Acetals intramolecular catalysis

Because esters 745 a, b of imidazole-acetic acid are unstable when stored for long periods, owing to intramolecular catalysis by the imidazole moiety, the esters should be converted into their salts or free acids and stored as such. Only tert-butyl imidazole-(4,5)acetates derived from tert-butyl 4-chloroacetoacetate seem to be stable [232, 233]. N-alkyl-substituted amidines give rise to a mixture of alkyl N-alkylimidazole-4- and 5-acetates [232, 233]. 

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. 

An interesting example of intramolecular catalysis of type A syntheses is provided by the ready condensation of certain histidylproline peptides. Treatment of the ditrityl derivative of the tripeptide 121 with 50% acetic acid at room temperature results in rapid detritylation followed by cyclization to give the diketopiperazine 122 with elimination of... 

The term intramolecular catalysis introduced by Bender is also widely used to describe neighboring group effects, especially when analogous intermolecular catalysis is observed. Thus this term is commonly used when referring to reactions that are subject to acid, base, and/or nucleophilic catalysis such as hydrolysis of esters, amides, and acetals the mutarotation of aldoses or the enolization of ketones. It is rarely used when referring to nucleophilic substitution reactions at saturated carbon. 

B. Capon and M. C. Smith (1965), Intramolecular catalysis in acetal hydrolysis. 

Intramolecular catalysis in the hydrolysis of 2(4-imidazolyl)phenyl acetate was discovered by Schmir and Bruice [54]. The pH-rate profile is sigmoid with the rate proportional to the concentration of the unprotonated form and the rate enhancement is substantial, but not larger than a factor of 1000 [55]. Schmir and Bruice explained their results by a mechanism which involved intramolecular nucleophilic catalysis (equation 9) [54]. A p-value of 1.67 for the hydrolysis of a... 

Intramolecular catalysis also occurs in the aminolysis of 2-pyridyl acetate by n-butylamine in chlorobenzene [66]. The rate constant for the reaction which is first-order in amine is substantially enhanced and that for the reaction which is second-order in amine is enhanced slightly (see Table 3). Now intramolecular nucleophilic catalysis... 

The reaction of p-nitrophenyl acetate with 1,3-diaminopropane in chlorobenzene is intramolecularly catalysed [72]. The reaction of n-butylamine with p-nitrophenyl acetate in chlorobenzene is second order (kj) in amine and no reaction which is first order in amine was detected. In contrast, the reaction with 1,3-diaminopropane has both terms of first and of second-order in amine, and the rate constant for the reaction which is first-order in amine is at least 300 times greater than that for the undetected reaction of n-butylamine, while the rate constant for the reaction which is second-order in amine is about 14 times greater than the analogous reaction of n-butylamine [72]. Since breakdown of the tetrahedral intermediate is rate-limiting in the aminolysis of aryl esters in aprotic solvents [32], the intramolecular catalysis presumably functions in this step, possibly as symbolized by 46. 

Attempts to evaluate the rate enhancement arising from the presumed intramolecular catalysis lead to conflicting results. One way is to compare the rate constant for reaction of acetic 2-methoxy-3,5-dinitrobenzoic anhydride with acetate (25.41 mol min at 39°C) with that for reaction of 3,5-dinitroaspirin (7.9 x 10 1 mol min ) with acetate. On the assumption that the latter reaction proceeds via a mixed anhydride and that this reacts at the same rate as acetic 2-methoxy-3,5-dinitrobenzoic anhydride with acetate, the concentration of the intermediate is calculated to be 0.03 per cent [83]. On this basis the rate of hydrolysis of the mixed anhydride 52 is 17... 

It is therefore clear that any intramolecular catalysis of the hydrolysis of the ionized form of the mixed acetic salicylic anhydride can produce only a small rate enhancement. This is reasonable since the ratio in the rates of hydrolysis of the ionized to un-ionized forms of p-nitrophenyl 5-nitrosalicylate is about 30 [28], and a reduced catalytic effect would be expected with a less basic dinitrophenolate ion. It has recently been claimed, on the basis of the variation of fc(ionized) with atom fraction of deuterium for hydrolysis in HjO—D2O mixtures, that the acetic salicylic anhydride reacts with 39 per cent attack at salicyl carbon and 61 per cent attack at acetyl carbon [86]. This conclusion does, however, depend on several unproven assumptions. 

---