Electronic Structure and Carcinogenic Activity of Aromatic Compounds I

Electronic Structure and Carcinogenic Activity of Aromatic Compounds I. Condensed Aromatic Hydrocarbons*

CHIIc@YosHI NAGATA, KENICHI FUKUI, TEIJIR0 YONEZAWA, AND YUSAKiJ TAGASHIRA

(Departments of Fuel Chemistry and of Pathology, Kyoto University, Kyoto, Japan)

Numerous attempts have been made from many diagram method they could give only qualitative points of view, both chemical and physical, to ac information as to these compounds.' Moreover, as count for the differencesin carcinogenicactivity of Boyland (3) and Kooyman and Heringua (18) various aromatic compounds (6, 7) and, thereby to pointed out, by considering the K-region alone it explore the riddle of carcinogenesis due to these seems difficult to explain the mechanism of car substances. The experimental approaches included cinogenesis. In spite of all the quantum-mechani investigations of chemical constitution (926), cal approaches attempted, therefore, it has not yet fluorescence (5), phosphorescence (920),absorption been possible to construct a complete theory of spectra (16, 17), etc., but no satisfactory explana carcinogenicity by a consideration of the ir-elec tion has ever been given for the exact nature of tron system. carcinogenic compounds. Some of the present authors (192, 13) have pre A large majority of the important carcinogens viously discovered the significance of what we call belong to the aromatic hydrocarbons, aromatic Irontierekctronsinchemicalreactionsofir-electron heterocyclics, and aromatic amines, which are systems and have succeeded in explaining the ex characterized by having a certain number of perimental results satisfactorily by means of cal mobile electrons, so-called ir-electrons. 0. Schmidt culating the frontier electron density. Further (927)first attempted to relate the carcinogenicity of more, it has been found that a distinct parallelism aromatic hydrocarbons with the distribution of exists between carcinogenicity and the frontier 7-electrons in these compounds, and thereafter electron distributions. In the present paper the re many physicists and theoretical chemists such as lation between the calculated frontier electron dis A. and B. Pullman (9292,92.5),Daudel (9), Berthier tributions and carcinogenicities of nonsubstituted and Coulson (92),Greenwood (14), and Dewar (10) aromatic hydrocarbons is reported, and at the have endeavored to explain carcinogenicity from same time some discussions are given about the the nature of ,r-electrons. Among these works the activity of carcinogens. The results on substituted Pullmans' â€œK-regiontheoryâ€• (8, 925)appears to be aromatic hydrocarbons, aromatic heterocyclics, a basis for further study. and aromatic amines will be reported in the near The Pullmans carried out the calculations of the future. r-electron distribution in molecules and developed their theory by means of a â€œmoleculardiagram OUTLINE OF TREORETICAL method.â€• Ilowever, this method was not appli TREATMENTS cable to large molecules on account of the com All the compounds which the present paper plexities of the calculations. The calculation is too treats belong to the ir-electron system. It is well laborious to make in the case of polycondensed known that w-electrons are very mobile and would aromatics, i.e., for the molecules with five or more be considerably influenced by outer disturbances. condensed benzene rings, to which group many p0- Consequently, absorption spectra, magnetic ani tent carcinogens belong. Thus, by the molecular sotropy, chemical reactivity, and many other physical and chemical properties which are charac * This work was aided by a grant from the Ministry of Education, Japanese Government. â€˜Under these circumstances the Pullmans used in their recent papers (23, 24) the localization method, of which men Received for publication August 11, 1954. tion is made in the next section. 9233

teristic of the w-electron system are ascribed to system has a maximum in the process of reaction, ir-electrons. by which the transition state is defined. In the Two methods exist in the quantum-mechanical transition state a hyperconjugation may take treatment of ir-electron systems. One is the â€œva-, place between the initial conjugated system and lence bond (V.B.) methodâ€• and the other is the the quasi-ir-orbital which may appear near the re â€œmolecular orbital (M.O.) method.â€• Because of action center. According to the theoretical treat the excessive tediousness of the exact yB. treat ment which has been given in detail in the litera ment for large molecules, several approximate ture (11), the activation energy, i@E, of the reac methods have been developed. They involve, how tion is given by ever, a considerable amount of arbitrariness which L@E (@E)@+ ([email protected])T, makes the results doubtful. On the other hand, the (1) MO. method has proved to be more readily appli where @ cable to large aromatic molecules such as the car N â€”v)C@ cinogenic compounds. Under these circumstances (@E)@='@'-@--â€” 72+v(ahâ€”aR), (2) most of the chemical and physical treatments of @_â€˜ ir-electron systems are based on the M.O. method. in which N is the total number of ,r-orbitals in the The discussion of chemical reactivity of the isolated conjugated molecule, v and C@are the r-electron system has been made through two dif number of electrons (0, 1, or 92)and the coefficient ferent ways of approach in the M.O. theory. The of the rth atomic T-orbital in the jth molecular first is called â€œlocalization methodâ€• of Wheland orbital in the conjugated molecule, respectively, (31). In this method, it is assumed that the rate of the energy of which is s. The value of is is deter reaction at a certain position in a molecule is de mined by the type of reaction in the sense of or termined by the â€œlocalizationenergyâ€• which is re ganic electronic theory, and is taken as 0, 1, or 92, quired in localizing a requisite number of ir-elec according to whether the reagent is electrophilic, trons at that position. The second is called the radical, or nucleophilic, respectively. a@,and aR are â€œstaticmethod.â€•2In this method the chemical re the Coulomb integrals of the quasi-w-orbital and activity at a position in a molecule is correlated of the orbital of the reaction center in the reagent, with the density of all the w-electrons at that po respectively. By the reason given in the original sition in the isolated molecule. paper, aa may in the present case be put equal to The fundamental supposition in the localization a, which is the Coulomb integral at a carbon atom method is that a parallelism would exist between inbenzene. the localization energy and the chemical reactivi The terms AE4@and v(aa aR) as well as â€˜yare ty. On the other hand, the basis of the static meth constant and may be disregarded in discussing od may be valid when the interaction between the reactivity if only the same type of reactions are molecule and the reagent is very small. In both of considered, as in the present case. The relative the two methods mentioned above, the chemical ease of reaction, therefore, can be measured by the feature of the process of reaction is not directly amount of the coefficient of â€˜y@inEquation (92). considered. Namely, in these methods the mech This quantityisreferredtoas â€œsuper-delocaliza anism of formation and dissociation of cr-bonds is bilityâ€• and denoted by S@,that is not taken into consideration. Accordingly, these two methods are not considered to be sufficiently satisfactory to describe the true process of chemi sr==@ (v,_;)C@2 (3) cal reaction. Frontier ekctron method.â€”Someof the present @ authors introduced the frontier electron method as where Xjis given by s3= a + X$ in which is the a third one of molecular orbital treatments of exchangeintegral between two adjacent 7-orbitals chemical reactivity (11â€”13).In that theory the in benzene. electronic interaction between the molecule and In the right side of Equation (3) one or two @ the reagent has been divided into o@-and 7r-parts. terms (denoted by suffix f) exist in which Xii is When certain relations hold between some inte small and v@â€”v 0. Hence, the magnitude of grals of o@-e1ectrons,the a-part of the energy of the Sr @5determined predominantly by these terms, especially in a large molecule such as condensed 3See, for example, E. Hilckel, Z. Physik, 72:812, 1981; aromatic hydrocarbons. We call the molecular or G. W. Wheland and L. Pauling, J. Am. Che,n. Soc., 57:2086, 1985; H. C. Longuet-Higgins and C. A. Coulson, Trans. Far. bitals corresponding to such terms the frontier or Soc., 43:87, 1947; C. A. Coulson and H. C. Longuet-Higgins, bilals. Thus, reactivity in these molecules can be Proc. Roy. Soc. London, s.A,191:39;s.A, 192:16, 1947. discussed by calculating only the contribution of

Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1955 American Association for Cancer Research. NAGATA et al.--Eleetronic Structure and Carcinogenic Activity ~35 the frontier orbitals. 3 In almost all the cases, the As generally used, the signs + and - indicate the frontier orbitals coincide with the highest occupied degree of carcinogenicity. The greater the number orbital in the electrophilic reaction, with the low- of + signs, the greater is the activity. The sign + est vacant orbital in the nucleophilic reaction, and indicates that the compound is very feebly car- with both the above orbitals in the radical reac- cinogenic; i.e., in some cases it has been reported tion. to be carcinogenic, but in other experiments was not carcinogenic. The - sign indicates that the APPLICATION TO THE CARCINOGENIC compound has not been reported to induce tumors. PROBLEM It can be seen in Table 1 that a close relation It has become clear that an intimate correlation exists between the value of super-delocalizability at exists between the carcinogenic activities and the p.o. and carcinogenic activity. It is rather striking frontier electron distributions of nonsubstituted from the physical point of view that such a rela- aromatic hydrocarbons. tion, connecting a biological phenomenon with We designated the position corresponding to the physics, has been obtained by a calculation in phenanthrene double bond and the position corre- which no arbitrary parameter was introduced. sponding to meso of anthracene the "principal car- The critical value of Sp, below which a com- cin0genophore TM and the "subsidiary carcinogeno- pound is not carcinogenic, is found to be about phore," respectively. The following relations have 0.65 (Table 1). This numerical value has a definite been found, and, according to these relations, non- meaning, because Sp is a dimensionless quantity. substituted aromatic hydrocarbons can be classi- The compounds of Class (A) have both the p.o. fied into three groups, i.e., (A), (B), and (C). and s.c.; the values of Sp are larger than the A) These compounds have both the principal threshold value, and almost all these compounds and the subsidiary carcinogenophores and at the are carcinogenic. The order of the values of S~ same time have sufficiently large values of super- roughly parallels the degree of activity of these delocalizability at the principal carcinogenophore compounds. However, in this connection, it should (Sp). They are carcinogenic. be noted that an attempt to explain very small B) These compounds have the principal car- differences in activity by means of Sp alone may be cinogenophore (p.c.) only. They are slightly car- rather meaningless, since the carcinogenicity varies cinogenie or noncarcinogenic, even if the values of with the experimental procedure, with the species St are above the critical value. of test animal, and with differences in the diffusion C) These compounds have the subsidiary car- of the carcinogen into the cell. cinogenophore (s.c.) only, are devoid of both the Hitherto it has been considered that 1,9.,benzan- principal and the subsidiary carcinogenophore, or thracene is noncarcinogenic (1, 4, 15, 19, 21, 98), have both carcinogenophores but small values of but, according to some recent experiments by Sp. They are all noncarcinogenic. Steiner et al. (29, 30), it has become clear that this The frontier electron densities calculated at compound is carcinogenic. As is seen from the cal- every carbon atom (fl -- $C{~) in each compound culations in Table 1, this compound would be ex- and the positions of principal and subsidiary car- pected to carcinogenic. The existing theories based cinogenophores are indicated in Charts 1 and 2. on the supposition that this compound was non- The values for the compounds which belong to carcinogenic, therefore, must be subjected to a Class (C) are omitted. modification, as has been pointed out by Steiner The calculated values of super-delocalizability at and Falk (30). the principal and subsidiary carcinogenophores are As exceptional cases we must refer to 2,3,7,8- shown in Table 1 and compared with the experi- dibenzphenanthrene and 2'3'-naphtho-3,4-py- mental carcinogenic activity. The value of Sp is the rene. In spite of the reported inactivity of these sum of the values of super-delocalizability of two compounds, the calculated values of Sp are larger carbon atoms at the principal carcinogenophore. 6 than the threshold value. Perhaps they should be s However, in the case when the next orbital is in close retested by experiments of longer duration as in proximity to the frontier orbital, the corresponding term must the case of 1,~-benzanthracene. be taken into account. In general, the value of S, is not so important 4This corresponds to the so-called K-region of the Pull- as that of S~, though the existence of s.c. relates to malls. the activity essentially, as will be stated below. s The theoretical ground for th~s summation is easily given Pullman's opinion (23, ~) that the larger the by the above-mentioned treatment of the frontier electron electron density of the meso position (correspond- theory extended to the case of simultaneous 1,~-addition or substitution, to which, we assume, the carcinogenic reaction ing to s.c.) the lower the carcinogenicity has not should belong. been cont%med by our resUlts. Thus, the values oi~

S. were rather large for 3,4-benzpyrene, which is values of 5,, for these compounds are below the one of the most potent carcinogens, as well as for threshold value. However, we feel this might be 3,4,8,9-dibenzpyrene, which is a relatively potent due to some other factors, for instance, the special carcinogen. steric circumstances in these compounds. The compounds of Class (B) have only p.c. and The compounds of Class (C) are devoid of the not s.c., and the carcinogenicity of these com p.c. or otherwise have a p.c. whose 5, is below the pounds is relatively weak, even though the value threshold value. Experimentally, these compounds of 5,, is comparatively large. From this fact, it may have been found to be noncarcinogenic. Therefore be possible to conclude that the existence of s.c. is the agreement of the calculated results with ex a necessary, though not a sufficient, condition for periments is very satisfactory. carcinogenicity. This is interesting in relation to Thus, the present authors conclude that the ex the opinions of Boyland (3) and Kooyman and istence of a p.c. whose 5, is larger than the thresh Heringua (18) who have pointed out the impor old value should be necessary for carcinogenic ac tance of the anthracene meso position.6 tivity; further, the value of 5,, is the most impor Although 3,4-benzphenanthrene and 1,92,3,4-di tant factor determining the degree of activity. benzphenanthrene are definitely carcinogenic, the From this point of view it can be said that the main center of reaction is p.c. With the existence â€˜However, Pullman (28, 24) has reported, against them, that the existence of K-region alone is sufficient for the of s.c. alone, there appears to be no activity, even carcinogenicity. if the value of 5, is large. But, as is seen from

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CHART 1.â€”Frontier electron distributions and the positions the frontier electron density at each position in the molecule of principaland subsidiarycarcinogenophoresinthe corn- f,; the principalcarcinogenophoreisshownby a thick line; pounds of Class (A). (Numerical values in the Chart indicate the subsidiary carcinogenophore is shown by a black spot.)

Table 1, the activity is remarkably decreased SUMMARY when the carcinogen lacks the s.c. even though the 1. The frontier electron method, one of the value of 5, is sufficiently large. Therefore, it seems quantum mechanical methods for explaining certain that, in a sense, the s.c. is connected with chemical reactivity, which has been proposed by the process of carcinogenesis. Consequently, it is some of the presentauthors,was appliedto the assumed that the s.c., though it is not the main problem of the carcinogenicactivityofnonsub center of reaction, plays a sort of subsidiary role in making more easy the chemicalcombinationbe stituted aromatic hydrocarbons. Frontier electron distributionsandthesuper-delocalizabilities,which tween the p.c. and protein. It is concluded, there fore, that the existence of s.c. is also necessary for are the quantitiesdeterminingthe chemicalre the occurrence of activity. activity of these compounds, were calculated, and The frontier electron method also appears ap the results were reported. plicable for explaining the structures of metabo 92.By comparingthecalculatedresultswithex lites of carcinogens. The results will be reported in perimental data, the present authors concluded the near future. that two different positions were necessary for the .055.055

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1:2-BENZPYRENE 1:2:5:6 -DIBENZPHENANTHRENE CI-IRYSENE

.175 .175 .123 .17/('@1I7 .272 .241.129 .129.24/ .IZ/ 1110 4200 @ 0 0 iO ,r@ ,r'?@ 117 0/5.0? .016.01 .I23(4@(/,@ C(58 .272 0754.05.172 .003 .04 042.04 1)12 @q.005 .200.05.22/ .175.175 .018.047 .167.167 .047.098 PI-/ENANTHRENE PYRENE PICENE

.000 .091 .042042 ./30(â€•@ ./?2@-f@'@.077 @ .%[email protected] .099 .09? ).2o2 @ .01'@2l2?.129(@[email protected] .07/ 263 00/ @ .2 .10 /02 2260 .014 , 65 .290 .0, 3/ .03 005 ./4&@@A@}â€¢@L@/4J @ .13? Â£138 .088 .139 .053 /64 .053 002 .06/ @ .181 071 .0?2.017 .0/7.092 J68 .168 .014 3:4:5:6-D/BfftjJf'/-/EftJANTHR,94E3:4-,5ENZP/-/ENANTHRENE /:2:34@-D/BENZm5@f4N77-/R@NE

CHART 2.â€”Frontier electron distributions and the positions of principal and subsidiary carcinogenophores in the corn pounds of Class (B). (Cf. notes in Chart 1.)

carcinogenic activity. They were designated the delocalizability at the principal carcinogenophore â€œprincipalâ€•and the â€œsubsidiaryâ€•carcinogeno was the most important factor determining the phores, respectively. An intimate correlation exist magnitude of carcinogenic activity. ed between the frontier electron densities or the 3. The center of reaction in carcinogenesis super-delocalizabilities at the two kinds of carcino might be the principal carcinogenophore, and the genophores and the magnitudes of carcinogenic subsidiary carcinogenophore might play some sub activity of these compounds. The value of super sidiary role in carcinogenesis.

TABLE 1 CoMPARIsoN OFTHE VALUESOFSUPER-DELOCALIZABILITIESATCARcIN0- GENOPHORES WITH CARcINoGENIc ACTiVITIEs

Super.delocaliz Super.delocalis ability at princi. ability at sub. psi carcinogeno sidiary carcino. phore genophore Carcinogenic Class Compound. (S,,) (8.) activity 8,4-Benzpyrene 0. 8151 1.0148 ++++ 1,2,5,6-Dibenzanthracene 0.7844 0.5725 +Ã·+ l,2,8,4-Dibenzpyrene 0.7818 0.9696 + A 2,8,7,8-Dibenzanthracene 0.7722 0 .8189 l,2-Benzanthracene 0.7594 0.8757 + 8,4,8,9-Dibenzpyrene 0.7440 1.0704 + 2',8'-Naphtho-8,4-pyrene 0.7209 1.0542 1,2,7,8-Dibenzanthracene 0 .6719 0.8980 + 1,2-Benzpyrene 0.8491 1,2,5,6-Dibenzphenanthrene 0 .8172 + Pyrene 0.7865 Chrysene 0.7811 Â± B Picene 0.7871 Phenanthrene 0.7806 Â± 3,4,5,6-Dibenzphenanthrene 0.7020 8,4-Benzphenanthrene 0.6144 + 1,2,8,4-Dibenzphenanthrene 0.5758 + 2',1'-Anthra-l,2-anthracene 0.6295 0.5970 2,8,5,6-Dibenzphenanthrene 0. 6084 0.8089 Anthanthrene 0 .5945 0.9725 1,2,7,8-Dibenznaphthacene 0. 5708 0.7899 l,2,8,4,&,6-Tribenzanthracene 0.5676 0.8989 1,2-Benznaphthacene 0.5580 0 .9741 1,2,9,1O-Dibenznaphthacene 0.5882 0.8649 C Pentaphene 0.4841 0.4287 V,2'-Anthra-1,2-anthracene 0.8682 0.5258 Pentacene 1.2818 Anthracene 0.9848 1,2,8,4-Dibenzanthracene 0.7159 Naphthacene 0.4876 Triphenylene Perylene 1,2,6,7-Dibenzpyrene

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Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1955 American Association for Cancer Research. Electronic Structure and Carcinogenic Activity of Aromatic Compounds: I. Condensed Aromatic Hydrocarbons

Chikayoshi Nagata, Kenichi Fukui, Teijiro Yonezawa, et al.

Cancer Res 1955;15:233-239.

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