Geometry of lidocaine-like molecules: 2. Crystal structures of 2-benzyl-2-(1-piperidinyl)-N-(2,6-dimethylphenyl) acetamide and its hydrochloride hemihydrate

The title compounds both crystallize in the monoclinic space group P21 (Z = 4), with a = 12.574(1), b = 9.653(1) c = 16.483(1) Å, and β = 91.84(1)° for the free base and a = 10.991(2), b = 16.864(3), c = 12.030(2) Å, β = 99.35(3)° for the hydrochloride. The most important factors affecting conformation of the molecules are: ortho-substitution of the benzene ring in the acetanilide system and substitution of the Cα atom. Surprisingly, the conformation does not depend on the protonation state of the amine nitrogen atom, which greatly affects packing and hydrogen bonding patterns in the crystalline state. The conformation in which the H atom of the charged amine group is in a trans position to the main backbone of the molecule, is probably responsible for the antiarrhythmic activity, while a gauche conformation promotes local anaesthetic action. The separation of the lipophilic (xylidine) and amine groups, being two important pharmacophores, equals about 4.7 Å in the studied compounds and other structures comprising the amino-2,6-dimethyl-acetanilide system.