Solution and Solid-State Conformational and Structural Analysis of the <i>N</i>-Methyl Derivatives of (±)-<i>threo</i>-Methylphenidate, (±)-<i>erythro</i>-Methylphenidate, and (±)-<i>threo</i>-<i>p</i>-Methyl-methylphenidate Hydrochloride Salts

The conformational preferences of <i>N</i>-methyl derivatives of the dopamine reuptake blocker <i>threo</i>-methylphenidate [Ritalin] and the <i>p</i>-methyl analogue were determined in the solid state and in solution and that of the <i>erythro</i> isomer in solution. The solid-state structures of (±)-<i>threo</i>-<i>N</i>-methyl-α-phenyl-2-piperidineacetic acid methyl ester hydrochloride [(±)-<i>threo</i>-<i>N</i>-methyl-methylphenidate hydrochloride] (<b>2</b>) and (±)-<i>threo</i>-<i>N</i>,<i>p</i>-dimethyl-α-phenyl-2-piperidineacetic acid methyl ester hydrochloride (<b>5</b>) were determined by single crystal X-ray diffraction analysis. (±)-<b>2</b> underwent spontaneous resolution to give crystalline chiral plates containing two independent molecules in the asymmetric ring, and at each site there is a disorder involving the <i>N</i>-methylpiperidinyl ring methylene and methyl carbon atoms with a 0.710(7):0.290(7) ratio of occupancy factors. The two (2<i>RS</i>,3<i>RS</i>,4<i>SR</i>) major disordered molecules have similar structures consisting of a <i>chair</i> conformation for the piperidine ring with <i>axial N</i>-methyl and CH(Ph)COOMe groups. The two (2<i>RS</i>,3<i>RS</i>,4<i>RS</i>) minor molecules in the disorder also have similar structures and differ from the major ones by epimerization at nitrogen and inversion of the piperidine ring to afford an <i>axial N</i>-methyl group, and an <i>equatorial</i> CH(Ph)COOMe group. (±)-<b>5</b> gave crystalline plates also containing <i>diaxially</i> disposed piperidinyl-ring substituents. Dissolution in D<sub>2</sub>O of either <b>2</b> or its <i>erythro</i>-epimer (<b>3</b>) each gives a 5:4 ratio of two species in which the major species exhibits an <i>axial</i> N-methyl group and an <i>equatorial</i> CH(Ph)COOMe group while the minor species has a <i>diequatorial</i> arrangement for both substituents. Both of the <i>axial N</i>-methyl <i>threo</i> or <i>erythro</i> major species in D<sub>2</sub>O are overwhelmingly conformationally biased in favor of an <i>antiperiplanar</i> H(2)···H(3) disposition and one piperidine ring invertomer. Dissolution of the <i>threo</i> or <i>erythro</i> epimers in CD<sub>2</sub>Cl<sub>2</sub> gives the same <i>axial N</i>-methyl/<i>equatorial</i> CH(Ph)COOMe and <i>diequatorially</i> disposed species but now in a reversed ratio [respectively 3:20 for <i>threo</i> and 4:5 for <i>erythro</i>].