Carboxylic derivs., reactions tetrahedral intermediates

In base the tetrahedral intermediate is formed m a manner analogous to that pro posed for ester saponification Steps 1 and 2 m Figure 20 8 show the formation of the tetrahedral intermediate m the basic hydrolysis of amides In step 3 the basic ammo group of the tetrahedral intermediate abstracts a proton from water and m step 4 the derived ammonium ion dissociates Conversion of the carboxylic acid to its corresponding carboxylate anion m step 5 completes the process and renders the overall reaction irreversible... 

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.

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. ... 

Solvolytic reactions, medium effects on the rates and mechanisms of, 14,1 Spectroscopic detection of tetrahedral intermediates derived from carboxylic acids and the investigation of their properties, 21,37... 

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. 

Until a few years ago there was only indirect evidence for the existence of the species postulated as tetrahedral intermediates in reactions of derivatives of carboxylic acids (cf. Kirby, 1972). Now, however, it is possible to generate some of them in solution at sufficiently high concentrations for their uv and nmr spectra to be measured and for their reactions to be studied. It is the purpose of this review to record progress that has been made in this area. 

The possibility that the reactions of derivatives of carboxylic acids might pass through tetrahedral intermediates (l) has long been considered (Lowry, 1926). In their important paper in which they classified the mechanisms of hydrolysis of carboxylic esters Day and Ingold (1941) wrote bimolecular... 

Solvolytic reactions, medium effects on the rates and mechanisms of, 14, 1 Spectroscopic detection of tetrahedral intermediates derived from carboxylic acids and the investigation of their properties, 21, 37 Spectroscopic observations ofalkylcarbonium ions in strong acid solutions, 4, 305 Spectroscopy, 13C NMR in macromolecular systems of biochemical interest, 13, 279 Spectroscopy of substituted phenylnitrenes, kinetics and, 36, 255 Spin alignment, in organic molecular assemblies, high-spin organic molecules and,... 

Theoretical studies have been reported for the neutral29 and alkaline30,31 hydrolysis of formamide. A theoretical study of the acid hydrolysis of iV-formylaziridine concluded that both N- and O-protonated pathways compete.32 In an historical overview of tetrahedral intermediates in the reactions of carboxylic acid derivatives with nucleophiles, several citations of amide reactions are included.33... 

Most SN reactions of carboxylic acids and their derivatives follow one of three mechanisms (Figures 6.2, 6.4, and 6.5). A key intermediate common to all of them is the species in which the nucleophile is linked with the former carboxyl carbon for the first time. In this intermediate, the reacting carbon atom is tetrasubstituted and thus tetrahedrally coordinated. This species is therefore referred to as the tetrahedral intermediate (abbreviated as Tet. Intermed. in the following equations). Depending on the nature of the reaction partners, the tetrahedral intermediate can be negatively charged, neutral, or even positively charged. 

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 ...

Chemoselective SN reactions of nucleophiles with carboxylic acid derivatives are guaranteed to take place without the risk of an overreaction when the substitution mechanism of Figure 6.4 applies. This is because as long as the nucleophile is present, only one reaction step is possible the formation of the negatively charged tetrahedral intermediate. Figure 6.40 summarizes this addition in the top line as Reaction 1 (— B). 

The Weinreb amide syntheses in Figure 6.50 proceeding via the stable tetrahedral intermediates B and F are chemoselective SN reactions at the carboxyl carbon atom of carbon acid derivatives that are based on strategy 1 of the chemistry of carboxylic acid derivatives outlined in Figure 6.41. Strategy 2 of the chemistry of carboxylic acid derivatives in Figure 6.41 also has a counterpart in carbon acid derivatives, as is demonstrated by a chemoselective acylation of an organolithium compound with chloroformic acid methyl ester in this chapter s final example ... 

B as an ester- or lactone-substituted aldehyde enolate. Such enolates undergo condensations with all kinds of aldehydes, including paraformaldehyde. An adduct E is formed initially, acy-lating itself as soon as it is heated. The reaction could proceed intramolecularly via the tetrahedral intermediate D or intermolecularly as a retro-Claisen condensation. In both cases, the result is an acyloxy-substituted ester enolate. In the example given in Figure 13.50, this is the formyloxy-substituted lactone enolate C. As in the second step of an Elcb elimination, C eliminates the sodium salt of a carboxylic acid. The a,/)-unsaturated ester (in Figure 13.50 the 0J,/3-unsaturated lactone) remains as the aldol condensation product derived from the initial ester (here, a lactone) and the added aldehyde (here, paraformaldehyde). 

On the basis of what we have already learned about the reactions of lithium aluminum hydride with aldehydes and ketones (Chapter 18) and the mechanisms presented so far in this chapter, we can readily predict the product that results when hydride reacts with a carboxylic acid derivative. Consider, for example, the reaction of ethyl benzoate with lithium aluminum hydride. As with all of the reactions in this chapter, this reaction begins with attack of the nucleophile, hydride ion, at the carbon of the carbonyl group, displacing the pi electrons onto the oxygen (see Figure 19.7). Next, these electrons help displace ethoxide from the tetrahedral intermediate. The product of this step is an aldehyde. But recall from Chapter 18 that aldehydes also react with lithium aluminum hydride. Therefore, the product, after workup with acid, is a primary alcohol. 

A lot of reactions were presented in this chapter. Remember to identify the electrophile (usually the carbonyl carbon of a carboxylic acid derivative) and the nucleophile. The nucleophile bonds to the carbonyl carbon to form the tetrahedral intermediate. Then the leaving group departs as the CO double bond reforms. The product may be subject to further nucleophilic attack. 

We don t expect you to be satisfied with the bland statement that tetrahedral intermediates are formed in these reactions of course, you wonder how we know that this is true. The first evidence for tetrahedral intermediates in the substitution reactions of carboxylic acid derivatives was provided by Bender in 1951. 

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