Synthesis of polychlorinated biphenyls (PCBs) using the Suzuki-coupling

Article abstract of DOI:10.1016/S0045-6535(00)00546-4

An improved synthesis of polychlorinated biphenyls (PCBs) utilizing a palladium-catalyzed cross-coupling reaction (Suzuki-coupling) is described. The coupling of (chlorinated) aryl boronic acids 1-3 with bromochlorobenzenes 4 using the standard conditions of the Suzuki-coupling gave the desired PCB congeners 5-7 in good to excellent yields. The self-coupling product of the aryl boronic acids is the major impurity of this reaction. 3,4,5-trichlorophenyl derivatives such as 10 can be synthesized by coupling of an aryl boronic acid with the corresponding bromochloroaniline 8. The approach offers the advantage of high selectivity and good yields compared to conventional methods Such as the Cadogan reaction and allows the use of less toxic starting materials.

Full text of DOI:10.1016/S0045-6535(00)00546-4

Chemosphere 45 ꢀ2001) 137±143
www.elsevier.com/locate/chemosphere
Synthesis of polychlorinated biphenyls ꢀPCBs) using the
Suzuki-coupling
*
Hans-Joachim Lehmler,Larry W. Robertson
Graduate Center for Toxicology, Chandler Medical Center, University of Kentucky, 306 Health Science Research Building, Lexington,
KY 40536-0305, USA
Received 28 August 2000; accepted 6 October 2000
Abstract
An improved synthesis of polychlorinated biphenyls ꢀPCBs) utilizing a palladium-catalyzed cross-coupling reaction
ꢀSuzuki-coupling) is described. The coupling of ꢀchlorinated) aryl boronic acids 1±3 with bromochlorobenzenes 4 using
the standard conditions of the Suzuki-coupling gave the desired PCB congeners 5±7 in good to excellent yields. The self-
coupling product of the aryl boronic acids is the major impurity of this reaction. 3,4,5-trichlorophenyl derivatives such
as 10 can be synthesized by coupling of an aryl boronic acid with the corresponding bromochloroaniline 8. The ap-
proach o€ers the advantage of high selectivity and good yields compared to conventional methods such as the Cadogan
reaction and allows the use of less toxic starting materials. Ó 2001 Elsevier Science Ltd. All rights reserved.
Keywords: Environmental contaminants; Biaryls; PCB; Cross-coupling; Palladium
1. Introduction
dicult,and many PCB congeners are only poorly
characterized.
Polychlorinated biphenyls ꢀPCBs) are persistent and
wide-spread environmental contaminants ꢀHansen,
1987,1994,1999). Their lipophilic character and their
resistance to degradation contribute to the tendency of
PCBs to accumulate in the food chain,where they rep-
resent an environmental and human health hazard
ꢀHansen,1999). PCBs' mechanisms of toxicity are varied
and still poorly understood,in part because technical
PCB products consist of complex mixtures of many of
the 209 possible PCB congeners. Studies of the biologi-
cal e€ects of PCBs as well as studies of their chemical
transport,degradation and remediation greatly bene®t
from the availability of single congeners. Unfortunately,
the ꢀlarge scale) synthesis of many PCB congeners is
Numerous reactions have been utilized for the syn-
thesis of PCBs,including the Ullmann reaction ꢀFanta,
1974),the Sandmeyer reaction ꢀNakatsu et al.,1982) and
the Cadogan reaction ꢀCadogan et al.,1962),which is a
modi®cation of the Gomberg Bachmann reaction
ꢀHutzinger et al.,1983). These and related reactions
have signi®cant drawbacks. The Ullmann reaction is
generally limited to symmetrical PCB congeners and
results in signi®cant amounts of highly toxic dib-
enzofuran byproducts ꢀMoron et al.,1973). The Cado-
gan reaction is more versatile,but is a very low yield
procedure ꢀ10±20%),and the by-products of this reac-
tion are not well characterized. The Sandmeyer reaction
can be used to synthesize several symmetrical PCB
congeners,for example 22, 0,5,50-tetra-,33, 0,4,40-tetra-
and 2,20,4,40,5,50-hexachlorobiphenyl,from benzidine
derivatives ꢀNakatsu et al.,1982). However,benzidine is
a known human carcinogen and chlorinated benzidines
are classi®ed as possible human carcinogens ꢀplease see:
http://ehis.niehs.nih.gov/roc/toc8.html).
* Corresponding author. Tel.: +1-606-257-3952; fax: +1-606-
323-1059.
E-mail address: lwrobe01@pop.uky.edu ꢀL.W. Robertson).
0045-6535/01/$ - see front matter Ó 2001 Elsevier Science Ltd. All rights reserved.
PII: S 0 0 4 5 - 6 5 3 5 ꢀ 0 0 ) 0 0 5 4 6 - 4

138
H.-J. Lehmler, L.W. Robertson / Chemosphere 45 22001) 137±143
Fig. 1. Synthesis of PCB congeners.
Over the last decades numerous biphenyl syntheses
Higher chlorinated di- ꢀ6b, 7c) and trichlorobiphenyls
ꢀ6d, 6g, 7e±g) were also synthesized selectively in good
yields using the same reaction conditions ꢀsee Table 1).
The trichlorobiphenyl compounds listed in Table 1 are
dicult to synthesize by other methods such as the
Cadogan coupling and are therefore hardly studied in
biological systems. For example,the Cadogan- ꢀMullin
et al.,1984) and the Ullmann coupling ꢀParkinson et al.,
1980) were used to synthesize 2,4,40-trichlorobiphenyl
ꢀ7e) resulting in three and two product mixtures,re-
spectively. The Suzuki-coupling now allows us to syn-
thesize large quantities of 2,4,40-trichlorobiphenyl ꢀ7e) in
a single step. Also,the introduction of one ortho-chloro
substituent did not pose a problem under the reaction
conditions investigated,as shown for 2-chloro- ꢀ 5a),
2,3,30-trichloro- ꢀ6d), and 2,4,40-trichlorobiphenyl ꢀ7e).
The synthesis of ortho-substituted PCB congeners is of
particular interest because their toxicity is poorly un-
derstood ꢀHansen,1999).
have emerged and are now standard reactions in organic
chemistry ꢀMiyaura and Suzuki,1995; Stanforth,1998;
Suzuki,1999). Only few of these reactions were used to
synthesize PCB congeners or PCB metabolites. We re-
cently described the preparation of several mono- and
dihydroxylated PCB metabolites with the Suzuki-coupling
ꢀBauer et al.,1995; McLean et al.,1996). The cross-cou-
pling of 4-chloro phenoltri¯ate with benzene boronic acid
in the presence of lithium chloride was utilized to syn-
thesize 4-chlorobiphenyl ꢀHuth et al.,1989). In a similar
reaction,4-chlorobiphenyl was prepared employing the
corresponding 4-chloro organozinc compound instead of
the boronic acid and Pdꢀdppf†2Cl2 ꢀdppf ˆ 1,10-bisꢀdiph-
enylphosphino) ferrocene) as a catalyst. The palladium-
catalyzed cross-coupling of arenediazonium salts ꢀSeng-
upta and Bhattacharyya,1997) or hypervalent aryliodo-
nium species ꢀKang et al.,1996ab,) with phenylboronic
acids was also used to synthesize 4-chlorobiphenyl. De-
spite the great need for single PCB congeners for biolog-
ical and environmental studies,the scope of these
reactions has never been extended to synthesize other and
higher chlorinated PCB congeners ꢀFig. 1).
The synthesis of PCB congeners with three chlorine
substituents in one phenyl ring is limited because only a
few trichloroanilines are available from commercial
sources. However, 3,5-dichloro- or 3,4,5-trichlorobi-
phenyls can be synthesized in moderate yields by
coupling a chlorinated benzeneboronic acid ꢀ3) with
4-bromo-2,6-dichloroaniline ꢀ8). The 4-aminobiphenyl 9
is obtained after column chromatography over alumina.
3,40,5-Trichloro- ꢀ7g) and 3,4,40,5-tetrachlorobiphenyl
ꢀ10) were obtained from the 4-aminobiphenyl derivative
9 by deamination with phosphoric acid or by Sandmeyer
reaction,respectively ꢀFig. 2).
Based on our experience with the synthesis of di-
hydroxylated PCB metabolites,we investigated the Su-
zuki-coupling of phenylboronic acid ꢀ1) and two
chlorinated benzeneboronic acids ꢀ2±3) with several
bromochlorobenzenes 4 ꢀMiyaura and Suzuki,1995). As
expected,2- ꢀ 5a),3- ꢀ 5b) and 4-chlorobiphenyl ꢀ5c),
important lower chlorinated PCB congeners,can easily
be synthesized using 3 mol% of PdꢀPPh3† as a catalyst
4
and 2 M sodium carbonate as a base ꢀTable 1) ꢀBauer
et al.,1995). All PCB congeners were pre-puri®ed by
passing them through a short Al2O3 column with
n-hexanes or petroleum ether as the eluent.
For biological and toxicological studies it is not only
important to have pure compounds,but also to know
which impurities are present. Fortunately,side reactions
of the Suzuki reaction,such as hydrolytic deboronation

H.-J. Lehmler, L.W. Robertson / Chemosphere 45 22001) 137±143
139

140
H.-J. Lehmler, L.W. Robertson / Chemosphere 45 22001) 137±143
Fig. 2. Synthesis of 3,40,5-trichloro and 3,4,40,5-tetrachlorobiphenyl.
ꢀMuller and Fleury,1991; Fukuyama et al.,1993),aryl±
aryl exchange between the palladium center and the
phosphine ligand ꢀKong and Cheng,1991; O'Keefe et al.,
1992; Segelstein et al.,1995) and self-coupling of aryl
with a Hewlett±Packard 5890 A Gas Chromatograph
equipped with a HP-1 ꢀmethyl silicone gum) column
ꢀHewlett±Packard,Avondale,PA) and determined
based on relative peak area. The following conditions
were used for the gas chromatographic analysis: injector:
255°C,detector ꢀFID): 300 °C,starting temperature:
40°C ®nal temperature: 245°C,heating rate: 10 °/min.
The melting points were determined on a MEL-TEMP
apparatus and are uncorrected. All solvents were ob-
tained from commercial sources and used without fur-
ther puri®cation. Caution. PCBs are reasonably
anticipated to be human carcinogens and should there-
fore be handled in an appropriate manner.
~
boronic acids ꢀMoreno-Manas et al.,1996; Smith et al.,
1997; Aramendia and Lafont,1999),are well studied.
All PCB congeners synthesized by the Suzuki-coupling
showed one major impurity that can be removed by
several recrystallizations from methanol or fractional
destilation. GC±MS analysis,retention time comparison
and co-injection with authentic standards revealed that
this major impurity is the self-coupling product of the
boronic acid. This side reaction is a result of traces of
oxygen which can only be excluded by using freeze thaw
cycles ꢀWallow and Novak,1994).
2.1. 2,6-Dichloro-4-bromoaniline 28) 2Godfrey and
Thrift, 1967)
We conclude that application of the Suzuki meth-
odology to the synthesis of PCB congeners has great
advantages over conventional methods. Studies to ex-
tend the synthesis to higher chlorinated PCB congeners
and to reduce the homocoupling of the boronic acids are
currently underway in our laboratory.
m.p. ˆ 86°C ꢀwhite needles from ethanol, >98% by
GC). 1H-NMR ꢀCDCl3,300 MHz) d 4.29 ꢀbr s,NH
,
2
2H),7.28 ꢀs,ArH,2H). 13C-NMR ꢀCDCl3,75 MHz) d
107.89,119.96,130.19 ꢀ2 Â C),139.39. IR ꢀcm À1): 3424,
3301,1615,1467,857. MS m/z ꢀrelative intensity,%):
239/241/243 ꢀ33),160 ꢀ5),124 ꢀ9),88 ꢀ7),61 ꢀ18),43
ꢀ100).
2. Experimental
All PCB congeners were characterized by 1H and 13
C
2.2. Synthesis of PCB congeners, general procedure of the
Suzuki-coupling 2Bauer et al., 1995; McLean et al.,
1996)
NMR,FT±IR and GC/MS spectroscopy. The IR spec-
tra were obtained using a Nicolet Magna-IR 560 Spec-
trometer E.S.P. The 1H and 13C NMR spectra were
recorded on a Varian VXR-400S NMR Spectrometer by
using CDCl3 ꢀCambridge Isotope Laboratories,Ando-
ver,MA) as solvent and TMS as internal standard un-
less otherwise noted. Combustion analysis of all PCB
congeners were performed by Atlantic Microlab ꢀAt-
lanta,GA). Deviations are smaller or equal Æ0.34%.
GC/MS analysis were performed in the Mass Spect-
rometry Facility of the University of Kentucky ꢀLex-
ington,KY). The purity of all compounds was analyzed
Sodium carbonate ꢀ5 ml,2 M aq.) was added to a
solution of a chloro-bromobenzene ꢀ5 mmol) and
PdꢀPPh3† ꢀ0.18 mg) in toluene ꢀ20 ml). A solution of a
4
chlorobenzene boronic acid ꢀ5 mmol) in ethanol ꢀ10 ml)
was added slowly to the solution of the bromo benzene
under a nitrogen atmosphere. The reaction mixture was
maintained at 80°C for 12±16 h. Hydrogenperoxide ꢀ0.5
ml,30%) was added slowly to the warm reaction mixture
to destroy unreacted boronic acid. The mixture was

H.-J. Lehmler, L.W. Robertson / Chemosphere 45 22001) 137±143
141
Table 2
Analytical data of PCB congeners
PCB
IR ꢀcmÀ1
)
MS-EI e/z ꢀInt.)a
188 ꢀ100,C
12H9ClŇ),
152 ꢀ30,M-HCl)
1H NMRb
5a
1467,1425,1036,748,699
7.13 ꢀ``t'', J ꢁ 7:6 Hz,d, J ˆ 2:0 Hz,4-H),7.17
ꢀ``t'', J ꢁ 7:4,d, J ˆ 1:6 Hz,4-H),7.23±7.40 ꢀm,
3,6,20,30,40,50,60-H)
5b
1593,1565,1473,753,696
188 ꢀ100,C
152 ꢀ30,M-HCl)
12H9ClŇ),
7.32 ꢀd, J ˆ 8:0 Hz,``t'', J ˆ 2:0 Hz,4-H),
7.34±7.41 ꢀm,4 ,5-H), 7.42±7.49 ꢀm, 30,50,6-H),
0
7.54±7.60 ꢀm,22, 0,60-H)
5c
6b
6d
1478,1098,832,758,688
1592,1384,1101,775,718
1388,774,692
188 ꢀ100,C
152 ꢀ30,M-HCl)
222 ꢀ100,C
12H8ClÅ2‡),
186 ꢀ8,M-HCl),152 ꢀ69,M-Cl
12H9ClŇ),
7.32±7.45 ꢀm,33, 0,4,40,5,50-H),7.47±7.55 ꢀm,
2,20,6,60-H)
7.29±7.42 ꢀm,44, 0,5,50,6,60-H),7.51 ꢀ``s'',22, 0-H)
)
2
256 ꢀ100,C 12H7ClÅ3‡),220 ꢀ4,M-HCl),
7.20 ꢀd, J ˆ 8:0 Hz,d, J ˆ 1:6 Hz,4-H),7.25 ꢀt,
J ˆ 8:0 Hz,5-H),7.26±7.30 ꢀm,4 0-H),7.35±7.38
186 ꢀ33,M-Cl 2),150 ꢀ10)
0
ꢀm,5 ,60-H),7.38±7.40 ꢀm,2 0-H),7.48 ꢀd,
J ˆ 8:0 Hz,d, J ˆ 1:6 Hz,6-H),
6g
7c
7e
1583,1553,854,782,682
1474,1088,1002,815,702
1465,807,734,730,541
256 ꢀ100,C
12H7ClÅ3‡),220 ꢀ4,M-HCl),
12H8ClÅ2‡),186 ꢀ8,M-HCl),
7.35±7.42 ꢀm,44, 0,50,60-H),7.43 ꢀd, J ˆ 2:0 Hz,
2,5-H), 7.53 ꢀm, 20-H)
186 ꢀ33,M-Cl 2),150 ꢀ10)
222 ꢀ100,C
256 ꢀ100,C
7.40 ꢀAA`XX' system,33, 0,5,50-H),7.48
ꢀAA`XX'system,22, 0,6,60)
152 ꢀ65,M-Cl
)
2
12H7ClÅ3‡),220 ꢀ5,M-HCl),
7.24 ꢀd, J ˆ 8:4 Hz,6-H),7.31 ꢀd, J ˆ 8:4 Hz,d,
J ˆ 2:0 Hz,5-H),7.34 ꢀAA`XX' system,
30,50-H),7.41ꢀAA`XX' system,2 0,60-H),7.50 ꢀd,
J ˆ 2:0 Hz,3-H)
186 ꢀ48,M-Cl 2),150 ꢀ15)
7f
1461,1091,807
256 ꢀ100,C 12H7ClÅ3‡),220 ꢀ4,M-HCl),
186 ꢀ33,M-Cl 2),150 ꢀ10)
7.33 ꢀd, J ˆ 8:0 Hz,d, J ˆ 2:0 Hz,6-H),
0
7.37±7.45ꢀAA`BB' system,2 ,30,50,60-H),7.47
ꢀd, J ˆ 8:0 Hz,5-H),7.59 ꢀd, J ˆ 2:0 Hz,2-H)
7.28 ꢀt, J ˆ 1:2 Hz,4-H),7.35 ꢀd, J ˆ 1:2 Hz),
7g
10
1555,1495,1093,822,800
256 ꢀ100,C
186 ꢀ42,M-Cl 2),150 ꢀ12)
290 ꢀ100,C 12H6ClÅ4‡),254 ꢀ3,M-HCl),
220 ꢀ40,M-Cl 2),150 ꢀ12,M-Cl
12H7ClÅ3‡),220 ꢀ5,M-HCl),
0
7.38 ꢀs,2 ,30,50,60-H)
0
7.41 ꢀs,2 ,30,50,60-H),7.53 ꢀs,26, -H)
c
1430,1091,828,813,802,
491
)
4
a The observed fragmentation patters ꢀM±HCl,M±Cl 2 and M±Cl2±HCl) are in agreement with literature data ꢀSafe and Hutzinger,
1972).
b The 1H chemical shifts of previously uncharacterized PCB congeners were assigned based on the paper of Yanagisawa et al. ꢀ1987).
c Recorded on a Varian Gemini 200 ꢀ200 MHz).
Table 3
13C chemical shifts of PCB congenersa
PCB
C-1
C-2
C-3
C-4
C-5
C-6
C-10
C-20
C-30
C-40
C-50
C-60
5a
5b
5c
6b
6d
6g
7c
7e
7f
140.46 132.43
143.08 127.84
139.62 128.35
131.30
134.65
128.44
126.74
129.86 139.32 127.97
125.28 139.81 127.10
129.37
128.87
127.52
129.37
127.97
127.10
127.24b 129.95
127.29b 128.87
128.87b 133.34
128.87b 128.35 139.94 126.95
128.85b 127.56
128.85b 126.95
141.54 127.86b 134.78
127.22b 130.10
125.22 141.54 127.86b 134.78
127.22b 130.10
125.22
129.35b 128.07
127.20b 130.26
125.21
140.84 131.02
142.70 125.61
138.42 128.20
137.91 133.23
139.91 128.75
142.91 125.47
139.94 127.01
133.72c 129.28b 127.24
129.89 141.36 129.39
125.61 140.28 128.47
128.20 138.42 128.20
129.85 136.69 128.44
126.13 137.14 128.15
125.47 136.95 128.30
127.01 136.12 128.15
133.98c 127.51
135.43
129.03
131.90
132.97
135.43
134.62
127.75b 135.43
133.76 129.03
134.12c 127.28
135.01
129.03
130.69
129.15
129.23
129.33
133.76
134.12c 130.69
129.03
128.20
128.44
128.15
128.30
128.15
131.78
127.47
134.90
130.77
135.43
134.62
134.30
134.71
130.57
129.15
129.23
129.33
7g
10d
a The 13C chemical shifts of previously uncharacterized PCB congeners were assigned based on the data published by Yanagisawa
et al. ꢀ1986).
b Assignment may be interchangeable with each other.
c Signals overlap.
d Recorded on a Varian Gemini 200 ꢀ50 MHz).

142
H.-J. Lehmler, L.W. Robertson / Chemosphere 45 22001) 137±143
Hansen,L.G.,1987. Environmental toxicology of PCBs.
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stirred at room temperature for additional 4 h and di-
luted with diethyl ether ꢀ30 ml). The reaction mixture
was extracted once with NaOH ꢀ10 ml,2 M aq.) and
three times with water ꢀ20 ml). The organic phase was
dried over MgSO4 and the solvents were removed under
reduced pressure. Column chromatography ꢀglass col-
umn,300 mm  25 mm i.d.) over Alumina ꢀAlumina
Adsorption 80±200 mesh,Fisher Scienti®c,Pittsburg,
PA) with n-hexanes or petroleum ether as eluent yielded
the desired PCB congener.The analytical data of all PCB
congeners are summarized in Tables 1±3.
Hansen,L.G.,1994. Halogenated aromatic compounds. In:
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compounds by palladium catalyzed reaction of aromatic
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Kang,S.-K.,Lee,H.-W.,Jang,S.-B.,Ho,P.-S.,1996a.
Palladium-catalyzed cross-coupling of organoboron com-
pounds with iodonium salts and iodanes. J. Org. Chem. 61,
4720±4724.
2.3. 3,30,40,5-Tetrachloro-4-aminobiphenyl 29)
1
m.p. ˆ 128°C ꢀ>99%). H-NMR ꢀCDCl3,200 MHz)
d 3.96 ꢀbr s,±NH ,2H),6.98±7.16 ꢀm,ArH,6H).
13C-
Kang,S.-K.,Yamaguchi,T.,Kim,T.-H.,Ho,P.-S.,1996b.
Copper-catalyzed cross-coupling and carbonylative cross-
coupling of organostannanes and organoboranes with hy-
pervalent iodine compounds. J. Org. Chem. 61,9082±9083.
Kong,K.-C.,Cheng,C.-H.,1991. Facile aryl±aryl exchange
between the palladium center and phosphine ligands in
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McLean,M.R.,Bauer,U.,Amaro,A.R.,Robertson,L.W.,1996.
Identi®cation of catechol and hydroquinone metabolites of 4-
monochlorobiphenyl. Chem. Res. Toxicol. 9,159±164.
Miyaura,N.,Suzuki,A.,1995. Paladium-catalyzed cross-
coupling reactions of organoboron compounds. Chem.
Rev. 95,2457±2483.
2
NMR ꢀCDCl3,50 MHz) d 119.93,126.15 ꢀCH),127.50,
128.98,130.34,133.19,137.29,139.46. IR ꢀcm À1): 3420,
3310,2921,2850,1474,1384,1309,1094,1084,1013.
MS m/z ꢀrelative intensity,%): 271/273/275/277 ꢀ100),
201 ꢀ18),129 ꢀ52),83 ꢀ36),69 ꢀ53),57 ꢀ53).
Acknowledgements
The authors want to thank John W. Layton from
the Nuclear Magnetic Resonance ꢀNMR) Facility of
the University of Kentucky and Jan St. Pyrek from the
Mass Spectrometry Facility of the University of Ken-
tucky for their support. This publication was made
possible by grant number P42 ES 07380 from NIEHS
with funding provided by EPA. Its contents are solely
the responsibility of the authors and not so necessarily
represent the ocial views of the NIEHS,NIH or
EPA.
~
ꢀ
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catalyzed suzuki-type self-coupling of arylboronic acids: a
mechanistic study. J. Org. Chem. 61,2346±2351.

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of bi¯avonoids via arylboronic acids. Tetrahedron Lett. 32,
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