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

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Carbon Dioxide in the Nitrosation of Amine: Catalyst or Inhibitor? Zhi Sun, Yong Dong Liu,* and Ru Gang Zhong College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, People's Republic of China

bS Supporting Information ABSTRACT: 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.

1. INTRODUCTION Nitrosamines have been studied for many years and are recognized as a class of undesired industrial and environmental pollutants. Since the potent hepatocarcinogenic effect of Nnitrosodimethylamine (NDMA) on rats was reported by Magee and Barnes1 in 1956, numerous nitrosamines have been demonstrated to be carcinogenic, mutagenic, and teratogenic.28 Significantly, nitrosamines are ubiquitous in the environment. As reported, they have been found in air, soil, water, food, cosmetics, rubber products, and many other materials.921 In view of their toxicity to animals and their ubiquity in the environment, understanding the mechanisms by which nitrosamines are formed is of particular importance.2230 Nitrosation is an important pathway responsible for the formation of nitrosamine. Under certain conditions, nitrosamine can be formed from primary,22 secondary,23 tertiary,31,32 and even quaternary amines.33,34 Secondary amine is generally believed to be the most important precursor for nitrosamine due to its high reactivity. Nitrosating agents share the basic form of ONY in which Y corresponds to different groups, as reported in our previous work.35 The most common nitrosating agents, such as dinitrogen trioxide ONNO2 (N2O3)36 and nitrosylchloride ONCl (ONCl),24 have been widely studied due to their strong nitrosating activities. In addition, several weak nitrosating agents, food preservative37,38 as well such as nitrite NO2 h (a widely used 39,40 ) and peroxynitrite ONOO as a metabolized product in vivo (a well-known powerful oxidant and cytotoxic species formed under a variety of pathophysiological conditions in vivo41,42), have recently attracted much attention because the relevant nitrosation reactions induced by them were found to be promoted in the presence of some catalysts. r 2011 American Chemical Society

Carbonyl compounds have been found to be a class of catalysts contributing to the reaction of amine and NO2.43,44 The proposed catalytic mechanism involves a reaction between amine and carbonyl compounds to give an iminium ion (IM-1 in Scheme 1) and a further reaction of IM-1 with NO2 to form nitrosamine. As carbonyl compounds and CO2 both contain the CdO structure, Lv et al.45 theoretically predicted that CO2 may also serve as a catalyst for the nitrosation of amine using NO2, and a stepwise mechanism (Scheme 2) similar to what Scheme 1 proposed. The prediction of CO2 as a catalyst is somewhat supported by an experiment of Choi and Valentine46 in which 2 μg L1 NDMA was formed by the reaction of 0.1 mM DMA and 0.1 mM NO2 at pH 7.0 ( 0.1 using 1 mM bicarbonate buffer (CO2 is in equilibrium with HCO3), although the catalytic role of CO2 was not clearly recognized. In addition to NO2, Uppu et al.47 reported that the nitrosation of amine by ONOO can also be promoted by a low concentration of CO2 (note that excess CO2 shows an inhibitory effect). The catalytic effect was assumed to occur in a radical process in which ONOO reacts with CO2 to form a peroxynitriteCO2 adduct (nitrosoperoxycarbonate, ONOOCO2), and the generated adduct dissociates into radicals (CO3• and •NO2) that further interact with other radicals and amine to give nitrosamine. It is worth noting that a crucial difference in the mechanisms between the reported CO2-catalyzed nitrosation by NO245 and ONOO47 is the “primary” targets that CO2 attacks (pathways shown by the solid lines in Scheme 3). In the reaction of Received: March 2, 2011 Revised: May 2, 2011 Published: June 13, 2011 7753

dx.doi.org/10.1021/jp202002m | J. Phys. Chem. A 2011, 115, 7753–7764

The Journal of Physical Chemistry A “amine þ NO2 þ CO2”, the amine molecule is the target of the CO2,45 while CO2 attacks ONOO in the reaction of “amine þ ONOO þ CO2”.47 Because NO2 and ONOO are similar species, new questions arise (pathways shown by the dashed lines in Scheme 3). Would it be possible that the interaction between CO2 and NO2 also plays an important role in “amine þ NO2 þ CO2”? Also, in “amine þ ONOO þ CO2”, could it be possible that previous studies4850 have focused too much on the formation of ONOOCO2 from the reaction of ONOO with CO2, therefore, overlooked the potential reaction of amine with CO2? It is known that the reaction of amine with CO2 has been widely used as an important technology to capture the greenhouse gas CO2.5153 One aim of this work is to answer these questions. Nitric oxide (NO) is an important signaling molecule in a wide range of physiological and pathological events and can be synthesized in various types of cells by nitric oxide synthase (NOS).54,55 In the presence of oxygen, the nitrosating agent N2O3 can be produced in vivo from the conversions of NO (eqs 1,2).56 If CO2 could also promote the nitrosation by N2O3, as it does in the case of NO2 and ONOO, there would be catastrophic consequences because toxic nitrosamines could be dramatically formed in vivo. Fortunately and interestingly, according to experiments performed by Kirsch et al.57 and Caulfield et al.,58 CO2 exhibits an inhibitory function in the nitrosation of secondary amine via a nitric oxide/oxygen mixture (NO/O2). However, the authors have different opinions as to which species, CO2 or the equilibrated HCO3, actually inhibits the nitrosation. In this paper, the inhibitory mechanisms based on these two different opinions will be reviewed and discussed using theoretical methods. Furthermore, because nitrosation by N2O3 can be inhibited by CO2, this inhibitory function may extend to nitrosation by other potent nitrosating agents, such as Scheme 1. Nitrosamine Formation from the Reaction of Amine and NO2 Catalyzed by Carbonyl Compounds

Scheme 2. Nitrosamine Formation from the Reaction of Amine and NO2 Catalyzed by Carbon Dioxide

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ONCl, and this hypothesis will also be evaluated.

•

2• NO þ O2 f 2• NO2

k1 ¼ 2:9 106 M2 s1

NO þ • NO2 h N2 O3

k2 ¼ 1:1 109 M1 s1 k2 ¼ 8:1 104 s1

ð1Þ

ð2Þ

As stated above, the influence of CO2 on the nitrosation of amine is a complex mechanistic question, thus, many open questions need to be resolved, especially at the mechanistic level. Therefore, the present study aims at a holistic understanding of the role of CO2 in the nitrosation of amine by different nitrosating agents. The similarities and differences between the relevant reaction mechanisms will be discussed and elucidated. New insights into the mechanisms will be presented. Dimethylamine (DMA), a probable precursor of the potent carcinogen NDMA,25,27 was selected as the model compound for amine. Four typical nitrosating agents, including NO2, ONOO, N2O3, and ONCl were taken into consideration. This work will be helpful to better understand nitrosation mechanisms and will help in the search for efficient methods to prevent the formation of carcinogenic nitrosamines.

2. COMPUTATIONAL METHOD The nitrosation of DMA in the absence and presence of CO2 was investigated using the B3LYP method (Becke’s three-parameter nonlocal exchange functional59 with the correlation functional of Lee, Yang, and Parr60), in conjunction with the 6-311þG(d,p) basis set.61 All the structures of the reactants, transition states, intermediates, and products were fully optimized. Vibrational frequencies were also calculated at the same level to characterize the nature of each stationary point. The Intrinsic Reaction Coordinate (IRC)62 calculation was performed to confirm that every transition state connects with the corresponding reactant and product through the minimizedenergy pathway. On the basis of optimized geometries at the B3LYP/6-311þG(d,p) level, the single-point energy of each stationary point was obtained using the CCSD(T)63 method in conjunction with the 6-311þG(d,p) basis set, also denoted as CCSD(T)/6-311þG(d,p)//B3LYP/6-311þG(d,p). All calculations were carried out with the Gaussian 03 program package.64 Because the reactions studied are expected to take place in aqueous solution, the solvent effect of water was also taken into account. As a widely used strategy,6568 based on the optimized geometries obtained at the B3LYP/6-311þG(d,p) level, the single-point energy calculation was carried out using the conductor-like polarizable continuum model (CPCM)69 at the CCSD(T)/6-311þG(d,p) level, also denoted

Scheme 3. Two Different Pathways (Solid and Dashed Line) Proposed for the CO2-Catalyzed Nitrosation of Amine by NO2 and ONOO, Respectively

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The Journal of Physical Chemistry A

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Scheme 4. Formation of NDMA from the Nitrosation of DMA in the Absence of CO2

Figure 1. Optimized geometries of all the transition states for the nitrosation of DMA in the absence of CO2 (distances in Å).

as CPCM-CCSD(T)/6-311þG(d,p)//B3LYP/6-311þG(d,p). According to calculation results from Takano and Houk,70 the UAKS cavity was selected to evaluate the aqueous solvation effects, and the rest of the parameters in the models kept the default values from the Gaussian 03 program package.

3. RESULTS AND DISCUSSION As a basis for comparison, the nitrosation of DMA by nitrosating agents (NO2, ONOO, N2O3, and ONCl) leading to NDMA in the absence of CO2 is investigated first. Following this, the study of NDMA formation from nitrosation in the 7755



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Table 1. Energy Barriers and Reaction Energies for the Nitrosation of DMA in the Absence of CO2 at the B3LYP/6-311þG(d,p) Level a reactions

ΔE‡0 K

ΔH298 K

ΔG298 K

ΔE‡b

ΔE‡solc

DMA þ NO2 f NDMA þ OH

42.05

41.06

44.07

46.09

54.19

DMA þ ONOO f NDMA þ OOH DMA þ N2O3 f NDMA þ HNO2

41.69 7.34

2.71 15.91

4.50 18.19

44.88 6.89

43.73 1.51

DMA þ ONCl f NDMA þ HCl

7.09

14.94

15.26

2.70

4.36

All energies are in kcal mol1. b Reaction barriers calculated at the CCSD(T)/6-311þG(d,p)//B3LYP/6-311þG(d,p) level in the gas phase. c Reaction barriers calculated at the CCSD(T)/6-311þG(d,p)//B3LYP/6-311þG(d,p) level in aqueous solution. a

presence of CO2 and a comparison of these mechanisms are provided to elucidate whether and how CO2 catalyzes or inhibits NDMA formation. 3.1. Nitrosation in the Absence of CO2. In the absence of CO2, the nitrosation of DMA occurs through the mechanisms shown in Scheme 4. The fully optimized transition structures are shown in Figure 1. Energy data are collected in Table 1. The transition state for the hypothetical reaction of DMA with NO2 leading to NDMA and OH (dashed line in Scheme 4) was not found. Attempts to locate such a transition state lead to a probable transition state TS1 shown in Figure 1, however, the forward IRC calculation fails to reach NDMA. Moreover, as shown in Table 1, the energy barrier of the forward reaction in the aqueous solution is rather high as 54.19 kcal mol1. These results indicate that NO2 is a very weak nitrosating agent, which is consistent with experimental result.43 As shown in Scheme 4, DMA can react with ONOO via a four-membered cyclic transition state TS2 (Figure 1) leading to NDMA and OOH. The energy barrier was calculated to be as high as 44.88 and 43.73 kcal mol1 in the gas phase and aqueous solution, respectively. Therefore, ONOO per se is not an effective nitrosating agent. Along with our previously reported high barrier (about 40.7 kcal mol1) for the nitrosation of NH3 by peroxynitrous acid (ONOOH),35 our results support the conclusion reached by Williams et al.71 that direct nitrosation by ONOO or ONOOH is unlikely to occur. This result is also consistent with the conclusion from Williams et al.71 that both O22 and OOH are poor leaving groups from the parent molecules (ONOO and ONOOH) for the purpose of generating the nitrosating species ONþ. In contrast to NO2 and ONOO, the nitrosation of DMA by N2O3 occurs very easily with a low energy barrier, 6.89 and 1.51 kcal mol1 in the gas phase and aqueous solution, respectively. From the gas phase to aqueous solution, the barrier is reduced by 5.38 kcal mol1. It can be attributed to the fact that the solvent effect reduces the absolute energy of TS3 to a larger extent than that of the corresponding reactant complex (RC3) (see the Supporting Information, SI). Moreover, the reaction is exothermic by 15.91 kcal mol1 at the B3LYP/6-311þG(d,p) level. The result agrees well with the established experimental result that N2O3 is an effective nitrosating agent.36 The energy barrier of the nitrosation of DMA by ONCl was calculated to be 2.70 kcal mol1 in the gas phase. Significantly, the barrier even disappears in aqueous solution with the corresponding value being 4.36 kcal mol1. Therefore, it can be viewed as a barrierless process. Similar negative energy barriers were also reported in some previous studies.7276 The results indicate clearly that DMA reacts very easily with ONCl to give NDMA, which is consistent with experimental observation that ONCl is an effective nitrosating agent.24

Scheme 5. Proposed Reaction Pathways for the NDMA Formation when CO2 First Interacts with DMA

3.2. Nitrosation in the Presence of CO2. 3.2.1. Effect of CO2 on DMA. As illustrated in Scheme 5, a stepwise reaction mechan-

ism leading to NDMA was proposed when the effect of CO2 on DMA was taken into consideration. This mechanism includes three steps: (1) formation of an anti-dimethylcarbamic acid (anti-DMCA) from the reactions of DMA with CO2; (2) isomerization of dimethylcarbamic acid from anti to syn conformation; (3) formation of NDMA from the reaction of syndimethylcarbamic acid (syn-DMCA) with the nitrosating agents ONY (Y = O, OO, NO2, and Cl). A. Formation of anti-DMCA (Step 1). In step 1, three pathways leading to anti-DMCA by the reaction of DMA and CO2 were found. As shown in Scheme 6, they are the nonassisted mechanism (DMA þ CO2), H2O-assisted mechanism (DMA þ H2O þ CO2), and DMA-assisted mechanism (2DMA þ CO2). The energy data are listed in Table 2. The fully optimized transition structures are shown in Figure 2. Energy data in Table 2 indicate that the direct reaction of DMA and CO2 (nonassisted mechanism) hardly occurs due to the high barrier 34.58 kcal mol1 in aqueous solution. The barriers of the H2O-assisted mechanism and DMA-assisted mechanism were calculated to be 18.71 and 0.43 kcal mol1, respectively. Consequently, the mechanisms assisted by a third molecule (H2O or DMA) are more preferred than the nonassisted mechanism to generate DMCA, which is mainly due to the stability of the six-membered cyclic transition states 7756



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Scheme 6. Formation of anti-DMCA from the Reaction of DMA and CO2

Table 2. Energy Barriers and Reaction Energies in the Formation of anti-DMCA from the Reaction of DMA and CO2 at the B3LYP/6-311þG(d,p) Levela reactions

ΔE‡0 K

ΔH298 K

ΔG298 K

ΔE‡b

ΔE‡solc

DMA þ CO2 f anti-DMCA

38.79

9.36

13.70

39.70

34.58

DMA þ CO2 þ H2O f anti-DMCA þ H2O

21.42

7.49

10.61

23.72

18.71

2DMA þ CO2 f anti-DMCA þ DMA

18.39

4.33

9.45

16.78

0.43


Figure 2. Optimized geometries of all the transition states in the formation of anti-DMCA from the reaction of DMA with CO2 (distances in Å).

TS5-water and TS5-dma in the third molecule participation system. Although a higher barrier (18.71 kcal mol1) was obtained for the H2O-assisted mechanism than the barrier (0.43 kcal mol1) of the DMA-assisted mechanism, the possibility of the participation of an H2O molecule in the reaction should not be ignored due to the high concentration of H2O in the solution as well as its small steric hindrance. Our results directly support the experimental conclusion from Crooks and Donnellan77 that the reaction between amine and CO2 is single-step and termolecular for both H2O and amine molecules being capable of assisting the reaction. In addition to CO2, possible reactions of DMA with equilibrated bicarbonate HCO3 were also examined, however, high barriers were found for the reactions. As carbonic acid H2CO3 is a

very short-lived intermediate,78,79 which dissociates rapidly in water at ambient temperature, it was not taken into consideration here. B. Isomerization of anti-DMCA to syn-DMCA (Step 2). The isomerization of anti-DMCA to syn-DMCA (step 2 in Scheme 5) occurs very easily (barrier: 2.36 kcal mol1 in aqueous solution). As illustrated in Figure 3, the main geometrical change during the isomerization is only the rotation of the C10O12 bond to convert the H13 atom from anti to syn position, which explains the low energy barrier. Moreover, the isomerization is exothermic by 8.37 kcal mol1. Therefore, syn-DMCA is more stable than anti-DMCA, which is consistent with the result of previous study.80 7757



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Figure 3. Optimized geometries of all the stationary points in the isomerization of DMCA (distances in Å).

Scheme 7. Formation of NDMA from the Reactions of syn-DMCA with Nitrosating Agents

C. Nitrosation of syn-DMCA (Step 3). The formed synDMCA may react with nitrosating agents to generate NDMA (step 3 in Scheme 5). The detailed mechanism is illustrated in Scheme 7, and the corresponding transition structures are depicted in Figure 4. Significantly, data in Table 3 show that the reactions of syn-DMCA with the four nitrosating agents hardly occur due to high barriers (barriers: 44.94 kcal mol1 for NO2, 38.29 kcal mol1 for ONOO, 28.12 kcal mol1 for N2O3, and 27.74 kcal mol1 for ONCl). The effect of CO2 on DMA can be elucidated by a comparison between the nitrosation of DMCA (Table 3 and Scheme 7) and DMA (Table 1 and Scheme 4). For NO2 and ONOO, although the barriers (44.94 and 38.29 kcal mol1, Table 3) for DMCA are slightly lower than those (54.19 and 43.73 kcal mol1, Table 1) for DMA, the nitrosation of DMCA is still very hard to occur to form NDMA because of the high barriers. For N2O3 and ONCl, a significant increase in energy barrier (ca. 30 kcal mol1) from

DMA to DMCA can be found, which indicates that DMA can be remarkably deactivated by CO2 via generating DMCA. This large discrepancy can be rationalized by frontier molecular orbital8184 analysis shown in Figure 5. The interaction between the HOMO of DMA (or DMCA) and the LUMO of nitrosating agents (N2O3 or ONCl) produces the highest stabilization because these orbitals are closest in energy. The inert DMCA is attributed to its low HOMO energy (lower than the HOMO of DMA by 0.030 hartree) which causes a larger HOMOLUMO energy gap than that for DMA. In addition to DMCA, possible reactions of N,N-dimethylcarbamate (Me2NCOO, the deprotonated species of DMCA, denoted as DMC, see eq 3) with the four nitrosating agents were also investigated. However, all attempts to find the relevant transition states failed. As for NO2 and ONOO, one explanation could be that the negatively charged DMC rejects the attacks of anions NO2 and ONOO. Another possible reason is that the 7758



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Figure 4. Optimized geometries of all the transition states in the nitrosation of syn-DMCA by nitrosating agents (distances in Å).

Table 3. Energy Barriers and Reaction Energies in the Reactions of syn-DMCA with the Nitrosating Agents at the B3LYP/6311þG(d,p) Levela ΔE‡0 K

ΔH298 K

ΔG298 K

ΔE‡b

ΔE‡solc

syn-DMCA þ NO2 f NDMA þ HCO3

51.99

17.98

16.64

48.63

44.94

syn-DMCA þ ONOO f NDMA þ HCO4

47.80

6.75

7.14

44.22

38.29

syn-DMCA þ N2O3 f NDMA þ HCO3NO

37.33

7.25

7.91

30.87

28.12

syn-DMCA þ ONCl f NDMA þ HCO2Cl

39.18

5.24

4.10

31.37

27.74

reactions


HOMOs of DMCA and DMC are substantially different from each other. As shown in Figure 6, the HOMO of DMCA has a considerable amplitude for the N and C atoms (reaction sites), whereas the corresponding distribution of HOMO for DMC is almost negligible. R 1 R 2 NCOOH h R 1 R 2 NCOO þ Hþ

ð3Þ

The stability of DMCA (or DMC) toward nitrosating agents explains the detection of significant amount of amine carbamate in the experiment performed by Kirsch et al.57 and demonstrates that the reaction between amine and CO2 is indeed a pathway to inhibit the nitrosation of amines by common nitrosating agents such as N2O3 and ONCl. In addition, the direct nitrosation of DMA (Scheme 5) by N2O3 or ONCl (to give NDMA) probably competes with the reaction of DMA and CO2 (to give DMCA and DMC) because of similar low barriers. This also agrees well with the result from Kirsch et al.57 that both N-nitrosomorpholine and morpholine carbamate were detected when morpholine reacts with N2O3 in the presence of HCO3, and the inhibitory efficiency is about 45% (inhibitory efficiency for piperazine is about 66%).

3.2.2. Effect of CO2 on Nitrosating Agents. A. Effect of CO2 on NO2 and ONOO. As shown in Scheme 8, a new mechanism is proposed that NO2 reacts first with CO2 to form ONOCO2 which then reacts with DMA via a six-membered cyclic transition state TS10 (Figure 7) to form NDMA via releasing HCO3. The formation of ONOCO2 from NO2 and CO2 is exothermic by about 7 kcal mol1. The energy barrier (Table 4) of the reaction of DMA with ONOCO2 was calculated to be 23.30 kcal mol1 in aqueous solution. Therefore, it is a feasible pathway (Scheme 8) for the formation of NDMA in the “amine þ NO2 þ CO2” reaction system.46 The overall reaction mechanism for “amine þ NO2 þ CO2” is summarized in Scheme 9. The feasible pathway of the NDMA formation (DMA þ ONOCO2) may be limited by the consumption of DMA and CO2 during the formation of inert DMC. However, the catalytic effect of CO2 should not be ignored because the hazardous concentration of NDMA in water could be very low (U.S. EPA lists a drinking water concentration resulting in a 106 risk of contracting cancer of 0.7 ng L1 for NDMA).85 To the best of our knowledge, few studies have directly aimed at the CO2-catalyzed N-nitrosation of amine by NO2, and 7759



Figure 5. Frontier molecular orbitals (energies in hartree) of DMA, synDMCA, and nitrosating agents (N2O3 and ONCl).

Figure 6. Highest occupied molecular orbitals (HOMOs) of synDMCA and DMC.

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further investigation should be carried out to check this possible catalysis due to the ubiquity of CO2 and NO2 in vitro as well as in vivo. Indirect evidence comes from the experiment86 in which wet SiO2 was used as an effective catalyst to synthesize nitrosamine under mild and heterogeneous conditions. Because both C and Si belong to group IVA, SiO2 may catalyze the reaction via a similar mechanism to the CO2-catalyzed nitrosation studied here. If this assumption is correct, other IVA elements (Ge, Sn, and Pb) in the form of GeO2, SnO2, and PbO2 may also have catalytic abilities. In addition, Andrzejewski et al.26,30,87,88 recently found that NDMA was produced from the aqueous solution of DMA treated with oxidants such as ClO2,26 MnO2,30 and O3.88 Due to the similar structures of these oxidants to CO2, the CO2-catalyzed nitrosation studied here may provide some useful information for further study of the oxidant-induced NDMA formation. A radical mechanism has been established experimentally for CO2-catalyzed nitrosation by ONOO.47,49,89 We present here a concerted mechanism (Scheme 10) that may be also involved in CO2-catalyzed nitrosation by ONOO. Similar to the mechanism for NO2 (Scheme 8), ONOO and CO2 interact first to form ONOOCO2, which then reacts with DMA to give NDMA via TS11 (Figure 7). The formation of ONOOCO2 from ONOO and CO2 is exothermic by about 17 kcal mol1, and the energy barrier for the further reaction of DMA with ONOOCO2 was calculated to be 20.78 kcal mol1 (Table 4) in aqueous solution. Therefore, the mechanism in Scheme 10 is feasible to form NDMA. Along with the experimentally proposed radical mechanism,47,49,89 our result again demonstrates the crucial role of ONOOCO2 in the CO2-catalyzed nitrosation by ONOO, and the newly proposed mechanism may also contribute to the formation of NDMA. B. Effect of CO2 on N2O3 and ONCl. In contrast to NO2 or ONOO, no possible reactions between CO2 with N2O3 or ONCl were found. This can probably be attributed to the fact that the chemistry of anions NO2 and ONOO is substantially

Scheme 8. Formation of NDMA from the reaction of DMA and ONOCO2

Figure 7. Optimized geometries of all the transition states in the reaction of DMA with ONOCO2 and ONOOCO2 (distances in Å). 7760



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Table 4. Energy Barriers and Reaction Energies in the Reaction of DMA with ONOCO2 as Well as ONOOCO2 at the B3LYP/ 6-311þG(d,p) Levela ΔE‡0 K

ΔH298 K

ΔG298 K

ΔE‡b

ΔE‡solc

DMA þ ONOCO2 f NDMA þ HCO3

23.72

16.49

12.40

26.83

23.30

DMA þ ONOOCO2 f NDMA þ HCO4

22.42

21.24

19.07

23.37

20.78

reactions


Scheme 9. Summarized Reaction Scheme for the “DMA þ NO2 þ CO2” Reaction System

Scheme 10. Formation of NDMA from the Reaction of DMA and ONOOCO2

Figure 8. Optimized geometries of all the transition states in the reactions of HCO3 with N2O3 and ONCl (distances in Å).

different from those of neutral N2O3 or ONCl. Caulfield et al.58 found that bicarbonate HCO3 shows an inhibitory effect for the

nitrosation in oxygenated nitric oxide solution where N2O3 is the main nitrosating agent (eqs 1-2), and the inhibitory effect was 7761



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Table 5. Energy Barriers and Reaction Energies in the Reactions of HCO3 with N2O3 and ONCl at the B3LYP/6-311þG(d,p) Levela reactions

ΔE‡0 K

ΔH298 K

ΔG298 K

ΔE‡b

ΔE‡solc

HCO3 þ N2O3 f HNO2 þ NO2 þ CO2 (pathway 1)

2.14

23.38

25.59

8.09

17.27

HCO3 þ N2O3 f HNO2 þ NO2 þ CO2 (pathway 2) HCO3 þ ONCl f HNO2 þ Cl þ CO2 (pathway 1)

7.92 1.27

12.45 23.96

13.08 25.67

10.75 5.46

10.67 13.10

HCO3 þ ONCl f HCO3NO þ Cl (pathway 2)

6.70

9.10

7.15

8.09

8.66


Scheme 11. Summarized Reaction Scheme for the “DMA þ N2O3 þ CO2” Reaction System

proposed to be the result of the scavenging of nitrosating agent N2O3 by HCO3. Therefore, the effect of equilibrated HCO3 on the nitrosating agents N2O3 and ONCl was investigated. Two different reaction pathways (pathways 1 and 2, with transition state TS12 and TS13, respectively, Figure 8) were found for the reaction of HCO3 and N2O3. The two pathways lead to the same products CO2, HNO2, and NO2 directly; however, data in Table 5 indicate that pathway 2 (barrier: 10.67 kcal mol1) is more favored than pathway 1 (barrier: 17.27 kcal mol1). The lower barrier of pathway 2 is caused by the more stable TS13 than TS12 in aqueous solution (see Table S12 in SI). To conclude, the reaction between HCO3 and N2O3 occurs easily, and HCO3 may serve as an effective scavenger of nitrosating agent N2O3. The total reaction scheme for the “DMA þ N2O3 þ CO2” reaction system is shown in Scheme 11. It proposes that, even in the presence of CO2, the direct nitrosation of DMA by N2O3 is still the leading pathway for the NDMA formation due to its low energy barrier (1.51 kcal mol1), whereas it is inhibited by CO2 and the equilibrated species HCO3. Note that the most favored pathway (DMA-assisted mechanism) leading to DMC (barrier: 0.43 kcal mol1, Table 2) is preferred over the reaction of N2O3 and HCO3 (barrier: 10.67 kcal mol1, Table 5), indicating that the deactivation of DMA by CO2 is the main reason responsible for the inhibitory effect. This result supports the conclusion from Kirsch et al.57 that CO2, but not HCO3 inhibits the nitrosation of secondary amines. However, HCO3 exists in a high concentration in vivo, and the barrier of the reaction “HCO3 þ N2O3” is quite low (ca. 10 kcal mol1). Therefore, along with CO2, HCO3 may also contribute to the inhibitory effect for the nitrosation by N2O3. The ONCl reacts with HCO3 via similar mechanisms (pathways 1 and 2, with TS14 and TS15, respectively, Figure 8) to those of N2O3. Again, pathway 2 is preferred over pathway 1, and

the barriers are around only 10 kcal mol1. Therefore, HCO3 may also serve as a strong scavenger of ONCl to inhibit the nitrosation, and the above conclusions for N2O3 are also applicable for ONCl. This inhibitory function of CO2 may be extended to other common nitrosating agents.

4. CONCLUSIONS To better understand the role of CO2 in the nitrosation of amine, the formation mechanism of N-nitrosodimethylamine (NDMA) from the nitrosation of dimethylamine (DMA) by four different nitrosating agents (NO2, ONOO, N2O3, and ONCl) in the absence and presence of CO2 was investigated using the DFT method. The reaction of DMA and NO2/ONOO can be catalyzed by CO2 to form NDMA. The catalytic mechanism involves the reaction of CO2 with NO2/ONOO to form more reactive ONOCO2/ONOOCO2 and the further reaction with DMA to form NDMA. However, the catalytic pathway may be limited by the easy reaction between DMA and CO2 to give inert dimethylcarbamate (DMC). For NO2, if tissue nitrite is really an important pool to generate the signaling molecule NO as recently reported by Feelisch et al.,90,91 then the catalysis of CO2 may provide a feasible pathway for the transformation from NO2 to NO in vivo. It would be worth carrying out further investigations to check these assumptions. In the “DMA þ N2O3 þ CO2” reaction system, the nitrosation of DMA by N2O3 was found to be inhibited in the presence of CO2 in two ways. One is because equilibrated HCO3 easily reacts with N2O3 to make this nitrosating agent scavenged. The other is because of the easy reaction of DMA with CO2, which generates inert DMC. It can be concluded that CO2 serves as an inhibitor in the nitrosation of amine by N2O3. Similar results were also found for the nitrosating agent ONCl. Therefore, the 7762


The Journal of Physical Chemistry A inhibitory function of CO2 may be extended and utilized in the nitrosation induced by other common nitrosating agents. To conclude, CO2 plays a “double-edged sword” role in the nitrosation of amine. The results will help further elucidate nitrosation mechanisms and help in the search of new inhibitors and methods to prevent the formation of hazardous nitrosamine.

’ ASSOCIATED CONTENT

bS

Supporting Information. Absolute energy data for all reactions and geometries (Cartesian coordinates) of all the transition states. This material is available free of charge via the Internet at http://pubs.acs.org.

’ AUTHOR INFORMATION Corresponding Author

*Fax: þ86-10-6739-2001. E-mail: [email protected].

’ ACKNOWLEDGMENT The authors thank Mark Jonikas in Beijing University of Technology and Clari Searle in University of Warwick for English language suggestions. This work was supported by National Natural Science Foundation of China (No. 20903006), Beijing Natural Science Foundation (No. 2092008), and Beijing Nova Program (No. 2008B09). ’ REFERENCES (1) Magee, P. N.; Barnes, J. M. Br. J. Cancer 1956, 10, 114–122. (2) Anderson, L. M.; Souliotis, V. L.; Chhabra, S. K.; Moskal, T. J.; Harbaugh, S. D.; Kyrtopoulos, S. A. Int. J. Cancer 1996, 66, 130–134. (3) Hecht, S. S. Chem. Res. Toxicol. 1998, 11, 559–603. (4) Goto, Y.; Matsuda, T.; Ito, K.; Huh, H. H.; Thomale, J.; Rajewsky, M. F.; Hayatsu, H.; Negishi, T. Mutat. Res., Fundam. Mol. Mech. Mutagen. 1999, 425, 125–134. (5) Lin, H. L.; Hollenberg, P. F. Chem. Res. Toxicol. 2001, 14, 562–566. (6) Wolf, T.; Niehaus-Rolf, C.; Luepke, N. P. Food Chem. Toxicol. 2003, 41, 561–573. (7) Dennehy, M. K.; Loeppky, R. N. Chem. Res. Toxicol. 2005, 18, 556–565. (8) Mittal, G.; Brar, A. P. S.; Soni, G. Exp. Toxicol. Pathol. 2008, 59, 409–414. (9) Oliver, J. E. J. Environ. Qual. 1979, 8, 596–601. (10) Sen, N. P.; Seaman, S.; Miles, W. F. J. Agric. Food Chem. 1979, 27, 1354–1357. (11) Stehlik, G.; Richter, O.; Altmann, H. Ecotoxicol. Environ. Saf. 1982, 6, 495–500. (12) Spiegelhalder, B.; Preussmann, R. J. Cancer Res. Clin. Oncol. 1984, 108, 160–163. (13) Yamamoto, M.; Iwata, R.; Ishiwata, H.; Yamada, T.; Tanimura, A. Food Chem. Toxicol. 1984, 22, 61–64. (14) Sen, N. P.; Kushwaha, S. C.; Seaman, S. W.; Clarkson, S. G. J. Agric. Food Chem. 1985, 33, 428–433. (15) Song, P. J.; Hu, J. F. Food Chem. Toxicol. 1988, 26, 205–208. (16) Tomkins, B. A.; Griest, W. H. Anal. Chem. 1996, 68, 2533–2540. (17) Mitch, W. A.; Sharp, J. O.; Trussell, R. R.; Valentine, R. L.; Alvarez-Cohen, L.; Sedlak, D. L. Environ. Eng. Sci. 2003, 20, 389–404. (18) Charrois, J. W. A.; Arend, M. W.; Froese, K. L.; Hrudey, S. E. Environ. Sci. Technol. 2004, 38, 4835–4841. (19) de Vocht, F.; Burstyn, I.; Straif, K.; Vermeulen, R.; Jakobsson, K.; Nichols, L.; Peplonska, B.; Taeger, D.; Kromhout, H. J. Environ. Monit. 2007, 9, 253–259.

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

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