Conformational Studies of Thyroid Hormones. I. The Diphenyl Ether Moiety

Abstract

Conformational flexibility round the diphenyl ether linkage in the thyroid hormones has been investigated by means of molecular orbital (AM1) and classical potential-energy calculations. The results obtained from these theoretical approaches are in qualitative agreement with those from n.m.r. spectroscopy, i.e., the barrier to rotation around this structural feature is sufficiently low to allow rapid interconversion between two stable conformers to occur at room temperature. Two pathways of rotation around the diphenyl ether bridge were explored and were both calculated to be approximately 14-15 kJ mol^-1 by the AM1 method. This compares with the experimental barrier of 36 kJ mol^-1. The potential-energy calculations gave barriers up to an order of magnitude larger which were inconsistent with experimental observations. A comparison of the AM1 data with results from previous studies with CNDO/2, which predicted a larger barrier, is also given. The detailed mode of interconversion around the two torsion angles involved in diphenyl ether rotation is investigated, as is the interplay of the bulky iodo substituents with the second aromatic ring during such conformational changes. The nature of torsion angle cooperation during rotations around this linkage is discussed.