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Ab initio study of syn and anti structures of N-nitroso compounds containing a carbonyl group
Journal of Molecular Structure (Theochem) 536 (2001) 213±218
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Ab initio study of syn and anti structures of N-nitroso compounds containing a carbonyl group Naofumi Nakayama, Osamu Kikuchi* Department of Chemistry, University of Tsukuba, Tsukuba 305-8571, Japan Received 6 June 2000; accepted 28 June 2000
Abstract A variety of ab initio molecular orbital methods, RHF, MP2 and B3LYP, have been applied to N-methyl-N-nitrosourea (1), N-methyl-N-nitrosoacetamide (2) and N-methyl-N-nitrosomethylcarbamate (3) and the anti and syn structures and the transition state (TS) structures connecting them have been examined. In each of these compounds, the anti structure was predicted to be more stable than the syn structure and the relative energy of the TS structure was considerably higher than those of the anti and syn structures. The energy difference between anti and syn of 1 is slightly smaller than those of 2 and 3 owing to the existence of hydrogen bonding between O in the nitroso group and H in the NH2 group. q 2001 Elsevier Science B.V. All rights reserved. Keywords: N-nitroso compound; Energy-minimum structure; Transition state structure; Ab initio calculation
1. Introduction N-nitroso compounds are typical mutagenic and carcinogenic compounds [1]. They are believed to owe their activity to conversion to highly reactive diazonium ions. Of these compounds, N-nitrosoureas, N-nitrosamides and N-nitrosocarbamates have a carbonyl group at the N atom (Scheme 1). Although these compounds have molecular structures similar to one another, they have different properties in their mutagenic potential. Brundrett et al. [2] and Aukerman et al. [3] compared the mutagenic properties and antitumor activity of nitrosoureas, nitrosamides and the nitrosocarbamates. They found that nitrosoureas were lower in mutagenic activity than nitrosamides and nitrosocarbamates. They also showed that nitrosoureas were very active antitumor agents against murine L 1210 leuke* Corresponding author.
mia cells, whereas analogous nitrosamides and nitrosocarbamates did not exhibit such property [2,3]. Nitrosoureas represent one of the most generally useful classes of anticancer agents, with a wide range of activity against various leukemias and solid tumors [4]. Understanding the divergent biological activities of these compounds may assist not only in the de®nition of relative carcinogenic potential but also in the search for more effective antitumor agents. Snyder and Stock [5] examined IR and NMR spectra and suggested that in N-methyl-N-nitrosourea and N,N 0 dimethyl-N-nitrosourea the syn conformer where the nitroso group is syn to the carbonyl group is more favored than the anti conformer (Scheme 2) and there is a strong intramolecular hydrogen bond [5]. On the other hand, the molecular structures of Nmethyl-N-nitrosourea and N,N 0 -dimethyl-N-nitrosourea determined by X-ray method are the anti conformers [6]. Sapse and coworkers [7,8] carried out the RHF/STO-6G level of calculations on some
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Scheme 1.
nitrosoureas and some nitrosamides for anti and syn conformers. They showed that in nitrosoureas, the syn conformer is more stable than the anti conformer, while in nitrosamides, the syn conformer is less stable than the anti conformer. However, in our preliminary calculations, anti conformer of nitrosourea was more stable than the syn conformer by the RHF/STO-6G level of full geometry optimization. 1 Relative stability between the anti and syn conformers and easiness of the conversion between them are very important to understand the reactivity of Nnitroso compounds, since the syn isomer is ready to undergo intramolecular reaction which breaks the N± C (carbonyl) bond (Eqs. (1) and (2)) [9,10]. It is thus very important to determine the stability of the conformers and the barrier height for the syn±anti conversion. 1
2
In the present study, we calculated the energyminimum structures of the anti and syn conformers for N-methyl-N-nitrosourea (1), N-methyl-N-nitrosoacetamide (2) and N-methyl-N-nitrosomethylcarbamate (3) (Scheme 3), and the transition-state (TS) 1
The energy difference between anti and syn of N-methyl-Nnitrosourea calculated by RHF/STO-6G level is 3.7 kcal mol 21 (using gaussian 98 program package [11]).
structures for the syn±anti isomerization by several levels of theories.
2. Methods Geometry optimizations and vibrational frequency calculations were carried out using gaussian 98 program package [11] on the DEC 500/500 workstation. The RHF and the MP2 methods were employed with the 6-31G p and 6-31G pp basis sets. These calculations were also carried out using the DFT method at the B3LYP level [12±15]. Vibrational frequency calculations were performed for all stationary points located to con®rm that they corresponded to a true minimum or a transition state. Zero-point energy corrections were also calculated using computed harmonic frequencies. The atomic charges were evaluated by the natural population analysis (NPA) [16]. 3. Results and discussion Tables 1 and 2 show the calculated total and relative energies of the anti and syn structures and the rotational TS structure connecting them for the Nnitroso compounds, 1±3. Two energy-minimum structures, anti and syn, have Cs symmetry for 2 and 3. For the anti structures of 1, the Cs and C1 structures were obtained depending on the method of calculation. However, the relative energies between Cs and C1 are less than 0.1 kcal mol 21. The structure of the rotational TS has C1 symmetry. The energies of the TS for the inversion path are higher than those of the
N. Nakayama, O. Kikuchi / Journal of Molecular Structure (Theochem) 536 (2001) 213±218
215
Scheme 2.
Scheme 3.
Table 1 Total energies (a.u.) of anti and syn conformers and the transition state connecting the two conformers for N-nitroso compounds, 1±3 Compound
Method
anti
syn
TS
1
RHF/6-31G p RHF/6-31G pp MP2/6-31G p MP2/6-31G pp B3LYP/6-31G p B3LYP/6-31G pp
2391.656313 2391.669408 2392.755117 a 2392.797738 a 2393.870548 a 2393.881591
2391.648481 2391.661553 2392.749202 2392.792004 2393.865866 2393.876934
2391.620361 2391.633069 2392.716785 2392.759426 2393.829822 2393.840606
2
RHF/6-31G p RHF/6-31G pp MP2/6-31G p MP2/6-31G pp B3LYP/6-31G p B3LYP/6-31G pp
2375.646128 2375.655916 2376.714638 2376.761964 2377.817865 2377.826268
2375.635049 2375.644814 2376.704308 2376.751769 2377.808237 2377.816614
2375.611056 2375.620749 2376.677283 2376.724716 2377.779999 2377.788346
3
RHF/6-31G p RHF/6-31G pp MP2/6-31G p MP2/6-31G pp B3LYP/6-31G p B3LYP/6-31G pp
2450.509257 2450.518870 2451.748371 2451.795960 2453.036636 2453.044760
2450.497180 2450.506699 2451.738458 2451.786089 2453.027247 2453.035261
2450.480287 2450.489784 2451.718678 2451.766312 2453.004979 2453.013029
a These structures have C1 symmetry in which the NH2 group is slightly pyramidalized and the corresponding Cs structures have one imaginary frequency. The total energies of Cs symmetry structures are 2392.755047 a.u. (MP2/6-31G p), 2392.797697 a.u. (MP2/6-31G pp) and 2393.870532 a.u. (B3LYP/6-31G p).
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Table 2 Relative energies (kcal mol 21) of anti and syn conformers and the transition state connecting the two conformers for N-nitroso compounds, 1±3 (the values in the parentheses are the energies after the zero-point energy correction) Compound
Method
anti
syn
1
RHF/6-31G p RHF/6-31G pp MP2/6-31G p MP2/6-31G pp B3LYP/6-31G p B3LYP/6-31G pp
0.0 0.0 0.0 0.0 0.0 0.0
4.9 4.9 3.7 3.6 2.9 2.9
(5.1) (5.1) (3.6) (3.5) (3.1) (3.0)
22.6 (22.0) 22.8 (22.1) 24.0 (22.9) 24.0 (22.9) 25.6 (24.6) 25.7 (24.8)
2
RHF/6-31G p RHF/6-31G pp MP2/6-31G p MP2/6-31G pp B3LYP/6-31G p B3LYP/6-3IG pp
0.0 0.0 0.0 0.0 0.0 0.0
7.0 7.0 6.5 6.4 6.0 6.1
(6.9) (6.9) (6.4) (6.4) (6.0) (6.0)
22.0 (20.9) 22.1 (21.0) 23.4 (22.1) 23.4 (22.0) 23.8 (22.5) 23.8 (22.6)
3
RHF/6-31G p RHF/6-31G pp MP2/6-31G p MP2/6-31G pp B3LYP/6-31G p B3LYP/6-31G pp
0.0 0.0 0.0 0.0 0.0 0.0
7.6 7.6 6.2 6.2 5.9 6.0
(7.3) (7.4) (5.9) (5.9) (5.6) (5.7)
18.2 (17.3) 18.3 (17.4) 18.6 (17.4) 18.6 (17.4) 19.9 (18.7) 19.9 (18.8)
rotational TS by ca. 50 kcal mol 21 (data not shown). Table 2 shows that the anti structure is more stable than the syn structure by 3±5 kcal mol 21 for 1, 6± 7 kcal mol 21 for 2 and 6±7.5 kcal mol 21 for 3. The relative energy between anti and syn of 1 is smaller than those of 2 and 3 by ca. 2±3 kcal mol 21. This difference is due to the stabilization of the syn structure in 1 by the hydrogen bonding between O atom in the nitroso group and H atom in the NH2 group. The Ê . The TS structure is O´ ´´H distance is 1.87±1.97 A higher in energy than the anti structure by 23± 26 kcal mol 21 for 1, 22±24 kcal mol 21 for 2 and 18±20 kcal mol 21 for 3. Although the barrier height for 3 is smaller than 1 and 2, it is still large for the interconversion. Tables 3 and 4 show the selected structural parameters of anti, syn and TS for 1±3 obtained by the 631G pp basis set. Similar structural parameters were obtained by the 6-31G p basis set. In the X-ray structure of 1 (anti structure), the N±N, N±O and N±C (carbonyl) bond lengths are 1.326, 1.231 and Ê , respectively, and the N±N±O and N±N±C 1.431 A
TS
(carbonyl) bond angles are 114.4 and 116.68, respectively [6]. The N±N length is in good agreement with the RHF results, whereas the N±O and N±C (carbonyl) lengths are in good agreement with the MP2 and B3LYP results. The N±N±O and N±N±C (carbonyl) bond angles are in accordance with the results of all methods. In the syn structure, the N±N±C(O) angle is larger than that of the anti structure by more than 108 in 1±3 (Table 3). Therefore, the instability of the syn structure is attributed to the distortion of the molecular framework. The N±N distance of TS is longer than Ê . It is seen from those of anti and syn by ca. 0.1 A Table 4 that the absolute value of the O±N±N± C(Me) and O±N±N±C(O) dihedral angles of TS are larger than 908, indicating that the central N atom has the sp 3 hybridization rather than the sp 2 at the TS structure. Table 5 shows the charge distributions obtained by MP2/6-31G pp. The negative charge of the central N atom and the positive charge of nitroso N atom of TS are larger than those of anti and syn. This also corresponds to change in the hybridization at the central N atom from sp 2 to sp 3.
N. Nakayama, O. Kikuchi / Journal of Molecular Structure (Theochem) 536 (2001) 213±218
217
Table 3 Ê ) and the selected bond angles (8) of anti and syn structures and the transition state connecting the two structures for The selected bond lengths (A N-nitroso compounds, 1±3, obtained by 6-31G pp basis set Structure Compound 1 anti
syn
TS
Compound 2 anti
syn
TS
Compound 3 anti
syn
TS
Method
N±N
N±O
N±C(O)
N±N±O
N±N±C(O)
RHF MP2 B3LYP RHF MP2 B2LYP RHF MP2 B3LYP
1.322 1.350 1.350 1.323 1.354 1.353 1.440 1.524 1.535
1.182 1.241 1.221 1.186 1.244 1.227 1.160 1.206 1.183
1.407 1.432 1.435 1.421 1.447 1.425 1.396 1.416 1.412
115.4 113.6 114.5 118.5 117.3 117.7 111.9 110.7 111.4
117.7 117.9 117.8 129.2 130.5 129.9 113.9 109.5 111.2
RHF MP2 B3LYP RHF MP2 B3LYP RHF MP2 B3LYP
1.329 1.362 1.364 1.336 1.375 1.378 1.435 1.500 1.513
1.181 1.238 1.218 1.179 1.234 1.215 1.159 1.209 1.185
1.400 1.417 1.419 1.411 1.426 1.430 1.386 1.401 1.397
115.0 113.0 113.8 117.7 116.3 116.8 112.1 110.8 111.5
117.2 117.2 117.3 128.5 129.6 129.4 116.3 114.0 116.0
RHF MP2 B3LYP RHF MP2 B3LYP RHF MP2 B3LYP
1.339 1.371 1.373 1.354 1.392 1.399 1.443 1.530 1.547
1.178 1.236 1.216 1.171 1.226 1.204 1.156 1.201 1.177
1.390 1.408 1.409 1.394 1.411 1.414 1.374 1.392 1.388
113.9 111.9 112.8 118.4 117.0 117.3 111.8 110.6 111.3
118.4 118.9 118.8 129.4 130.4 130.2 115.2 111.1 112.4
4. Conclusion The syn and anti structures and the rotational transition structure between them were calculated for three N-nitroso compounds containing a carbonyl group. The anti structures are more stable than the syn structures. It is attributed to the distortion of the molecular framework in the syn isomers. The energy difference between anti and syn conformers of 1 is slightly smaller than those of 2 and 3, because the hydrogen bonding exists in 1 between O atom in the nitroso group and the H atom in the NH2 group.
Table 4 The selected dihedral angles (8) of the transition state structure for N-nitroso compounds, 1±3, obtained by 6-31G pp basis set Compound
Method
O±N±N±C(Me)
O±N±N±C(O)
1
RHF MP2 B3LYP
2109.8 2112.3 2110.4
118.0 124.2 122.4
2
RHF MP2 B3LYP
2108.9 2109.7 2105.7
111.2 117.2 115.7
3
RHF MP2 B2LYP
2110.1 2112.7 2110.6
111.7 119.3 117.5
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Table 5 The NPA charges [16] of selected atoms obtained by MP2/6-31G pp in the N-nitroso compounds, 1±3 Compound
N (center)
N (nitroso)
O (nitroso)
C (carbonyl)
O (carbonyl)
1 anti syn TS
20.292 20.295 20.471
10.166 10.195 10.287
20.328 20.361 20.193
10.810 10.789 10.797
20.593 20.596 20.590
2 anti syn TS
20.297 20.314 20.437
10.191 10.204 10.278
20.319 20.319 20.184
10.690 10.677 10.673
20.528 20.526 20.554
3 anti syn TS
20.324 20.347 20.454
10.227 10.213 10.296
20.316 20.277 20.176
10.931 10.915 10.913
20.588 20.589 20.597
The transition state which connects the anti and the syn structures lies higher than the anti structure by ca. 20 kcal mol 21. Therefore, the isomerization between anti and syn structures is not very easy and is expected that the reactions of the nitroso compounds occur from the conformer which is produced in vivo or in vitro without the conformational interconversion. In the structural aspects, there are few differences among the three nitroso compounds. Therefore, their different properties in vivo and in vitro are probably due to the differences of reaction mechanism in the formation of the diazonium ion. References [1] R.N. Loeppky, C.J. Michejda (Eds.), Nitrosamines and Related N-nitroso Compounds ACS Symposium Series, vol. 553, American Chemical Society, Washington, DC, 1994. [2] R.B. Brundrett, M. Colvin, E.H. White, J. McKee, P.E. Hartman, D.L. Brown, Cancer Res. 39 (1979) 1328. [3] S.L. Aukerman, R.B. Brundrett, J. Hilton, P.E. Hartman, Cancer Res. 43 (1983) 175. [4] C.T. Gnewuch, G. Sosnovsky, Chem. Rev. 97 (1997) 829. [5] J.K. Snyder, L.M. Stock, J. Org. Chem. 45 (1980) 886. [6] K. Prout, J. Fail, S. Hernandez-Cassou, F.M. Miau, Acta Crystallogr. B38 (1982) 2176.
[7] A.M. Sapse, G. Snyder, L. Osorio, Cancer Res. 44 (1984) 1904. [8] A.M. Sapse, G. Snyder, Int. J. Quantum Chem. Symp. 10 (1983) 175. [9] E.H. White, C.A. Aufedermarsh Jr., J. Am. Chem. Soc. 83 (1961) 1174 (for Eq. (1)). [10] J.A. Montgomery, Cancer Treat. Rep. 60 (1976) 651 (for Eq. (2)). [11] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, V.G. Zakrzewski, J.A. Montgomery, R.E. Stratmann, J.C. Burant, S. Dapprich, J.M. Millam, A.D. Daniels, K.N. Kudin, M.C. Strain, O. Farkas, J. Tomasi, V. Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli, C. Adamo, Clifford, J. Ochterski, G.A. Petersson, P.Y. Ayala, Q. Cui, K. Morokuma, D.K. Malick, A.D. Rabuck, K. Raghavachari, J.B. Foresman, J. Cioslowski, J.V. Ortiz, A.G. Baboul, B.B. Stefanov, G. Liu, A. Liashonko, P. Piskorz, I. Komaromi, R. Gomperts, R.L. Martin, D.J. Fox, T. Keith, M.A. AlLaham, C.Y. Peng, A. Nanayakkara, C. Gonzalez, M. Challacombe, P.M.W. Gill, B.G. Johnson, W. Chen, M.W. Wong, J.L. Andres, M. Head-Gordon, E.S. Replogle, J.A. Pople, gaussian 98, Revision A.7, Gaussian Inc., Pittsburgh, PA, 1998. [12] A.D. Becke, J. Chem. Phys. 96 (1992) 2155. [13] A.D. Becke, J. Chem. Phys. 97 (1992) 9193. [14] A.D. Becke, J. Chem. Phys. 98 (1993) 5648. [15] C. Lee, W. Yang, R.G. Parr, Phys. Rev. B 37 (1988) 785. [16] A.E. Reed, L.A. Curtiss, F. Weinhold, Chem. Rev. 88 (1988) 899.
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Ab initio study of syn and anti structures of N-nitroso compounds containing a carbonyl group Naofumi Nakayama, Osamu Kikuchi* Department of Chemistry, University of Tsukuba, Tsukuba 305-8571, Japan Received 6 June 2000; accepted 28 June 2000
Abstract A variety of ab initio molecular orbital methods, RHF, MP2 and B3LYP, have been applied to N-methyl-N-nitrosourea (1), N-methyl-N-nitrosoacetamide (2) and N-methyl-N-nitrosomethylcarbamate (3) and the anti and syn structures and the transition state (TS) structures connecting them have been examined. In each of these compounds, the anti structure was predicted to be more stable than the syn structure and the relative energy of the TS structure was considerably higher than those of the anti and syn structures. The energy difference between anti and syn of 1 is slightly smaller than those of 2 and 3 owing to the existence of hydrogen bonding between O in the nitroso group and H in the NH2 group. q 2001 Elsevier Science B.V. All rights reserved. Keywords: N-nitroso compound; Energy-minimum structure; Transition state structure; Ab initio calculation
1. Introduction N-nitroso compounds are typical mutagenic and carcinogenic compounds [1]. They are believed to owe their activity to conversion to highly reactive diazonium ions. Of these compounds, N-nitrosoureas, N-nitrosamides and N-nitrosocarbamates have a carbonyl group at the N atom (Scheme 1). Although these compounds have molecular structures similar to one another, they have different properties in their mutagenic potential. Brundrett et al. [2] and Aukerman et al. [3] compared the mutagenic properties and antitumor activity of nitrosoureas, nitrosamides and the nitrosocarbamates. They found that nitrosoureas were lower in mutagenic activity than nitrosamides and nitrosocarbamates. They also showed that nitrosoureas were very active antitumor agents against murine L 1210 leuke* Corresponding author.
mia cells, whereas analogous nitrosamides and nitrosocarbamates did not exhibit such property [2,3]. Nitrosoureas represent one of the most generally useful classes of anticancer agents, with a wide range of activity against various leukemias and solid tumors [4]. Understanding the divergent biological activities of these compounds may assist not only in the de®nition of relative carcinogenic potential but also in the search for more effective antitumor agents. Snyder and Stock [5] examined IR and NMR spectra and suggested that in N-methyl-N-nitrosourea and N,N 0 dimethyl-N-nitrosourea the syn conformer where the nitroso group is syn to the carbonyl group is more favored than the anti conformer (Scheme 2) and there is a strong intramolecular hydrogen bond [5]. On the other hand, the molecular structures of Nmethyl-N-nitrosourea and N,N 0 -dimethyl-N-nitrosourea determined by X-ray method are the anti conformers [6]. Sapse and coworkers [7,8] carried out the RHF/STO-6G level of calculations on some
0166-1280/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S 0166-128 0(00)00631-X
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N. Nakayama, O. Kikuchi / Journal of Molecular Structure (Theochem) 536 (2001) 213±218
Scheme 1.
nitrosoureas and some nitrosamides for anti and syn conformers. They showed that in nitrosoureas, the syn conformer is more stable than the anti conformer, while in nitrosamides, the syn conformer is less stable than the anti conformer. However, in our preliminary calculations, anti conformer of nitrosourea was more stable than the syn conformer by the RHF/STO-6G level of full geometry optimization. 1 Relative stability between the anti and syn conformers and easiness of the conversion between them are very important to understand the reactivity of Nnitroso compounds, since the syn isomer is ready to undergo intramolecular reaction which breaks the N± C (carbonyl) bond (Eqs. (1) and (2)) [9,10]. It is thus very important to determine the stability of the conformers and the barrier height for the syn±anti conversion. 1
2
In the present study, we calculated the energyminimum structures of the anti and syn conformers for N-methyl-N-nitrosourea (1), N-methyl-N-nitrosoacetamide (2) and N-methyl-N-nitrosomethylcarbamate (3) (Scheme 3), and the transition-state (TS) 1
The energy difference between anti and syn of N-methyl-Nnitrosourea calculated by RHF/STO-6G level is 3.7 kcal mol 21 (using gaussian 98 program package [11]).
structures for the syn±anti isomerization by several levels of theories.
2. Methods Geometry optimizations and vibrational frequency calculations were carried out using gaussian 98 program package [11] on the DEC 500/500 workstation. The RHF and the MP2 methods were employed with the 6-31G p and 6-31G pp basis sets. These calculations were also carried out using the DFT method at the B3LYP level [12±15]. Vibrational frequency calculations were performed for all stationary points located to con®rm that they corresponded to a true minimum or a transition state. Zero-point energy corrections were also calculated using computed harmonic frequencies. The atomic charges were evaluated by the natural population analysis (NPA) [16]. 3. Results and discussion Tables 1 and 2 show the calculated total and relative energies of the anti and syn structures and the rotational TS structure connecting them for the Nnitroso compounds, 1±3. Two energy-minimum structures, anti and syn, have Cs symmetry for 2 and 3. For the anti structures of 1, the Cs and C1 structures were obtained depending on the method of calculation. However, the relative energies between Cs and C1 are less than 0.1 kcal mol 21. The structure of the rotational TS has C1 symmetry. The energies of the TS for the inversion path are higher than those of the
N. Nakayama, O. Kikuchi / Journal of Molecular Structure (Theochem) 536 (2001) 213±218
215
Scheme 2.
Scheme 3.
Table 1 Total energies (a.u.) of anti and syn conformers and the transition state connecting the two conformers for N-nitroso compounds, 1±3 Compound
Method
anti
syn
TS
1
RHF/6-31G p RHF/6-31G pp MP2/6-31G p MP2/6-31G pp B3LYP/6-31G p B3LYP/6-31G pp
2391.656313 2391.669408 2392.755117 a 2392.797738 a 2393.870548 a 2393.881591
2391.648481 2391.661553 2392.749202 2392.792004 2393.865866 2393.876934
2391.620361 2391.633069 2392.716785 2392.759426 2393.829822 2393.840606
2
RHF/6-31G p RHF/6-31G pp MP2/6-31G p MP2/6-31G pp B3LYP/6-31G p B3LYP/6-31G pp
2375.646128 2375.655916 2376.714638 2376.761964 2377.817865 2377.826268
2375.635049 2375.644814 2376.704308 2376.751769 2377.808237 2377.816614
2375.611056 2375.620749 2376.677283 2376.724716 2377.779999 2377.788346
3
RHF/6-31G p RHF/6-31G pp MP2/6-31G p MP2/6-31G pp B3LYP/6-31G p B3LYP/6-31G pp
2450.509257 2450.518870 2451.748371 2451.795960 2453.036636 2453.044760
2450.497180 2450.506699 2451.738458 2451.786089 2453.027247 2453.035261
2450.480287 2450.489784 2451.718678 2451.766312 2453.004979 2453.013029
a These structures have C1 symmetry in which the NH2 group is slightly pyramidalized and the corresponding Cs structures have one imaginary frequency. The total energies of Cs symmetry structures are 2392.755047 a.u. (MP2/6-31G p), 2392.797697 a.u. (MP2/6-31G pp) and 2393.870532 a.u. (B3LYP/6-31G p).
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Table 2 Relative energies (kcal mol 21) of anti and syn conformers and the transition state connecting the two conformers for N-nitroso compounds, 1±3 (the values in the parentheses are the energies after the zero-point energy correction) Compound
Method
anti
syn
1
RHF/6-31G p RHF/6-31G pp MP2/6-31G p MP2/6-31G pp B3LYP/6-31G p B3LYP/6-31G pp
0.0 0.0 0.0 0.0 0.0 0.0
4.9 4.9 3.7 3.6 2.9 2.9
(5.1) (5.1) (3.6) (3.5) (3.1) (3.0)
22.6 (22.0) 22.8 (22.1) 24.0 (22.9) 24.0 (22.9) 25.6 (24.6) 25.7 (24.8)
2
RHF/6-31G p RHF/6-31G pp MP2/6-31G p MP2/6-31G pp B3LYP/6-31G p B3LYP/6-3IG pp
0.0 0.0 0.0 0.0 0.0 0.0
7.0 7.0 6.5 6.4 6.0 6.1
(6.9) (6.9) (6.4) (6.4) (6.0) (6.0)
22.0 (20.9) 22.1 (21.0) 23.4 (22.1) 23.4 (22.0) 23.8 (22.5) 23.8 (22.6)
3
RHF/6-31G p RHF/6-31G pp MP2/6-31G p MP2/6-31G pp B3LYP/6-31G p B3LYP/6-31G pp
0.0 0.0 0.0 0.0 0.0 0.0
7.6 7.6 6.2 6.2 5.9 6.0
(7.3) (7.4) (5.9) (5.9) (5.6) (5.7)
18.2 (17.3) 18.3 (17.4) 18.6 (17.4) 18.6 (17.4) 19.9 (18.7) 19.9 (18.8)
rotational TS by ca. 50 kcal mol 21 (data not shown). Table 2 shows that the anti structure is more stable than the syn structure by 3±5 kcal mol 21 for 1, 6± 7 kcal mol 21 for 2 and 6±7.5 kcal mol 21 for 3. The relative energy between anti and syn of 1 is smaller than those of 2 and 3 by ca. 2±3 kcal mol 21. This difference is due to the stabilization of the syn structure in 1 by the hydrogen bonding between O atom in the nitroso group and H atom in the NH2 group. The Ê . The TS structure is O´ ´´H distance is 1.87±1.97 A higher in energy than the anti structure by 23± 26 kcal mol 21 for 1, 22±24 kcal mol 21 for 2 and 18±20 kcal mol 21 for 3. Although the barrier height for 3 is smaller than 1 and 2, it is still large for the interconversion. Tables 3 and 4 show the selected structural parameters of anti, syn and TS for 1±3 obtained by the 631G pp basis set. Similar structural parameters were obtained by the 6-31G p basis set. In the X-ray structure of 1 (anti structure), the N±N, N±O and N±C (carbonyl) bond lengths are 1.326, 1.231 and Ê , respectively, and the N±N±O and N±N±C 1.431 A
TS
(carbonyl) bond angles are 114.4 and 116.68, respectively [6]. The N±N length is in good agreement with the RHF results, whereas the N±O and N±C (carbonyl) lengths are in good agreement with the MP2 and B3LYP results. The N±N±O and N±N±C (carbonyl) bond angles are in accordance with the results of all methods. In the syn structure, the N±N±C(O) angle is larger than that of the anti structure by more than 108 in 1±3 (Table 3). Therefore, the instability of the syn structure is attributed to the distortion of the molecular framework. The N±N distance of TS is longer than Ê . It is seen from those of anti and syn by ca. 0.1 A Table 4 that the absolute value of the O±N±N± C(Me) and O±N±N±C(O) dihedral angles of TS are larger than 908, indicating that the central N atom has the sp 3 hybridization rather than the sp 2 at the TS structure. Table 5 shows the charge distributions obtained by MP2/6-31G pp. The negative charge of the central N atom and the positive charge of nitroso N atom of TS are larger than those of anti and syn. This also corresponds to change in the hybridization at the central N atom from sp 2 to sp 3.
N. Nakayama, O. Kikuchi / Journal of Molecular Structure (Theochem) 536 (2001) 213±218
217
Table 3 Ê ) and the selected bond angles (8) of anti and syn structures and the transition state connecting the two structures for The selected bond lengths (A N-nitroso compounds, 1±3, obtained by 6-31G pp basis set Structure Compound 1 anti
syn
TS
Compound 2 anti
syn
TS
Compound 3 anti
syn
TS
Method
N±N
N±O
N±C(O)
N±N±O
N±N±C(O)
RHF MP2 B3LYP RHF MP2 B2LYP RHF MP2 B3LYP
1.322 1.350 1.350 1.323 1.354 1.353 1.440 1.524 1.535
1.182 1.241 1.221 1.186 1.244 1.227 1.160 1.206 1.183
1.407 1.432 1.435 1.421 1.447 1.425 1.396 1.416 1.412
115.4 113.6 114.5 118.5 117.3 117.7 111.9 110.7 111.4
117.7 117.9 117.8 129.2 130.5 129.9 113.9 109.5 111.2
RHF MP2 B3LYP RHF MP2 B3LYP RHF MP2 B3LYP
1.329 1.362 1.364 1.336 1.375 1.378 1.435 1.500 1.513
1.181 1.238 1.218 1.179 1.234 1.215 1.159 1.209 1.185
1.400 1.417 1.419 1.411 1.426 1.430 1.386 1.401 1.397
115.0 113.0 113.8 117.7 116.3 116.8 112.1 110.8 111.5
117.2 117.2 117.3 128.5 129.6 129.4 116.3 114.0 116.0
RHF MP2 B3LYP RHF MP2 B3LYP RHF MP2 B3LYP
1.339 1.371 1.373 1.354 1.392 1.399 1.443 1.530 1.547
1.178 1.236 1.216 1.171 1.226 1.204 1.156 1.201 1.177
1.390 1.408 1.409 1.394 1.411 1.414 1.374 1.392 1.388
113.9 111.9 112.8 118.4 117.0 117.3 111.8 110.6 111.3
118.4 118.9 118.8 129.4 130.4 130.2 115.2 111.1 112.4
4. Conclusion The syn and anti structures and the rotational transition structure between them were calculated for three N-nitroso compounds containing a carbonyl group. The anti structures are more stable than the syn structures. It is attributed to the distortion of the molecular framework in the syn isomers. The energy difference between anti and syn conformers of 1 is slightly smaller than those of 2 and 3, because the hydrogen bonding exists in 1 between O atom in the nitroso group and the H atom in the NH2 group.
Table 4 The selected dihedral angles (8) of the transition state structure for N-nitroso compounds, 1±3, obtained by 6-31G pp basis set Compound
Method
O±N±N±C(Me)
O±N±N±C(O)
1
RHF MP2 B3LYP
2109.8 2112.3 2110.4
118.0 124.2 122.4
2
RHF MP2 B3LYP
2108.9 2109.7 2105.7
111.2 117.2 115.7
3
RHF MP2 B2LYP
2110.1 2112.7 2110.6
111.7 119.3 117.5
218
N. Nakayama, O. Kikuchi / Journal of Molecular Structure (Theochem) 536 (2001) 213±218
Table 5 The NPA charges [16] of selected atoms obtained by MP2/6-31G pp in the N-nitroso compounds, 1±3 Compound
N (center)
N (nitroso)
O (nitroso)
C (carbonyl)
O (carbonyl)
1 anti syn TS
20.292 20.295 20.471
10.166 10.195 10.287
20.328 20.361 20.193
10.810 10.789 10.797
20.593 20.596 20.590
2 anti syn TS
20.297 20.314 20.437
10.191 10.204 10.278
20.319 20.319 20.184
10.690 10.677 10.673
20.528 20.526 20.554
3 anti syn TS
20.324 20.347 20.454
10.227 10.213 10.296
20.316 20.277 20.176
10.931 10.915 10.913
20.588 20.589 20.597
The transition state which connects the anti and the syn structures lies higher than the anti structure by ca. 20 kcal mol 21. Therefore, the isomerization between anti and syn structures is not very easy and is expected that the reactions of the nitroso compounds occur from the conformer which is produced in vivo or in vitro without the conformational interconversion. In the structural aspects, there are few differences among the three nitroso compounds. Therefore, their different properties in vivo and in vitro are probably due to the differences of reaction mechanism in the formation of the diazonium ion. References [1] R.N. Loeppky, C.J. Michejda (Eds.), Nitrosamines and Related N-nitroso Compounds ACS Symposium Series, vol. 553, American Chemical Society, Washington, DC, 1994. [2] R.B. Brundrett, M. Colvin, E.H. White, J. McKee, P.E. Hartman, D.L. Brown, Cancer Res. 39 (1979) 1328. [3] S.L. Aukerman, R.B. Brundrett, J. Hilton, P.E. Hartman, Cancer Res. 43 (1983) 175. [4] C.T. Gnewuch, G. Sosnovsky, Chem. Rev. 97 (1997) 829. [5] J.K. Snyder, L.M. Stock, J. Org. Chem. 45 (1980) 886. [6] K. Prout, J. Fail, S. Hernandez-Cassou, F.M. Miau, Acta Crystallogr. B38 (1982) 2176.
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