A Hybrid Quantum Mechanical/Molecular Mechanical Approach For Reaction Pathway Calculations: Application To The S_N2 Reactions

The bimolecular nucleophilic substitution reaction of methyl chloride inaqueous solution was investigated on the basis of a combined quantum mechanicaland molecular mechanics method. A multilayered representation approach isemployed to achieve high accuracy results at the CCSD（T） level of theory. And weapply the hybrid QM/MM approach to the NWChem computational chemistrypackage.22We have studied the mechanisms of the reactions CH₃Cl + OH^- and OH^- （H₂O） + CCl₄in aqueous solution.The SN2 mechanism for the reaction of CH₃Cl + OH^- in aqueous solution wasinvestigated using combined quantum mechanical and molecular mechanicsmethodology. We analyzed structures of reactant, transition and product states alongthe reaction pathway. The free energy profile was calculated using the multi-layeredrepresentation with the DFT and CCSD（T） level of theory for thequantum-mechanical description of the reactive region. Our results show that theaqueous environment has a significant impact on the reaction process. We find thatsolvation energy contribution raises the reaction barrier by ¹8.9 kcal/mol and thereaction free energy by ²4.5 kcal/mol. The presence of the solvent also inducesperturbations in the electronic structure of the solute leading to an increase of 3.5kcal/mol for the reaction barrier and a decrease of 5.6 kcal/mol for the reaction freeenergy respectively. Combining the results of two previous calculation results onCHCl3+ OH^- and CH₂Cl₂⁺ OH^- reactions in water, we demonstrate that increase inthe chlorination of the methyl group （from CH₃Cl to CHCl3） is accompanied by thedecrease in the free energy reaction barrier, with the CH₃Cl + OH^- having the largestbarrier among the three reactions.We investigate water assisted mechanism of the OH^- （H₂O）+CCl₄reactionprocess in aqueous solution using combined quantum mechanical and molecular mechanics approach. Unlike the direct mechanism of the OH^- +CCl₄reactioninvestigated previously, here the overall reaction mechanism for channel 1 consistsof two concerted steps -- the proton transfer process in which the H₂O donates one Hatom to OH^- and the nucleophilic substitution in which the new formed OH^- attacksthe C center atom. And for channel 2, although the original H₂O does not donateproton , it hinders the reaction and then lowers the intrinsic nucleophilicity by formhydrogen bond with OH^- . We find that the free energy activation barrier of 38.2kcal/mol and 36.39 kcal/mol at CCSD（T）/MM level of theory for channel 1 and 2separately, which is about 10.3 kcal/mol and 7.52 kcal/mol higher than that of thedirect nucleophilic substitution mechanism of the OH^- + CCl₄reaction . Thissituation for channel 2 is mainly due to the extra hydrogen bonding formed by OH^- with H₂O which lowers the intrinsic nucleophilicity. And about channel 1 , this is notonly due to the extra hydrogen bonding formed by OH^- with H₂O but also for theextra energy cost of the proton transfer process. So, the OH^- +CCl₄is the preferredreaction in water than OH^- （H₂O） + CCl₄reaction.This paper is organized as follows. The first chapter gives a brief introduction ofthe Nucleophilic Substitution Reaction.In the second chapter，we show the combinedquantum mechanical and molecular mechanics approach. And then, The mainwork of this paper are listed in the third and the fourth chapter, we have discussedthe reaction of CH₃Cl + OH^- and OH^- （H₂O） + CCl₄in aqueous solutionrespectively.At last,we briefly summarize the total subject and give an expectationfor the future work.