Document RJoMypzo2ZOded4pZvn5oLj68

fe 'oiLiu//ne-^hiMis^. 5'i INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, VOL. XXV, 493-502 (1984) . ^Some Reactive Properties of Chlorooxirane, a Likely Carcinogenic Metabolite of Vinyl Chloride PATRICIA R.(LAURENCE%d>PETER(POLITZER> Den&tmtai pf Chem/ttrrr Unilfatty of Sew Orleans. Sew Orleans. i.onisiama 70148. V.Sr. Vr- d2> >> " <*) <4 @)ua Abstract We have carried out a computational study of the reactive properties of chlorooxirane, the metabolically produced epoxide of vinyl chloride that is believed to be a direct-acting carcinogenic form of this molecule. An ab initio scf-mo procedure (GAUSSIAN 70) was used to compute the energy requirements for stretching the C--Cl and both C--O bonds (Ss 1 reactivity) and to determine the course of the epoxide's possible 5^2 reactions with ammonia, taken as a model for nucleophilic sites on DNA. The epoxide was assumed to be protonated; both the oxygen- and chloro-protonatcd forms were considered. At each step along the various reaction pathways, the structure of the system was reoptimized. For the oxygen-protonated epoxide, the C1--O bond has a significantly lower energy barrier to stretching than does the C;--O. (The carbon bearing the chlorine is designated C|.) However, both are very much higher than that of the C--Cl bond in the chloro-protonated form, confirming our earlier finding of the relative weakness of this bond. In the 5S2 processes involving ammonia, intermediate complexes are formed with both carbons of the oxygen-protonated epoxide, the Cj-complex being the more stable. However, the most stable ammonia complex occurs at C, of the chloro-protonated epoxide. Our calculated results, both the energies and also the geometry changes, allow us to propose two possible mechanisms for the formation of the 7-N-Coxoethyl) derivative of guanine that has been observed to be the major in vivo DNA alkylation product of vinyl chloride and has been suggested as possibly being responsible for its carcinogenicity. One of these mechanisms is SN l and starts with the chloro-protonated epoxide; the other is 5S2 and involves the oxygen-protonated form. 1. Introduction Numerous studies on animals, cell cultures, and bacteria have shown vinyl chloride (1) to be both mutagenic and carcinogenic in these systems [1-5], In addition, an increased incidence of certain types of cancer has been observed among industrial workers who are exposed to vinyl chloride [6, 7]. Experimental evidence indicates that the first step in the mutagenic and carcinogenic action of vinyl chloride is its metabolic conversion to the epoxide, a process that is catalyzed by the mixed function oxidase system [2, S-ll]: Cl H \=cy /\ HH I ----- ooa A cl7c~cCH HH II This epoxide, chlorooxirane (II), is a strong mutagen [2, 10,12], and is regarded as very likely to be a direct-acting carcinogen, an "ultimate" carcinogenic form of vinyl chloride [8, 10-13]. 1984 John Wiley and Sons. Inc. CCC 0020-7608/84/030493-10S04.00 30 B (ft o 03 03 "4  3 494 j LAURENCE AND POLITZER Chlorooxirane is known to alkylate various nucleic acid bases, as well as DNA, " ? pi !flf RNA, and protein residues [2, 13-16], forming covalent bonds to nucleophilic sites on these systems, and it has also been found to alkylate DNA in vivo [17]. Such interactions could lead to miscoding [11, 16, 18], and might result in 3 replicational and transcriptional errors [17a, 19]. and the development of tumors. We have earlier computed the structures and various properties for chlorooxirane and its oxygen- and chloro-protonated forms (structures III and IV) [20].* Protonation of the oxygen was found to weaken both C--O bonds. H* /\ Cl^ci cj~H s\ ci-/Ci C^H C:; 3J nizt ft : c< </> GU o IS b o 4* CO CO 00 Pt . C- ing either approachii HH III H IV H chlorooxir C--O dist particularly the C(--O.t (The chlorine-bearing carbon shall be designated Cj.) An even more sriking effect was the very marked weakening of the C--Cl bond that resulted from protonation of the chlorine. This suggests that rupture of this stretch thi vs. 32 kcal strengths t bond may conceivably play a significant role in the biological functioning of this molecule. In order to understand better the alkylating properties of chlorooxirane, we have now made a detailed computational study of its behavior in both SN1 and Sn2 reactions. To simulate the former processes, we simply stretched each of the key bonds in turn, and computed the energy requirements for doing so. For SN2 reactions, the ammonia molecule was used as a model nucleophile. As shall be Oxyg*nr Cj`C Be Be shown, one of the consequences of this investigation is that it permits us to suggest 5 mechanisms for the formation of the primary in vivo DNA alkylation product C,*0 that has been observed for vinyl chloride [17]. ;i* 2. Methods ! Chlorine .* The oxygen-protonated epoxide was used for investigating the SN1 reactivities of the C--O bonds. To simulate SN1 ring opening, each bond separately was stretched in several incremental steps, the entire structure being reoptimized at et'c: r It each step. Essentially the same procedure was used to study the SN1 reactivity of the C--Cl bond, but involving now the chloro-protonated form of the epoxide. * The extent to which chlorooxirane is protonated in vivo is uncertain. However, there are known to exist subcellular regions with high proton activities [21]. It is of particular interest that the nuclear membrane contains certain redox enzymes [22], among which are the cytochrome P-450 systems As one toward a m from apprr that activate some carcinogens, including vinyl chloride [10, 11. 23]. These redox processes are ; believed to generate high local proton activities [2lc, 24]. It seems significant that the eynzymatic lengths alx is a signific * processes involved in DNA replication are also localized in the nuclear membrane. In addition, there panies the is evidence specifically forchlorooxirane which suggests that its biological activity involves a protonated form [25]. > An exa t Bond weakening was inferred from increases in bondlengths and decreases in force constants. in these sy "Spw r!V PROPERTIES OF CHLOROOXIRANE 495 SN2 processes were examined by allowing the ammonia to approach either Ci or C2; at each different C--N distance, all structural parameters were again reoptimized. This was done for both the oxygen- and chloro-protonated species. The computational method used for this work was the GAUSSIAN 70 ab initio self-consistent-field molecular orbital procedure, at the sto-3G level [26]. This has been shown to be an effective technique for structure calculations [27], 3. Results and Discussion (a) C--O bonds: The energies of opening the epoxide ring by simply stretch ing either C--O bond from its equilibrium distance of 1.50 A, without any approaching nucleophile, were investigated for the oxygen-protonated form of chlorooxirane. The relative energies of the reoptimized structures at each different C--O distance are given in Table I. Significantly more energy is required to stretch the C2--O bond by the arbitrary amount of 0.7 A than the C,--O: 44 vs. 32 kcal/mol. This is consistent with our earlier findings concerning the relative strengths of these two bonds [20]. Table l. Calculated relative energies for bond-stretching processes. Oxygen-Protonated Chlorooxirane: Cj-0 Bond: Bond Length (A): 1.S0 Relative Energy: (kcal/mole) 0.0 0 Bond: Bond Length (A): 1.S0 Relative Energy: (kcal/mole) 0.0 1.52 0.1 1.60 2.9 1.52 0-3 1.60 . 3.6 ,ne-Protonated Chlorooxirane: Cl Bond: Bond Length (A): 2 * 07 Relative Energy; (kcal/mole) 0.0 2.23 0.3 2.50 1.5 1.75 13.0 1.75 15.7 2.75 2.1 1.90 23.0 1.90 2B.6 3.00 2.7 2.20 32.4 2.20 44.0 3.25 3.5 3.50 4.0 As one C--O distance is increased, the other carbon is observed to move toward a more tetrahedral configuration; for instance, its H--C--C angles change from approximately 120 to roughly 112. The C--C and the other C--O bond lengths also change toward their normal single bond values. One notable feature is a significant shortening of the --Cl bond, from 1,77 to 1.71 A, that accom panies the C,--O stretch. An examination of the calculated atomic charges (population analysis [28]) in these systems shows a pattern very similar to what was observed in a previous 496 LAURENCE AND POLITZER study of protonated ethylene oxide [29], As one of the C--O bonds is stretched, there is a general movement of electronic charge from that carbon and its attached atoms (whether H or Cl) to the remainder of the molecule. Most of this apparent charge shift (the total amount of which is about 0.25 e.u.) goes to the oxygen and the proton. Thus the bond openings can be regarded as having a C"* 0~* character. (b) C--Cl bond: Table I also lists the energies involved in stretching the C!--Cl bond from its equilibrium value in the chloro-protonated epoxide, 2.07 A, to 3.50 A. Only 4 kcal/mol are required, much less than for either C--O bond. This is again in agreement with our earlier work [20], and demonstrates the weakness of the C--Cl bond in chlorooxirane. A marked decrease in the Ct--O distance, from 1.37 to 1.28 A, accompanies the stretching of the C,--Cl bond, whereas the C.--O bond lengthens from 1.46 to 1.50 A. These changes can be explained by noting that the large increase in the C--Cl distance is nearly equivalent to removing HCI, which the calculated atomic charges show to come off as a neutral entity. The resulting positive charge on C[ [structure V(a)] can be delocalized by contributions from resonance structures V(b) and V(c), which should concomitantly shorten the Ci--O bond and lengthen the C?--O: & / 1 Cj~H H V,.) H ,01? cf--C^H H\ V(b) HH V(c) The fact that the Ct--O bondlength is 1.28 A, which is quite close to the standard ^C=0 value of 1.21 A [30], suggests that structures V(b) and V(c) make significant contributions. B. Sn2 Processes (a) Interactions of ammonia with oxygen-protonated chlorooxirane: In attacking either carbon atom, the ammonia molecule was given complete freedom regarding its line and angle of approach. These interactions led to the formation of two stable intermediate complexes, structures VI and VII. H* I Cl ,.v h ->c;--c,- lN NHj VI H* \ ?'- H Cl'rc' v H NH, vu -- Property Distinct: c.-c, optin .......-* plant its initial a| The var shotui in 1 during the about 2.2 /' the chlorim epoxide, str distance in ft JljLU. PROPERTIES OF CHLOROOXIRANE 497 Property Table IT. Calculated structures.* O-Proconated . Chlorooxirane0 (III) Cl-Protonated. CMorooxiranc (IV) Ammonia Complexes O-Protonatcd CMorooxirane ai Cj (VI) at C7 (VII) Cl-Protonated Chlorooxirane iviiij Distance: Cj-o CyO crc: crct CrH c2-h 0-H* Cl-H* C-N tn*le;* o-q-c* .O-Cz-C, ll-Cz-Cj CI-Cj-C2 Cj-Cj-H^ Ci-Cz-Hb' H-Cz-Cl H.-Cj-Hi, H'-O-Cj H*-0-Cj H*-Cl-Cj ' N-C-C USD i.so I.$0 1,7? 1,10 l.U 1.00 -- .... 60 60 120 121 120 120 116 117 114 114 ... *-* 1.26 1.40 1 - 48 2.07 1.10 1.10 .... 1.34 .... 62 55 140 112 lit 119 99 117 ... ... 105 2.34 1.42 1.56 1.80 1.10 1.10 0.99 1.55 36 120 in 113 108 no 109 209 124 10S . ... 112 1.40 2.32 i.ss i.i 1.10 1.09 0.99 .... 1. S3' 105 36 112 107 111 no 106 no 106 146 ... Ill 1.42 1.44 1.49 3.52 1.09 1.09 .... 2.SI 1.54 * 59 58 126 196 120 118 62 115 *" -- 164 118 * Distances are in A; angles are in degrees. bThe structures given for the protonated chlorooxiranes are essentially the same as in ref. 20, with some small changes due to further optimization. c Hm is trans to Cl. Their optimized geometries are given in Table II. In both cases, the nitrogen is in the plane of the ring and forms a roughly tetrahedral N--C--C angle, although its initial approach was approximately perpendicular to the C--C bond. The variation of the total energy during the course of each interaction is shown in Table III. In the formation of VI, a small energy barrier is observed during the early stages of the process, reaching its peak at a C,--N distance of about 2.2 A. This appears to reflect the presence of a hydrogen bond between the chlorine and the proton in the equilibrium form of the oxvgen-protonated epoxide, structure III. This interpretation is supported by the fact that the Cl--H-" distance in III is 2,74 A, a reasonable value for this type of hydrogen bond [31]. 3fl0o CD O 043k  "lilT ^ ' fr--A,,J..J...^ -.,t ihtoii "1 iifJ **" 498 LAURENCE AND POLITZER Table III. Calculated interaction energies for reactions with ammonia. Cxypcn-Protonated Chlorooxirunt: Reaction at Cj: Cj-N Distance (A): 3.00 Interaction Energy; (keal/fiole) -10.5 Reaction at Cj* C,*N Distance (A): 3.00 Interaction Energy: (kcal/mole) -10.6 2.50 -10.3 2.50 -12.0 2.20 -9.3 2.20 -12.8 2.00 -26.6 2.00 -24.5 1.80 -55.9 1.80 -57.7 i.:s -72.1 1.53 -86.9 Chlorine*Proton*ted Chlorooxirane: Reaction at Cj (approach along Cj-Cl line): Cj*S Distance (A): 3-50 3*00 2*50 Interaction Energy: (kcal/mole) --9.8 --11,2 -14.9 Reaction at Cj (approach along C^-H line): Distance (A): 3.SO 3*00 2,50 Interaction Energy: (kcal/mole) -13.5 -23.8 -3S.6 2.20 -37.4 2.20 -4.S 2.00 -54.6 1.60 -75.1 1.54 -95.9 In addition, the calculated charge on the proton, which was varying quite gradually at large C--N separations, changes very markedly (from +0.33 to +0.25) as the C--N distance decreases from 2.2 to 2.0 A. Table III shows that the intermediate complex formed by 5N2 attack at C- is the more stable of the two possibilities, the computed interaction energies being -87 keal/mol for VII and -73 keal/mol for VI. This is in interesting contrast to the observation discussed above, that in the absence of a nucleophile it is the C,--O bond that opens more readily. The changes in geometry that accompany these two SN-2 processes are essen tially similar (Table II). The C--O bond involving the carbon being attacked lengthens to approximately 2.3 A, and there is inversion of the attached hydrogen atoms (or hydrogen and chlorine). The lengths of the C--O and C--C bonds involving the other carbon change in the direction of more typical single-bond values, and the orientation of the bonds around each carbon becomes more tetrahedral. A notable feature of the reaction at C; is the concomitant lengthening of the Ci--Cl bond from 1.76 to 1.84 A. Some possible implications of this will be discussed later. (b) Interaction of ammonia with ehloro-protonated chiorooxirane: In its interaction with the ehloro-protonated epoxide, the favored position for the ammonia is essentially in line with the C)--Cl bond (toward the carbon), and hence not in the plane of the ring (structure VIII). The optimized geometry of the intermediate complex that is formed is given in Table II. The major structural effects are the lengthening of the C,--Cl bond, from 2.07 to 3.52 A. and of the C,--O bond, from 1.37 to 1.42 A, plus an inversion of the hydrogen attached 31 t Re s l : oO W u N3 11 1 n :i sf if: .o ammonia 1 stable one 1 bondlengtl strongly wi become the Ct--H line C PossibU The re> pathways 1 in the presi a DNA-eh cinogcnic ;; Recent 7-N-(2-ox. alkylation t aldehyde. 1 It was prop in DNA th; As poir. chlorooxira required fo rujijpMj .S3 ick at C: is rgies being contrast to ile it is the ; are essenig attacked d hydrogen '--C bonds single-bond omes more ining of the this will be rane: In its ion for the arbon), and geometry of ar structural , and of the en attached properties of chlorooxirane 499 VIII to C,. As seen from Table III, the product is more stable (A = -96 kcal/mol) than either of the complexes formed with the oxygen-protonated epoxide (VI and VII). On the other hand, we found no significant tendencies for complex formation between ammonia and C;. While examining various possible paths that the NHj could follow in attacking Ci, it was found that initially approach along the line of the C|--H bond (toward the H) is favored over the C,--Cl line. (See Table III.) This may reflect another instance of hydrogen bonding, this time involving (rather surprisingly) the ammonia nitrogen and the hydrogen on C,. This route of attack is the more stable one until the Q--N distance is approximately 2.5 A; meanwhile the Ci--H bondlength increases from 1.1 to 1.35 A, as the hydrogen interacts increasingly strongly with the ammonia. Eventually the approach along the Ct--Cl line does become the preferred one, although there is an energy barrier in going from the C(--H line to the C,--C), breaking the hydrogen bond in the process. C. Possible Mechanisms of Interaction with DNA The results that have been presented in this paper suggest several reactive pathways that chlorooxirane can follow. Two of these are of particular interest in the present context, because they represent possible routes to the formation of a DNA-chlorooxirane reaction product that may play a key role in the carcinogenic action of vinyl chloride. Recent studies have concluded [17], in support of earlier work [15], that the 7-N-(2-oxoethyl) derivative of guanine (structure IX) is the major in vivo DNA alkylation product of vinyl chloride. (There is some evidence suggesting that this aldehyde, IX, may be in equilibrium with a cyclic hemiacetal involving 0-6 [17a].) It was proposed that the formation of IX may correspond to the "primary lesion" in DNA that might be responsible for the carcinogenicity of vinyl chloride [17b]. As pointed out earlier, the C--Cl bond in the chloro-protonated form of chlorooxirane is weakened to such an extent that only a small energy input is required for the removal H-C=0 CH, N-H \ R8tS 004343 mm 3 '"N 500 LAURENCE AND POLIT2ER of the chlorine. This leaves behind a charged species (V) having considerable aldehyde character. One can then readily envision the highly nucleophilic [32] N-7 position on guanine reacting with C2 to produce IX. The sequence of steps would be: H\*<5__r>__c/<--\cj~h H ;c-- c^h HH /--1Ci-H HH /c&,l--0 c(2*-) h HH SOlcCHH /Cl ^ H IX N7 (guanine) We can also account for the formation of IX by means of an SN2 process involving oxygen-protonated chlorooxirane. Table II shows that the interaction of ammonia with C2 that leads to the intermediate VII is accompanied by a rather surprising increase in the C,--Cl bondlength, presumably indicating a significant weakening of this bond, as well as a shortening of the C|--O distance, from 1.49 to 1.41 A. This suggests the following mechanism, again involving N-7 of guanine: H* I H* \' /O\ jN, (guanine) RH v. / LI Cl/c.--CJ"H a-?c'-S' HH H H H 1/ / u C,--n "" H -I PH /JCt,--C/j HH H H \ :0 H __ Cy-H Cp/C' H *N<' IX n . E1 mOmk Thus, t mechanism IX. On pu one, since i and the nu formed (T; This st chlorooxir; the chlorin chloride. C molecule b to the forn vivo DNA investigatir | guanine. The aut | o> ckey Wc iding of ter Polit u ; Enviro mmercia ; also gr:s :nt prog Orleans G [1] C. Main [2J U. Ranr [3] C. B. H. Health 7 [4] J. M. Ri. [5] J. D. Fat [6] l. J. Sell N.Y. Ac [7] P. F. Ini [8] B. L. Va j [9] T. Greet [10] H. Bart> [11] F. ZajJc 352 t I9.L * Our calc 169 kral/mol I lanWiftffi n rt iiderable lilic [32] of steps l process terdjfei /arTMr ignificant rom 1.49 guanine: PROPERTIES OF CHLOROOXIRANE sot Thus, the results obtained in this work allow us to propose reasonable mechanisms, both SN1 and SN2, for the formation of the key alkylation product, IX. On purely thermodynamic grounds, the SN2 process should be the favored one, since it starts with the more stable of the two possible protonated epoxides* and the nucleophile goes to the carbon, C2, at which the more stable product is formed (Table III). 4. Summary This study indicates several possible reactive pathways that protonated chlorooxirane can follow. It supports the suggestion [20] that the departure of the chlorine may play an important role in the biological mode of action of vinyl chloride. Of particular importance with regard to the carcinogenic activity of this molecule is the establishing of two possible routes, one SN1 and the other SN2, to the formation of what has been observed experimentally to be the primary in vivo DNA alkylation product of vinyl chloride, structure IX [17], We are currently investigating mispairing possibilities that could result from this modification of guanine. Acknowledgments The authors greatly appreciate several very helpful discussions with Dr. G. Rickey Welch. They thank the U.S. Environmental Protection Agency for partial funding of this work under assistance agreement number CR808866-0I-0 to Peter Politzer. The contents do not necessarily reflect the views and policies of the Environmental Protection Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. They are also grateful for the financial support provided bv the Research and Develop ment program of the Louisiana Board of Regents and the University of New Orleans Computer Research Center. Bibliography [1] C. Maltoni, Environ. Health Perspec. 21, 1 (1977). [2] U. Rannug, R. Gothe, and C. A. Wachtmeister, Chem. Biol. Interact. 12, 251 (1976). [3] C. B. Hong, J. M. Winston, L. P. Thombure, C. C. Lee, and J. S. Woods, J. Toxicol. Environ. Health 7, 909 (1981). [4] J. M. Rice, Environ. Health Perspec. 41, 179 (1981), [5] J. D. Fabricant and M. S. Legator, Environ. Health Perspec. 41. 189 (1981). [6] I. J. SelikofT and E. C. Hammond, Eds., Toxicity of Vinyl Chloride-Polyvinyl Chloride, Ann. N.Y. Acad. Sci. 246 (1975). [7] P. F. Infante, Environ. Health Perspec. 41, 89 (1981). [8] B. L. Van Duuren, Ann. N.Y. Acad. Sci. 246. 258 (1975). [9] T. Green and D. E. Hathway, Chem. Biol. Interact. 17. 137 (1977). [10] H. Bartsch, C. Malaveille, C. Barbin. and G. Planche, Arch. Toxicol, 41, 249 (1979). [11] F. Zajdela, A. Croisv. A. Barbin, C. Malaveille, L Tomatis, and H. Bartsch, Cancer Res. 40, 352(1980). * Our calculated proton affinity for the oxygen in chlorooxirane is 216 keal/mol, compared to 169 kcal/mol for the chlorine [20]. ,'.U ' 502 LAURENCE AND POLITZER [12] J. D. Elmore. J. L. Wong. A. D. Laumbach. and U. N. Streips. Biochcm. Biophys. Acta 442, 405 (1976). [13] T. E. Green and D. E. Halhway. Chcm. Biol. Interact. 22, 211 (1978). [14] A. Barbin, H. Bresil, A. Croisy, P. Jacquignon. C. Malaveille, R. Montesano, and H. Bartsch, Biochem. Biophys. Res. Commun. 67, 596 (1975). [15] S. Osterman-Golkar, D. Hultmark, D. Segerback, C. J. Calleman, R. Gothe. L. Ehrenberg, and C. A. Wachtmeistcr, Biochem. Biophys. Res. Commun. 76. 259 (1977). [16] A. Barbin. H. Bartsch. P. Leconte, and Nl. Radman. Nucl. Acids Res. 9, 375 (1981). [17] (a) E. Scherer. C. J. Van Der Laken. L. M. Gwinner. R. J. Laib. and P. Emmelot. Carcinogenesis 2.671 (1981); (b) R. J. Laib. L. M.Gwinner.and H. M. Bolt.Chem. Biol. Interact. 37,219 (1981). [18] D. E. Halhway and G. F. Kolar, Chcm. Soc. Rev. 9. 241 (1980). [19] S. Spengler and B. Singer. Nucl. Acids Res. 9. 365 (1981). [20] P. Politzer and T. R. Proctor. Int. J. Quantum Chem. 22. 1271 (1982). [21] (a) A. D. McLaren, Enzymologia 21, 356 (1960); (b) A. Sols and R. Marco. Curr. Top. Cell. Regu. 2, 227 (1970); (c) G. R. Welch and M. N. Berry, in Coherent Excitations in Biological Systems, H. Frohlich and F. Kremer. Eds. (Springer-Verlag, Heidelberg, in press). [22] J. W. DePierre and L. Ernster. Ann. Rev. Biochem. 46, 201 (1977). [23] C. Walsh, Enzymatic Reaction Mechanisms (Freeman, San Francisco, 1979), Chap. 15. [24] (a) D. B. Kell, Biochim. Biophys. Acta 549. 55 (1979); (b) M. N. Berry, A. R. Grivell, and P. G. Wallace, in Comprehensive Treatise on Electrochemistry, Vol. 10, Bioelectrochemistry, S. Srinivasan and Y. A. Bhizmadzhev, Eds. (Plenum, New York, in press). [25] S. Hussain and S. Osterman-Golkar. Chem. Biol. Interact. 12. 265 (1976). [26] W. J, Hehre, W. A. Lathan, R. Ditchfield. M. D. Newton, and J. A. Pople, Quantum Chem. Program Exchange 11, 236 (1973). [27] J. A. Pople, in Applications of Electronic Structure Theory, H. F. Schaefer III, Ed. (Plenum, New York, 1977), Vol. 4, Chap. 1. [28] R. S. Mulliken. J. Chem. Phys. 23. 1833 (1955). [29] P. Politzer and V. M. Estes, in Catalysis in Chemistry and Biochemistry. Theory and Experiment, B. Pullman, Ed. (Reidel. Dordrecht, 1979), p. 305. [30] Tables of Interatomic Distances and Configuration in Molecules and Ions, L. E. Sutton, Ed. (The Chemical Society, London. 1965), Supplement, Spec. Pub. No. 18. [31] P. Kollman, J. McKelvey, A. Johansson, and S. Rothenberg, J, Am. Chem. Soc. 97,955 {1975). [32] B. Singer, J. Toxicol. Environ. Health 2. 1279 (1977). Received January 25, 1983 Accepted for publication April 28, 1983 [ interna ti. iI i ! sQuanti j ^of the i j i ---------- 7 Monte (' and n wate interactions its equilihri' aqueous >ur opposed to investigated the H;Q, m Over ; j important i condensei ate pair p ! data and/, j tion [4-7' jj and in oil The p I one H;0. as rigid, a potential whereas a the literal 33 *> CO O O cob a> Hydro diffraction ent levels potential Permar 1984 Job