X-ray crystallography studies and CP-MAS ¹³C NMR spectroscopy on the solid-state stereochemistry of diphenhydramine hydrochloride, an antihistaminic drug

The solid-state structure of diphenhydramine hydrochloride [(CH ₃)₂NCH₂CH₂OCH(Ph) ₂·HCl], an antihistaminic drug, was determined by single crystal X-ray diffraction analysis. Diphenhydramine hydrochloride gave crystals belonging to the orthorhombic Pn2₁a space group, and at ambient temperature: a = 10.592(2), b = 10.761 (2), c = 14.280(2) Å, V = 1 627.6(8) ų, Z = 4, R(F) = 0.063, R_w(F) = 0.068. Since the molecule (1) is placed half-way between the a-glides perpendicular to c, and (2) its molecular conformation shows almost mirror symmetry {through N, C(4) [-CH₂O-], benzhydryl-C(5), and between the phenyls}, the C-face appears to act as a plane of pseudo-mirror symmetry enabling the unit cell to have pseudo-centring of the B-face [Bb2₁m apparent symmetry]. The molecule shows an almost eclipsed geometry for the oxydimethyleneamino moiety [38(1)° O-C-C-N torsion angle] and a non-helical 'open book' disposition for the diphenylmethane moiety. The CP-MAS ¹³C NMR spectrum for diphenyhydramine HCl is unusually simplified due to the pseudo-mirror symmetry of the structure. Internally diastereotopic pairs of nuclei, e.g. (CH ₃)₂N, the two ipso-carbons, etc. appear to be pseudo-enantiotopic due to negligible differences in chemical shifts from pairs of what should be anisochronous carbons.