Study On The Mechanism Of Trifluoromethylation Of Styrene And Its Derivatives And Aromatic Amino Acids

Fluorinated organic compounds have been widely used in medicine and other fields because of their good physical and chemical properties.Through three fluorine carbon carbon double bond of styrene and its derivative methyl reagent of a radical and free radical of aromatic amino acids aromatic ring to replace is a kind of convenient and mild conditions for preparing the three means of fluorinated methyl compounds,determine the reaction mechanism and the influence of reaction conditions on the reaction of fluoride compounds in the field of synthesis and related application have important guiding significance.In this paper,Gaussian 09 quantum chemistry calculation software was used to explore the mechanism of the reaction at B3LYP/6-31+G（D,P）level.Firstly,the reaction mechanism and energy change of difunctionalization（trifluoromethylation and oxime）on styrene were investigated by using Langlois reagent（CF₃SO₂Na）as trifluoromethylation reagent and tert-butyl nitrite（TBN）as oxidant and oxime source under vacuum condition.Calculate the reaction energy barrier,reaction enthalpy change,Gibbs free energy change and reaction rate constant of each step in the reaction process.The reaction path ofα-trifluoromethyl ethyl ketone oxime consists of 7steps,starting from the decomposition of tert-butyl nitrite（TBN）to generate tert-butyl oxygen free radical and nitric oxide free radical.The sixth step of oxime reaction is rate-limiting step.In vacuum environment,the energy barrier is 57.80 kcal/mol,and the reaction rate constant is 9.607×10^-31 s.In order to study the effect of the type and location of substituents on the reaction,the effects of three substituents,methoxy（-CH₃O）,methyl（-CH₃）and fluorine（-F）,as well as the substitution sites of the benzene ring and double bondβ-c on the difunctionalization of styrene were investigated.When the electron-donating substituent—CH₃O is in the opposite position of the benzene ring,the fourth step can be greatly reduced by 99.88%.However,the substituents at different positions had almost no effect on the speed control step（Step 6）,indicating that the overall reaction rate could not be improved simply by changing the substituents at different positions or types.The influence of solvent effect on the reaction process was investigated.By quantum chemical calculation,PCM solvent model was used to calculate the energy change of the reaction process when dimethyl sulphoxide（DMSO）,ethanol and water were used as solvents at B3LYP/6-31+G（D,P）level.It was found that the solvent effect had little influence on the energy barrier change of the speed control step.Therefore,in practical experiments,DMSO with high boiling point and good solubility can be used as the reaction solvent to improve the reaction temperature and promote the reaction.The effect of water molecule-mediated proton transfer on the sixth step of difunctionalization of styrene and its derivatives oxime reaction was investigated.It was found that the proton transfer energy barrier of hydrogen atom fromβ-carbon atom to oxygen atom with N=O mediated by two water molecules in aqueous solution was reduced by 77.8%to 12.98 kcal/mol.In DMSO,the energy barrier of proton transfer mediated by two water molecules also decreased significantly,reaching 12.98 kcal/mol.In both aqueous and aqueous organic solvents,the proton transfer mediated by water molecules can significantly reduce the energy barrier of the rate-control step,and thus increase the overall reaction rate.The mechanism of aromatic ring radical substituting trifluoromethylation of phenylalanine,tyrosine and tryptophan initiated by Langlois reagent and tert-butyl nitrite was investigated using PCM aqueous solvent model.The results showed that the corresponding trifluoromethylated amino acids were obtained by substituting the hydrogen atom of the aromatic C-H bond with the trifluoromethylated amino acid by the trifluoromethylated free radical,and the reaction energy barrier was lower than 15 kcal/mol,indicating that the trifluoromethylated amino acid C atom was relatively easy to proceed.By comparing the reaction rate constants,it is found that the reaction products of phenylalanine are mainly in the para-position,the reaction products of tyrosine are mainly in the ortho position,and the reaction products of tryptophan are mainly in the 1st and 5th position.