The Importance of Conformation of the Tetrahedral Intermediate in the Hydrolysis of Esters and Amides

A new stereoelectronic theory for the cleavage of the tetrahedral intermediate in the hydrolysis of esters and amides is presented. In this new theory, the precise conformation of the intermediate hemi-orthoester or hemi-orthoamide controls the nature of the hydrolysis products. It is postulated that the breakdown of a conformer of a tetrahedral intermediate depends upon the orientation of the lone pair orbitals of the heteroatoms. Specific cleavage of a carbon— oxygen or a carbon—nitrogen bond in any conformer is allowed only if the other two heteroatoms (oxygen or nitrogen) each have an orbital oriented antiperiplanar to the leaving O-alkyl or N-alkyl group. Experimentally, the oxidation of acetals by ozone and the acid hydrolysis of a series of cyclic orthoesters demonstrates clearly that there is indeed a stereoelectronic control in the cleavage of hemi-orthoesters. Similarly, a study of the basic hydrolysis of a variety of N,N-dialkylated imidate salts shows that the same stereoelectronic control is operating in the cleavage of hemi-orthoamides. It is generally accepted that the most common mechanism for the hydrolysis of esters and amides proceeds through the formation of a tetrahedral intermediate. The conformation of this tetrahedral intermediate (hemiorthoester from ester and hemi-orthoamide from amide) has never yet been considered to be an important parameter in order to obtain a better understanding of the hydrolysis reaction'. We wish to report a new stereoelectronic theory in which the precise conformation of the tetrahedral intermediate plays a major role. In this new theory, the nature of the products formed from the hydrolysis of an ester or amide depends upon the conformation of the tetrahedral hemiorthoester or hemi-orthoamide intermediate. It is further postulated that the breakdown of a tetrahedral conformer depends upon the orientation of the lone pair orbitals of the heteroatoms. A specific cleavage of a carbon—oxygen or a carbon—nitrogen bond is allowed only if the other two heteroatoms (oxygen or nitrogen) of the tetrahedral intermediate each have an orbital oriented antiperiplanar to the leaving O-alkyl or N-alkyl group. This new theory originated from our study on the oxidation of acetals to 351 PIERRE DESLONGCHAMPS esters with ozone2. We will first describe this reaction and then disclose the theory of stereoelectronic control in the cleavage of hemi-orthoesters3 which provides an explanation for the formation of products in the ozonolysis of acetals. We will then furnish independent experimental evidence that specific cleavage of hemi-orthoesters does indeed take place, based upon a study of the acid hydrolysis of cyclic mixed orthoesters. Finally, the theory of stereoelectronic control in the cleavage of hemi-orthoamides will also be presented4. Our study on the basic hydrolysis of imidate salts will confirm that stereoelectronic control in the cleavage of hemi-orthoamides does occur. OZONOLYSIS OF ACETALS We reported in 1971 that ozone reacts in a completely specific fashion with the acetal function derived from an aldehyde to give the corresponding ester and alcohol. This reaction is a general one; the nature of the alkyl groups / R—C +03 R—COOR + R—OH + °2 HO—R of the acetal function does not influence the final result, and this reaction proceeds in essentially quantitative yield. However, we have found that there is a tremendous difference in the rate of reaction depending on the nature of the acetal function (Figure 1); cyclic acetals react much faster (a few minutes at —78°) than the acyclic ones ( 15 h at — 78°). The observed large difference in rates of oxidation of cyclic as compared to acyclic acetals was the first indication that there was a direct relationship between the conformation of the acetal function and its reactivity toward ozone. We believe that this reaction proceeds via the iisertion of ozone into the C—H bond of the acetal forming an intermediate such as 1 or 2, which can then break down to give the reaction products, the ester and the alcohol. We next investigated the oxidation of acetals where the OR groups were not identical. It was of interest to examine such substrates because a tetrahedral intermediate formed during the oxidation of such unsymmetrical acetals, could decompose in two different ways. For instance, a substrate such as 3 (Figure 2) should lead to an intermediate such as 4. Intermediate 4 could decompose to give the hydroxy-ester 5, or the lactone 6, plus the alcohol. We found experimentally that ozone reacts smoothly with tetrahydropyranyl ethers in a completely specific manner, yielding the hydroxy-ester5 exclusively. No trace of lactone 6 could be detected. Thus, it can be immediately concluded that if the ozonolysis reaction proceeds through the formation of hemiorthoester 4 or its equivalent, this intermediate must decompose in a very specific manner! After completing our work on the simple tetrahydropyranyl ethers, the next logical step was to study this new reaction on tetrahydropyranyl ethers which possessed a rigid chair conformation. Consequently, the oxidation of a series of conformationally rigid xand p3-methyl glycopyranosides was 352 P R-C HYDROLYSIS OF ESTERS AND AMIDES