Indolyne and aryne distortions and nucleophilic regioselectivites

Abstract

Density functional theory computations reproduce the surprisingly high regioselectivities in nucleophilic additions and cycloadditions to 4,5-indolynes and the low regioselectivities in the reactions of 5,6-indolynes. Transition-state distortion energies control the regioselectivities, activating the 5 and 6 positions over the 4 and 7 positions, leading to high preferences for 5- and 6-substituted products from 4,5- and 6,7-indolynes, respectively. Orbital and electrostatic interactions have only minor effects, producing low regioselectivities in the reactions of 5,6-indolynes. The distortion model predicts high regioselectivities with 6,7-indolynes; these have been verified experimentally. The regioselectivities found with other arynes are explained on the basis of distortion energies that are reflected in reactant geometries.

Figure 1

B3LYP/6-31G(d) optimized 4,5-indolyne and TSs for aniline addition. Energies in kcal/mol.

Figure 2

B3LYP/6-31G(d) optimized benzyne and TS for aniline addition. Energies in kcal/mol.

Figure 3

B3LYP/6-31G(d) optimized 5,6-indolyne and TSs for aniline addition. Energies in kcal/mol.

Figure 4

B3LYP/6-31G(d) optimized 6,7-indolyne and TS for aniline addition. Energies in kcal/mol.

Figure 5

B3LYP/6-31G(d) optimized structures of benzynocyclo-n-alkenes (n=4,5,6), naphthalyne and 3-methoxybenzyne. TS (with aniline) distortion energies (activation energies) in kcal/mol.

Figure 6

Distortion model for regioselective nucleophilic addition to fused benzynes (X = electron-withdrawing group). The effect of X is larger than the more remote X’.