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Theoretical studies of imidazole nitrenium and carbenium ions
Journul of Molecular Structure (Theochem), 165 (1988) 379-389 Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands
THEORETICAL STUDIES OF IMIDAZOLE NITRENIUM CARBENIUM IONS
379
AND
JUDY L. BOLTON and ROBERT A. MCCLELLAND Department of Chemistry, University of Toronto, Toronto, Ontario, M5S IA1 (Canada) (Received 12 August 1987)
ABSTRACT Ab initio calculations with the split-valence 3-21G basis set and gradient geometry optimization have been carried out with 2-hydroxylaminoimidazole (2)) 2-hydroxymethylimidazole (S), the nitrenium ion (3) and carbenium ion (6) derived by loss of OH- from these, and the 5-hydroxy non-aromatic isomers of these. The ring geometries of the two cations show significant deviations from the geometry of imidazole itself, being consistent with a major resonance contributor where the positive charge is delocalized into the imidazole ring. An isodesmic calculation on the equilibrium 6 + 2 =5 + 3 shows the nitrenium ion side favored by 22 kcal mol-‘. This can be attributed in part to a stabilization of the imidazole nitrenium ion by the heterocyclic ring, but relative destabilization of the imidazole hydroxylamine must also play an important role. Imidazole hydroxylamines and nitrenium ions are formed upon biological reduction of nitroimidazole drugs and the charged species may be responsible for some of the biological effects. These calculations shed some light on the reasons why such nitrenium ions are so easily formed.
INTRODUCTION
Extensive biological and biochemical examinations of 2-nitroimidazole radiation sensitizers such as misonidazole (Figs. 1, la) have shown a number of effects associated with reductive metabolism [ 11. These include a preferential toxicity toward hypoxic cells as compared to aerobic cells [ 21, mutagenicity [ 31, chemosensitization [ 41, and, at the biochemical level, DNA binding [ 51 and depletion of cellular thiols [ 61. The implication is that biological reducHO
-N\ NOz 1 a; R
NHOH 2
q
CH,CHOHCH,OCH,
Fig. 1.2-Nitroimidazole
0166-1280/88/$03.50
NR -
3
Y *NH
OH
HN;
NR
Y 4
NH,
b;R=H
reduction.
0 1988 Elsevier Science Publishers B.V.
380
tion is producing a reactive product (or products) capable of interacting with cellular components. In investigations of the chemistry, 2-hydrdxylamino reduction products 2 have been prepared [ 71, and, as shown in Fig. 1, were found to be unstable, decomposing to cyclic guanidinium ions 4 via a cationic intermediate 3 [ 8,9]. This novel nitrenium ion is an obvious candidate for the biologically important reactive species, and does appear to react with biological molecules [9,10]. Indications are that it is a relatively long-lived electrophile, surviving in aqueous solutions for lo-100 microseconds [ 111. In comparison with benzenoid nitrenium ions which are more difficult to form, but once formed are much more reactive [ 121,the behavior of the imidazole derivatives is unusual, suggesting that there is a strong interaction between the -NH+ center and the imidazole ring. In this paper, theoretical calculations for the nitrenium ion 3b, the hydroxylamine 2b and an isomeric form of this are reported. In addition, the effects of replacing the external nitrogen by carbon are investigated with calculations for alcohol and carbenium ion analogs. As will be discussed the imidazole nitrenium ion and carbenium ion systems exhibit pronounced experimental differences. METHOD Ab initio computations of imidazole derivatives were carried out with the split-valence 3-21G basis set [ 131 within the restricted Hartree-Fock formalism [ 141 using the analytic gradient [ 151 of the SCF energy with respect to the internal geometrical parameters. Calculations for the simple aliphatic models were performed with the 3-21G+ basis set which contains diffuse functions. The Optimally Conditioned (OC) minimization technique [ 161 was used to determine the optimal geometry at each minimum, with the VA05AD sum of squares method [ 171to confirm the order of the minima. The order of a critical point is equal to the number of negative eigenvalues of the Hessian or force constant matrix (second derivatives of the energy with respect to the internal geometrical parameters). The order of minima must be zero. Optimizations were terminated when the gradient length, defined by the equation lgl =
(W&d2/nl
[ i
j
i
where qi are the internal parameters and the sum was taken over the n optimized parameters, was reduced to below 5 x 10-l mdyn. This criterion yields structures within 0.01 pm or 0.01’ of the true theoretical optimum, and energies stable below the microhartree level. All computations were performed on the Gould 32/9705 computer system at the University of Toronto with the MONSTERGAUSS ab initio program [ 181.
381
RESULTS AND DISCUSSION
The imidazole derivatives 2,3, and 5-9 (Fig. 2) were investigated at the 321G basis set level, with some simple analogs (Table 1) being studied at the 3-21G+ level. Bond lengths, bond angles and dihedral angles defining the optimized geometries are given in Tables 1-3, with energies in Table 4. In general, the initial calculations proceeded with the constraint that the imidazole ring atoms lay in a common plane. A check of the critical point order revealed that the geometries calculated with this constraint did represent true minima in the case of 3,6, and 7, but not with the others. In these cases a full optimization was then carried out. In several cases, two or more critical point minima were located. As shown in Table 1 these represent structures with rotation about C-C, C-N, or C-O bonds. The first interesting feature to come out of the calculations concerns a comH
Ii
‘c-c’
I’
N:,~-H C
2b
Nn
I
N
Y
N,
H/N6 77
H
H
\
I
A
H
”
3b(A)
H
WI
7
N’1N
N\N
Y
C \/
0
H
Y
/C 0
A 5(D)
6(C)
OH H
d+
N
Y N\
6 Fig. 2. Structures
6(A)
0)
H
9
382 TABLE 1 3-21G+ Optimized geometries (bond lengths are in Hngstriim and angles in degrees) CH,OH
c-o O-H C-H C-H’ C-H’ ’ L C-O-H LO-C-H L O-C-H’ L O-C-H’ ’
NHzOH 1.4543 0.9648 1.0772 1.0831 1.0831 113.29 105.44 111.03 111.03
N-O O-H N-H N-H’ L N-O-H L O-N-H L O-N-H’ rH-O-N-H TH-O-N-H’
NH2+ 1.4578 N-H 0.9715 N-H’ 1.0055 L H-N-H’ 1.0055 110.39 109.04 109.04 62.61 297.39
CH,+ 1.0391 C-H 1.0391 C-H’ 120.00 C-H” L H-C-H’ L H-C-H’ ’
1.0778 1.0778 1.0778 120.00 120.00
parison of the optimized geometries with that of imidazole itself. Pertinent bond lengths are summarized in Fig. 3. Not unexpectedly, the imidazole rings of 2-hydroxyaminoimidazole and of 2-hydroxymethylimidazole do not vary significantly from that of the unsubstituted imidazole. On the other hand, very large perturbations are observed with the nitrenium ion and the carbenium ion. Both of these ions have two significant resonance structures, as shown in Fig. 4. The optimized geometry for the imidazole carbenium ion has a C4-C5 bond length increased from 1.35 A from that of imidazole to 1.46 A, the difference is even more dramatic for the nitrenium ion where a bond stretching to 1.50 A is observed. Similar dramatic changes, in this case bond shortenings, are observed with the exocyclic C&N_ or Cz-Cero bonds - 1.40 A to 1.23 A in converting the hydroxylamine to the nitrenium ion and 1.49 A to 1.32 A in comparing the alcohol and carbenium ion: other bond length changes can also be noted. The conclusion is that the predominant resonance structure for the charged compounds is the imminium ion which has the charge in the ring, and not the structure corresponding to the classic nitrenium ion or carbenium ion. This conclusion was supported by a charge distribution analysis using the Mulliken Population Index (see Fig. 4). In the case of the carbenium ion this shows that approximately 60% of the positive charge is located in the imidazole ring, while with the nitrenium ion all the charge is in the ring. The pertinent experimental observations for the two systems are summarized in Fig. 5, with two important distinctions to be noted between the nitrenium and carbenium systems. Firstly the imidazole nitrenium ion undergoes addition of water and other nucleophiles at the ring carbon C5 [ 8,9], while the carbenium ion is trapped at the external methylene carbon [ 111. Secondly, in aqueous solution the hydroxylamino undergoes relatively facile N-O bond heterolysis producing nitrenium ion and OH- [ 8,111, the first-order rate constant, for example, for a l-methyl derivative being 10-2s-’ [ 81. The analogous
383 TABLE 2 3-21G Optimized geometries (bond lengths are in Hngstriimand angles in degrees) Parameters
N,-C, G-K N,-C, ccG G-&i x6-07 N,-H C,-H CS-H X6-H X6-H’ 0,-H
N&-N3 C&-N& L N,-Q-C, L N,-C,-X,
L L
L c,-xc-0, L C&,-H
L C&,-H L CS-N,-H L f&-&-H L C2-X6-H’ L X,-07-H TN,-C.&-H TN,-C,-C,-H rC,-N,-C,-C, 7N1-C2-N3-C4 7C,-N,-C,-X, rC,-C,-N,-H TN,-C&-X,-O7 TN,-C,-G-H TN,-C2-X6-H’ 7&-&-0,-H
2b 1.3532 1.2959 1.4005 1.3479 1.3963 1.4518 0.9934 1.0624 1.0622 1.0048
WA) 1.4716 1.4267 1.2698 1.5016 1.2253 1.0079 1.0642 1.0682 1.0132
0.9681
112.54 105.31 110.05 122.25 109.27 128.79 132.13 128.55 113.15
104.98 109.06 109.87 121.95 124.71 128.22 128.20 119.64
103.75 179.51 180.03 0.30 -0.27 182.60 174.74 159.15 238.65 127.73
180.00 180.00 0.00 0.00 180.00 180.00 180.00
S(A) 1.3553 1.3003 1.3951 1.3540 1.4909 1.4431 0.9951 1.0627 1.0628 1.0829 1.0829 0.9643
6 1.4342 1.3967 1.2887 1.4592 1.3212 1.0046 1.0632 1.0671 1.0712 1.0713
111.62 105.82 109.67 121.23 105.77 128.86 131.78 129.28 109.55 109.55 111.44
106.14 108.82 109.32 127.37
180.00 180.00 0.00 0.00 180.00 180.00 180.00 120.49 239.51 180.00
180.00 180.00 0.00 0.00 180.00 180.00
126.01 129.03 125.84 118.38 122.83
180.00 180.00
reaction producing carbenium ion and OH- however does not occur with the alcohol in water, much better leaving groups such as Cl- being required to observe C-X heterolysis [ 111. The first-order rate constant for C-Cl heterolysis in water, again for a l-methyl derivative, is 1 s-l [111.In other words, NH-OH and CH,-Cl have similar reactivities in solution. Figure 6 lists isodesmic and isomerization equilibrium for which data at the
384 TABLE 3 3-21G Optimized geometries (bond lengths are in Bngstriimand angles in degrees) Parameters
N,-G C,-Ns N,-C, G-G G-X6 G-07
N,-H C,-H C&-H X,-H X,-H’ 0,-H
N,-C2-N3 C,-N,-C, L N,-C,-C, L N,-C,-X, L L
7
8 1.3681 1.3000 1.3938 1.3526 1.0630 0.9943
1.0624 1.0633
111.13 106.25 109.70 122.75 128.69
131.61
111.38
rH-c,-c5-o
TN,-c,-N,-c,
180.00 0.00 0.00
TH-N&-N, TH-N&,-X, TN,-&-X,-H TN,-C,-&-H' TN,-C,-C,-H T&-N,-C,-X, TH-N,-C,-C,
106.40 108.26 114.22 126.25 105.54 121.84 110.27 121.59 114.75
1.3978 1.4442 1.2628 1.5217 1.3155 1.4338 0.9936 1.0669 1.0821 1.0682 1.0705 0.9669 106.49 108.70 114.08 130.13 106.08 122.27 109.88 123.54 119.19 122.11 111.18
126.28
TN,-c,-c,-0, TC,-c,-0,-H TN,-c&,-H TC&&-&-&
1.3885 1.4577 1.2603 1.5249 1.2428 1.4311 0.9940 1.0670 1.0813 1.0086 0.9668
L c,-c,-0, L C&,-H L C&-H L C,-N,-H L C,-X,-H L C&X,-H L &0,-H L C,-N,-H
9
118.14 188.80 301.17 208.76 1.29 0.90 174.78 355.89 178.19
117.69
187.52 300.56 207.89 1.30 1.43 171.85 353.11 177.96 357.55
180.00 180.00 180.00
computational level are available. Reaction 1, which has the imidazole hydroxylamine transfering an OH group to the carbenium ion to form alcohol plus nitrenium ion, lies far to the right with AZ= -22.1 kcal mol-‘. This is of course consistent with the experimental observation that nitrenium ion forms
385
TABLE 4 Total SCF energies (hartree)
- 352.661979
2b 3b(A) 3b(B) 5(A) 5(B) 5(C) 5(D) 6 7
8(A) S(B) 9 CH30H NH,OH NH*+ CH,+
- 277.408762 - 277.395742 - 336.808346 - 336.808243 - 336.793505 - 336.792391 -261.519957 -223.549115
NHOH
H
CH,OH
1.50
1.46
l.27nl.33 'T/-k !&2"
l.W3 11.32
11.23
+CH3
+NH
Fig. 3. Imidazole bond lengths. H.4
c-,
I @NH
Hm4
-““\;y
.4H/
NNC,NH I
@CH,
Fig. 4. Resonance contributors.
-He5
IL .6
-2
-352.692343 -352.684257 -336.775342 - 114.426083 - 130.288091 - 54.824105 - 39.009434
386 OH
/-\
-
-OH-
N,
NR
Y H/N
I-\ N,
Y
NR
NH
+NH
OH c
/-\ N,
NR
-
-cd-
/-\
/-\ N,
Y +bH*
Y dH,CI
NR
NR-N, -OH-
(2)
Y k~,0H
Fig. 5. Experimental observations.
/-\
N,
NH
+
CH,OH
N//NH
+
+
NH,OH
+9 \
NHIOH
-16.8 G+
CH,OH
(1) I NH
Y
+CH,
NVH
+
+NH2
(2)
Y CHz OH
OH
Fig. 6. Equilibria ( AE in kcal mol-‘).
more easily than carbenium ion. The origin of this difference lies either in the 2-hydroxymethylimidazole being more stable than the 2-hydroxyaminoimidazole, or in the imidazole nitrenium ion being more stable than the imidazole carbenium ion (or of course a combination of both these effects). Reaction 2 of Fig. 6 shows that the imidazole ring has a profound influence. This isodesmic equilibrium, similar to that of reaction 1 but now without the imidazole ring, lies far to the reagent side, thus avoiding the bare nitrenium ion NH2+. The contrast with equilibrium 1 implies that the resonance stabilization by the imidazole ring is more important for the nitrenium ion than for the carbenium
387
ion. This is borne out by consideration of equilibrium 3 where the charged species are imidazole substituted, and the equilibrium shifts dramatically to the nitrenium ion side. The hydroxylaminoimidazole: hydroxymethylimidazole relative stabilities however must also be important, as is illustrated by a comparison of the isomerization equilibria 4 and 5 of Fig. 6. With the hydroxymethyl system, isomerization to the non-aromatic 5-OH isomer is a highly endothermic process, undoubtedly due to the loss of aromatic resonance energy. A similar isomerization with the hydroxylamine however is highly exothermic. These comparisons obviously offer a further rationalization behind the products of nucleophilic addition to the cations, since in each case it is in fact the more stable product which is formed. The unusual favoring of the non-aromatic isomer in the hydroxylamine system may be related to a weak N-O bond, since there are indications that the bond dissociation energy of such bonds is relatively low, particularly when attached to aromatic rings. Thus the bond dissociation energy of the N-O bond of hydroxylamine is 61 kcal mol-’ [ 191. This is comparable to a value of 56 kcal mol-’ for the N-N bond of hydrazine [ 201, and in that system substitution of one hydrogen by phenyl lowers the energy to 40 kcal mol - ’ [ 211. Bond dissociation energies for aromatic hydroxylamines have not been reported. However, a benzenoid hydroxylamine derivative has been found to undergo thermal N-O homolysis at relatively low temperatures (90’ C) [ 211. Interestingly, the present computations show that the optimum geometry (Fig. 7) of the imidazole hydroxylamine has the NHOH group twisted with respect to the plane of the imidazole ring (which in fact is not entirely planar). Moreover, the geometry about the nitrogen of the NHOH group itself is not planar. In other words there appears to be minimal x delocalization involving the formal electron pair of the NHOH group and the imidazole ring. As already noted [ 81, compared to benzenoid hydroxylamines such as Nphenylhydroxylamine, the imidazole hydroxylamine is highly unusual in its undergoing N-O bond heterolysis so readily at pH 7. The benzenoid systems do form nitrenium ions, but only under acidic conditions, or after esterification of the OH group to give a better leaving anion [ 22-241. That significant biological effects associated with DNA alkylation can accompany nitrenium ion formation has been well established [ 251. The ease of formation of the imidazole versions of these at least in part may explain the pronounced biological effects observed with imidazole drugs. In summarizing the present calculaOH N
N,
21° N 1
59O
q
H
Fig. 7. Optimum geometry of the imidazole hydroxylamine.
388
tions, the key feature is that they do provide a rationale for the chemistry since they show significant stabilizing interaction accompanying the placing of a nitrenium ion center on the imidazole ring. There are some significant biological differences between nitrobenzenes and 6-atom nitroheterocycles on the one hand and 5-atom nitroheterocycles on the other [ 261. As previously postulated [ 261 one source of the difference may lie in the properties of the respective nitrenium ions [ 271. ACKNOWLEDGMENTS
The financial support of the Natural Sciences and Engineering Research Council of Canada and the National Cancer Institute of Canada is gratefully acknowledged.
REFERENCES 1 2
3 4 5
6 I 8 9 10 11 12 13 14 15 16
17 18
19 20 21
A.M. Rauth, Int. J. Radiat. Oncol. Biol. Phys., 10 (1984) 1293. J.M. Brown, Int. J. Radiat. Oncol. Biol. Phys., 8 (1982) 1491. J.B. Chin, D.M.K. Sheinin and A.M. Rauth, Mutat. Res., 58 (1978) 1; B.M. Kacinski, Z. Mroczkowski and W.D. Rupp, Cancer Clin. Trials, 3 (1980) 69. N.J. McNally, Int. J. Radiat. Oncol. Biol. Phys., 8 (1982) 593. A.J. Varghese, S. Gulyas and J.K. Mohindra, Cancer Res., 36 (1976) 3761; A.J. Varghese and G.F. Whitmore, Cancer Res., 40 (1980) 2165; A.R.J. Silver, P. O’Neill and T.C. Jenkins, Biochem. Pharmacol., 19 (1985) 3537. E.A. Bump, Y.C. Taylor and J.M. Brown, Cancer Res., 43 (1983) 997. R.A. McClelland, J.R. Fuller, N.E. Seaman, A.M. Rauth and R. Battistella, Biochem. Pharmacol., 33 (1984) 303. R.A. McClelland, R. Panicucci and A.M. Rauth, J. Am. Chem. Sot., 107 (1985) 1762. R.A. McClelland, R. Panicucci and A.M. Rauth, J. Am. Chem. Sot., 109 (1987) 4308. A.J. Varghese and G.F. Whitmore, Chem. Biol. Interact., 56 (1985) 269. J.L. Bolton and R.A. McClelland, unpublished observation. J.C. Fishbein and R.A. McClelland, J. Am. Chem. Sot., 109 (1987) 2824. J.S. Binkley, J.A. Pople and W.J. Hehre, J. Am. Chem. Sot., 102 (1980) 939. C.C.J. Roothaan, Rev. Mod. Phys., 23 (1951) 69. Program FORCE, H.B. Schlegel, Ph. D. Thesis, Queens University, Kingston, Ontario, Canada, 1975. W.C. Davidon, Mathematical Programming, 9 (1975) 1. The routine is described in Technical memos 303 and 306, by WC. Davidon and L. Nazareth, Applied Mathematics Division, Argonne National Laboratories, Argonne, IL, U.S.A. M.J.D. Powell, Program VA05AD, AERE Subroutine Library, Harwell, U.K. Program MONSTERGAUSS, M.R. Peterson and R.A. Poirier, University of Toronto, Toronto, Ontario, 1981. MONSTERGAUSS incorporates the Gaussian 80 integral, SCF, and analytic gradient routines, with automatic geometry optimization (with or without constraints) by the OC and VA05AD techniques. R.A. Beck and J. Betts, Can. J. Chem., 43 (1965) 2157. J.A. Kerr, Chem. Rev., 66 (1966) 415. M. Novak and B.A. Brodeur, J. Org. Chem., 49 (1984) 1142.
389
22 23 24 25 26 27
T. Sone, Y. Tokudo, T. Sakai, S. Shinkai, and 0. Manahe, J. Chem. Sot., Perkin Trans. 2, (1981) 1596. P.G. Gassman and J.E. Granrud, J. Am. Chem. Sot., 106 (1984) 1498. M. Novak, M. Pelecanou, A.K. Roy, A.F. Andronica, F.M. Plourde, T.M. Olefirowicy and T.J. Curtin, J. Am. Chem. Sot., 106 (1984) 5623. E.C. Miller, Cancer Res., 38 (1978) 1479. G.D. Hartman and R.D. Hartman, Mutat. Res., 117 (1983) 271. For quantum chemical calculations involving of benzenoid nitrenium ions see: G.H. Loew, J. Phillips and G. Pack, Cancer Biochem. Biophys. 3 (1979) 101; G.P. Ford and J.D. Scribner, J. Am. Chem. Sot., 103 (1981) 4281; G.D. Hartman and H.B. Schelgel, Chem. Biol. Interact., 36 (1981) 319.
THEORETICAL STUDIES OF IMIDAZOLE NITRENIUM CARBENIUM IONS
379
AND
JUDY L. BOLTON and ROBERT A. MCCLELLAND Department of Chemistry, University of Toronto, Toronto, Ontario, M5S IA1 (Canada) (Received 12 August 1987)
ABSTRACT Ab initio calculations with the split-valence 3-21G basis set and gradient geometry optimization have been carried out with 2-hydroxylaminoimidazole (2)) 2-hydroxymethylimidazole (S), the nitrenium ion (3) and carbenium ion (6) derived by loss of OH- from these, and the 5-hydroxy non-aromatic isomers of these. The ring geometries of the two cations show significant deviations from the geometry of imidazole itself, being consistent with a major resonance contributor where the positive charge is delocalized into the imidazole ring. An isodesmic calculation on the equilibrium 6 + 2 =5 + 3 shows the nitrenium ion side favored by 22 kcal mol-‘. This can be attributed in part to a stabilization of the imidazole nitrenium ion by the heterocyclic ring, but relative destabilization of the imidazole hydroxylamine must also play an important role. Imidazole hydroxylamines and nitrenium ions are formed upon biological reduction of nitroimidazole drugs and the charged species may be responsible for some of the biological effects. These calculations shed some light on the reasons why such nitrenium ions are so easily formed.
INTRODUCTION
Extensive biological and biochemical examinations of 2-nitroimidazole radiation sensitizers such as misonidazole (Figs. 1, la) have shown a number of effects associated with reductive metabolism [ 11. These include a preferential toxicity toward hypoxic cells as compared to aerobic cells [ 21, mutagenicity [ 31, chemosensitization [ 41, and, at the biochemical level, DNA binding [ 51 and depletion of cellular thiols [ 61. The implication is that biological reducHO
-N\ NOz 1 a; R
NHOH 2
q
CH,CHOHCH,OCH,
Fig. 1.2-Nitroimidazole
0166-1280/88/$03.50
NR -
3
Y *NH
OH
HN;
NR
Y 4
NH,
b;R=H
reduction.
0 1988 Elsevier Science Publishers B.V.
380
tion is producing a reactive product (or products) capable of interacting with cellular components. In investigations of the chemistry, 2-hydrdxylamino reduction products 2 have been prepared [ 71, and, as shown in Fig. 1, were found to be unstable, decomposing to cyclic guanidinium ions 4 via a cationic intermediate 3 [ 8,9]. This novel nitrenium ion is an obvious candidate for the biologically important reactive species, and does appear to react with biological molecules [9,10]. Indications are that it is a relatively long-lived electrophile, surviving in aqueous solutions for lo-100 microseconds [ 111. In comparison with benzenoid nitrenium ions which are more difficult to form, but once formed are much more reactive [ 121,the behavior of the imidazole derivatives is unusual, suggesting that there is a strong interaction between the -NH+ center and the imidazole ring. In this paper, theoretical calculations for the nitrenium ion 3b, the hydroxylamine 2b and an isomeric form of this are reported. In addition, the effects of replacing the external nitrogen by carbon are investigated with calculations for alcohol and carbenium ion analogs. As will be discussed the imidazole nitrenium ion and carbenium ion systems exhibit pronounced experimental differences. METHOD Ab initio computations of imidazole derivatives were carried out with the split-valence 3-21G basis set [ 131 within the restricted Hartree-Fock formalism [ 141 using the analytic gradient [ 151 of the SCF energy with respect to the internal geometrical parameters. Calculations for the simple aliphatic models were performed with the 3-21G+ basis set which contains diffuse functions. The Optimally Conditioned (OC) minimization technique [ 161 was used to determine the optimal geometry at each minimum, with the VA05AD sum of squares method [ 171to confirm the order of the minima. The order of a critical point is equal to the number of negative eigenvalues of the Hessian or force constant matrix (second derivatives of the energy with respect to the internal geometrical parameters). The order of minima must be zero. Optimizations were terminated when the gradient length, defined by the equation lgl =
(W&d2/nl
[ i
j
i
where qi are the internal parameters and the sum was taken over the n optimized parameters, was reduced to below 5 x 10-l mdyn. This criterion yields structures within 0.01 pm or 0.01’ of the true theoretical optimum, and energies stable below the microhartree level. All computations were performed on the Gould 32/9705 computer system at the University of Toronto with the MONSTERGAUSS ab initio program [ 181.
381
RESULTS AND DISCUSSION
The imidazole derivatives 2,3, and 5-9 (Fig. 2) were investigated at the 321G basis set level, with some simple analogs (Table 1) being studied at the 3-21G+ level. Bond lengths, bond angles and dihedral angles defining the optimized geometries are given in Tables 1-3, with energies in Table 4. In general, the initial calculations proceeded with the constraint that the imidazole ring atoms lay in a common plane. A check of the critical point order revealed that the geometries calculated with this constraint did represent true minima in the case of 3,6, and 7, but not with the others. In these cases a full optimization was then carried out. In several cases, two or more critical point minima were located. As shown in Table 1 these represent structures with rotation about C-C, C-N, or C-O bonds. The first interesting feature to come out of the calculations concerns a comH
Ii
‘c-c’
I’
N:,~-H C
2b
Nn
I
N
Y
N,
H/N6 77
H
H
\
I
A
H
”
3b(A)
H
WI
7
N’1N
N\N
Y
C \/
0
H
Y
/C 0
A 5(D)
6(C)
OH H
d+
N
Y N\
6 Fig. 2. Structures
6(A)
0)
H
9
382 TABLE 1 3-21G+ Optimized geometries (bond lengths are in Hngstriim and angles in degrees) CH,OH
c-o O-H C-H C-H’ C-H’ ’ L C-O-H LO-C-H L O-C-H’ L O-C-H’ ’
NHzOH 1.4543 0.9648 1.0772 1.0831 1.0831 113.29 105.44 111.03 111.03
N-O O-H N-H N-H’ L N-O-H L O-N-H L O-N-H’ rH-O-N-H TH-O-N-H’
NH2+ 1.4578 N-H 0.9715 N-H’ 1.0055 L H-N-H’ 1.0055 110.39 109.04 109.04 62.61 297.39
CH,+ 1.0391 C-H 1.0391 C-H’ 120.00 C-H” L H-C-H’ L H-C-H’ ’
1.0778 1.0778 1.0778 120.00 120.00
parison of the optimized geometries with that of imidazole itself. Pertinent bond lengths are summarized in Fig. 3. Not unexpectedly, the imidazole rings of 2-hydroxyaminoimidazole and of 2-hydroxymethylimidazole do not vary significantly from that of the unsubstituted imidazole. On the other hand, very large perturbations are observed with the nitrenium ion and the carbenium ion. Both of these ions have two significant resonance structures, as shown in Fig. 4. The optimized geometry for the imidazole carbenium ion has a C4-C5 bond length increased from 1.35 A from that of imidazole to 1.46 A, the difference is even more dramatic for the nitrenium ion where a bond stretching to 1.50 A is observed. Similar dramatic changes, in this case bond shortenings, are observed with the exocyclic C&N_ or Cz-Cero bonds - 1.40 A to 1.23 A in converting the hydroxylamine to the nitrenium ion and 1.49 A to 1.32 A in comparing the alcohol and carbenium ion: other bond length changes can also be noted. The conclusion is that the predominant resonance structure for the charged compounds is the imminium ion which has the charge in the ring, and not the structure corresponding to the classic nitrenium ion or carbenium ion. This conclusion was supported by a charge distribution analysis using the Mulliken Population Index (see Fig. 4). In the case of the carbenium ion this shows that approximately 60% of the positive charge is located in the imidazole ring, while with the nitrenium ion all the charge is in the ring. The pertinent experimental observations for the two systems are summarized in Fig. 5, with two important distinctions to be noted between the nitrenium and carbenium systems. Firstly the imidazole nitrenium ion undergoes addition of water and other nucleophiles at the ring carbon C5 [ 8,9], while the carbenium ion is trapped at the external methylene carbon [ 111. Secondly, in aqueous solution the hydroxylamino undergoes relatively facile N-O bond heterolysis producing nitrenium ion and OH- [ 8,111, the first-order rate constant, for example, for a l-methyl derivative being 10-2s-’ [ 81. The analogous
383 TABLE 2 3-21G Optimized geometries (bond lengths are in Hngstriimand angles in degrees) Parameters
N,-C, G-K N,-C, ccG G-&i x6-07 N,-H C,-H CS-H X6-H X6-H’ 0,-H
N&-N3 C&-N& L N,-Q-C, L N,-C,-X,
L L
L c,-xc-0, L C&,-H
L C&,-H L CS-N,-H L f&-&-H L C2-X6-H’ L X,-07-H TN,-C.&-H TN,-C,-C,-H rC,-N,-C,-C, 7N1-C2-N3-C4 7C,-N,-C,-X, rC,-C,-N,-H TN,-C&-X,-O7 TN,-C,-G-H TN,-C2-X6-H’ 7&-&-0,-H
2b 1.3532 1.2959 1.4005 1.3479 1.3963 1.4518 0.9934 1.0624 1.0622 1.0048
WA) 1.4716 1.4267 1.2698 1.5016 1.2253 1.0079 1.0642 1.0682 1.0132
0.9681
112.54 105.31 110.05 122.25 109.27 128.79 132.13 128.55 113.15
104.98 109.06 109.87 121.95 124.71 128.22 128.20 119.64
103.75 179.51 180.03 0.30 -0.27 182.60 174.74 159.15 238.65 127.73
180.00 180.00 0.00 0.00 180.00 180.00 180.00
S(A) 1.3553 1.3003 1.3951 1.3540 1.4909 1.4431 0.9951 1.0627 1.0628 1.0829 1.0829 0.9643
6 1.4342 1.3967 1.2887 1.4592 1.3212 1.0046 1.0632 1.0671 1.0712 1.0713
111.62 105.82 109.67 121.23 105.77 128.86 131.78 129.28 109.55 109.55 111.44
106.14 108.82 109.32 127.37
180.00 180.00 0.00 0.00 180.00 180.00 180.00 120.49 239.51 180.00
180.00 180.00 0.00 0.00 180.00 180.00
126.01 129.03 125.84 118.38 122.83
180.00 180.00
reaction producing carbenium ion and OH- however does not occur with the alcohol in water, much better leaving groups such as Cl- being required to observe C-X heterolysis [ 111. The first-order rate constant for C-Cl heterolysis in water, again for a l-methyl derivative, is 1 s-l [111.In other words, NH-OH and CH,-Cl have similar reactivities in solution. Figure 6 lists isodesmic and isomerization equilibrium for which data at the
384 TABLE 3 3-21G Optimized geometries (bond lengths are in Bngstriimand angles in degrees) Parameters
N,-G C,-Ns N,-C, G-G G-X6 G-07
N,-H C,-H C&-H X,-H X,-H’ 0,-H
N,-C2-N3 C,-N,-C, L N,-C,-C, L N,-C,-X, L L
7
8 1.3681 1.3000 1.3938 1.3526 1.0630 0.9943
1.0624 1.0633
111.13 106.25 109.70 122.75 128.69
131.61
111.38
rH-c,-c5-o
TN,-c,-N,-c,
180.00 0.00 0.00
TH-N&-N, TH-N&,-X, TN,-&-X,-H TN,-C,-&-H' TN,-C,-C,-H T&-N,-C,-X, TH-N,-C,-C,
106.40 108.26 114.22 126.25 105.54 121.84 110.27 121.59 114.75
1.3978 1.4442 1.2628 1.5217 1.3155 1.4338 0.9936 1.0669 1.0821 1.0682 1.0705 0.9669 106.49 108.70 114.08 130.13 106.08 122.27 109.88 123.54 119.19 122.11 111.18
126.28
TN,-c,-c,-0, TC,-c,-0,-H TN,-c&,-H TC&&-&-&
1.3885 1.4577 1.2603 1.5249 1.2428 1.4311 0.9940 1.0670 1.0813 1.0086 0.9668
L c,-c,-0, L C&,-H L C&-H L C,-N,-H L C,-X,-H L C&X,-H L &0,-H L C,-N,-H
9
118.14 188.80 301.17 208.76 1.29 0.90 174.78 355.89 178.19
117.69
187.52 300.56 207.89 1.30 1.43 171.85 353.11 177.96 357.55
180.00 180.00 180.00
computational level are available. Reaction 1, which has the imidazole hydroxylamine transfering an OH group to the carbenium ion to form alcohol plus nitrenium ion, lies far to the right with AZ= -22.1 kcal mol-‘. This is of course consistent with the experimental observation that nitrenium ion forms
385
TABLE 4 Total SCF energies (hartree)
- 352.661979
2b 3b(A) 3b(B) 5(A) 5(B) 5(C) 5(D) 6 7
8(A) S(B) 9 CH30H NH,OH NH*+ CH,+
- 277.408762 - 277.395742 - 336.808346 - 336.808243 - 336.793505 - 336.792391 -261.519957 -223.549115
NHOH
H
CH,OH
1.50
1.46
l.27nl.33 'T/-k !&2"
l.W3 11.32
11.23
+CH3
+NH
Fig. 3. Imidazole bond lengths. H.4
c-,
I @NH
Hm4
-““\;y
.4H/
NNC,NH I
@CH,
Fig. 4. Resonance contributors.
-He5
IL .6
-2
-352.692343 -352.684257 -336.775342 - 114.426083 - 130.288091 - 54.824105 - 39.009434
386 OH
/-\
-
-OH-
N,
NR
Y H/N
I-\ N,
Y
NR
NH
+NH
OH c
/-\ N,
NR
-
-cd-
/-\
/-\ N,
Y +bH*
Y dH,CI
NR
NR-N, -OH-
(2)
Y k~,0H
Fig. 5. Experimental observations.
/-\
N,
NH
+
CH,OH
N//NH
+
+
NH,OH
+9 \
NHIOH
-16.8 G+
CH,OH
(1) I NH
Y
+CH,
NVH
+
+NH2
(2)
Y CHz OH
OH
Fig. 6. Equilibria ( AE in kcal mol-‘).
more easily than carbenium ion. The origin of this difference lies either in the 2-hydroxymethylimidazole being more stable than the 2-hydroxyaminoimidazole, or in the imidazole nitrenium ion being more stable than the imidazole carbenium ion (or of course a combination of both these effects). Reaction 2 of Fig. 6 shows that the imidazole ring has a profound influence. This isodesmic equilibrium, similar to that of reaction 1 but now without the imidazole ring, lies far to the reagent side, thus avoiding the bare nitrenium ion NH2+. The contrast with equilibrium 1 implies that the resonance stabilization by the imidazole ring is more important for the nitrenium ion than for the carbenium
387
ion. This is borne out by consideration of equilibrium 3 where the charged species are imidazole substituted, and the equilibrium shifts dramatically to the nitrenium ion side. The hydroxylaminoimidazole: hydroxymethylimidazole relative stabilities however must also be important, as is illustrated by a comparison of the isomerization equilibria 4 and 5 of Fig. 6. With the hydroxymethyl system, isomerization to the non-aromatic 5-OH isomer is a highly endothermic process, undoubtedly due to the loss of aromatic resonance energy. A similar isomerization with the hydroxylamine however is highly exothermic. These comparisons obviously offer a further rationalization behind the products of nucleophilic addition to the cations, since in each case it is in fact the more stable product which is formed. The unusual favoring of the non-aromatic isomer in the hydroxylamine system may be related to a weak N-O bond, since there are indications that the bond dissociation energy of such bonds is relatively low, particularly when attached to aromatic rings. Thus the bond dissociation energy of the N-O bond of hydroxylamine is 61 kcal mol-’ [ 191. This is comparable to a value of 56 kcal mol-’ for the N-N bond of hydrazine [ 201, and in that system substitution of one hydrogen by phenyl lowers the energy to 40 kcal mol - ’ [ 211. Bond dissociation energies for aromatic hydroxylamines have not been reported. However, a benzenoid hydroxylamine derivative has been found to undergo thermal N-O homolysis at relatively low temperatures (90’ C) [ 211. Interestingly, the present computations show that the optimum geometry (Fig. 7) of the imidazole hydroxylamine has the NHOH group twisted with respect to the plane of the imidazole ring (which in fact is not entirely planar). Moreover, the geometry about the nitrogen of the NHOH group itself is not planar. In other words there appears to be minimal x delocalization involving the formal electron pair of the NHOH group and the imidazole ring. As already noted [ 81, compared to benzenoid hydroxylamines such as Nphenylhydroxylamine, the imidazole hydroxylamine is highly unusual in its undergoing N-O bond heterolysis so readily at pH 7. The benzenoid systems do form nitrenium ions, but only under acidic conditions, or after esterification of the OH group to give a better leaving anion [ 22-241. That significant biological effects associated with DNA alkylation can accompany nitrenium ion formation has been well established [ 251. The ease of formation of the imidazole versions of these at least in part may explain the pronounced biological effects observed with imidazole drugs. In summarizing the present calculaOH N
N,
21° N 1
59O
q
H
Fig. 7. Optimum geometry of the imidazole hydroxylamine.
388
tions, the key feature is that they do provide a rationale for the chemistry since they show significant stabilizing interaction accompanying the placing of a nitrenium ion center on the imidazole ring. There are some significant biological differences between nitrobenzenes and 6-atom nitroheterocycles on the one hand and 5-atom nitroheterocycles on the other [ 261. As previously postulated [ 261 one source of the difference may lie in the properties of the respective nitrenium ions [ 271. ACKNOWLEDGMENTS
The financial support of the Natural Sciences and Engineering Research Council of Canada and the National Cancer Institute of Canada is gratefully acknowledged.
REFERENCES 1 2
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6 I 8 9 10 11 12 13 14 15 16
17 18
19 20 21
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T. Sone, Y. Tokudo, T. Sakai, S. Shinkai, and 0. Manahe, J. Chem. Sot., Perkin Trans. 2, (1981) 1596. P.G. Gassman and J.E. Granrud, J. Am. Chem. Sot., 106 (1984) 1498. M. Novak, M. Pelecanou, A.K. Roy, A.F. Andronica, F.M. Plourde, T.M. Olefirowicy and T.J. Curtin, J. Am. Chem. Sot., 106 (1984) 5623. E.C. Miller, Cancer Res., 38 (1978) 1479. G.D. Hartman and R.D. Hartman, Mutat. Res., 117 (1983) 271. For quantum chemical calculations involving of benzenoid nitrenium ions see: G.H. Loew, J. Phillips and G. Pack, Cancer Biochem. Biophys. 3 (1979) 101; G.P. Ford and J.D. Scribner, J. Am. Chem. Sot., 103 (1981) 4281; G.D. Hartman and H.B. Schelgel, Chem. Biol. Interact., 36 (1981) 319.