Effect of the amino versus the acylamino substituent on the product isomer distribution in the methanolysis of 5-(substituted)-2-[(methylsulfonyl)oxy]isoindole-1,3-diones

The effect of the NH2 versus the CH3CONH and PhCH2CONH substituents at the 5-position in 5-(substituted)-2-[(methylsulfonyl)oxy]isoindole-1,3-diones, on the product isomer distribution resulting from methanolysis, was investigated both experimentally and at the RHF/3-21G∗, RHF/6-31+G∗ and B3LYP/6-31+G∗ levels of theory. The influence of solvent on the transition structure was investigated using the Onsager SCRF model. The influence of these substituents on the transition state (TS) leading to tetrahedral intermediate was studied. The 5-amino (para to C-1) function makes the C-1 carbonyl carbon more electron-rich and less reactive toward nucleophilic attack. A predominance of the isomer formed from initial nucleophilic attack at C-3 is observed for the NH2 substituent, whereas this selectivity is greatly reduced for the acylamino substituents. Examination of the LUMO from ab initio calculations performed on the starting materials at the RHF/6-31G∗ level give a good qualitative description of the regioselectivity observed from experiment. Calculated ΔEa values of this initial reaction step give a qualitative description of the experimentally observed regioselectivity in agreement with the LUMO model and resonance argument.