Theoretical Investigation of <i>N</i>-Nitrosodimethylamine Formation from Dimethylamine Nitrosation Catalyzed by Carbonyl Compounds

The carbonyl-compound-catalyzed nitrosation of amines to form carcinogenic nitrosamines under nonacidic condition is different from the classic nitrosation via acidification of nitrite anion. The mechanistic pathways of N-nitrosodimethylamine (NDMA) formation by the reactions of dimethylamine (DMA) with the nitrite anion catalyzed by carbonyl compounds have been investigated using the DFT/B3LYP method at the 6-311+G(d,p) level. The computational results show that the energy barriers of the nucleophilic addition reaction, which were calculated as 27−40 kcal/mol, increase significantly with methylation but vary slightly with chloromethylation on the carbonyl group. Comparison of energy barriers of this nucleophilic addition reaction and the electrophilic substitution reaction indicates that the former is the rate-determining step, from which the order of the catalytic activity is obtained as formaldehyde > chloral > acetaldehyde > acetone. Furthermore, analysis of electronic and steric effects on catalytic activity reveals that electron-withdrawing substituents decrease the energy barrier but electron-donating substituents and steric hindrance will block this catalytic reaction. Based on this discovery, fluoral is proposed as a good catalyst for the nitrosation of DMA by nitrite anion, which has a calculated energy barrier of about 26 kcal/mol. The results obtained in this work will help elucidate the mechanisms of formation of nitrosamines

Theoretical Investigation of Nitration and Nitrosation of Dimethylamine by N₂O₄

Reactive nitrogen oxygen species (RNOS) contribute to the deleterious effects attributed to reacting with biomolecules. The mechanisms of the nitration and nitrosation of dimethylamine (DMA), which is the simplest secondary amine by N2O4, a member of RNOS, have been investigated at the CBS-QB3 level of theory. The nitration and nitrosation proceed via different pathways. The nitration of DMA follows three pathways. The first is the abstraction of the hydrogen atom of the amino group of DMA by the NO2 radical followed by a recombination reaction of the resulting aminyl radical with another NO2 radical. The second is DMA directly reacting with symmetrical O2NNO2 leading to dimethylnitramine via a concerted and a stepwise mechanism. The third is the reaction of DMA with asymmetrical ONONO2. By computation, the main pathway for the formation of dimethylnitramine in the gas phase is by DMA directly reacting with asymmetrical ONONO2. As to the nitrosation, a concerted mechanism for the reaction of DMA with asymmetrical ONONO2 plays a major role in nitrosodimethylamine (NDMA) formation. In addition, the solvent effect on these nitration and nitrosation reactions has been also studied by using the implicit polarizable continuum model. Two major pathways of the formation of dimethylnitramine in water were found, and they are the radical process involving NO2 and the concerted mechanism starting from symmetrical O2NNO2. The result of the nitrosation of DMA in water is consistent with that in the gas phase. Comparison of the energy barriers of each mechanism leads to the conclusion that the nitrosation is more favorable than the nitration in the reaction of DMA with N2O4. This conclusion is in good agreement with the experimental results. The results obtained here will help elucidate the mechanism of the lesions of biomolecules by RNOS

Theoretical Investigation of <i>N</i>-Nitrosodimethylamine Formation from Nitrosation of Trimethylamine

Tertiary amines have been demonstrated to be capable of undergoing nitrosative cleavage to produce carcinogenic N-nitrosamines. The reaction mechanism of the nitrosation of trimethylamine (TMA) to produce N-nitrosodimethylamine (NDMA) was investigated at the CBS-QB3 level of theory. The formation of NDMA from TMA was proposed to be initiated by the formation of an iminium ion, Me2N+CH2. Two different mechanisms (NOH elimination mechanism and oxidation abstraction mechanism) leading to Me2N+CH2 were investigated, and the oxidation abstraction mechanism was found to be mainly operative. This result indicates that the oxidation abstraction mechanism plays an important role in the nitrosation of both N,N-dialkyl aromatic and tertiary aliphatic amines. Starting from the iminium ion, two experimentally proposed mechanisms (pathways 1 and 2) and one new mechanism (pathway 3) were examined. Pathway 1 proposes that the iminium ion undergoes hydrolysis to give dimethylamine (DMA), which then can be further nitrosated to NDMA; pathway 2 proposes that the iminium ion reacts with NO2− and forms a neutral intermediate, which then collapses to NDMA. In pathway 3, the iminium ion reacts with N2O3 to give NDMA. Calculation results indicate that in aqueous solution pathway 1 is more feasible than pathways 2 and 3; moreover, the transformation from the iminium ion to NDMA is the rate-determining step. This work will be helpful to elucidate the formation mechanisms of the carcinogenic N-nitrosamines from the nitrosation of tertiary amines

Carbon Dioxide in the Nitrosation of Amine: Catalyst or Inhibitor?

Nitrosamines are a class of carcinogenic, mutagenic, and teratogenic compounds generally produced from the nitrosation of amine. This paper investigates the mechanism for the formation of nitrosodimethylamine (NDMA) from the nitrosation of dimethylamine (DMA) by four common nitrosating agents (NO2–, ONOO–, N2O3, and ONCl) in the absence and presence of CO2 using the DFT method. New insights are provided into the mechanism, emphasizing that the interactions of CO2 with amine and nitrosating agents are both potentially important in influencing the role of CO2 (catalyst or inhibitor). The role of CO2 as catalyst or inhibitor mainly depends on the nitrosating agents involved. That is, CO2 shows the catalytic effect when the weak nitrosating agent NO2– or ONOO– is involved, whereas it is an inhibitor in the nitrosation induced by the strong nitrosating agent N2O3 or ONCl. To conclude, CO2 serves as a “double-edged sword” in the nitrosation of amine. The findings will be helpful to expand our understanding of the pathophysiological and environmental significance of CO2 and to develop efficient methods to prevent the formation of carcinogenic nitrosamines

Reactions of Amine and Peroxynitrite: Evidence for Hydroxylation as Predominant Reaction and New Insight into the Modulation of CO₂

Peroxynitrite is related to numerous diseases including cardiovascular diseases, inflammation, and cancer. In order to expand the understanding for the toxicology of peroxynitrite in biological system, the reactions of amine (morpholine as a probe) with peroxynitrite and the modulation of CO₂ were investigated by using DFT methods. The results strongly indicate that the hydroxylation of amine by peroxynitrous acid ONOOH, which was previously overlooked by most studies, is predominant relative to the widely reported nitration and nitrosation in the absence of CO₂. The product <i>N</i>-hydroxylamine is proposed to be mainly generated via nonradical pathway (two-electron oxidation). The modulation of CO₂ exhibits two main functions: (1) inhibition of hydroxylation due to the promoted consumption of peroxynitrite via fast reaction of CO₂ with ONOO¯ to form ONOOCO₂¯; (2) dual effect (catalysis and inhibition) of CO₂ toward nitration and nitrosation. As a new insight, amine does react with CO₂ and produce inert amine carbamate R₂NCOO¯. This reaction has the potential to compete with the reaction of CO₂ and ONOO¯, which leads to inhibition of nitration and nitrosation. The concentration of CO₂ could be a critical factor determining the final effect, catalysis or inhibition. As a new finding, HCO₃¯ is probably an effective catalyst for the reaction of amine and CO₂. Moreover, further studies on how the different types of the amine might affect the outcome of the reactions would be an interesting topic

Theoretical Investigation of the Gas-Phase S_N2 Reactions of Anionic and Neutral Nucleophiles with Chloramines

The SN2 reactions at nitrogen center (SN2@N) play a significant role in organic synthesis, carcinogenesis, and the formation of some environmentally toxic compounds. However, the SN2@N reactions specifically for neutral compounds as nucleophiles are less known. In this work, reactions of dimethylamine (DMA) and F– with NH2Cl were investigated as model reactions to validate an accurate functional from 24 DFT functionals by comparing with the CCSD­(T) reference data. M06-2X functional was found to perform best and applied to systematically explore the trends in reactivity for halides (F– and Cl–) and simple amines toward the substrates NH2Cl and NHCl2 (SN2@N) as well as CH3Cl and CH2Cl2 (SN2@C). The computational results show that the backside inversion channel dominates most the SN2@N reactions except for the case of F– + NHCl2, which reacts preferentially via proton transfer. The overall activation free energies (ΔG‡) of the inversion channel for the SN2 reactions of F– and Cl– with chloramines are negative, whereas those for amines as nucleophiles are around 30–44 kcal/mol. The SN2@N reactions for all the nucleophiles investigated here are faster than the corresponding SN2@C. Moreover, amines react faster when they have a higher extent of methyl substitution. Additionally, the energy gap between the HOMO of nucleophile and LUMO of substrate generally correlates well with ΔG‡ of the corresponding SN2 reactions, which is consistent with previous results

Reaction Mechanisms of Histidine and Carnosine with Hypochlorous Acid Along with Chlorination Reactivity of N‑Chlorinated Intermediates: A Computational Study

Hypochlorous acid (HOCl) released from activated leukocytes not only plays a significant role in the human immune system but is also implicated in numerous diseases including atherosclerosis and some cancers due to its inappropriate production. Histidine (His) and carnosine (Car), as a respective mediator and protective agent of HOCl damage, have attracted considerable attention; however, their detailed reaction mechanisms are still unclear. In this study, using a His residue with two peptide bond groups (HisRes) as a model, the reaction mechanisms of HisRes and Car including NεH and NδH tautomers with HOCl along with the chlorination reactivity of N-chlorinated intermediates were investigated by quantum chemical methods. The obtained results indicate that in the imidazole side chain, the pyridine-like N is the most reactive site rather than the pyrrole-like N, and the kinetic order of all of the possible reaction sites in HisRes follows pyridine-like N > imidazole Cδ ≫ imidazole Cε > pyrrole-like N, while that in Car is pyridine-like N ≫ imidazole Cδ ≫ amide N. As for N-chlorinated intermediates at imidazole, although the unprotonated form has a low chlorination reactivity as expected, it can still chlorinate tyrosine. Especially, the protonated form exhibits similar ability to HOCl, causing secondary damage in vivo. N-Chlorinated Car features higher internal chlorine migration ability than its intermolecular transchlorination, preventing further HOCl-induced damage. Additionally, a generally overlooked nucleophilic Cl– shift is also found in N-chlorinated Car/HisRes, indicating that nucleophilic sites in biomolecules also need to be considered. The outcomes of this study are expected to expand our understanding of secondary damage and protective mechanisms involved in HOCl in humans

Computational Investigations of Reaction Mechanisms and Transformation Products of Olefins with Hypochlorous Acid

Hypochlorous acid (HOCl) as the main component in chlorination and also as the innate immune factor relevant to immune defense has attracted considerable attention. Electrophilic addition reaction of olefins with HOCl, one of the most important prototype of chemical reactions, has been intensively studied for a long time; however, it has not been fully understood yet. In this study, addition reaction mechanisms and transformation products of model olefins with HOCl were systematically investigated by the density functional theory method. The results indicate that the traditionally believed stepwise mechanism with a chloronium-ion intermediate is only suitable for olefins substituted with electron-donating groups (EDGs) and weak electron-withdrawing groups (EWGs) but it is a carbon-cation intermediate that is favorable for EDGs featuring p−π or π–π conjugation with the CC moiety. Moreover, olefins substituted with moderate or/and strong EWGs prefer the concerted and nucleophilic addition mechanisms, respectively. Epoxide and truncated aldehyde as the main transformation products can be generated from chlorohydrin through a series of reactions involving hypochlorite; however, their generation is kinetically not as feasible as the formation of chlorohydrin. The reactivity of three chlorinating agents (HOCl, Cl2O, and Cl2) and the case study of chlorination and degradation of cinnamic acid were also explored. Additionally, APT charge on the double-bond moiety in olefin and energy gap (ΔE) between the highest occupied molecular orbital (HOMO) energy of olefin and the lowest unoccupied molecular orbital (LUMO) energy of HOCl were found to be good parameters to distinguish the regioselectivity of chlorohydrin and reactivity of olefin, respectively. The findings of this work are helpful in further understanding the chlorination reactions of unsaturated compounds and identifying complicated transformation products

Formation Mechanism of NDMA from Ranitidine, Trimethylamine, and Other Tertiary Amines during Chloramination: A Computational Study

Chloramination of drinking waters has been associated with <i>N</i>-nitrosodimethylamine (NDMA) formation as a disinfection byproduct. NDMA is classified as a probable carcinogen and thus its formation during chloramination has recently become the focus of considerable research interest. In this study, the formation mechanisms of NDMA from ranitidine and trimethylamine (TMA), as models of tertiary amines, during chloramination were investigated by using density functional theory (DFT). A new four-step formation pathway of NDMA was proposed involving nucleophilic substitution by chloramine, oxidation, and dehydration followed by nitrosation. The results suggested that nitrosation reaction is the rate-limiting step and determines the NDMA yield for tertiary amines. When 45 other tertiary amines were examined, the proposed mechanism was found to be more applicable to aromatic tertiary amines, and there may be still some additional factors or pathways that need to be considered for aliphatic tertiary amines. The heterolytic ONN­(Me)₂–R⁺ bond dissociation energy to release NDMA and carbocation R⁺ was found to be a criterion for evaluating the reactivity of aromatic tertiary amines. A structure–activity study indicates that tertiary amines with benzyl, aromatic heterocyclic ring, and diene-substituted methenyl adjacent to the DMA moiety are potentially significant NDMA precursors. The findings of this study are helpful for understanding NDMA formation mechanism and predicting NDMA yield of a precursor