JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (Registered in U. S. P a t e n t Office)
VOLUME
(0Copyright, 1957,by the American Chemical Society)
KOVEMBER 23, 1957
79
NUMBER 22
PHYSICAL AND INORGANIC CHEMISTRY [CONTRIBUTION FROM THE
Theoretical
LABORATORY O F PHYSICAL
CHEMISTRY,
FACULTY O F SCIENCE, UNIVERSITY
O F VALENCIA]
Study of Nitrogen Heterocyclics. 11. Molecular Diagrams Carcinogenic Activities of Some Mono- and Dibenzocarbazoles
and
BY J. I. FERNANDEZ-ALONSO, L. CARBONELL VILAAND R. DOMINGO RECEIVED JUNE 20, 1956 Molecular-orbital calculations of structural static parameters (bond orders, r-electron densities and free valences) and dynamic indexes (atom, ortho- and pura-localization energies) are presented for a number of mono- and dibenzocarbazoles. The results are used to predict the chemical properties of the molecules. A correlation was found between carcinogenic activity and the static complex indexes used to characterize the K region.
Some years ago Longuet-Higgins and Coulsonl calculated the molecular diagram of carbazole. Since then, little attention has been given to the theoretical study of carbazole and its derivatives and few molecular diagrams of these compounds have been calculated. Recently, Pullman and PullmanZ published the molecular diagram for 3,4,5,6-and 1,2,T,8-dibenzocarbazoles, calculated by the M O mcthod using the approximation, homocyclic c o n j ~ g a t i o n " ~in; this approximation i t is assumed that the atomic orbitals of all the atoms are equivalent, aiid, in consequence, the electron-pair of nitrogen atom is considered as belonging to the carbon atom which occupies its place. Their results are not satisfactory, because analysis of their molecular diagrams shows different gradations of the bond order and the n-electron density for the K region. Thus, they could not predict the chemical reactivity in this region for both molecules, and consequently could not predict their carcinogenic activities. I n contrast to the polycyclic carcinogenic compounds, the physiological activity of the carbazoles has attracted little attention. Recently, however, Buu-Ho'i and his co-workers5 have synthesized a
great number of these derivatives, and Lacassagne and his co-workers6have published experimental results for 42 members of this series. In this paper we present the molecular diagrams of the following compounds: 1,2- (I), 2,3- (11), 3,4-benzocarbazole (111), 2,3,6,7- (IV), 1,2,7,8(V) and 3,4,5,6-dibenzocarbazole( V I ) . (The enumeration used in calculations and results is standard, as indicated in the respective diagrams.) From the calculated structural static and dynamic indexes, we have tried to establish a quantitative relation between carcinogenic activity and molecular structure.
I
111
H
H
\'I
(1) H C . Longuet-Hiygins a n d C . A. Coulson, Trans. Favnday Soc., 43, 87 (1947).
( 2 ) A . Pullman a n d B. Pullman, "Cancerisation p a r les substances chimiqucs e t structure molkulaire," hlasson e t Cie, Paris, 1955, p. 190. (3) E. Huckel, Z . P h y s i k , T O , 042 (1931); 76, 634 (1932); R. S. blulliken, J . Chcm. Phys., 7, 340 (1939). (4) G.Berthier a n d B. Pullman, Conzp. v e n d . , 231, 774 (1950),have calculated b y this approximation a molecular diagram for carbazole. ( 5 ) N.-P. Buu-Hol a n d P . J a c q u i g n o n , J . Chcm. Soc., 513 (1954), a n d former papers.
(6) A. Lacassagne, N . - P . Buu-Ho!, F. Zajdela and iX,D. Kuong,
Bull. Cancer, 42, 3 (1955).
5839
J. I. FERNANDEZ-ALONSO, L. C. VILA AND K. DOMINGO
5840
Method of Calculation.--We have used the MO method in the simplest LCAO approximation. We have not taken into account the overlap integrals between adjacent atomic oribitals, due to the complexity of the calculation, although the importance of this factor is admitted.' The three dibenzocarbazole molecules have the symmetry Czv, which has been given consideration in the resolution of the corresponding secular determinants. TABLEI T-ELECTRON MOLECULAR-ORBITAL ENERGY LEVELS(Ei) . .. IN ORDER OF IXCREASING ENERGY Benzocarbazole
mi
3,4-
1 2 3 4 5
12
1
5 1 2 3 4
5 Dibenzocarbazole
i
(E.
-
6 7 8 9
1.0000 1.0000 0.5797 0.4941
6 7 9
1.1634 0.8574 .6801 .4339
6 7 8 9
1,1501 0.8631 ,6842 ,379s
1.4142
2.6596 2.1616 1.7186 1.6225 1.2649 2.6428 2.1976 1.7641 1.5442 1,3031
2 3 4 23
mi = a)/@
=
- e)/B 2.6547 2.1728 1.7886 1.4609
(:E;
i
jym."
8
Vol. 79
the parameters given by Fukui and his co-workers,ll 6 = 1 and p = 1, ;.e., QN = ac Pc,c and PC,N = Pc,c. (This value for 6 is very near that adopted by Jaff6,lo 6 = 1.2.) We have not taken the inductive effect into account. The molecular-orbital energies are indicated for the six compounds studied in Table I. The MO coefficients being known, we have calculated the n-electron densities and the bond orders according to Coulson and Longuet-Higgins.l 2 I n spite of Moffitt's consideration^,'^ we have adoDted a single value for the maximum bond order,*14N m a x = 3l f 2 . in the calculation of the free valences. The bond orders and the n-electron densities for 1,2-benzocarbazole are shown in diagram VIIa, and the free valences in VIIb. VIIIa and VIIIb, and IXa and I X b give similar static indexes for 2,3and 3,4-benzocarbazole, respectively. The structural static indexes are shown in X , X I and XI1 for 2,3,6,7-, 1,2,7,8- and 3,4,5,6-dibenzocarbazole; the values indicated by arrows (on the right of the figures) correspond to the n-electron densities and those on the left to the free valences.
+
v
Sym."
1.2453 1 2.6602 7 s S 2 'I 1.0000 2.2700 8 S 2.0915 9 A 0.8592 3 S .5206 4 1.5792 10 A S A 1.5094 11 S .3467 5 A 1.2798 6 h A 1.2094 2.6885 7 1,2,7,81 2 2.2700 8 A 1.0000 S A 1.9918 9 s 0.8592 3 A ,5206 4 1.6634 10 S 1.5094 11 A ,4434 5 S 1,2798 6 S 1.1798 A 2.6317 7 1 S 3,4,5,61.0000 .I 2.2440 8 A 2 0.7845 2.0511 9 s 3 S .5858 A 1,5801 10 S 4 1.4791 11 A .4434 5 S 1.3763 6 S a The wave functions symmetrical in respect with the plane of symmetry are labeled S, those anti-symmetrical about the plane of symmetry are labelled A . Their correct designations according t o group-theory, are A2 and BI, respectively. See H. Eyring, J . m'alter and G. E. KiCimball, "Quantum Chemistry," John \Tiley and Sons, h-ew York, S.Y . , 1944, p . 376. 2,3,6,7-
The Coulomb integral of the nitrogen atom, QN, and the resonance integral for the CN bond, @(!,N, have the following form: QN = QC -/- 6P and @C,N = p PC,C, respectively. The selection of the best values for the 6 and p parameters is a difficult cluestion.i-*O For our calculations we have chosen (7) U W Davies, T i a m . Faroday SOL.,51, 449 (1953, when previuus references are given about the introduction of the overlap.
(8) L. E. Orgel, T. L. Cottrell, W. Dick and L . E. S u t t o n , i b i d . , 41. 1136 (1931). (9) P.-O. I.dwden, J . Chctn. P h y s . , 21, 496 (1953). (10) €I. H. Jaff6, THISJ O U R N A L 77, 4448 (1956).
1.0866
IO151
f 6L06
VIIIa
0
0'565
I5001
0.'573
0.5069
04391
4074
..
044'2
VIIIb :,0038 L
J
1,0282
i 61
1.0.515 " I
IXa (11) K . Fukui, T. Yonezawa, C. Kagata a n d H. Shingu, J . Chem. Phys., 22, 1433 (1954). (12) C. A. Coulson and H . C. Longuet-Higgins, Proc. R o y , SOL.
(London), Al91, 39 (1947). (13) W. E. Moffitt, Tram Foraday SOL.,46: 373 (1949). ( 1 4 ) H H . Greenwimrl, i b i d , 48, 077 (1952).
MOLECULAR STRUCTURE
Nov. 20, 1957
A N D CARCINOGENICITY OF
The atom localization energies, A (- p), have been calculated by the standard method,15 and those of the ortho-localization, o ( - p ) , and paralocalization energies, p ( -@), by the methods described by Brown.18 TABLE I1 ATOM LOCALIZATION ENERGIES A.( -8)
'14-8)
1 1' 2' 1 7 8 3 4 7 8 1 2 7 8
2.050 2.200 2.421 2.068 2.453 2.196 2.097 2.346 2.406 2.225 2.285 2.230 2.378 2.223
2.220 2.256 2.444 2.113 2.476 2.366 2.294 2.362 2.480 2.362 2.344 2.281 2.448 2.361
2.389 2.313 2.46;i 2.157 2.500 2.535 2.492 2.377 2.554 2.499 2.403 2.332 2.519 2.500
1 1' 2' 3' 4' 4 3 4 1 2
1,931 2.206 2.420 2.336 2.258 2.097 2.117 2.328 2.291 2.190
2.115 2.268 2.430 2.421 2.265 2.119 2.294 2.351 2.343 2.264
2.300 2.330 2.440 2.506 2.272 2.141 2.471 2.374 2.395 2.338
Benzocarbazole Positions
2,3-
1.2-
3,4-
A.(--8)
DIBENZOCARBAZOLES 5841
in which positions the different types of substitution reactions should occur. Electrophilic attack should occur initially a t the position (or positions) of maximum ?r-electron density and minimum A,; nucleophilic substitution a t the position of minimum a-electron density and A,; and the radical attack a t the position of maximum free valence and minimum A,. These predictions are given for the carbazoles in Table V. Some results, however, cannot be considered as definitive because the entire localization energies have not been calculated. We can sum up these considerations concerning chemical reactivity by plotting the static indexes against the dynamic, e.g., Fig. 1 in which the values
1.10
1
1.04
I
5
Dibenzocarbazole
2,3,6,7-
1,2,7,83,4,5,6-
TABLEI11 Ortho-LOCALIZATION ENERGIES Benzocarbazole Positions 4-69 2,3l', 2' 1.232 1.360 7, 8 1,23, 4 1.139 1.343 7, 8 1, 2 1.129 3,41.339 7, 8
1
1
1
2.00 2.10 2.20 Atom-localization energy A , ( -P). Fig, 1.-Variation of the x-electron densities with the atom localization energies for the position of initial electrophilic attack: (1) 2,3,6,7-dibenzocarbazole; (2) 2,3-benzocarbazole; (3) 1,Z-benzocarbazole; (4) 1,2,7,8-dibenzocarbazole; (5) 3,4,5,6-dibenzocarbazole; (6) 3,4-benzocarbazole.
of the ?r-electron density are plotted against A , for the positions of the initial electrophilic attack. The agreement between these indexes is excellent, with the exception of 3,4,5,6-dibenzocarbazole.
Di benzocarbazole
l', 2' 3', 4' 3, 4 1, 2
2,3,6,7-
1,2,7,83,4,5,6-
1.236 1.234 1.131 1.124
TABLE IV Para-LOCALIZATION ENERGIES Benzocarbazole
2,3-
Positions
9(-8)
1, 4
3.461
1, 4 11, 4' l', 4' 1'. 4'
3.482 3.666 3.738 3.739
Dibenzocarbazole
2,3,6,71,2,7,83,4,5,6-
Chemical Reactivity.-Although little is known about the chemical behavior of the mono- and dibenzocarbazoles, we shall indicate, on the basis of our static (a-electron densities and free valences) and dynamic indexes (atom localization energies), (15) G.W. Wheland, TEISJOURNAL, 64, 900 (1942). (IS) R. D.Brown, Australian J . Sci. Res., AZ, 564 (1949); J . Chcm. SOC.,691 (1950).
1
0.4433
J. I. FERNANDEZ-ALONSO, L. c. VILA AND R.DOMINGO
5842
Vol. 79
TABLE T.’ 10064
1,0016
0 7 0 8 8 OblSb
0 4412
POSITIOXS AT KIIICHSCBSTITUTION R F~ C T I O V S Srror-r.~ OCCVRINITIALLY Renzocarbazole
2,31,23,4-
T y p e of substitution reaction Electrophilic Sucleophilic Radical Po-ition I’osition 1’w;ition
1
4‘“ 4
1
3
H
1In
>
J”
I
Dibenzocarbazole
2,3,6,71,2.7,8-
3,4,5,6a Uncertain, since A , for this position is u n k n o w i . certain, since A , for this position is unknown.
0 4017
0 ..-I?
9 4492
YIIb
From their study of the ultraviolet absorption spectra of the benzocarbazoles, Clemo and Feltonl’ have postulated that the electronic polarization leads to a $-quinoid structure, which indicates the initial position a t which substitution by electrophilic reagents should take place; for 2,3-benzocarbazole ( 1 7 ) G R Clemo a n d D G I. Feltoa, J . Chem. SOL, 1658 (1952).
Un-
electrophilic attack should occur a t position G, for 3,4benzocarbazole at position 2, and for 1,2benzocarbazole a t position 3. Their conclusions agree with the theoretical results (x-electron densities) q f ‘I-onguet-F-Iigginsa n d Cotilson,’ and also nil‘; t;ie esperimental findings. They agrce with oiir results only for l,2-benzocarbazole. Siriiilnr rcsults were obtained by FeltonlY for 1,2,T,C;-, 3,3,5,0- and 1,2,~,A-diberizocarba~(~l~!. Carcinogenic Activity and Molecular Structure.-IT‘e have tricd to establish a yuaiititative relationship between the niolccalnr structure of these non no- and dibenzocarhnzoles aricl their carcinogenic activity. I t is well known that condensect carbazoles (especially derivatives of 1,2-benzocarbazole, I 9 ) and the di-angular benzocarbazoles6,2’J(particularly S,4,5,B-dibenzoc~rbazole) show irlarlied carcinogenic activity. -211 theories which relate n:oleculnr structure to the carcinogenic activi ty of the iiitrogen heterocyclics are based on the assumption that carcinogenically active niolecules possess---in a form similar to the polycyclic aromatic hydrocarbons--a i?zeso-pheiiaiithreriicregion called the E; region, which is cheinicaily very active, and is the seat of physiological activity. Iiurtheniic.)rc, according to Pullinan and Pullman, L’l if the rnolccule has a nteso-anthracenic region, cdled the L region, the latter must have little activity; otherwise, the K region cannot enter into the carcinogenic process. In diagrams I, 11, V and VI, we represent the K region by a thick line. -1s 2,3-benzocarbazole and 2,3,6,7-dibenzocarbazole are not carcinogenic, we cannot properly speak of their I( region; however, for comparative purposes we designated l ‘, 2’ as the K region for 2,3-benzocarbazole, and l’, 2’ and 7’, 8’ as the K region for 2,~,6,;-dibenzocarbazole. The chemical reactivity for the K region cai: be characterized by the bond order (static index) and by the ortho-localization energy (dynamic index). (IS) D. G I. Feiton, i h i d . , lf$CS(1932). (19) 0. Schuruh a n d A. Winterstein, 2. phyriol. Chem., 236, 79 (1935); A . Laczssagne, X . - P . But!-Hoi, E. Roycr aiid F. Znjdela, C. R Soc. Biol., 141, 6 3 5 (1047). ( 2 0 ) E. Boyland a n d A . R I . Brues, Prec R u y . Soc. (Lo?idort),B122, 429 (1937); E. Boyland a n d E. H. Mamson, Riochem. a‘., 32, l4(jO (1938); G . R I . Badger, J , W. Zouk, C L. H e i r e t t , E. I.. Keniia.!sy, A-. M . K e n n a w a y , R. H. M a r t i n and A. 11.Robinson, Pia,. R o y . .Soc. (London). B131, 170 (1942): A , H. Kirby a n d P. I
