Abraham R J, Medforth C J, Smith P E
Robert Robinson Laboratories, University of Liverpool, U.K.
J Comput Aided Mol Des. 1991 Jun;5(3):205-12. doi: 10.1007/BF00124339.
The conformational free energies (-delta G degree) of a number of 4-substituted piperdines and piperidinium salts have been determined by the J-value method. For the 4-substituted piperdines (R = Me, Phenyl, CO2Et, Br, OH, F) the relative conformer energies are almost identical to those of the analogous cyclohexanes. The methyl and phenyl compounds showed no change in the couplings on protonation, implying no change in the conformer energies. In contrast, in the remaining compounds with polar 4-substituents an almost constant stabilisation of the axial conformer of ca. 0.7 -0.8 kcal mol-1 was observed on protonation. In three cases (R = F, OH and Br) the conformational preference is reversed on protonation and the axial form is favored. The conformer energies of both the free bases and the piperidinium salts can be quantitatively predicted by molecular mechanics calculations using the COSMIC force-field, in which the electrostatic interactions are calculated by a simple Coulombic model with the partial atomic charges in the molecules given by the CHARGE2 routine, and an effective dielectric constant of five. The precise agreement obtained demonstrates conclusively that the electrostatic interactions between the substituents and the protonated nitrogen are the cause of the conformational changes on protonation, and that these can be modelled successfully using existing force-fields.
已通过J值法测定了多种4-取代哌啶和哌啶鎓盐的构象自由能（-ΔG°）。对于4-取代哌啶（R = 甲基、苯基、CO2Et、溴、羟基、氟），其相对构象体能量与类似环己烷的几乎相同。甲基和苯基化合物在质子化时偶合没有变化，这意味着构象体能量没有变化。相反，在其余具有极性4-取代基的化合物中，质子化时观察到轴向构象体几乎恒定地稳定化，约为0.7 - 0.8千卡/摩尔。在三种情况下（R = 氟、羟基和溴），质子化时构象偏好发生反转，轴向形式更受青睐。游离碱和哌啶鎓盐的构象体能量都可以通过使用COSMIC力场的分子力学计算进行定量预测，其中静电相互作用通过简单的库仑模型计算，分子中的部分原子电荷由CHARGE2程序给出，有效介电常数为5。所获得的精确一致性最终证明，取代基与质子化氮之间的静电相互作用是质子化时构象变化的原因，并且可以使用现有的力场成功地对这些进行建模。
