R. Glaser et al., Eight-membered-ring solid-state conformational interconversion via the atom-flip mechanism, a CPMAS C-13 NMR and crystallographic stereochemical study, J ORG CHEM, 65(20), 2000, pp. 6345-6353
Nefopam methohalide (chloride, bromide, and iodide) medium-ring quaternary
ammonium salts of the non-narcotic analgesic tertiary amine drug give cryst
als belonging to the identical monoclinic P2(1)/c space group, and all of t
hese pseudopolymorphs exhibit the same packing motif. A singular boat-boat
(BB) more compact conformation is observed in the nefopam methochloride cry
stal. Larger halide anions (bromide and iodide) increase the void distance
between the 2(I)-screw axis related adjacent ammonium cations to accommodat
e void-size dependent equilibrium quantities of the twist-chair-chair (TCC)
more extended conformation. The BB:TCC occupancy factors are 0.961(5):0.03
9(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 0.59
2(7):0.408(7) [293 K] were measured for the methiodide. Above a minimum of
ca. 2.53 Angstrom the occupancy factors were found to be linearly correlate
d to the intermolecular (TCC)Me-eq-H ... H-Me-ax(TCC) distance between abut
ting methyl group protons in BI-screw axis related neighbors. Temperature-d
ependent occupancy factors for the two conformers are interpreted in terms
of a medium ring atom-flip facile interconversion between the two low energ
y conformations in crystals containing the appropriate size intercation voi
d. A BB/TCC atom-flip interconversion in the methochloride unit cell would
result in van der Waals interactions due to an estimated 2.31 Angstrom clos
e intermolecular (TCC)Me-eq-H ... H-Me-ax(TCC) distance between adjacent 2(
1)-screw symmetry ammonium cations. The 203 K low-temperature CPMAS C-13 NM
R spectrum of the methiodide salt showed two slow exchange limit (SEL) delt
a 57.91 [BB] and delta 63.10 [TCC] OCH2CH2N peaks. A variable low-temperatu
re CPMAS NMR investigation of the sold methiodide showed complex dynamic be
havior that cannot be interpreted solely on the basis of an atom-flip confo
rmational interconversion. Local magnetic fields from the gem-dimethyl rapi
dly rotating proton magnetic dipoles provide a distance-dependent T-1 relax
ation mechanism for neighboring carbons in the solid-state.