Eight-Membered-Ring Solid-State Conformational Interconversion via the Atom-Flip Mechanism, a CPMAS¹³C NMR and Crystallographic Stereochemical Study

Abstract

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 P2(1)/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 iodide) increase the void distance between the 2(1)-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 A, 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 2(1)-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 A close intermolecular (TCC)Me(eq)-H...H-Me(ax)(TCC) distance between adjacent 2(1)-screw symmetry ammonium cations. The 203 K low-temperature CPMAS 13C NMR spectrum of the methiodide salt showed two slow exchange limit (SEL) delta 57.91 [BB] and delta 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.

The TACO Puzzle: A Phase-Transition Mystery Revisited

“…Some experimental evidence suggests that conformational interchanges of medium-size rings probably occur by stepwise mechanisms rather than via synchronized changes involving the whole cycle. [40][41][42] Our gas-phase findings agree with such a model: the ring inversion in TACO is achieved through a two-step mechanism, each of which implies the inversion of a half of the cycle at a time. The latter is obtained through a step-by-step displacement of a pair of -CH 2 -groups across the main ring plane.…”

“…A rapid conformational exchange has been detected by NMR in pefluorocyclo-octane in solution at room T. 38 Orientational and conformational disorder in a liquid-like cyclooctane included in thiourea crystals has been reported, 39 while the dynamic nature of the ring flip (half-ring inversion from BB to TCC conformation) in ammonium salts of nefopam has been characterized by CPMAS-NMR and variable-T diffraction measurements. 40 c. Computational Evidence. Our in vacuo quantum simulations (Figure 8) confirm that the two resulting enantiomeric boat−chair conformations are perfectly equivalent, with electronic energies differing by less than 1.0 kJ• mol −1 (Table S2, Supporting Information).…”

The solid-state and solution-state reassigned structures of tagitinin A, a 3,10-epoxy-germacrolide from Tithonia diversifolia, and the interconversion of 3,10-epoxy-germacrolide conformational families via a ring-atom flip mechanism

“…15 Flipped ring-atoms conformations have been observed by X-ray diffraction analysis: two ring atom-flipped eight-membered ring conformations superimpose upon each other in conformationally dynamically disordered crystals of nefopam methobromide or methiodide quaternary ammonium salts. 44,45 The above stereochemical analysis can be combined with an earlier observation by Gershenzon et al 39 who isolated 11b (a 1 -hydroxyl cis-tetrahydrofurano analogue) and the corresponding 1,2-dehydrofurano germacrolide lactone from the Viguiera microphylla plant. The authors J. Braz.…”

NMR studies of organic polymorphs & solvates

“…Measurements of 13 C relaxation times can also be of value for understanding molecular-level mobility and have been carried out 88,89,94,130,135,136,138,139,[143][144][145] for cases relevant to polymorphism. Such work is time-consuming and again will only have unambiguous value if full temperature-dependence is examined, as has been done for a handful of cases.…”

“…Matsunaga et al, for example, showed 182 that for one form of candesartan cilexetil, variabletemperature 13 C NMR indicated the occurrence of chair « boat interchange of a cyclohexane ring. Glaser et al have examined 144 ring-flip dynamics involving -OCH 2 CH 2 Ngroups in nefopam methiodide salt. The methyl carbons of the t-butyl groups in the finasteride polymorphs give rise 197 to a single peak in the 13 C spectrum, indicating that the t-butyl group is rotating rapidly on the NMR timescale.…”