【作者】 肖科科；

【导师】 施介华；

【作者基本信息】 浙江工业大学 ， 药物化学， 2009， 硕士

【摘要】 本论文应用色谱法和分子模型法相结合研究手性固定相的识别机理,即采用熵焓补偿原理、分子模拟计算和QSERR方法,从分子水平上阐述手性识别的本质,了解手性识别作用在固定相上的部位及其作用力等。采用气相色谱法在Cyclodex B手性柱上拆分扁桃酸甲酯、α-氯代丙酰替苯胺和α-氯丙酸酯对映异构体,考察了柱温对分离效果影响;通过对映异构体分离过程中的热力学参数的计算,探讨光学异构体分离过程的驱动力和手性识别机理。结果表明所分析的对映异构体在Cyclodex B柱上的分离过程是一个焓驱动过程并存在着焓熵补偿关系。首次采用运用量子力学PM3方法,成功的模拟研究了天然的β-环糊精和α-氯丙酸乙酯((R/S)-ECPA)主客相互作用,探讨(R/S)-ECPA在β-CD上的手性识别机理。结果表明,(R/S)-ECPA对映体与β-CD形成稳定结合物的结合方式完全不同,(R)-ECPA位于β-CD空腔宽口端,形成缔合物;(S)-ECPA插入β-CD空腔内形成包结物。而且,(S)-ECPA—β-CD的结合稳定能低于(R)-ECPA—β-CD。在(R/S)-ECPA—β-CD结合物中,(R/S)-ECPA中的手性碳接近葡萄糖单元的C(2)和C(3)。则ECPA与β-CD之间的手性识别与葡萄糖单元的C(2)和C(3)所提供的手性环境和ECPA与β-CD结合的紧密程度密切相关。首次采用运用量子力学PM3方法,模拟研究了运用量子力学PM3方法模拟α-氯丙酸甲酯((R/S)-ECPA)与全甲基-β-环糊(PMBCD)的手性识别过程。结果表明,(R/S)-MCPA对映体与β-CD形成稳定结合物的结合方式完全不同。在(R/S)-MCPA—β-CD结合物中,(R/S)-MCPA中的手性碳接近葡萄糖单元的C(2)和C(3)。则MCPA与PMBCD之间的手性识别与葡萄糖单元的C(2)和C(3)所提供的手性环境和MCPA与PMBCD结合形成的氢键作用模式相关。而且,通过比较作用能之差(ΔE)以预示手性分离色谱流出顺序,其结果与气相色谱实验结果一致。运用量子化学中的Hartree-Fock程序(6-31G基组)方法计算质子化α-氨基酸溶质的分子结构参数,借助于逐步多元线性回归法建立了α-氨基酸光学异构体在冠醚手性固定相上的色谱保留与其分子结构参数之间的定量结构-对映异构体保留(QSERR)模型。结果表明,α-氨基酸光学异构体的保留因子与溶质的分子结构描述参数之间具有较好的线性相关性。在QSERR模型中,采用的结构参数物理意义明确。所建立的QSERR模型具有较好的稳定性和预测能力。同时,通过QSERR模型探讨了这种冠醚固定相可能的色谱保留和手性识别机理。更多还原

【Abstract】 In this thesis,the deeper studies of recognition mechanism of chiral stationary phase were carried out by integrating chromatography and molecular modeling method,including the enthalpy-entropy compensation effects of statistic analysis,molecular simulation calculation and QSERRs methods.The nature of chiral recognition was stated from the molecular level in order to understand the positions and the forces of chiral recognition on the stationary phase.The separation of enantiomers of methyl mandelate,α-chloro-N-phenyl propanamide andα-chloropropionates on the Cyclodex B chiral column containing had been studied by gas chromatography.The effect ofα-chloropropionate structure and column temperature on the separation of enantiomers ofα-chloropropionates had been investigated.On the other hand,the thermodynamic parameters in the process of separation of enantiomers were determined in order to discuss driven power and chiral discrimination mechanism in the process of separation of enantiomers. The experimental results showed that the separation for enantiomers of methyl mandelate,α-chloro-N-phenyl propanamide and α-chloropropionate was enthalpy-driven process and there was enthalpy-entropy compensation.The host-guest complexation ofβ-cyclodextrin(β-CD) with enantiomers of ethylβ-chloropropionates((R/S)-ECPA) was successfully simulated by Quantum Mechanics PM3 method for the first time.Chiral recognization mechanism of(R/S)-ECPA enantiomers onβ-CD was investigated.The modeling results showed the stabilization complexation structures which formed with(R/S)-ECPA enantiomers andβ-CD were different.(R)-ECPA was located the cavity wide mouth end ofβ-CD to form associated molecule.(S)-ECPA was inserted inβ-CD cavity to form inclusion molecule.The stabilization energy of(S)-ECPA—β-CD complex was less than that of(R)-ECPA—β-CD.And,the chiral carbon in ECPA for(R/S)-ECPA—β-CD complexes was close to C(2) and C(3) in glucose unit.So,the chiral recognization mechanism was closely related to the chiral environment provided to C(2) and C(3) in the glucose unit and hydrogen bond forms of(R/S)-ECPA andβ-CD.Chiral recognization mechanism of Methylβ-cyclodextrin(PMBCD) with enantiomers of methylα-chloropropionates((R/S)-MCPA was simulated by Quantum Mechanics PM3 method for the first time.The modeling results showed the stabilization complexation structures which formed with(R/S)-MCPA enantiomers and PMBCD were different.The chiral carbon in MCPA for(R/S)-MCPA-β-CD complexes was close to C(2) and C(3) in glucose unit.So,the chiral recognization mechanism was closely related to the chiral environment provided to C(2) and C(3) in the glucose unit and inclusion degree to(R/S)-MCPA andβ-CD.In addition,and the interactive energy diference(ΔE) between two enantiomers was compared to predict the chromatographic elution-order. The results were in accordance with that of GC experiments.Theα-amino acids soluted-related structure descriptors parameters was computed by Hartree-Fock program(6-31G method) in Quantum chemistry,the QSERR modeling of chromatographic retention of the optical isomers ofα-amino acids on the crown chiral stationary phases and their molecular structure descriptors parameters were set with stepwise multiple linear regression method.The results showed there is better linear relationship between capacity factors of the optical isomers ofα-amino acids and their molecular structure descriptors parameters. The physical meaning of these molecular structure descriptors parameters in the QSERR modeling is definite.The QSERR modeling had better stability and predictability.The chromatographic retention and chiral discrimination mechanism in the separation process of the optical isomers ofα-amino acids on the crown stationary phases were investigated.更多还原