Ethyl orthoacetate, hydrolysis

This approach has been extended by Tieckelmann, Mulvey, and Gottis to 2-amino-5-cyanonicotinamides (16 and 18), whiob were prepared directly by partial hydrolysis of the corresponding dir itriles. Diethyl carbonate, ethyl orthoacetate, and ethyl orthoformate all underwent reaction to yield the corresponding pyrido[2,3-( ]pyri-midines (17 and 19). 

In equation 8.2-6a, the slope of -1 with respect to pH refers to specific hydrogen-ion catalysis (type B, below) and the slope of + 1 refers to specific hydroxyl-ion catalysis (Q if k0 predominates, the slope is 0 (A). Various possible cases are represented schematically in Figure 8.5 (after Wilkinson, 1980, p. 151). In case (a), all three types are evident B at low pH, A at intermediate pH, and C at high pH an example is the mutarotation of glucose. Cases (b), (c), and (d) have corresponding interpretations involving two types in each case examples are, respectively, the hydrolysis of ethyl orthoacetate, of P -lactones, and of y-lactones. Cases (e) and (f) involve only one type each examples are, respectively, the depolymerization of diacetone alcohol, and the inversion of various sugars. 

It seems much more likely that the transfer of the proton is actually involved in the rate-limiting step for the hydrolysis of carboxylic orthoesters. This is consistent with the observed catalytic constants. If Bunton and Dewolfe s estimate of Ka = 107 is accepted for the dissociation constant of the conjugate acid of an orthoester, and if the rate coefficient for the loss of the proton, k2, is of the order of 10" sec-1, then k, will be about 104 l mole-l sec-1, close to the value observed, for example, for the catalytic coefficient for the acid-catalyzed hydrolysis of ethyl orthoacetate at 20°C103. 

The hydrolysis reactions of acetals, ketals, and orthoesters are catalyzed by acids but not by bases. It has been found that these three groups of substrates are hydrolyzed via a common general mechanism — involving similar types of intermediates — though the rate-determining step may vary from case to case. In the hydrolyses of ethyl orthoacetate, orthopropionate, and orthocarbonate, general acid catalysis was unambiguously established for the first time by Bronsted and Wynne-Jones [158]. 

By contrast, the hydrolysis of 1,1,1-triethoxyethane (ethyl orthoacetate, 79) to acetic acid (82) is subject to general acid catalysis (reaction 5.44), as discussed in Chapter 2 (reaction 2.32). When the reaction is carried out in a m-nitrophenol/m-nitrophenolate buffer, terms in [H30] +, [m-02NC6H4OH] and [H20] are found in the rate equation. In reaction (5.44), the first step to give the protonated compound 80 is rate determining, followed by a rapid second step. 

The A2 mechanism can be excluded with certainty for the hydrolyses of all orthoesters discussed. This is done on the basis of the determined volume of activation, AF = +2.4 cm3 (Table 1) for ethyl orthoformate [32], on the basis of the strongly increased rate in comparison to orthoformate (no steric hindrance) for orthoacetate and orthopropionate, and on the basis of the results of experiments with added nucleophiles for orthobenzoate [183] and orthocarbonate [192]. The observed AS values (Table 12) are in agreement with these conclusions. Consequently, the mechanism of orthoester hydrolysis must be either A1 or A-SE2, or possibly a concerted process with proton transfer and carbonium ion formation in the same step. 

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