Computational Studies on Biphenyl Derivatives. Analysis of the

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Computational Studies on Biphenyl Derivatives. Analysis of the Conformational Mobility, Molecular Electrostatic Potential, and Dipole Moment of Chlorinated Biphenyl: Searching for the Rationalization of the Selective Toxicity of Polychlorinated Biphenyls (PCBs)† Antonio Chana, Miguel A. Concejero, Mercedes de Frutos, Marıá J. Gonza´lez, and Bernardo Herradoń* Instituto de Quı´mica Orga´ nica General, Consejo Superior de Investigaciones Cientı´ficas (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain. Received August 9, 2002

With the objective to understand how the pattern and degree of chlorination influence on the properties of the title molecules, a computational study on biphenyl and all the chlorinated biphenyls (from 1 to 10 chlorine atoms, 209 congeners) has been undertaken. The study includes conformational searches (and further refinement by molecular dynamics simulations) and the ab initio calculation of the molecular electrostatic potential (MEP) and the dipole moments for all the congeners. The most significant property is the MEP, finding a good correlation between the MEPs and the substitution pattern on chlorinated biphenyls. The most toxic congeners possess highly positive values of electrostatic potential on the aromatic rings and highly negative values of electrostatic potential on the chlorine atoms. Additionally, we have found that the toxic congeners possess conformations with low dipole moments, a fact that may be linked to the ready accumulation on the adipose tissue. The results on the geometry and electrostatic properties of chlorinated biphenyls can be useful to rationalize their selective toxicities.

Introduction Polyhalogenated aromatic compounds (PHAs)1 are persistent environmental pollutants (5). Some of the most toxic contaminants possess dibenzo-p-dioxin (PCDDs), dibenzofuran (PCDFs), and biphenyl (PCBs) backbones (Figure 1). These chemicals are broadly distributed in a variety of systems (atmosphere, water, food). Due to their lipophilic/hydrophobic character, they accumulate in the adipose tissue, being difficult to metabolize and remove (6-8), causing long-term pernicious effects. Although many data on the toxicology of PHAs have been published, most of them have dealt with the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TeCDD), and they are highly dependent on the species as well as on some experimental parameters (9).2 The toxicity scale most frequently used is the toxic equivalency factor (TEF), which is essentially a weighting factor by which the † (a) “Studies on Aromatic Compounds”. For previous papers see refs 1-4. (b) Taken in part from the projected Ph. D. thesis of A.C. (c) Dedicated to the memory of Dr. Manfred Stud. * To whom correspondence should be addressed. Phone: +34915618806. Fax: +34915644853. E-mail: [email protected]. 1 Abbreviations: PCB, polychlorinated biphenyl; MEP, molecular electrostatic potential; PHA, polyhalogenated aromatic compound; PCDF, polychlorinated dibenzofuran; PCDD, polychlorinated dibenzop-dioxin; TeCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEF, toxic equivalency factor; AhR, aryl hydrocarbon receptor; MSEP, molecular surface electrostatic potential; IUPAC, international union of pure and applied chemistry; PC, personal computer; MD, molecular dynamics; MM, molecular mechanics; MMFF, Merck molecular mechanics force field; EP, electrostatic potential.

Figure 1. Generic structural types of polyhalogenated aromatic compounds.

toxicity of a congener (or a mixture) is compared to that of TeCDD (10). Furthermore, the TEF scale is logarithmic, lacking accuracy. Despite their biological and social relevancies, it is surprising the scarcity of studies on the mechanism of the biological action of PHAs, most of them have tackled with the agonist effect of TeCDD on the aryl hydrocarbon receptor (AhR) (11). However, there is not full compelling evidence that this receptor is the primary toxic-mediated biological target for all the PHAs, thus, some alternative biological targets, such as the thyroxine transport protein (12) and steroid receptors (13), have been proposed, although not extensively studied. The lack of studies on the origin of the biological activity (toxicity) of chlorinated biphenyls is particularly striking (14-17), thus, the affinity for the AhR has been reported for only 13 PCBs with more than 4 chlorine atoms (18).2 Although it has been claimed that the cause 2 There are claims on the difficulty to reproduce results. A source of inconsistency on the toxicology of PHAs is the use on nonpure congeners. This effect is noteworthy in the case of some PCBs, especially the toxicity of 3,3′,4,4′-tetrachlorobiphenyl (PCB no. 77), that once was considered as one of the most toxic PCBs, but its toxicity was due to the presence of other congeners as impurities (9).

10.1021/tx025596d CCC: $22.00 © 2002 American Chemical Society Published on Web 12/16/2002

Molecular Electrostatic Potential of PCBs

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Figure 2. Chemical structures of TeCDD, biphenyl, and the PCBs whose molecular surface electrostatic potentials (MSEPs) are indicated in Figures 3-7. The MSEPs of the remaining PCB congeners are included as Supporting Information. The IUPAC numbers and the TEF values of the congeners are indicated into brackets. The IUPAC numbers for PCBs can be found in the Internet (http:// www.epa.gov/toxteam/pcbid/table.htm, last accessed Nov 2002). The values of TEFs are taken from ref 9, and they refer to mammals. The absence of the TEF value is due to either the congener is not toxic or its toxicity has not been determined.

of the toxicity of PCBs is the same as PCDDs and PCDFs (that is, AhR-mediated response), some PCBs are known to produce toxic effects that are not related to the activation of AhR (16, 17). Therefore, there is a necessity to deepen the understanding of the mechanism of bioactivity of PCBs. A significant structural difference between PCBs and PCDDs/PCDFs is the conformational mobility. While PCDDs and PCDFs are quite rigid molecules, PCBs may exist in a variety of conformations that arise through rotation around the bond connecting both aromatic rings. The conformational population of any biphenyl derivative depends on the substitution pattern as well as on the environment (solvent, experimental conditions, supramolecular interaction with a biomacromolecular target, and so on) (19). The limited structure-toxicity relationship studies (20-23) on PCBs have shown that the biological activity

is highly dependent on the number of chlorine atoms as well as on the substitution pattern (the values of TEFs for the PCB congeners are depicted in Figure 2). The PCBs with 5 and 6 chlorine atoms (e.g., 12 and 18) are the most toxic, and the congeners with ortho-substitution are less toxic than the analogues without ortho-substitution (e.g., compare 18 with 19 or 12 with 13). It must be mentioned that the toxicity of a PCB congener has been linked to the fact that its aromatic rings become coplanar (5, 18), but this assertion has not been unequivocally demonstrated. In connection with our long-standing interest on the structure (1-4) and reactivity (24-27) of aromatic compounds, we have undertaken a thorough computational study on chlorinated biphenyls. Comprehensive research on the bioactivity of chlorinated biphenyls requires a complete set of physicochemical properties. Although these data may be obtained experimentally (28-31), this

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approach is hampered by the high number of congeners (209) and the elevated toxicity of some of them. Additionally, some chlorinated biphenyls are not available in an isomerically pure state. Therefore, a viable alternative is the computational one. Any structure-activity study on chlorinated biphenyls should explain the data indicated above, that is, the influence of the degree and pattern of chlorination on the toxicity. The chlorinated biphenyls have been scarcely studied from a computational point of view. Most of the published results have dealt with the modeling of physicochemical properties of a limited number of congeners (32-40). Our working hypothesis was that, as usual in chemistry, the shape (both geometry and electron distribution) of a molecule determines its properties (41, 42). We have been interested in the qualitative comparison of some electrostatic properties of the chlorinated biphenyls, especially on the charge distribution on both aromatic rings and on the chlorine atoms. The goals of our study were as follows: (a) How the electrostatic potential and the charge distribution on the aromatic rings and on each chlorine atom change upon increasing the chlorination degree and pattern?3,4 (b) What is the effect of a polar ortho C-Cl bond on the electrostatic potential and the electron distribution on the vicinal ring? The molecular electrostatic potential [MEP, V(r)] at the point r is a representation of the electrostatic interaction energy between a molecule and a test charge of magnitude e (that is a proton) placed at that point, supposing that the molecule is not polarized by the test charge (44, 45) The MEP is calculated by eq 1

V(r) )

∑ A |R

ZA A

- r|

F(r′)

-

∫ |r - r′| dr′

(1)

where ZA is the charge on nucleus A, located at RA, that is considered to be a point charge, and the second term arises from the electron density, F(r′), of the molecule that can be obtained computationally (46) or experimentally (42, 47-50). The MEP is a useful tool that has been employed to understand a variety of chemical and physical properties (51-53), including bonding (54, 55), solvent effects (5658), chemical reactivity (59-61), molecular similarity (62), and supramolecular structure (63, 64). For the purpose of the present research, it must be mentioned that the MEP has been used to rationalize the interaction between a biological active compound and its biomacromolecular target (65-68) [i.e., the interaction of PCBs with AhR (11) or other putative receptor (12, 13)], as well as an indicator of the charge distribution in a molecule 3 Our assumption was the following: On the basis of the relatively small difference in electronegativity between the chlorine atom and an aromatic sp2-carbon,4 the C-Cl bond will be slightly polarized toward the Cl, causing a decrease in the electron density on the aromatic ring and, therefore, increasing the effective electronegativity of this aromatic ring (i.e., a C6H4Cl group is more electronegative than the C6H5 group). When the number of chlorine atoms is big enough (i.e., more than 7 Cl atoms on the biphenyl system), the C-Cl bonds will be hardly polar, and the electron densities on each chlorine atom will be lower than the corresponding on the less-chlorinated congeners. 4 Electronegativity values (Pauling scale) are 3.0 for Cl and 2.72 for C6H5. (b) There is an ample debate on the meaning and calculation of electronegativity; for a recent discussion, see ref 43.

(69-71) where the regions with higher negative values of V(r) are richer in electron density.5 Although as indicated by eq 1, the value of the electrostatic potential is contributed by both the nuclear and electronic charges, useful information on the electron density can be obtained when the electrostatic potential around the same kind of atoms is compared. On the basis of these characteristics, we reasoned that the comparison of the MEPs of different chlorinated biphenyls can help to understand the properties and the selective toxicity of these chemicals. Up to the best of our knowledge, the analysis of the molecular electrostatic potentials of chlorinated biphenyls and their relation to biological activity have not been reported, and the only related research has been the STO-5G computation of the MEPs of 2,3,6,7-tetrachlorodibenzo-p-dioxin (TeCDD, 1) and 2,3,6,7-tetrachlorodibenzofuran (75).

Materials and Methods The calculations were performed in a Silicon Graphics O2 R5000 computer, with Irix 6.5 operating system, and in a PC computer, equipped with two 867 MHz processors and running Linux operating systems. The starting geometry for the quantum-chemical calculation of each congener indicated in Figures 3-7 (except for 15 and 22) was generated through a conformational search on each halogenated biphenyl, using MM2 force field as implemented in Sybyl version 6.5 software (Sybyl molecular modeling system, Tripos Associated Inc., St. Louis, MO). To assess the relative stability of the conformer resulting from each search, we performed a molecular dynamics (MD) simulation for each chlorinated biphenyl indicated in Figures 3-7. All the MD simulations were carried out in the vacuum at 300 K for 1 ps using MMFF94 force field (76, 77), as implemented in Sybyl version 6.5. The MD simulations were done taking into account the charge distribution (Mulliken) in the molecules. The dynamics proved that, except for PCB nos. 123 (15) and 189 (22), the geometry obtained in each conformational search was either the most stable or was energetically close to the most stable one (see footnote to Table 1). The only exceptions were PCB nos. 123 and 189, for which the conformational searches yielded structures nearly coplanar (ca. 0° as dihedral angle between the aromatic rings),6 but the MD simulations indicated that these conformations were about 50 kJ mol-1 less stable than the conformers having dihedral angles between the aromatic rings of ca. 80°. Thus, the starting geometry for the ab initio calculations on PCB nos. 123 and 189 were obtained from the MD simulations. The geometries obtained in the MD simulations/conformational searches were further refined by ab initio calculations (B3LYP/6-31G*) and characterized by harmonic vibrational frequency computation, which showed that all the structure were minima on the potential energy surface.7 The molecular electrostatic potentials (MEPs) and dipole moments (µ) of biphenyl and of all the chlorinated biphenyls (209 congeners) were computed in the vacuum. It is likely that the pernicious effects of PCBs are related to their capacity to accumulate in the adipose (low dielectric media) tissue; thus, the computation of properties at the vacuum is a quite realistic situation. The calculations were carried out at the B3LYP hybrid Hartree-Fock/density functional scheme (78-82) using the 5 Actually, the MEP is a good parameter to gauge the basicity and nucleophilicity of molecules (72-74). 6 The conformations of PCB nos. 194 and 206 (included as Supporting Information) were also obtained in MD simulations. The conformational searches yielded structures with small dihedral angles (lower than 10°) between the aromatic rings, what seemed unlikely. 7 It must be mentioned that the optimized geometries and the energy differences between different conformers reported in the present paper agree with a recent DFT study on (only) six PCBs (40).



Figure 3. MSEPs for biphenyl (2) (a); the two enantiotopic faces of 2-chlorobiphenyl (3) (b and c); 3-chlorobiphenyl (4) (d); and 4-chlorobiphenyl (5) (e). 6-31G* basis set, as implemented in the Gaussian 98 program (83). Since it has been stated that MEP calculations are relatively insensible to the basis set (84, 85), we have not employed different basis sets. In preliminary investigations, we compared the hybrid B3LYP with pure Hartree-Fock methodology (on the MEP calculations of PCB nos. 77, 126, and 157), finding that both methods yielded essentially the same results, although the hybrid HF/DFT method is much faster. The molecular surface electrostatic potentials (MSEPs) of the computed MEPs have been generated using the program gopenmol (Web address: http://www.csc.fi/gopenmol/, last accessed Nov 2002) (86, 87). The electrostatic potentials are plotted on an isoelectronic density surface of 0.005 e bohr-3. The plots show regions ranging from positive (red) to negative (blue) electrostatic potentials; the values of the electrostatic potentials (in atomic units) are indicated in the scale at the left to the plot (Figures 3-7). For the sake of saving space, the results for the 210 molecules are collected as Supporting Information.

Results and Discussion The MEPs of the chlorinated biphenyls present interesting features that can help understand their properties. An illustrative selection of molecular surface electrostatic potentials (MSEPs) is presented below (Figures 3-7). To facilitate comparison of results, the surface electrostatic potentials of some molecules are indicated in more than one figure. Although strictly speaking, we have represented the values of the electrostatic potentials (EPs), occasionally in the forthcoming discussion we will use the EP as an indicator of the electronic charge density in the different regions of the molecule, bearing in mind the circumstances indicated previously. As complementary

research, we are currently studying the pattern of electron density (88) and its topology (by analysis of the Laplacian, 89) on PCBs, finding a good correlation between the EP in some regions of the molecule and the electron density on the corresponding atoms.8 It must be stressed that the analysis of the EP presents several advantages over the electron density. On one hand, the representation of the maps of EP is visually more helpful than that corresponding to the electron density, giving quite straightforward information on the different regions of the molecules able to interact with the target biological receptor as well as to permit direct comparison between different congeners. On the other side, the method of computation as well as the usefulness and significance of the electron density has been challenged (90). The influence of an ortho-chlorine on the electrostatic potential of chlorinated biphenyls is evidenced on comparing the MSEPs of biphenyl (2, Figure 3a) and its 2-chloro- (3, Figures 3b and 3c for the two enantiotopic faces), 3-chloro (4, Figure 3d), and 4-chloro (5, Figure 3e) derivatives. On one hand, each substituted ring in the three chlorinated derivatives (3-5) possess similar patterns in the electrostatic potential (EP), and they are less negative than in the aromatic rings of biphenyl. On the other hand, a striking difference is observed on the charge distribution on the unsubstituted ring of these compounds: while the corresponding rings in 4 and 5 are poorer in electron density than biphenyl, the cognate ring in 3 is richer in electron density than biphenyl. This 8

A. Chana and B. Herradoń, unpublished results.

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Figure 4. MSEPs for 3-chlorobiphenyl (4) (a); 3,5-dichlorobiphenyl (6) (b); 3,4,5-trichlorobiphenyl (8) (c); 3,4-dichlorobiphenyl (7) (d); and 4-chlorobiphenyl (5) (e).

result indicates that there is a partial transfer of electron density from the ortho C-Cl bond to the vicinal ring, and this fact is not due to resonance effect, as proved by the remarkable difference between the ortho-chlorinated derivative (3) and the isomer having a chlorine atom at the 4-position (compound 5). Due to the substitution pattern, the two faces of 2-Cl-BP are enantiotopic (19), showing slight differences in their electrostatic potentials. This fact has been observed in other ortho-chlorinated congeners, and it can be significant in the interaction with the (chiral) biomacromolecule. The trend observed in the electrostatic potential of the monochlorinated biphenyls is quite general in other congeners. Figure 4 displays the surface electrostatic potentials of the computed MEPs of 3-chlorobiphenyl (4, Figure 4a), 3,5-dichlorobiphenyl (6, Figure 4b), 3,4,5trichlorobiphenyl (8, Figure 4c), 3,4-dichlorobiphenyl (7, Figure 4d), and 4-chlorobiphenyl (5, Figure 4e) that illustrates the variation of the electron distribution on increasing the number of non-ortho-carbon-chlorine bond in the same ring. As expected, the positive value of the EP on each aromatic ring increases on augmenting the number of chlorine atoms, being more pronounced in the chlorinated ring. Figure 5 depicts the molecular surface electrostatic potentials of 3,4,5-trichlorobiphenyl (8, Figure 5a), 2′,3,4,5tetrachlorobiphenyl (10, Figure 5b), 3,4,4′,5-tetrachlorobiphenyl (9, Figure 5c), 3,3′,4,4′,5-pentachlorobiphenyl (12, Figure 5d), and 3,3′,4,4′,5,5′-hexachlorobiphenyl (18, Figure 5e), that exemplifies the variation of the electro-

static potential of PCB congeners on increasing the number of chlorine atoms at the second ring that follows the tendency mentioned above. Except for the congener with the ortho-chlorine (10), the electron density on both aromatic rings decreases rapidly on increasing the chlorination degree. On the other hand, when the number of chlorine atoms increases, the electrostatic potential on each chlorine atom becomes less negative (i.e., there is a lowering in the electron density on these atoms; compare panels a and e in Figure 5). The examination of the surface electrostatic potentials of 10 (Figure 5b) and of 9 (Figure 5c) significantly illustrates the effect of orthochlorine substitution on the electrostatic potential: while the trichlorinated aromatic ring of the congener having the ortho-chlorine (10) possesses a region with negative value of the electrostatic potential, the related ring of 9 presents a positive value of this property. Figure 6 depicts the surface electrostatic potentials of the computed MEPs of 3,4,5-trichlorobiphenyl (8, Figure 6a) as well as of the densely chlorinated congeners 2,3,4,5-tetrachlorobiphenyl (11, the two enantiotopic faces, Figure 6, panels b and c), 2,2′,3,4,5-pentachlorobiphenyl (16, the two enantiotopic faces, Figure 6, panels d and e), 2,3,4,4′,5-pentachlorobiphenyl (17, Figure 6f), and 2,2′,3,3′,4,5,5′,6,6′-nonachlorobiphenyl (23, Figure 6g). On comparing the MSEPs of 8 with the higher homologue 11, it is observed that the electron density on the halogenated ring decreases on augmenting the number of chlorine atoms, but the electron density of the unsubstituted ring is slightly higher in the more substi-



Figure 5. MSEPs for 3,4,5-trichlorobiphenyl (8) (a); 2′,3,4,5-tetrachlorobiphenyl (10) (b); 3,4,4′,5-tetrachlorobiphenyl (9) (c); 3,3′,4,4′,5pentachlorobiphenyl (12) (d); and 3,3′4,4′,5,5′-hexachlorobiphenyl (18) (e).

tuted congener, especially on the syn face to the orthocarbon-chlorine bond (Figure 6c). Following the previous tendencies, the pentachlorinated congeners 16 (Figure 6, panels d and e) and 17 (Figure 6f) have lower electron densities on both aromatic rings than the less halogenated biphenyls, and this effect is more pronounced in the congener with only one ortho-chlorine-carbon bond. The MSEPs of the highly chlorinated congener 23 (Figure 6g) indicates that the EPs on both aromatic rings are highly positive, and the electrostatic potentials on the chlorine atoms are nearly neutral. As additional examples, the surface electrostatic potentials of several biologically relevant mono-orthosubstituted PCBs are shown in Figure 7. They include 2,3,3′4,4′-pentachlorobiphenyl (13, Figure 7a), 2,3′,4,4′,5pentachlorobiphenyl (14, Figure 7b), 2′,3,4,4′,5-pentachlorobiphenyl (15, Figure 7c), 2,3,3′,4,4′,5-hexachlorobiphenyl (21, Figure 7d), 2,3,3′,4,4′,5′-hexachlorobiphenyl (19, the two enantiotopic faces, Figure 7, panels e and f), 2,3′,4,4′,5,5′-hexachlorobiphenyl (20, the two enantiotopic faces, Figure 7, panels g and h), and 2,3,3′,4,4′,5,5′heptachlorobiphenyl (22, Figure 7i). The MEPs in these congeners follow the general trends observed in other chlorinated biphenyls. Thus, the EP on an aromatic ring becomes more positive on augmenting the number of chlorine atoms, and there is a transfer of electron density from the ortho-carbon-chlorine bond to the neighbor ring, causing a less positive EP on this ring. An advantage of the use of the molecular surface electrostatic potential (MSEP) as a representation of the

electrostatic potential is that it allows a direct visual comparison of results. On observing the MSEPs of the chlorinated biphenyls (shown in Figures 3-7 as well as in the Supporting Information), we can unequivocally assign regions with different electrostatic potentials that clearly show the influence of the pattern and degree of chlorination on the MEP (and, as commented above, on the charge distribution) in biphenyl derivatives. Additionally, the pattern of the MESP of chlorinated biphenyls can help rationalize the selective toxicity of these compounds. To the best of our knowledge, only 11 chlorinated biphenyls have been assigned a value of TEF (9). Since more data on bioactivity is needed, a complete quantitative structure-activity picture cannot be elaborated, but a quite good qualitative relationship between toxicity and the MEPs can be established. Table 1 collects data on the electrostatic potentials (EPs) of the 11 PCBs whose TEFs have been published. The analysis of the EPs is 2-fold: on one hand, a visual inspection of the MSEPs allows the classification of the EPs from highly positive to highly negative; on the other, we have included numerical values of the EPs on the aromatic rings and on the chlorine atoms (see footnote d to Table 1 and Figure 8). It is apparent that the toxicity of the most active congeners is due to the combined existence of highly positive values of the electrostatic potential on (at least) one aromatic ring and highly negative values of the electrostatic potential on the chlorine atoms.

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Figure 6. MSEPs for 3,4,5,-hexachlorobiphenyl (8) (a); the two enantiotopic faces of 2,3,4,5-tetrachlorobiphenyl (11) (b and c); the two enantiotopic faces of 2,2′,3,4,5-pentachlorobiphenyl (16) (d and e); 2,3,4,4′,5-pentachlorobiphenyl (17) (f); and 2,2′,3,3′,4,5,5′,6,6′nonachlorobiphenyl (23) (g).

Table 1 also gathers the values of the computed dipole moments (µ) as well as the conformational properties of the chlorinated biphenyls that include the values of the dihedral angles (φ) between the two aromatic rings in the conformations shown in Figure 8 as well as the range of dihedral angles that are energetically accessible in the MD simulation (see footnote a to Table 1). It has been proposed, although not proved experimentally, that the toxic effects of PCBs are due to the fact that they adopt a coplanar conformation (5, 18). Our computational results on the conformational preferences of PCBs indicate that a coplanar conformation is very

unlikely for most of the congeners.9 Actually, the only congeners that can be coplanar are those that have nearly free rotation around the aryl-aryl bond [i.e., PCB nos. 126 (12) and 169 (18)]. The most stable conformer of PCB no. 81 (9) has the two aryl groups in a slightly staggered conformation, and this congener might become coplanar on interacting with the biological receptor. The other 9 Our results on the conformational preferences of PCBs are quite consistent with previous computational reports on a scarce number of PCB congeners (33, 37, 40). Some reports have tried to stabilize coplanar conformers through the modeling of intermolecular interactions (i.e., with water molecules), although with limited success (37).



Figure 7. MSEPs for 2,3,3′4,4′-pentachlorobiphenyl (13) (a); 2,3′,4,4′,5-pentachlorobiphenyl (14) (b); 2′,3,4,4′,5-pentachlorobiphenyl (15) (c); 2,3,3′,4,4′,5-hexachlorobiphenyl (21) (d); the two enantiotopic faces of 2,3,3′,4,4′,5′-hexachlorobiphenyl (19) (e and f); the two enantiotopic faces of 2,3′,4,4′,5,5′-hexachlorobiphenyl (20) (g and h); and 2,3,3′,4,4′,5,5′-heptachlorobiphenyl (22) (i).

PCBs indicated in Table 1 are very unlikely to have a coplanar conformation. Therefore, we hypothesize that coplanarity is a secondary requirement for bioactivity, which might operate as a modulating factor for toxicity (reinforcing the effect). Another computed property is the dipole moment.10 The data shown in Table 1 indicate that most of the toxic PCBs have conformations with low polarity. It must be mentioned that since the calculations have been per10 The values of the computed dipole moments of all the chlorinated congeners (in the indicated conformation) are included as Supporting Information.

formed in the vacuum, the method will preferentially yield low polar structures. As commented above, the chlorinated biphenyls accumulate in lipophilic, low-polar, tissues; thus, the congeners having conformations with low polarity could be absorbed preferentially.11

Conclusions This paper reports a comprehensive computational structural study on chlorinated biphenyls. We have calculated the molecular electrostatic potentials (MEPs) of these compounds as an indication of the charge distribution on the molecule. The results presented herein can rationalize the following facts:

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Table 1. Comparative Data on PCBsa V (r) PCB no. (compd)b

Lg (TEF) c

aromatic rings (atomic units)d

126 (12) 169 (18) 114 (17)

-1.0 -2.0 -3.3

156 (21)

-3.3

157 (19)

-3.3

81 (9) 105 (13)

-4.0 -4.0

118 (14) 123 (15) 189 (22)

-4.0 -4.0 -4.0

167 (20)

-5.0

208 (23)

Computational Studies on Biphenyl Derivatives. Analysis of the

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