Explicit Solvent Simulation Of The Solvent Effect Of Hexafluoroisopropanol In Electrophilic Substitution Reactions

Over the past decade,hexafluoroisopropanol(HFIP)has received much attention in the chemistry community for facilitating a variety of challenging reactions.Compared with traditional solvents,HFIP has been extensively employed in many types of organic reactions and showed significant promotion and regulation of reaction results,that is baceuse HFIP has unique physical and chemical properties.Along with the continuous achievements of HFIP in the experimental field,theoretical exploration of its properties has also been increasing.However,elucidation of the promotion effect of HFIP at the molecular level still faces great challenges due to the effects of complex dynamic H-bonding networks and other possible solvent-substrate interactions of HFIP.In this thesis,we used ab initio molecular dynamics(AIMD)and metadynamics simulation to perform explicit solvent simulations in order to understand the solvent effect of HFIP.Based on the dynamic features of key transition states,the major factors affecting reactivity of electrophilic substitution reactions in different types of solvents were identified.The main contents and results of this thesis are as follows.The first part describes the promotion effect of HFIP on the Friedel-Crafts alkylation reaction of epoxides.The cycloalkylation reaction of epoxides was investigated using AIMD and metadynamics simulations under explicit solvent environments to investigate the effect of the reactivity in different solvents.The results show that the reaction undergo a concerted mechanism.To understand the dynamic feature of solvent-substrate interactions,we performed AIMD simulations of the transition states,revealing key H-bonding networks and solventsubstrate interactions.While the strength of H-bonding interactions contributes to the reactivity,we also identified underappreciated HFIP-substrate C-H/π interactions for the enhanced reactivity by orbital and charge analyses.This type of C-H/π interaction also emphasizes the uniqueness of HFIP solvent.The second section describes the solvent effect of HFIP on the mechanism of FriedelCrafts acylation of acyl chloride compounds.The intramolecular Friedel-Crafts acylation reactions were investigated using AIMD and metadynamics simulations under explicit solvent environments,and two different classes of reaction mechanisms were obtained in four different solvents.The acylation reactions undergo the SN1 mechanism in perfluoro-2-methylpropan-2of(PFTB)and HFIP,while the SN2 mechanism in trifluoroethanol(TFE)and trifluoroethanethiol(TFET).We also calculated the intermolecular Friedel-Crafts acylation reactions in HFIP and TFE,and the results were consistent with the intramolecular acylation reactions.To explore the solvent effect on the mechanism and efficiency,we investigated the solvent-substrate interaction and found that the solvent cage is critical for facilitating the C(acyl)-Cl bond cleavage and stabilizing the leaving chloride anion.The third section describes the synergistic effect of HFIP with Br?nsted acid catalysts on facilitating electrophilic substitution of highly electronically deactivated benzylic alcohols.On the one hand,the electrophilic substitution reactions of the same electronically deactivated benzylic alcohols were investigated using AIMD and metadynamics simulations under explicit solvent environments,and the SN2 mechanism was obtained in three different solvents.On the other hand,six substrates with different degrees of electron deficiency were investigated in HFIP using AIMD and metadynamics simulations,and two different reaction mechanisms of SN1 and SN2 were obtained.For different substrates,HFIP can pre-activate TfOH catalysts to help hydroxyl group of benzyl alcohol leave and HFIP can stabilize the hydroxyl group to improve the reactivity.The effect of the different substrates on the reaction mechanism is divided into two aspects:steric effect and electronic effect.The steric hindrance effect is the dominant factor of the low electron unactivation of benzyl alcohol,leading to the SN1 mechanism.In the highly electron-unactivated benzyl alcohol,the reactions undergo the SN2 mechanism even though the benzyl sites exist steric hindrance.