Studies on phenethylamine hallucinogens. 2. Conformations of arylmethoxyl groups by carbon-13 NMR

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Abstract
13C chemical shift (.delta.) and spin-lattice relaxation time (T1) measurements were used to determine the conformation around the Ar-OCH3 bond of the arylmethoxyl groups in a series of substituted phenethylamines. Methoxyl groups flanked by 2 ortho substituents have .delta. 13C values higher (60.5-62.5 ppm) than those with 1 or no ortho substituents (55.5-57.5 ppm) and T1 values considerably longer than those of the other methoxyl groups in the same molecule. These measurements indicate that methoxyl groups with 2 ortho substituents acquire the out-of-plane conformation, while those with 1 or no ortho substitutents exist in the planar conformation. Phenethylamine analogs with methoxyl groups in the out-of-plane conformation have low or no psychotomimetic activity in animals. A possible explanation is that the out-of-plane methoxyl group interferes with the binding of the electron-rich methoxy-substituted aromatic ring to a corresponding electron-deficient component on the active site of the receptor.

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