Article
pubs.acs.org/JPCA

Absolute Conﬁguration of Atropisomeric Polychlorinated Biphenyl
183 Enantiomerically Enriched in Human Samples
Mitsunobu Toda,† Chisato Matsumura,‡ Masahiro Tsurukawa,‡ Toshihiro Okuno,‡ Takeshi Nakano,*,§Yoshihisa Inoue,† and Tadashi Mori*,††

Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871,
Japan‡
Hyogo Prefecture Institute of Environmental Science, 3-1-27, Yukihira, Suma-ku, Kobe, Hyogo 654-0037, Japan§
Research Center for Environmental Preservation, Osaka University, 2-4, Yamada-oka, Suita, Osaka 565-0871, JapanS Supporting Information*

ABSTRACT: Polychlorinated biphenyls (PCBs) are still of serious concern as apotential health hazard due to their persistency and bioacumulation. Of 209
possible PCB congeners, with varying number and position of chlorine atom(s), 19
are chiral. These are mostly highly chlorinated and tend to remain longer against thebiological decompositions, suﬀering biological deracemization in the environment.
In this work, we have unequivocally determined the absolute conﬁgurations ofimportant chiral PCBs 183 and 171, as well as 132, through the combined
theoretical and experimental investigations of the chiroptical properties (circulardichroism and optical rotation), which will be valuable in elucidating the mechanismof biological enantiomer enrichment of PCBs in the environment.

A

dioxin-like and coplanar PCBs generally show higher toxic
equivalency factors for human and other mammalians.9
However, recent investigation underlined that nondioxin
PCBs are also toxic, showing the endocrine-disrupting andneurotoxic eﬀects.10 This demonstrates that more precise andcomprehensive assessment of the overall activity of persistentorganic pollutants is absolutely necessary.11 Over a decade, thePCBs metabolism has been debated in broadly deﬁned
biological samples.12−18
Naturally, a pair of PCB atropisomers show signiﬁcantly
diﬀerent biological and toxicological behavior,19,20 and therefore the analytical separation of PCB atropisomers have been
extensively investigated by means of chiral GC−MS, (multidimensional) GC, HPLC, and capillary electrophoresis,21,22 toreveal indeed the enantiomer enrichment of some chiral PCBsin environmental samples.10 The enantiomerically enriched
PCB-183 (2,2′,3,4,4′,5′,6-heptachlorobiphenyl) and PCB-171(2,2′,3,3′,4,4′,6-heptachlorobiphenyl) found in human samples
were ascribed to the uptake of nonracemic PCBs through thediet.8,23,24 The diversity of the enantiomeric excess (ee) of
PCBs retrieved from various species supports this view.25 The
absolute conﬁgurations of methylsulfonylated metabolites ofsome PCBs have recently been elucidated by using vibrational
circular dichroism.26,27 Nonetheless, the absolute conﬁgurations

tropisomers are stereoisomers resulting from hinderedrotation around a single bond, where the rotational barrier
is high enough to allow isolation of each conformer.1 The
atropisomeric behavior was ﬁrst recognized by Cristie for 6,6′dinitro-2,2′-diphenic acid in 1922,2 but the term “atropisomerism” was coined by Kuhn in 1933.3,4 Atropisomeric compounds
are often found in natural products, such as vancomycin,
knipholone, gossypol, mastigophorene A, or murrastifoline F,
and the atropisomerism has been extensively utilized inasymmetric synthesis as well.5 Although the steric hindrance
to cause atropisomerism is rather arbitrary, the existence ofatropisomer may be noticed when the half-life of theinterconversion is longer than 1000 s at ambient temperatures.3,4 Thus, the size (and number) of substituents
introduced to the ortho positions of biaryl critically inﬂuences
the atropisomers equilibrium, accelerating the rate withdecreasing bulkiness of the substituent: I > Br ≫ CH3 > Cl
> NO2 > CO2H ≫ OCH3 > F > H. Hence, unsymmetricallypolychlorinated biphenyls (PCBs) exhibit the atropisomerism,
when three or four chlorine atoms are introduced to the ortho
positions. Among the 209 PCB congeners, 19 PCBs are known
to be chiral at ambient temperatures.6
PCBs are legacy pollutants and now ubiquitous in theenvironment. Commercial PCBs and environmental extracts
contain a variety of PCB congeners,7 and hence congenerspeciﬁc analysis of PCBs in environmental extracts is of
growing importance in ecological risk assessment.8 Structuretoxicity correlation studies revealed that, among the congeners,© XXXX American Chemical Society

Received: June 28, 2012
Revised: August 20, 2012A

dx.doi.org/10.1021/jp306363n | J. Phys. Chem. A XXXX, XXX, XXX−XXXThe Journal of Physical Chemistry A

Articleof the parent PCBs have never been determined,28 probably
due to the limited availability and the relatively diﬃcult opticalresolution.29
In this combined theoretical and experimental study todetermine the absolute conﬁguration of chiral PCB, we chose
PCB-183, PCB-171, and PCB-132 (2,2′,3,3′,4,6′-hexachlorobiphenyl), shown in Chart 1, because PCB-183 and -171 aresuccessful under the same conditions; Figure S1 in the
Supporting Information. Because the resolution factors(Rs)31,32 were moderate for the enantiomeric PCBs (Table
S1, Supporting Information), we were unable to perfectly
resolve the enantiomers. Accordingly, the optically pure ﬁrst
fractions (>99% ee) and the optically enriched second fractions(74%, 90%, and 71% ee for PCB-183, 171, and 132,
respectively) were used in the spectral investigations. The
electronic circular dichroism (CD) spectra of the second
fractions numerically corrected for the optical purities
determined by chiral HPLC were almost identical in shapeand intensity to those of the corresponding ﬁrst fractions,indicating that our resolved samples were optically (for the ﬁrst
fractions) and chemically pure (for PCB-183, see Figure S2a in
the Supporting Information).
The experimental CD spectra of the enantiomeric PCB-183
pair, obtained in hexane at 25 °C (Figure 2a), were exactly
mirror-imaged but slightly diﬀerent in intensity. The ﬁrst
fraction exhibits fairly strong positive-negative-positive (“trisignate”) Cotton eﬀects (CEs) (from longer λ) at 200−250 nm
and additional much weaker negative-positive CEs at 250−310
nm. The characteristic trisignate pattern is shared by relevantchiral biaryl systems, such as polyhalogenated bipyridine
atropisomers33and the chiral metabolites of PCB.27 Furthermore, the spectra of dynamically chiral (nonhalogenated)biaryls also show very similar CD patterns with much reduced
intensities.34 However, a close inspection of the theoreticalresults revealed that the apparently trisignate CE pattern isactually a more complicated ensemble of multiple overlappingtransitions (vide infra).
Recent combined theoretical and experimental studies35−37
have successfully simulated the chiroptical properties anddetermined the absolute conﬁgurations of a number of naturaland synthetic chiral molecules.38−41 An approach similar to thatfor conformationally ﬂexible chiral PCBs requires some priorconsiderations for the potential energy change associated with

Chart 1. (aR)- or (M)- and (aS)- or (P)-Enantiomers ofAtropisomeric PCB-183 and (aS/P)-Enantiomers of PCB171 and PCB-132

highly chlorinated and tend to remain longer against thebiological decompositions, suﬀering deracemization in theenvironment, whereas PCB-132 was chosen as a lesschlorinated reference.8,30
The enantiomers of PCB-183, -171, and -132 were resolved
by semipreparative chiral HPLC on a Chiralcel OJ-H column(Figure 1). The optical resolution of other chiral congers, suchas PCB-174 (2,2′,3,3′,4,5,6′-heptachlorobiphenyl), was not

Figure 1. Chiral HPLC chromatograms (monitored by a UV detector at 291 nm) of racemic mixture (top), ﬁrst- (middle), and second-eluted
enantiomer (bottom) of PCB-183 (left), 171 (middle), and 132 (right) on a Daicel Chiralcel OJ-H column (4.6 mm i.d. × 15 cm) at 38 °C, elutedby n-hexane at a ﬂow rate of 0.5 mL min−1.
Bdx.doi.org/10.1021/jp306363n | J. Phys. Chem. A XXXX, XXX, XXX−XXXThe Journal of Physical Chemistry A

ArticleFigure 2. (a) Experimental CD spectra of ﬁrst (black) and second (red) fractions of PCB-183 in hexane at 25 °C. Note that the enantiomeric excess(ee) of the second fraction was 74%. (b) Potential energy curve calculated for PCB-183 in the gas phase as a function of dihedral angle θ at the DFTD3-B-LYP/def2-TZVP level.

Figure 3. (a) Comparison of experimental (black) and theoretical (blue) CD spectra of PCB-183. The theoretical spectrum was calculated for (aS/P)-enantiomer at the RI-CC2/aug-def2-TZVPP level and 0.4 eV red-shifted, whereas the rotational strengths were not scaled. (b) Bar presentationof the rotational strengths calculated for PCB-183 with the corresponding Gaussian-expanded theoretical spectrum. The excitation energies androtational strengths were not shifted or scaled.

Figure 4. Comparison of experimental (black) and theoretical (blue) CD spectra of (a) PCB-171 and (b) PCB-132. The experimental spectra wereobtained in n-hexane at 25 °C for the ﬁrst fractions on chiral HPLC on a Daicel Chiralcel OJ-H column. The theoretical spectrum was obtained for(aS/P)-enantiomer at the RI-CC2/aug-def2-TZVPP level. The theoretical spectra were scaled to 1/3 and 0.3 eV red-shifted.

spectra. The kinetic energy at room temperature (kBT ≈ 0.6
kcal mol−1) allows these PCBs to populate in a θ range of 72−
108°, which is, however, much narrower than those reported
for less-chlorinated PCBs (ca. 50−130°)49 and 2,2′-dimethoxybinaphthyl (ca. 60−120°),42 rationalizing the approximation.
Theoretical CD calculations were run at the resolution-ofidentity, linear response, approximate coupled cluster method(RI-CC2)50−53 with augmented def2-TZVPP basis-sets on the
DFT-D3-B-LYP/def2-TZVP optimized structures (Figure 3a).
An excellent reproduction of the experimental CD spectrum of
PCB-183, in both excitation energy and rotational strength, wasachieved by this state-of-the-art theoretical method, allowing us
to directly assign the absolute conﬁguration of the ﬁrst elutefrom the chiral HPLC column as aS or P, which turned out toelute as the ﬁrst fraction also in the chiral GC/MS analyses(Figures S1 and S4 in the Supporting Information). Although
the calculated CD spectrum nicely reproduced the trisignate
CEs observed at the main band, a closer inspection of thethe dihedral angle (θ) between the two benzene rings.42−44
Hence, the potential energy curve for PCB-183 was calculated
by optimizing the geometries of rotamers with varying θ from
70° to 110° at every 2° by the cost-eﬀective, yet accurate,
dispersion-corrected DFT-D3-B-LYP/def2-TZVP method(Figure 2b).45,46 The optimization of PCB-183 without ﬁxing
θ at the same level led to a perpendicular geometry (θ = 89.9°),and the same was true for PCB-171 and 132 (θ = 90.1−90.2°).
Molecular mechanics calculation also predicted a perpendicular
structure (θ = 90°) for triply ortho-chlorinated PCB-84(2,2′,3,3′,6-pentachlorobiphenyl).47 On the other hand, X-ray
crystallographic studies revealed less-twisted structures for
PCB-84 (θ = 81.5°)47 and PCB-95 (2,2′,3,5′,6-pentachlorobiphenyl) (θ = 75.3°),48 suggesting considerable rotational
tolerance or shallow potential well for PCBs. Nevertheless, it isa reasonable approximation to employ the perpendiculargeometries of these PCBs as local minima (and not to reﬂect
the dynamic behavior)42−44 in the theoretical prediction of CDCdx.doi.org/10.1021/jp306363n | J. Phys. Chem. A XXXX, XXX, XXX−XXXThe Journal of Physical Chemistry A

Articleenvironmental processes for these legacy pollutants. Amongthe ﬁve atropisomeric heptachlorinated biphenyls, PCB-175
and -176 were not contained in the manufactured PCBs andtherefore barely found in air or biological samples. In contrast,
PCB-174 and -183 are the main components (among
heptachlorinated biphenyls) found in air samples, and thelatter is the only congener found in biological samples.23,25 Our
study allowed us to assign the absolute conﬁguration of the ﬁrst
elute of PCB 183 from chiral HPLC (Chiralcel OJ-H; based on
cellulose tris(4-methylbenzoate)) and GC (BGB Analytik BGB172; based on tert-butyldimethylsilyl β-cyclodextrin) as aS/P.
This reveals that (aR/M)-(+)-PCB-183 is enriched indeed (inca. 40% ee) in adipose tissue (Figure S4, Supporting
Information),57 as a consequence of the combined eﬀect ofenantiomeric accumulation through food chain and theenantioselective metabolism of racemic PCBs. The bio/
environmental origins of enantiomerically enriched PCBs areremained to be elucidated by further biological andtoxicological studies.

theoretical result (see the bar spectrum in Figure 3b) revealed
that the observed CD spectrum is a consequence of overlapping(more than 10) same/oppositely signed transitions, which are
not readily assignable. The theoretical calculation also
reproduced correctly the bisignate CE at longer wavelengths,
which is composed of only two transitions, but the
conﬁguration analysis revealed that the nature of the transitions
is quite intricate.
Direct comparison of the experimental and theoretical CD
spectra of PCB-171 and -132, shown in Figure 4 (and Figure S3
in the Supporting Information), allows us to unambiguously
assign the absolute conﬁgurations of the ﬁrst-eluted enantiomers of these two PCBs as aS or P. It should be noted thatﬁrst elutes from our HPLC became the second elutes in the
GC−HRMS/MS analysis for PCB-171 and -132 (Figure S1,
Supporting Information). It is interesting to note thatenantiomeric PCB-171 and -132 also exhibit strong trisignate
CEs at the main band but inverted in sign (negative-positivenegative) despite the same aS/P conﬁguration. This ispresumably due to the biphenyl’s electric/magnetic dipole
moments altered by the substitution pattern. The second CEs
at longer λ tend to be split to a pair of transitions in experiment.
The negative CEs at longer λ were the same in sign with that of
PCB-183, which was nevertheless very well reproduced bytheory. The apparently broad CE at this band was actuallycomposed of two negative rotational contributions, as judged
from the conﬁgurational analyses.
Speciﬁc rotation ([α]D) sometimes plays a supplementaryrole in determining absolute conﬁguration of chiral molecule.54,55 Hence, the experimental [α]D of enantiomeric PCB183, -171, and -132 measured in hexane were compared withthe corresponding values calculated by the TD-DFT method.56
As shown in Table 1, the signs of [α]D were correctly■

EXPERIMENTAL DETAILSThe circular dichroism (CD) spectra were measured in aconventional quartz cell (path =1 cm) ﬁtted with temperature
controller under the following conditions: bandwidth, 2 nm;
scan rate, 100 nm min−1, response, 4 s; accumulation, 4 times;
data interval, 0.5 nm. Aqueous solution of (+)-ammonium
camphorsulfonate-d10 (0.06%) was used for a calibration of thespectrometer sensitivity and wavelength (θ = 0.1904° at 290.5
nm). The three PCBs were purchased from AccuStandard [Lot#960607LB-AC (PCB-183), #041993 (PCB-171),#081706MT-AC (PCB-132)]. The concentrations of PCB
solutions were calculated using ε209 = 73000 (for PCB-183),
ε208 = 80800 (for PCB-171), or ε205 = 58400 M−1 cm−1 (for
PCB-132), respectively. The spectra were combined for datawith two diﬀerent concentrations to adjust detection limit: 0.2
μM for main band region (185−255, −260, and −240 nm for
PCB-183, -171, and -132, respectively) and 1.0 μM for the
longer wavelength region. HPLC analyses were performed with
Daicel Chiralcel OJ-H (4.6 mm i.d. × 15 cm) using n-hexane aseluent with a ﬂow rate of 0.5 mL min−1 at 38 °C (Tosoh CO8020, Shimadzu LC-10AT). The absolute conﬁguration of theﬁrst elute was assigned as aS/P by comparison with theoreticalone (vide supra). The adipose tissue sample was obtained after
receipt of written informed consent. About 2 g of sample wasadded to cleanup spike solution (2.5 mL of diethyl ether and 5
mL of ethanol) and was extracted twice with 10 mL of nhexane. The combined extract was puriﬁed by passing throughdouble layer column (1 g of ﬂorisil and 1 g of silica gel,
Supelco), eluted with 15 mL of 15% diethyl ether/n-hexane
solution. This was concentrated to ca. 0.1 mL under a gentle
stream of nitrogen, and syringe spike solution was added into
this concentrated sample. The combined sample was thenanalyzed as follows.58 The enantiomeric excess of PCB-183 inhuman sample was determined by chiral GC−HRMS/MS
using BGB-172 column (30 m × 0.25 mm i.d., ﬁlm thickness =0.25 μm, BGB Analytik AG) using helium as carrier gas (JEOL
JMS-800D). The injector and transfer line temperatures were
230 and 245 °C, respectively, and the column temperature wasinitially kept at 120 °C, which was increased to 180 °C (at arate of 4 °C min−1) and then to 230 °C (1 °C min−1), and kept
at this temperature for 10 min. The ion source was operated in
the electron-impact mode (EI, 38 eV, 250 °C). The ﬁrst
fraction in this GC−HRMS/MS analysis for PCB-183 wasTable 1. Experimental and Theoretical Speciﬁc Rotations([α]D) of (aS/P)-enantiomers of PCB-183, -171, and -132atheoretical
PCB

Experimental (c)b

BH-LYP/
augT

BH-LYP/
augD

B3-LYP/
augD

183
171
132

−15 ± 3 (0.013)c+44 ± 6 (0.0052)d+39 ± 15 (0.0020)e

−4.9
+38
+52

−4.7
+38
+51

−6.2
+46
+62

a
Speciﬁc rotation at sodium-D line (589 nm) in deg cm3 g−1 dm−1.
The theoretical values were calculated for (aS/P)-enantiomers by the
TD-DFT method with B3-LYP or BH-LYP functional by using
Dunning’s aug-cc-pVDZ (augD) or aug-cc-pVTZ (augT) basis-set.
b
Experimental [α]D of the ﬁrst-eluted enantiomers on chiral HPLC;
measured in n-hexane at 25 °C. Concentration (c) in g/100 mL.
c
Original [α]D was obtained for an 88% ee sample and the value wascorrected for the enantiomeric excess (ee). [α]D = +(8 ± 2) (c 0.021)
was obtained for the 84% ee sample of the (aR/M)-enantiomer. d[α]D= −(32 ± 4) (c 0.010) was obtained for the 90%ee sample of (aR/M)enantiomer. e[α]D = −(31 ± 8) (c 0.0036) was obtained for the 71%ee
sample of (aR/M)-enantiomer.

reproduced and the absolute values were in modest agreementwith the theoretical ones within the relatively large
experimental error (due to the limited availability) in all theexamined cases, supporting the above CD spectral assignments.
Atropisomeric PCBs in environmental biota are often
nonracemic, indicating the existence of stereoselective biotransformation/accumulation.10 Hence, the chiral analysis of
PCBs provides indispensable insights into biological andDdx.doi.org/10.1021/jp306363n | J. Phys. Chem. A XXXX, XXX, XXX−XXXThe Journal of Physical Chemistry A■

again assigned as aS/P, but the absolute conﬁgurations of ﬁrst
fractions for PCBs 171 and 132 in GC−HRMS/MS were
determined as aR/M. The ﬁrst elutes in GC−HRMS/MS
always possess negative optical rotations at the sodium-D line.

THEORETICAL CALCULATIONSAll calculations were performed on Linux-PCs using the
TURBOMOLE 6.3 program suite.59 Geometries of PCBs were
optimized at the DFT-D3-B-LYP/def2-TZVP level45,46 (H,[3s1p]; C, [5s3p2d1f]; Cl, [5s5p2d1f]) with numericalquadrature grid m5. The resolution of identity (RI)
approximation was employed in all calculations,60 and thecorresponding auxiliary basis sets were taken from the
TURBOMOLE basis-set library. The convergence criterion
for the optimization regarding the change of total energy
between two subsequent optimization cycles was set to 10−7 Eh.
All excited-state calculations were performed with the
optimized ground-state geometries of aS/P atropisomers andwere calculated by the resolution of the identity, timedependent approximate coupled cluster (RI-CC2) method50−52
with the basis sets of aug-def2-TZVPP quality. (H, [4s3p2d];
C, [6s4p3d2f]; Cl, [6s6p4d2f]). A preﬁx aug denotes adding of
the diﬀuse spd functions taken from the Dunning’s correlationconsistent aug-cc-pVTZ basis-set to more accurately describe
Rydberg and related states.61 The spectra of PCB-183 were also
compared with those calculated at the nonaugmented RI-CC2/
def2-TZVPP level. The spectra obtained with the latter basis
sets provided a similar pattern in the predicted CD with thoseobtained using aug-TZVPP basis sets, but with slight shifts inrotational strengths and excitation energies (Figure S2b in the
Supporting Information). Thus, the spectra at the RI-CC2/augdef2-TZVPP level were reported in the main text. The UV andCD spectra were simulated by overlapping Gaussian functions
for each transition from the length-gauge representations where
the width of the band at 1/e height is ﬁxed at 0.4 eV. Due tothe systematic errors of the theoretical transition energies
compared to the experimental ones, the spectra were uniformly
red-shifted by 0.3 or 0.4 eV.62−65
ASSOCIATED CONTENT

S Supporting Information*

Details of experimental CD spectra, enantiomeric analyses, andtheoretical calculations for PCBs. This information is available
free of charge via the Internet at http://pubs.acs.org.

■

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■■

ArticleAUTHOR INFORMATION

Corresponding Author*E-mail: tmori@chem.eng.osaka-u.ac.jp.
Notes

The authors declare no competing ﬁnancial interest.

■

ACKNOWLEDGMENTS
Financial supports of this research by Grant-in-Aid for ScientiﬁcResearch (No. 23350018, 24655029, and 21245011) from
JSPS, the Mitsubishi Chemical Corporation Fund, theSumitomo Foundation, the Shorai Foundation for Scienceand Technology, and the Kurata Memorial Hitachi Science andTechnology Foundation are gratefully acknowledged.
E

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