Stereoelectronic Control in Hydrolytic Reactions

Now that we have seen examples of hydrolytic reactions and acetal hydrolysis by enzymes, we may wonder how important the stereochemistry of the products and reactants is in these transformations. 

This section is devoted to this question through the presentation of a relatively new concept in organic chemistry, stereoelectronic control, exploited by P. Deslongchamps from the University of Sherbrooke (114,115). It uses the properties of proper orbital orientation in the breakdown of tetrahedral intermediates in hydrolytic reactions. This concept is quite different from Koshland s orbital steering hypothesis where proper orbital alignment is invoked for the formation of a tetrahedral intermediate. Here we are interested by the process that follows the cleavage of the tetrahedral intermediate in the hydrolysis of esters and amides. 

It is generally accepted that the most common mechanism for the hydrolysis of esters and amides proceeds through the formation of a tetrahedral intermediate. Deslongchamps argued that the conformation of this tetrahedral intermediate (hemiorthoester from ester and hemiorthoamide from amide) is an important parameter in order to obtain a better understanding of the hydrolysis reaction. 

Since 1971, he has developed a new stereoelectronic theory in which the precise conformation of the tetrahedral intermediate plays a major role. In other words, the stereochemistry and the ionic state of the tetrahedral intermediate, the orientation of nonbonded electron pairs, and the relative energy barriers for cleavage and for molecular rotation are the key parameters in the stereoelectronically controlled cleavage of the tetrahedral intermediate formed in the hydrolysis of an ester or an amide. He postulated that the precise conformation of the tetrahedral intermediate is transmitted into the product of the reaction and that the specific decomposition of such an inter- 

Experimental evidence to prove this postulate come from four sources. A study of the oxidation of acetals by ozone, acid hydrolysis of cyclic orthoesters, concurrent carbonyl-oxygen exchange and hydrolysis of esters by using oxygen-18 labeling, and basic hydrolysis of N,N-dialkylated imidate salts. We will briefly examine results from the last three approaches. Then we will try to apply this concept to the hydrolysis of ester and amide substrates by serine proteases. 

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P. Deslongchamps (1977), Stereoelectronic control in hydrolytic reactions. 26th lUPAC, Tokyo, Japan. 

P. Deslongchamps (1977) Stereoelectronic Control in Hydrolytic Reactions. Heterocycles 1, 1271-1317. 

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