2-Methoxymethoxybenzoic acid

Suitably substituted acetals have been shown to hydrolyse rapidly by a mechanism that involves intramolecular general acid catalysis similar to that proposed for Glu-35 in (34), The largest effects have been found for acetals with the salicylate ion as the leaving group. For example, the spontaneous hydrolysis (35) of 2-methoxymethoxybenzoic acid [73] occurs 300-fold more rapidly than the same reaction of 4-methoxymethoxybenzoic acid [74] and ca. 600-fold more rapidly than the reaction of 2-methoxymethoxybenzoic acid methyl ester [75] (Capon et al, 1969 Dunn and Bruice, 1970). The... 

In another estimate (Kirby and Percy, 1989), the carboxyl group in l-methoxymethoxy-8-naphthoic acid and the dimethylammonium group in the l-methoxymethoxy-8-A, A -dimethylnaphthylammonium ion are estimated to lead to rate increases by intramolecular catalysis of < ca. 900 and 1.9 X 10 compared to the value of ca. 1 x 10 calculated for the intramolecular catalytic effect of the carboxyl group in 2-methoxymethoxybenzoic acid. The salicylate ion remains the most efficient leaving group thus far discovered that can take part in hydrogen-bond catalysis of the hydrolysis of acetals. 

Original references I II and III, IV and V, VI and VII. The kinetically equivalent nucleophilic pathway cf. Figure 3.17) can be rejected on stereoelectronic grounds (the 6-emfo-tet cyclisations violate Baldwin s rules), but nonetheless the methoxyiuethyl ester of salicylic add was synthesised and shown not to be formed in the hydrolysis of 2-methoxymethoxybenzoic acid, but to be stable under the reaction conditions. " ... 

The hydrolysis of 2-methoxymethoxybenzoic acid 3 was investigated in some detail [6]. Since this compound is an unsymmetrical acetal, two modes of bond fission are possible in the rate-determining step. It was shown by p.m.r. spectroscopy that methanolysis in CD3OD occurs with fission of the aryloxy-carbon bond and hence it seems probable that hydrolysis does also. The possibility that the fcj-term arose from a specific hydrogen ion catalysed reaction of the ionized form with the carboxylate group acting as an intramolecular nucleophilic catalyst as shown in equations 2 and 3 was excluded by... 

Capon et al. considered three possible mechanisms [equation (47)] for hydrolysis of o-methoxymethoxybenzoic acid. Mechanisms (a) and (b) involve nucleophilic attack by the carboxylate anion on the protonated acetal, and mechanism (c) proceeds with intramolecular gener2il acid catalysis. Capon was able to rule out mechanisms (a) and (b) since the synthetically prepared intermediate in (a) is stable under the reaction conditions. That in (b) leads to products at... 

Dunn and Bruice (1970, 1971) presented evidence that the mechanism of hydrolysis of methoxymethoxybenzoic acid is actually A-1. Evidence included a Bronsted coefficient for intramolecular catalysis of DO, based upon points for the unsubstituted compound and the 5-NO2 derivative, and p -values that were the same (—3-0) for both the methyl ester and the carboxyl derivatives of [72] when... 

R was varied. Since the mechanism for the methyl ester is certainly A-1 and since intramolecular general acid catalysis should give a different transition state structure and therefore a different p value, it was concluded that the mechanism was A-1 in both cases. The rate enhancement provided by the carboxyl group substituent was ascribed to electrostatic catalysis whereby a proton is stabilized on the acetal oxygen, thus lowering the dissociation constant of the conjugate acid. Complete protonation of methoxymethoxybenzoic acids might be required because of the unstable carbonium ion intermediate. 

Craze and Kirby (1974) have recently proposed that hydrolysis of methoxymethoxybenzoic acids proceeds with intramolecular general acid catalysis with little proton transfer from the carboxyl group and aleurge amount of bond breaking in the transition state. This suggestion was, however, based solely on substituent effects and a graphical analysis using the extended 4-parameter Hammett Equation (see Section 2). 

Intramolecular carboxyl group catalysis has been found in a number of salicyl acetals. Capon et al. (1969) preferred intramolecular general acid catalysis as the mechanism of carboxyl group participation in the hydrolysis of o-carboxyphenyl 3-D-glucoside and o-methoxymethoxybenzoic acid although the kinetically equivalent possibilities were not convincingly eliminated in the case of the glucoside. 

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