Lee Yong-Sok, Pike Victor W, Hodoscek Milan
Center for Molecular Modeling, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Building 12A, Room 2049, Bethesda, Maryland 20892, USA.
J Phys Chem A. 2008 Feb 21;112(7):1604-11. doi: 10.1021/jp077738o. Epub 2008 Jan 30.
The inversion of four 1,4-benzodiazepines was investigated with the ab initio "replica path method" with density functional theory at the B3LYP/6-31G* level. The reaction path constructed with this method for the inversion provides an approximate transition state (TS) geometry, which, upon further TS optimization, leads to the TS geometry characterized by a single vibrational frequency. 1,4-Benzodiazepines lacking a 5-phenyl ring have a single reaction path for the inversion with Cs symmetry at the TS. In contrast, the inversion of benzodiazepines with a 5-phenyl ring, such as the peripheral benzodiazepine receptor ligand 4'-chlorodiazepam (Ro5-4864) and its N1-desmethyl analog (Ro5-2752), can proceed through multiple reaction paths having a TS with or without Cs symmetry. Notably, the replica path method found a path connecting two asymmetric TSs of 4'-chlorodiazepam via a symmetrical TS, suggesting that these inversion paths can be readily crossed from one to another. The stabilization energies gained by 4'-chlorodiazepam and its N1-desmethyl analog from the breaking of Cs symmetry at the TS were calculated to be 0.10 and 0.07 kcal/mol, respectively. The origin of the broken symmetry of Cs was traced to the coupling of the puckering of the diazepine ring with the rotation of the chlorophenyl ring. These results show the advantages of the replica path method for locating the TSs as well as for constructing the reaction paths for the inversion of 1,4-benzodiazepines.
采用密度泛函理论在B3LYP/6 - 31G*水平下的从头算“复制路径法”研究了四种1,4 - 苯二氮䓬的翻转。用该方法构建的翻转反应路径提供了一个近似过渡态（TS）几何结构，进一步对TS进行优化后，得到了以单一振动频率为特征的TS几何结构。缺乏5 - 苯基环的1,4 - 苯二氮䓬在TS处具有单一的具有Cs对称性的翻转反应路径。相比之下，具有5 - 苯基环的苯二氮䓬，如外周苯二氮䓬受体配体4'-氯地西泮（Ro5 - 4864）及其N1 - 去甲基类似物（Ro5 - 2752）的翻转，可以通过具有或不具有Cs对称性的TS的多条反应路径进行。值得注意的是，复制路径法发现了一条通过对称TS连接4'-氯地西泮的两个不对称TS的路径，这表明这些翻转路径可以很容易地从一个跨越到另一个。计算得出4'-氯地西泮及其N1 - 去甲基类似物在TS处由于Cs对称性破坏而获得的稳定能分别为0.10和0.07千卡/摩尔。Cs对称性破坏的起源可追溯到二氮䓬环的褶皱与氯苯基环的旋转之间的耦合。这些结果显示了复制路径法在定位TS以及构建1,4 - 苯二氮䓬翻转反应路径方面的优势。
