Anion Binding Affinity: Acidity versus Conformational Effects

High-level
quantum chemical calculations were used to elucidate
the gas- and solution-phase conformational equilibria for a series
of symmetrically substituted (thio)­ureas, (thio)­squaramides, and croconamides.
Gas-phase calculations predict that the thermodynamic conformer of
many of these anion receptors is not the dual-hydrogen-bond-facilitating
anti–anti conformer as is commonly assumed. For N,N′-diaryl thiosquaramides and croconamides,
the syn–syn conformer is typically the predominant conformer.
Solution-phase calculations show that the anti–anti conformer
is increasingly stabilized as the polarity of the solvent increases.
However, the syn–syn conformer remains the lowest energy conformation
for croconamides. These predictions are used to explain the acidity
versus chloride binding affinity correlations recently reported for
some of these compounds. The chloride binding constants for thioureas
and croconamides are significantly lower than expected on the basis
of their pKa values, and this may be due
in part to the need for these receptors to reorganize into the anti–anti
conformer. Experimental NMR nuclear Overhauser effect (NOE) measurements
of an asymmetrically substituted squaramide and its thio analogue
are consistent with the syn–syn conformation being predominant
at 298 K. The conformational equilibria should therefore be an important
consideration for the design and development of future anion receptors
and organocatalysts.