Hemi-orthoamide

Further experimental evidence supporting the principle of stereoelectronic control in the cleavage of hemi-orthoamide tetrahedral intermediates has been obtained from studies on the carbonyl-oxygen exchange during the basic hydrolysis of amides, and from the hydrolysis of imidate salts. These experiments are described next. 

Carbonyl-oxygen exchange has been observed in the course of the basic hydrolysis of primary amides (23, 24). The exchange, observed by using Relabeling (0 = occurs vi a a tetrahedral hemi-orthoamide intermediate... 

When a hemi-orthoamide tetrahedral intermediate exists in the T ionic form, the amide ion is not ejected previous to protonation by the solvent, to give the secondary amine. The formation of an amide ion 24-25 is a process so high in energy, that both the protonation and the ejection processes must be synchronized 24 - 26 - 27 (28). This means that in aqueous solution, the nitrogen electron pair must first be hydrogen bonded with the solvent, so that the group can leave as a secondary amine. 

The stereoelectronically controlled reaction of hydroxide ion with an anti imidate salt (62) must give the hemi-orthoamide conformer 60 where the nitrogen and the oxygen of the OR group have each an electron pair anti peri -planar to the C -OH bond also, the 0 —R bond and the N —R bond which were anti peri planar to the C-R bond in anti imidate salt 62 remain in the same relative orientation in intermediate 60. 

Stork, Jacobson, and Levitz (51) have recently reported that the reaction of the lithium carbanion 234 with benzaldehyde followed by reduction with sodium borohydride gave the phenylcarbinol 235. The sequence of events in the transformation of 234 to 23S was shown to be as depicted below. Convincing spectral evidence was obtained for 236, 238, and 239. Thus, the hemi-orthoamide tetrahedral intermediate 237 which was generated in situ gave the ami nobenzoate 238, the expected product from stereoelectronic control. 

Halogenation of ketones, 275 Hemi-orthoester, 63 Hemi-orthoamide, 103-105 Hemi-orthothioamide, 144 Hemi-orthothiol esters, 93-97 Hinesol, 250... 

In cases where Y is an alkoxy group, there is the possibility of forming either an ester or an amide function, and the proportion of each will depend on the conformation of the tetrahedral intermediate. The nine different gauche conformers for such a hemi-orthoamide tetrahedral intermediate are shown in Fig. 1, and the stereoelectronically controlled cleavages are described in Table 1. 

The ionic state of the hemi-orthoamide tetrahedral intermediate must also be considered (9-12). In acidic medium, the intermediate will exist in... 

Using the equilibrium constants estimated by Guthrie (12) for hemi-orthoamide tetrahedral intermediates (derived from N,N-dimethylformamide and N,N-di-methylacetamide) and the activation parameters described in Table 2, it was possible to obtain the free energy of activation for the breakdown UG ieav) and for conformational change (aG onf) of the tetrahedral interme.-diates derived from the N-benzyl-N-methyl derivatives of formamide, acetamide and propionamide. These values are the following. 

The hydrolysis of imidate salts is a technique to generate in situ hemi-orthoamide tetrahedral intermediates (44), and to observe their breakdown to yield the reaction products under kinetically controlled conditions. Such conditions can be ascertained by verifying that the reaction products are not ihterconverted (amide + alcohol ester +amine) during the reaction. This technique can therefore be used to test the principle of stereoelec-tronic control in the cleavage of tetrahedral intermediates derived from amides. 

A hemi-orthoamide tetrahedral intermediate can take several ionic forms, T+, T, T°, and T, depending on the pH of the reaction medium. In acidic medium, it will exist in the T form, in slightly basic medium (near the pKa of the intermediate, pH =10), it will exist as T and in basic medium (pH >11), as T". In systems where the nitrogen can be readily protonated, T° is neglected since it is rapidly converted into the T form which has a low energy barrier for fragmentation. 

P. Deslongchamps, U. O. Cheriyan, J. -P. Pradere, P. Soucy, and R. J. Taillefer (1979), Hydrolysis and isomerization of syn unsymmetrical A,A-dialkylated immidate salts. Experimental evidence for conformational changes and for stereo-electronically controlled cleaves in hemi-orthoamide tetrahedral intermediates. Nouv. J. Chim. 3, 343-350. 

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