile and the position of the equilibria involving intermediates. We therefore have to consider how the substituent might affect the energy of the tetrahedral intermediate. 

In contrast, the carbonyl group of an aldehyde or a ketone is attached to a group that is too strong a base (H or R ) to be eliminated under normal conditions, so it cannot be replaced by another group. Consequently, aldehydes and ketones react with nucleophiles to form addition products, not substitution products. Thus, aldehydes and ketones undergo nucleophilic addition reactions, whereas carboxylic acid derivatives undergo nucleophilic acyl substitution reactions. 

Hydride reductions of carboxylic acid derivatives such as conversion of esters to alcohols involve elimination steps in addition to hydride transfer. In the case of... 

As we begin now to explore the syntheses of carboxylic acid derivatives, we shall find that in many instances one acid derivative can be synthesized through a nucleophilic addition—elimination reaction of another. The order of reactivities that we have presented gives us a clue as to which syntheses are practical and which are not. In general, less reactive acyl compounds can be synthesissed from more reactive ones, but the reverse is usually difficult and, when possible, requires special reagents. 

Carbonyl addition-elimination n. The single most important type of reaction mechanism which has been applied to the preparation of step-growth polymers is the addition-elimination reaction of the carbonyl double bond of carboxylic acids and carboxylic acid derivatives included in this general type of reaction are esterification amidation and anhydride formation from carboxylic acids, esters, amides, anhydrides and acid halides. 

The net result of this process is substitution of the —OR group of the alcohol for the —OH group of the acid. Hence the reaction is referred to as nucleophilic acyl substitution. But the reaction is not a direct substitution. Instead, it occurs in two steps (1) nucleophilic addition, followed by (2) elimination. We will see in the next and subsequent sections of this chapter that this is a general mechanism for nucleophilic substitutions at the carbonyl carbon atoms of carboxylic acid derivatives. 

Another FGI that gives carboxylic acid products is the hydrolysis of carboxylic acid derivatives, such as esters and nitriles. Such hydrolysis reactions can either be acid catalyzed (H3O+) or base promoted (1. NaOH, H2O 2. H3O ) and involve an acyl substitution mechanism (addition-elimination) that replaces any acyl leaving group with a hydroxyl group. The synthesis of carboxylic acids via nitriles is especially noteworthy since the introduction of the cyano group via Sn2 with CN involves the formation of a new C-C bond (adds one new carbon to the alkyl halide carbon chain). 

The interconversion of carboxylic acid derivatives relies on the ability to replace one leaving group with another (addition-elimination mechanism involving collapse of a CTl). 

The canonical formulation of the mechanism of the Favorskii rearrangement involves initial deprotonation of the a-carbon to generate an enolate, intramolecular displacement of the leaving group on the a -carbon by the enolate to generate a cyclopropanone, addition of a nucleophile to the cyclopropanone ketone followed by elimination to generate the more stable of two possible carbanions, and protonation to yield the rearranged carboxylic acid derivative. 

This type of nucleophilic aromatic substitution for halogen has been studied extensively, and it has been determined that reaction occurs in two steps nucleophilic addition followed by elimination. For the majority of reactions of this type, addition of the nucleophile in Step 1 is the slow, rate-determining step. Elimination of halide ion in Step 2 gives the product. This reaction thus resembles reactions of carboxylic acid derivatives in that it proceeds by an addition-elimination mechanism rather than by direct substitution. 

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