Flexible Biphenyl Chromophore as a Circular Dichroism Probe for Assignment of the Absolute Configuration of Carboxylic Acids

A general and nonempirical approach to determine the absolute configuration (AC) of 2-substituted
chiral carboxylic acids by circular dichroism (CD) spectroscopy has been developed. In this protocol, the
chiral acids are converted to the corresponding biphenyl amides, in which a flexible biphenyl probe gives
rise to a Cotton effect at 250 nm (A band) in the CD spectrum, the sign of which is related to the acid AC.
Two different mechanisms of transfer of chirality from the acid stereogenic center to the biphenyl moiety
are operative in amides derived from 2-alkyl- and 2-aryl-substituted acids, respectively. For both classes
of compounds, a model has been defined which allows one to predict, for a given acid AC, the preferred
twist of the biphenyl moiety and thus the sign of the A band in the CD spectrum, related to the biphenyl
torsion. Interestingly, while in alkyl-substituted substrates the preferred biphenyl twist is determined only
by steric interactions, in the aryl-substituted ones the structure of the prevalent conformer and thus the
biphenyl twist are dictated by arene−arene edge-to-face stabilizing interactions. Following this protocol,
the AC of a 2-substituted chiral acid can be established simply by preparing its biphenyl amides, recording
the CD spectrum, and looking at the sign of the A band. From the sign of such a band, the torsion of the
biphenyl can be deduced and then the acid AC. Substrates having different structures and functionalities
have been investigated, always obtaining reliable AC assignments by this simple protocol.