Eight-membered-ring solid-state conformational interconversion via the atom-flip mechanism, a CPMAS 13C NMR and crystallographic stereochemical study

Robert Glaser, Artem Novoselsky, Dror Shiftan, Marc Drouin

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16 Scopus citations


Nefopam methohalide (chloride, bromide, and iodide) medium-ring quaternary ammonium salts of the non-narcotic analgesic tertiary amine drug give crystals belonging to the identical monoclinic P21/C space group, and all of these pseudopolymorphs exhibit the same packing motif. A singular boat-boat (BB) more compact conformation is observed in the nefopam methochloride crystal. Larger halide anions (bromide and iodidei increase the void distance between the 21-screw axis related adjacent ammonium cations to accommodate void-size dependent equilibrium quantities of the twist-chair-chair (TCC) more extended conformation. The BB:TCC occupancy factors are 0.961(5):0.039(5) [193 K], 0.780(5):0.220(5) [293 K], and 0.755(6):0.245(6) [343 K] for the methobromide crystal, while values of 0.657(5):0.343(5) [193 K] and 0.592(7):0.408(7) [293 K] were measured for the methiodide. Above a minimum of ca. 2.53 Å, the occupancy factors were found to be linearly correlated to the intermolecular (TCC)Me(eq)-H···H-Me(ax)(TCC) distance between abutting methyl group protons in 21-screw axis related neighbors. Temperature-dependent occupancy factors for the two conformers are interpreted in terms of a medium ring atom-flip facile interconversion between the two low energy conformations in crystals containing the appropriate size intercation void. A BB/TCC atom-flip interconversion in the methochloride unit cell would result in van der Waals interactions due to an estimated 2.31 Å close intermolecular (TCC)Me(eq)-H···H-Me(ax)(TCC) distance between adjacent 21-screw symmetry ammonium cations. The 203 K low-temperature CPMAS 13C NMR spectrum of the methiodide salt showed two slow exchange limit (SEL) δ 57.91 [BB] and δ 63.10 [TCC] OCH2CH2N peaks. A variable low-temperature CPMAS NMR investigation of the solid methiodide showed complex dynamic behavior that cannot be interpreted solely on the basis of an atom-flip conformational interconversion. Local magnetic fields from the gem-dimethyl rapidly rotating proton magnetic dipoles provide a distance-dependent T1 relaxation mechanism for neighboring carbons in the solid-state.

Original languageEnglish
Pages (from-to)6345-6353
Number of pages9
JournalJournal of Organic Chemistry
Issue number20
StatePublished - 6 Oct 2000

ASJC Scopus subject areas

  • Organic Chemistry


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