Quantum Chemical Simulation Of The Reaction Mechanism Of Nicotine With Nitrite And Hydroxyl Radicals

Smoking seriously harms people’s health.Previous studies have found that smoking leads to cancer,heart disease,and some lung diseases.Moreover,exposure to cigarette smoke will also increase the risk of atherosclerosis and cardiovascular diseases.Nicotine（1-methyl-2-（3-pyridyl）pyrrolidine）is one of the main organic nitrogen compounds in tobacco product and smoke.In the gas-phase environment,the previous studies have found that nicotine can react with nitrous acid,hydroxyl radicals,and ozone.The reaction mechanisms between nicotine and oxidants are very complicated,and thus it is difficult to accurately explain the overall chemical process only by experimental methods.In addition,the experimental research is costly,time-consuming,and the research cycle is usually long.Some important intermediates involved in the reaction process may also not be detected by the experiments.Therefore,it is necessary to develop theoretical calculation and prediction methods to study the coversion mechanism of nicotine in the gas-phase environment at the molecular level.This study aims to use quantum chemistry calculations to（1）explore the reaction mechanism of nicotine with nitrous acid and hydroxyl radicals,and（2）clarify the major reaction paths and products.The research results are helpful for understanding the mechanisitic details and relevant,kinetics and reaction thermodynamics,and provide a scientific basis for the environmental conversion,ecological and health risk assessment of this environmental pollutant.In this paper,the reaction mechanism of nicotine with nitrous acid and hydroxyl radical is studied based on quantum chemical calculation methods.The specific research content is as follows:（1）Theoretical Study on the Reaction Mechanism of Nicotine with Nitrite to Form Tobacco-Specific Nitrosamines（TSNAs）.Previous experimental studies have found that part of the nitrous acid in the atmosphere can be converted into highly reactive nitricoxide（NO⁺）,and then reacted with nicotine to form TSNAs.Based on density functional theory（DFT）calculations,we simulated the chemical process of the reaction of NO⁺with nicotine.The calculations suggest that NO⁺can attack the three carbon sites（C₁,C₂,C₃）its of nicotine by capturing the hydrogen anions to form respective cationic intermediates,followed by the NO₂^--assisted hydrolysis by nitrite to generate the hydroxylated intermediates.The intermediates susequently undergo the concerted hydrogen transfer and C-N bond cleavage,NO⁺attack at amino group,and proton departure to form three TSNAs,namely 4-(N-methylnitrosamine-1-（3-pyridyl）-1-butanone（NNK）,and N-nitrosonicotine（NNN）and 4-（N-methyl-N-nitrosamine）-4-（3-pyridyl）butyraldehyde（NNA）.The reaction barrier of NO⁺attack at C₂ site of nicotine is 8.38 kcal/mol,which is much lower than those of NO⁺attack at C1 and C3 sites（14.8 kcal/mol and 9.8 kcal/mol）,indicating that NNN is major product.This study proposed the detailed reaction mechanism between nicotine and nitrous acid,which can provided a strong theoretical basis for subsequent related experimental research.（2）Theoretical study on the Reaction of Nicotine with Hydroxyl Radical to Form Formamide and Isocyanate.Experimental studies have found that hydroxyl radicals（·OH）can react with nicotine in the gas phase to form isocyanate and formamides.Based on density functional theory（DFT）,we simulated the reaction between nicotine and·OH.The results show that·OH can attack the 5 carbon sites of pyrrolidine moiety of nicotine through the initial hydrogen atom abstractions and·OH addition steps to generate the hydroxylated intermediates.The hydroxylated nicotine subsequent undergo the intramolecular ring opening and multiple·OH-mediated hydrogen abstraction/addition reactions to form products isocyanate and formamide,which have been detected by the experiments.The·OH attack at C5 site has the lowest rate-determining barrier（14.23 kcal/mol）,suggesting it to be the major reaction pathway.Besides,the reaction barrier of rate-determining step for·OH attack at C4 site is calculated to be 16.4 kcal/mol,indicating that the demethylation to be main reaction of nicotine by·OH.This study reasonably speculates the intermediate products involved in the nicotine oxidation by·OH,which can provide a meaningful guidance for the further study of nicotine conversion in the gas-phase environment.Overall,this study employed the quantum chemical calculation methods to construct the chemical reaction model,and to analyze the complete reaction mechanism and the relevant kinetics.The results will provide effective theoretical support for subsequent research in the related fields.