Orthoesters, hydrolysis

This is known as general acid catalysis, general because the catalysis is by proton donors in general, and not by H3O alone. General acid catalysis often only becomes important at hi er pHs, e.g. pH 7 when [H3O ] 10 , while [HA] may be 1-2, molar general acid catalysis will still occur at lower pHs, but may then be masked by the greater contribution by H3O . The above orthoester hydrolysis is believed to proceed (only HA is shown here but HjO will do the same thing). 

Treatment of compound 95 with DDQ produces the hydrolysis of the orthoester when wet acetone is used as solvent and the oxidation of the allylic alcohol when dry benzene is employed. Apparently, the mechanism of the orthoester hydrolysis involves a charge-transfer intermediate, with no influence from the acidity of the generated DDQ hydroquinone. 

This feature of PLNM immediately explains why least motion effects are not observed in cleavage of acetals, but are observed in cleavage of orthoesters and other substrates at the acyl level of oxidation the transition state for acetal cleavage is late, whereas that for orthoester hydrolysis is more central (Sinnott, 1984 Cordes and Bull, 1974). 

We won t go through the mechanism again—you ve already seen it as the reverse of acetal formation (and you have a hint of it in the orthoester hydrolysis just discussed), but the fact that acetals are stable to base is really a very important point, which we will use on the next page and capitalize on further in Chapter 24. 

The most probable mechanism for the rate determining step involves a transition state, such as 3, in which the proton transfer either precedes or is concerted with covalent bond breaking. The mechanisms of orthoester hydrolysis have been summarized and discussed by DeWolfe and Jensen (1963), Wenthe and Cordes (1964), Bunton and DeWolfe (1966), Cordes (1967), DeWolfe (1969), and Jencks (1969). 

General Acid Catalysis of Acetal, Ketal. and Orthoester Hydrolysis. Fife, T. H. Acc. Chem. Res. 1972, 5, 264. 

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. 

The importance of stereoelectronic effect in orthoester hydrolysis could be gleaned from the reaction of 85. Should the stereoelectronic effects not be invoked, the reaction could generate all three different products, 89-91. When Ri and R2 are same, there will be only two products, 89 and 90. We shall learn below from a meaningful consideration of the prevailing stereoelectronic effects that only the 89-like product is expected to predominate. 

Let us examine each step of the orthoester hydrolysis under the operating stereoelectronic effects that vary with the variation in the conformational profile. Consider the acetal 92 and the nine well-defined conformers 92a-92i. The con-formers 92c and 92e suffer from severe steric interactions between the methyl groups as shown and, hence, their concentration at equilibrium should be expected to be negligible. Likewise, conformers 92g-92i also suffer from severe steric interactions between the methyl of the axial methoxy group and the axial hydrogen atoms on ring positions 4 and 6 as shown for 92 g. The equilibrium concentration of each of these conformers also should be expected to be negligible like those of 92c and 92e. We may eliminate all these conformers from further discussion. 

The loss of an alkoxy group, after protonation, is the starting point of hydrolysis. An orthoester can provide for this loss to take place with the assistance from one or two stereoelectronic effects, the latter being obviously favored over the former. The conformer 92d does not allow any stereoelectronic effects. This conformer may therefore be treated as the slow reacting or even as the neutral conformer. This prediction has been verified experimentally by studying the hydrolysis of 93, a rigid 92d conformer, which was found to be stable to the normally employed mild acidic conditions for orthoester hydrolysis [2-5]. Therefore, the conformer 92d is also eliminated from further discussion. 

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