The pharmaceutical
compound entacapone ((E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide) is important
in the treatment of Parkinson’s disease, exhibiting interesting
polymorphic behavior upon crystallization from solution. It consistently
produces its stable form A with a uniform crystal size distribution
on the surface of an Au(111) template while concomitantly forming
its metastable form D within the same bulk solution. Molecular modeling
using empirical atomistic force-fields reveals more complex molecular
and intermolecular structures for form D compared to form A, with
the crystal chemistry of both polymorphs being dominated by van der
Waals and π–π stacking interactions with lower
contributions (ca. 20%) from hydrogen bonding and electrostatic interactions.
Comparative lattice energies and convergence for the polymorphs are
consistent with the observed concomitant polymorphic behavior. Synthon
characterization reveals an elongated needle-like morphology for form
D crystals in contrast to the more equant form A crystals with the
surface chemistry of the latter exposing the molecules’ cyano
groups on its {010} and {011} habit faces. Density functional theory
modeling of surface adsorption reveals preferential interactions between
Au and the synthon GAinteractions of form A on the Au
surface. Molecular dynamics modeling of the entacapone/gold interface
reveals the entacapone molecular structure within the first adsorbed
layer to show nearly identical interaction distances, for both the
molecules within form A or D with respect to the Au surface, while
in the second and third layers when entacapone molecule–molecule
interactions overtake the interactions between those of molecule–Au,
the intermolecular structures are found to be closer to the form A
structure than form D. In these layers, synthon GA(form
A) could be reproduced with just two small azimuthal rotations (5°
and 15°) whereas the closest alignment to a form D synthon requires
larger azimuthal rotations (15° and 40°). The cyano functional
group interactions with the Au template dominate interfacial interactions
with these groups being aligned parallel to the Au surface and with
nearest neighbor distances to Au atoms more closely matching those
in form A than form D. The overall polymorph direction pathway thus
encompasses consideration of molecular, crystal, and surface chemistry
factors.