Selective Anion Complexation by a Calix[4]pyrrole Investigated by Monte Carlo Simulations

The complexation of anions by octamethylcalix[4]pyrrole 1 and 2,5-dimethylpyrrole has been investigated by energy minimizations in the gas phase and by Monte Carlo (MC) simulations in dichloromethane using the OPLS force field. In agreement with experiment, the 1,3-alternate conformation of 1, in which adjacent pyrrole rings are pointing in opposite directions, was shown to be the most stable conformation in the absence of a halide anion. The cone conformer of 1, having all pyrrole units in a parallel orientation, is not stable in the absence of a halide anion, but it is the most stable conformation upon anion binding due to the formation of four NH−halide hydrogen bonds. The relative free energies of binding of chloride, bromide, and iodide with the cone of 1 in dichloromethane are calculated with free energy perturbation (FEP) simulations to be in excellent agreement with experiment. However, the calculations predict a far greater affinity for fluoride ion than was measured. This can be explained by the presence of trace amounts of water. For reference, MC/FEP calculations were also carried out for 2,5-dimethylpyrrole, which was predicted to bind only fluoride ion, consistent with NMR experiments. On the technical side, the MC sampling efficiency of alternative internal-coordinate representations of the complexes was also considered.