How Hexafluoroisopropanol Solvent Promotes Cycloadditions Reaction:ab Initio Metadynamics Simulations

Solvent changes often have a significant impact on the reactivity and regioselectivity of liquid-phase organic reactions.Fluoroalcohol solvents have been extensively employed in many types of organic reactions,the most representative fluoroalcohol solvent is hexafluoroisopropanol(HFIP).Compared with other fluoroalcohol solvents,HFIP is more acidic and less nucleophilic,so it does not compete with other nucleophiles and has fewer side reactions.Due to its stronger H-bond networks,HFIP solvent can stabilize intermediates and transition states.The high polarity and low nucleophilicity allow cationic species to be stabilized in HFIP solvents while maintaining reactivity.Therefore,HFIP solvents are widely used in many different types of organic reactions,particularly in regulating the reactivity and selectivity of cycloaddition reactions.The commonly used implicit solvent model and the mixed implicit-explicit solvent model cannot sufficiently describe HFIP H-bond networks and its dynamic feature.To better understand the influence of HFIP solvent effects on cycloaddition reactions,we use ab initio molecular dynamics(AIMD)simulation combined with enhanced sampling techniques(e.g.metadynamics)to reveal the regulation of HFIP solvents on reactivity and selectivity.The first part of the study explores the selectivity and activity of the Diels-Alder cycloaddition reaction of acrolein and isoprene with HFIP solvent.The experimental results show that the Diels-Alder cycloaddition reactivity and selectivity between acrolein and isoprene in HFIP are significantly improved.AIMD simulations under explicit solvent environment are used to obtain the activation barrier.The simulation results are consistent with the experimental observations.In order to further explore the promoting effect of HFIP in this reaction,the approach of energy decomposition analysis(EDA)is used.The results indicate that the decrease of Pauli repulsion is the decisive factor for the enhancement of both reactivity and selectivity.Similarly,the reactivity of Diels-Alder cycloaddition reaction between cyclopentadiene and methyl acrylate is also enhanced in HFIP solvent.We use the same method to investigate the origin of difference in reactivity in different solvents.The decrease in Pauli repulsion is also a decisive factor for promoting the reactivity.The second part of the study explores the effect of HFIP solvent on regulating the reactivity of cycloaddition reaction of 2-nitrosopyridine and diphenylacetylene.The experimental results show that HFIP significantly improve the reaction reactivity,following by trifluoroethanol(TFE),while almost no reaction products are observed in benzene.The explicit solvent model is used for AIMD simulations,and the obtain reaction energy barrier is consistent with the experimental trend.The reaction in HFIP and TFE occurred through a stepwise mechanism.In contrast,it occur through a concerted mechanism.We futher analyze the difference in reactivity between HFIP and TFE solvents.The results reveal that,compared with TFE,HFIP can affect the transition state structure,strengthening orbital interactions and lowering the reaction energy barrier.However,the reaction energy barrier in benzene solution is high because the substrate cannot be activated in advance and the reaction is carried out in a concerted manner.In the above reaction,when the substrate contains multiple heteroatoms,there are multiple interaction sites for the hydrogen bond interaction between the solvent and the substrate,and it is necessary to be able to identify the specific interaction sites before analysis.AIMD simulations of the cycloaddition reactions of ethyl vinyl ether and Nbenzenesulfonyl-3-methyl-1-aza-butadiene in different solvents were performed to prove that the calculation method is suitable for determining the predominant site of solute interaction.Through AIMD simulations of reactions in HFIP,TFE,tetrahydrofuran and acetic acid,it is known that only TFE can form a H-bond networks through nitrogen atoms due to its small molecular size,which is not found in other solvents.Additionally,the H-bond networks formed by TFE connecting nitrogen atoms surrounded the substrate,changing the structure of the substrate and promoting the reaction by forming a C-H/π interaction between the benzene ring in the diene substrate and the dienophile.