Orthocarbonates, hydrolysis

Condensation of prednisone, 40 with tetraethyl orthocarbonate leads to the cyclic orthocarbonate 41 hydrolysis proceeds by protonation on the most accessible ether oxygen (that on carbon 21) to give the 17 mixed carbonate ester 42, Acylation with propionyl chloride proceeds on the remaining hydroxyl group to afford prednicarbate (43) [10],... 

For similar reasons the stability of polyalkoxymethanes to acid-catalyzed hydrolysis is unexpectedly dependent on the number of carbon-bound alkoxy groups. Contrary to chemical intuition, orthocarbonates are more difficult to hydrolyze than orthoesters [51] (Scheme 3.13), although a carbocation substituted with three alkoxy groups is more stable than one with only two alkoxy groups. Similarly, the tendency of fluoride to add to fluorinated alkenes is much greater than that of other halides [53], despite its low nucleophilicity (see also Section 4.2.2). 

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]. 

In the NMR experiments carried out by Wenthe and Cordes [187] with methyl orthobenzoate and methyl orthocarbonate in CD3OD—D20 solutions, the rate coefficients for the disappearance of orthoester and those for the formation of CH3OD and of carboxylic ester have been found identical within experimental error (Table 15). This indicates that there is no exchange of methoxy groups prior to hydrolysis. The same result has been obtained from product analysis studies of the carboxylic esters formed. Consequently, the rate-determining step must be carbonium ion formation or a previous step. The findings do not support an A2 mechanism, for the following reason. As the nucleophilic reactivities of water and methanol are similar, the A2 reaction with attack of water... 

If the hydrolysis of methyl orthobenzoate in weakly acidic solution is carried out in the presence of various amounts of added nucleophiles, such as hydroxylamine or semicarbazide, a considerable fraction of the orthoester is transformed to the product of the reaction with the amine rather than to methyl benzoate, while the rate coefficient remains unchanged [183]. Similarly, the rate of hydrolysis of ethyl orthocarbonate in aqueous cacodylic acid buffer is the same in the presence of 0.04 M NaC104 and of 0.04 M Nal [192]. Thus, nucleophilic catalysis is absent even under conditions when general acid catalysis is effective. 

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. 

Where the third term is negligible we have curve e, examples being the hydrolysis of orthoacetates and orthocarbonates (Skrabal and Baltadschiewa, 31). 

There are two instances in which the value of kD/kH depends upon the conditions under which a reaction is carried out. In the acid-catalyzed hydrolysis of ethyl orthocarbonate Wynne-Jones (110) finds fcD/fcH > 1 for catalysis by hydrogen ions, but kD/kK < 1 for catalysis by acetic acid. 

The dimethoxymethylene group is potentially useful for the protection of glycol systems. Ribonucleosides undergo acid-catalyzed exchange with tetramethyl orthocarbonate to give 2 3 -0-dimethoxymethylene derivatives [176]. Such cyclic orthocarbonates are stable in alkaline media, but are converted into the corresponding 2, 3 -cyclic carbonates under mild conditions of acidic hydrolysis [176]. Thus the half-time of hydrolysis of 2 3 -0-dimethoxymethyleneadenosine (101) is 10 min [176] in O.OlTV-hydrochloric acid at 20°. 

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