| The bimolecular nucleophilic substitution（SN2）is one of the most important reactions in the organic and biological chemistry.Recent research results indicate that the SN2 reaction at nitrogen center（SN2@N）plays a significant role in the mechanism of carcinogenicity and the formation of some environmental carcinogenic compounds.However,the studies of the reaction mechanisms of SN2@N are few compared to the well-studied SN2 reaction at carbon center（SN2@C）.In this paper,the reaction mechanisms of some SN2@N reactions were investigated by using computational methods from the following two aspects.In one aspect,the SN2@N reactions of DMA and F-with NH2Cl were chosen as model reactions,and the most accurate method was screened out from the 24 popularly-used DFT methods.In the other aspect,the reaction mechanisms of nucleophilic anions F-and Cl-along with some neutral amines,i.e.,ammonia（NH3）,methylamine（MA）,dimethylamine（DMA）,trimethylamine（TMA）,and the model of ranitidine（R-Model）with chloramine（NH2Cl and NHCl2）were investigated by using the above best method.1.Validation of DFT functionals on the SN2@N reactionFirstly,the reaction of DMA as nucleophile with NH2Cl was chosen to be investigated by using 27 theoretical calculation methods,and the present most reliable CCSD（T）method was used as benchmark to find a suitable method from 24 DFT functionals belonging to three categories.It can be found that the DFT functionals in Hybrid meta-GGA category provide more accurateΔG≠values for the SN2 reaction of DMA with NH2Cl than those in RSH and Hybrid GGA categories,and CAM-B3LYP,M05-2X,B1B95,BMK,and M06-2X are the top 5 functionals among all the 24 DFT functionals investigated here.Then,the potential energy surface（PES）of the traditional SN2@N reaction involving in F-and NH2Cl was studied by using the above five methods.Three reaction channels,i.e.,Inversion channel attacked by the nucleophilic agent from the back side,Retention channel,attacked by the nucleophilic agent from the front side,and Proton Transfer have been discussed.The calculated results indicate that M06-2X functional offers more accurate results compared with other four functionals.Therefore,M06-2X function will be used for the following investigation of SN2@N reactions.2.Theoretical study of mechanisms for SN2@N reactionsIn this study,seven nucleophiles were chosen,including the traditional anionic nucleophiles,fluorine and chloride anions as well as other five neutral nucleophiles,i.e.,methylamine,dimethylamine,trimethylamine,TMA,and R-Model,and the reaction pathways of these nucleophiles reacting with chloramines were investigated.For comparison,the analogous SN2@C reactions of above seven nucleophiles with chloromethanes（CH3Cl and CH2Cl2）were also investigated.The computational results indicate that the backside Inversion channel dominates all the SN2 reactions except for the case of F-with NHCl2,in which the Proton transfer channel is preferred.Comparing the reactivities of the neutral nucleophiles,NH3,MA,DMA,and TMA,it can be found that amines with higher extent of methyl substitution are more reactive than those with less.Furthermore,the SN2@N reactions for all the nucleophiles investigated here are faster than those corresponding SN2@C reactions.In addition,it was found that there is a strong correlation between the energy diference of the HOMO of nucleophile and LUMO of chloramines or chloramethanes with the activation free energy in the SN2 reactions.In this work,24 DFT functionals were chosen to validate a suitable method for the SN2 reactions and finally an appropriate method was found to uncover the reaction mechanisms of the neutral nucleophiles with chloramines.The results would not only provide a reference for chosing a suitable theoretical calculation method in further exploring the SN2 reactions,but also expand our understanding of the mechanisms of carcinogenesis and the formation of the ecvironmental carcinogens,which is of theoretical significance for the maintenance of human health. |
