Glaser R, Novoselsky A, Shiftan D
Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
J Org Chem. 2000 Oct 6;65(20):6345-53. doi: 10.1021/jo000146g.
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.
非麻醉性镇痛叔胺药物的甲卤酸奈福泮（氯化物、溴化物和碘化物）中环季铵盐形成属于相同单斜P2(1)/c空间群的晶体，并且所有这些假多晶型物都表现出相同的堆积模式。在甲氯奈福泮晶体中观察到一种独特的船-船（BB）更紧凑构象。较大的卤离子（溴化物和碘化物）增加了与2(1)-螺旋轴相关的相邻铵阳离子之间的空隙距离，以容纳扭曲椅-椅（TCC）更伸展构象的与空隙大小相关的平衡量。对于甲溴酸盐晶体，BB:TCC占有率因子在193 K时为0.961(5):0.039(5)，在293 K时为0.780(5):0.220(5)，在343 K时为0.755(6):0.245(6)；而对于甲碘酸盐，在193 K时测量值为0.657(5):0.343(5)，在293 K时为0.592(7):0.408(7)。在至少约2.53 Å以上，发现占有率因子与2(1)-螺旋轴相关相邻基团中相邻甲基质子之间的分子间（TCC）Me(eq)-H...H-Me(ax)(TCC)距离呈线性相关。两种构象的温度依赖性占有率因子是根据含有适当大小阳离子间空隙的晶体中两种低能构象之间的中环原子翻转容易相互转化来解释的。甲氯奈福泮晶胞中的BB/TCC原子翻转相互转化将由于相邻2(1)-螺旋对称铵阳离子之间估计为2.31 Å的紧密分子间（TCC）Me(eq)-H...H-Me(ax)(TCC)距离而导致范德华相互作用。甲碘酸盐的203 K低温CPMAS 13C NMR谱显示两个慢交换极限（SEL）δ57.91 [BB]和δ63.10 [TCC] OCH2CH2N峰。对固体甲碘酸盐进行的可变低温CPMAS NMR研究显示出复杂的动态行为，不能仅基于原子翻转构象相互转化来解释。来自偕二甲基快速旋转质子磁偶极子的局部磁场为固态中的相邻碳提供了一种距离依赖性T1弛豫机制。
