The stereochemistry of isoquinoline Reissert compounds: a unique platform for observation of steric and electronic interactions

Isoquinoline Reissert compounds (2-acyl-1,2-dihydroisoquinaldonitriles) with either 3-H (1) or 3-CH3 (2) substituents and various N-acyl groups have been examined in detail by 1H and 13C NMR spectroscopy and X-ray crystallography. In all cases the trans amide conformation, with reference to the carbonyl oxygen and the 3-position of the isoquinoline ring, predominates in solution. In the solid state the nitrile moieties are pseudo-axial and the amides exist almost exclusively in the trans form, except for the case of 2-isobutyryl-3-methyl-1,2-dihydroisoquinaldonitrile (2c), which exists exclusively as the cis amide form in the solid state. In N-aroyl 3-CH3 compounds with two ortho-aroyl substituents both amide isomerism and hindered aryl/carbonyl rotation are observed by 1H NMR spectroscopy. In other N-aroyl derivatives only hindered aryl/carbonyl rotations are observed by NMR and in N-alkanoyl compounds amide isomerism is observable only at very low temperatures. X-ray crystallography reveals the two rotamers in the solid state in four cases of ortho-substituted benzoyl compounds; with one exception, the rotamer with the larger ortho-aroyl substituent syn to the pseudo-axial cyano group is favored. Unusual solubility and reactivity patterns observed with these compounds are rationalized in terms of the interplay between steric and electronic factors.