Copper-mediated synthesis of mono- and dichlorinated diaryl ethers

Article abstract of DOI:10.1016/j.tetlet.2014.06.035

An efficient synthesis of polychlorinated diphenyl ethers (PCDEs) using the Cu(OAc)₂-catalyzed Chan-Lam coupling reaction is described. A library of all possible mono- and dichlorinated diphenyl ether congeners was prepared and characterized using MS, ¹H, and ¹³C NMR spectroscopy, and Kovats retention indices. Our approach, using the optimized reaction conditions (i.e., reaction temperature, oxidizing atmosphere and base), significantly improves and simplifies the process compared to previously reported syntheses.

Full text of DOI:10.1016/j.tetlet.2014.06.035

Tetrahedron Letters 55 (2014) 4185–4188
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Tetrahedron Letters
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Copper-mediated synthesis of mono- and dichlorinated diaryl ethers
⇑
ˇ
Jan K. Cermák , Vladimír Církva
Institute of Chemical Process Fundamentals of the ASCR, v. v. i., Rozvojova 135, 165 02 Prague 6, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of polychlorinated diphenyl ethers (PCDEs) using the Cu(OAc)2-catalyzed Chan–
Lam coupling reaction is described. A library of all possible mono- and dichlorinated diphenyl ether cong-
eners was prepared and characterized using MS, 1H, and 13C NMR spectroscopy, and Kovats retention
indices. Our approach, using the optimized reaction conditions (i.e., reaction temperature, oxidizing
atmosphere and base), significantly improves and simplifies the process compared to previously reported
syntheses.
Received 15 April 2014
Revised 26 May 2014
Accepted 5 June 2014
Available online 14 June 2014
Keywords:
O-arylation
Ó 2014 Elsevier Ltd. All rights reserved.
Chan–Lam coupling
Polychlorinated diphenyl ethers
Environmental pollutants
Kovats indices
Polychlorinated diphenyl ethers (PCDEs) are persistent environ-
mental contaminants identified in various biota and abiota
matrices.1 With high lipophilicity and possible bioaccumulation
and biomagnification in the food chain, these compounds are con-
sidered to exhibit potentially harmful effects in humans and the
environment.2 PCDEs are formed as a byproduct of the manufac-
ture of technical chlorophenols,3 chlorinated phenoxyacetic acid,
or during incomplete combustion in municipal waste incinerators.4
Unlike other well-known persistent organic pollutants, such as
polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans
(PCDFs), and biphenyls (PCBs), the distribution, experimental tox-
icities, or human health effects of PCDEs are less well described.
For further investigations, the preparation and identification of
PCDE congeners are clearly necessary. More than half of the 209
possible PCDE congeners (Fig. 1) with different numbers and posi-
tions of the chlorine atoms have been synthesized and character-
ized.5 However, to the best of our knowledge, a complete list of
all possible mono- and dichlorinated diphenyl ethers (DEs) has
not been published.
Figure 1. Polychlorinated diphenyl ethers (PCDEs).
problematic due to the harsh conditions. The coupling reaction of
diphenyliodinium salts with chlorinated phenols8 is successful,
but requires inefficient preparation of diphenyliodinium salts in
the first step, and overall is a time-consuming procedure.
A large volume of research deals with copper-mediated cross-
coupling reactions of aryl boronic acids and phenols, which was
first reported by Chan9 and Lam10 in 1998. In the present article,
we report on the optimization and application of the Chan–Lam
coupling reaction to the synthesis of a complete library of mono-
and dichlorinated DEs (Scheme 1).
The formation of 2-chlorodiphenyl ether (6b) from phenylbo-
ronic acid (2) and 2-chlorophenol (1b) was selected as a model
reaction. To investigate the behavior of the reactants, we first
applied the usual Evans11 coupling conditions (Fig. 2). At room
temperature a reaction time of seven hours was required to give
2-chlorodiphenyl ether (6b) in 81% yield (GC). To improve this pro-
tocol we tried to increase the reaction temperature using conven-
tional or microwave heating. Both, microwave and conventional
heating led to low yields and immediate cessation of the reaction
in both cases (30% and 37%, respectively, after 7 h). On the con-
trary, cooling the reaction mixture in an ice bath increased the
yield, and after six hours, the reaction was complete yielding 93%
A large number of physiologically active compounds including
antibiotics, antitumor, and anti-HIV agents contain the diaryl ether
moiety.6 The search for efficient and convergent methods for the
formation of such ethers has generated considerable interest.
One of the most common methods for the O-arylation of phenols
is the well-known copper-catalyzed Ullmann coupling reaction7
from aryl halides. However, applications of this reaction have been
⇑
Corresponding author. Tel.: +420 220 390 141; fax: +420 220 920 661.
ˇ
E-mail address: jan.cermak@icpf.cas.cz (J.K. Cermák).
http://dx.doi.org/10.1016/j.tetlet.2014.06.035
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

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J. K. Cermák, V. Církva / Tetrahedron Letters 55 (2014) 4185–4188
Scheme 1. Synthesis of mono- and dichlorinated DE congeners.
Time [h]
Air
Argon
Oxygen
Oxygen bubbling
a Yields determined by GC.
b Reactions were performed using 1b (1.0 mmol), 2 (2
mmol), Cu(OAc)2 (1.0 mmol), Et3N (5 mmol), 4 Å MS
(1.0 g), CH2Cl2 (5 ml), 0 °C.
Time [h]
Room temperature
Reflux, 39.6 °C
Ice bath, 0 °C
Figure 3. Plot of the yield of 6b against time using different reaction atmospheres.
Microwave heating, 50 °C
Cooled, -20 °C
spheres (air, oxygen and oxygen bubbling) (Fig. 3). In agreement
with the proposed mechanism, we observed an important positive
effect of the presence of oxygen over the use of an argon atmo-
sphere. However, there was no significant difference between the
reaction under an air atmosphere and that in an oxygen-rich
atmosphere.
a Yields determined by GC.
b Reactions were performed using 1b (1.0 mmol), 2 (2
mmol), Cu(OAc)2 (1.0 mmol), Et3N (5 mmol), 4 Å MS
(1.0 g), CH2Cl2 (5 ml), air atmosphere.
Figure 2. Plot of the yield of 6b against time for various reaction temperatures.
Also, the choice of an appropriate base is critical since the reac-
tion yield is dependent on its nature. We have screened the effect
of various tertiary amine bases and their molar ratios with respect
to 1b in our model O-arylation reaction (Table 1). Surprisingly, our
first base of choice, triethylamine, was found to be the most active
(Table 1, entries 1 and 2), and other bases all exhibited lower activ-
ity, with product yields of up to 58%.
of the desired product. Attempts to further increase the yield by
cooling to ꢀ20 °C were unsuccessful. The results seem to indicate
that low temperatures are crucial for the stability of the reaction
intermediates, and for our model reaction, a temperature of 0 °C
and reaction time of six hours were the most appropriate to
achieve high yields.
Oxygen plays an important role in the proposed mechanism for
the Chan–Lam coupling reaction. After initial transmetalation of
the arylboronic acid and coordination of phenol, the aryl-CuII-phe-
nol intermediate undergoes a plausible oxidation to give a CuIII
complex. Subsequent reductive elimination affords the product
and a CuI species. Rapid oxidation of CuI to a CuII complex com-
pletes the catalytic cycle.12 Therefore, during the optimization pro-
cess, we focused our investigation on determining the influence of
the oxidizing atmosphere on our model reaction. We compared the
reaction under an inert (argon) atmosphere with oxidizing atmo-
Using the above-mentioned optimized reaction parameters,13
we have synthesized a complete library of mono- and dichlorinat-
ed DEs, that is, compounds 6a–p. In the majority of cases very good
reaction yields were achieved. The results are summarized in
Table 2. Reaction yields were lower with sterically demanding phe-
nolic substrates (Table 2, 6e and 6k), but we found no evidence of
any effects due to electronic factors.
Usually there were several typical side products (Scheme 2)
detected (GC/MS) in the crude reaction mixture. Even under seem-
ingly anhydrous conditions (activated powdered 4 Å molecular
sieves, dried solvent), we detected traces of by-products associated

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J. K. Cermák, V. Církva / Tetrahedron Letters 55 (2014) 4185–4188
4187
Table 1
Table 2
Effect of the base in the preparation of 6ba
Synthesis of mono and dichlorinated DEs from chlorinated phenols and (chlorinated)
phenylboronic acids
Entry
Base
Equivb
Yieldc (%)
No.a
PCDE
Chlorine
position
Phenol
Phenyl-boronic
acid
Yieldb (%)
RIc
1
2
2
5
80
93
—
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
—
2
3
4
1a
1b
1c
1d
1b
1e
1b
1f
1b
1g
1h
1c
1i
2
2
2
2
3
2
4
2
5
2
2
4
2
5
2
5
85
89
86
90
8d
84
81
81
70
74
54
81
79
84
65
80
1436.9
1613.4
1620.8
1637.1
1621.1
1820.1
1794.6
1782.3
1818.5
1770.3
1743.0
1806.5
1824.6
1828.0
1764.8
1850.2
3
4
2
5
10
34
5
6
2
5
19
23
2,20
2,3
2,30
2,4
2,40
2,5
2,6
3,30
3,4
3,40
3,5
4,40
7
8
2
5
10
44
9
10
2 + 2
58
9
10
11
12
13
14
15
11
12
2
5
48
56
1c
1j
1d
13
14
2
5
—
3
a
b
c
Suggested numbering analogous to PCBs.8
Yields are given for isolated products.
Retention indices.14,15
15
16
2
5
6
9
d
2,20-Dichlorobiphenyl was isolated as the major product.
a
Reaction conditions: 1b (1.0 mmol), 2 (2 mmol), Cu(OAc)2 (1.0 mmol), 4 Å MS
(1.0 g), CH2Cl2 (5 ml), 0 °C, under air atmosphere.
b
Molar ratio of base with respect to 1b.
Yield determined by GC.
ortho-chlorines 6b,e–k. This mass spectrometric ortho effect16 was
observed for monochlorinated diphenyl ethers, where the loss of
Cl. from (M+) is the lowest-energy process. In agreement with this
the ions (MꢀCl)+ for 6b or (Mꢀ2Cl)+ for 6e–k were observed as the
base peaks in the mass spectrum. Also for 2,4-(6h) and 2,40-(6i)
substituted congeners, the ion M+ was almost as intense as the
fragment (Mꢀ2Cl)+.
c
In conclusion we have developed a copper-catalyzed protocol
for the synthesis of chlorinated diaryl ethers. This protocol was
successfully applied to the synthesis of mono- and dichlorinated
DEs.
Acknowledgments
Scheme 2. By-products in the PCDE congener synthesis.
We gratefully acknowledge Prof. Eduardo Cepeda and other
members of the Departament de Química Orgànica, Universitat
Jaume I, Castelló de la Plana, Spain for helpful discussions. The
research was supported by ICPF CAS.
with the presence of water.11 Phenylboronic acid undergoes O-ary-
lation with water and gives the corresponding phenol 7. Subse-
quent coupling of newly generated phenol 7 affords diaryl ether
8. This was supported, among others, by the observation of 1a
and 6a in the reaction of phenylboronic acid (2) with 2-chlorophe-
nol (1b). Also, biphenyl 9 was detected as the product of homocou-
pling of arylboronic acids. With 2-chlorophenylboronic acid, 2,20-
dichlorobiphenyl was observed as the major product. Therefore,
we avoided the use of this sterically hindered phenylboronic acid,
when possible.
Supplementary data
Supplementary data (experimental procedures, analytical
instrumentation, 1H and 13C NMR, and mass spectra) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2014.06.035. These data include MOL
files and InChiKeys of the most important compounds described
in this article.
We have also performed control experiments using phenol and
chlorinated phenylboronic acids for the preparation of monochlo-
rinated DEs 6b–d. The yields were comparable for 3-chloroDE
(6c) and 4-chloroDE (6d), but as mentioned above, 2-chlorophenyl-
boronic acid (3) gave 2,20-dichlorobiphenyl as the major product.
All the PCDE congeners were purified using silica gel flash chro-
matography and compounds 7, 8, and 9 were completely separated
from the desired product. The purified products were characterized
by MS, 1H, and 13C NMR spectroscopy (see Supplementary data),
and using Kovats14 retention indices (Table 2). Both retention indi-
ces and mass spectra are crucial in routine environmental analysis.
Although it is difficult to distinguish between congeners with the
same number of chlorine atoms, mass spectral patterns give
important clues about the chlorine positions. We found the molec-
ular ion (M+) to be the major peak in all cases except for those with
References and notes
1. (a) Lake, J. L.; Rogerson, P. F.; Norwood, C. B. Environ. Sci. Technol. 1981, 15, 549;
(b) Stafford, C. J. Chemosphere 1983, 12, 1487; (c) Kuehl, D. W.; Durhan, E.;
Butterworth, B.; Linn, D. Environ. Int. 1984, 10, 45; (d) Paasivirta, J.; Tarhanen, J.;
Soikkeli, J. Chemosphere 1986, 15, 1429; (e) Koistinen, J.; Vuorinen, P.;
Paasivirta, J. Chemosphere 1993, 27, 2365; (f) Koistinen, J.; Paasivirta, J.;
Suonpera, M. Environ. Sci. Technol. 1995, 29, 2541.
2. For reviews, see: (a) de Boer, J.; Denneman, M. Rev. Environ. Contam. Toxicol.
1998, 157, 131; (b) Koistinen, J. In The Handbook of Environmental Chemistry;
Paasivirta, J., Ed.; Springer: Berlin, 2001; Vol. 3K, pp 157–201; (c) Domingo, J.
Environ. Int. 2006, 32, 121.
3. Frankki, S.; Persson, Y.; Tysklind, M.; Skyllberg, U. Environ. Sci. Technol. 2006, 40,
6668.
4. Kurz, J.; Ballschmiter, K. Fresenius J. Anal. Chem. 1995, 351, 98.
5. (a) Norström, Å.; Andersson, K. Chemosphere 1977, 5, 237; (b) Kurz, J.;
Ballschmiter, K. Fresenius J. Anal. Chem. 1994, 349, 533; (c) Nevalainen, T.;

ˇ
J. K. Cermák, V. Církva / Tetrahedron Letters 55 (2014) 4185–4188
4188
Koistinen, J.; Nurmela, P. Environ. Sci. Technol. 1994, 28, 1341; (d) Kurz, J.;
12. Rao, K. S.; Wu, T.-S. Tetrahedron 2012, 68, 7735.
Ballschmiter, K. Chemosphere 1999, 38, 573.
13. General procedure for the preparation of compounds 6a–p: To a solution of
phenol (1a–j) (1.0 mmol) and phenylboronic acid (2–5) (2 mmol) in dry CH2Cl2
(5 ml) were added powdered activated 4 Å molecular sieves (1.0 g), Cu(OAc)2
(1.0 mmol) and Et3N (5 mmol). The mixture was cooled to 0 °C and stirred for 6
h under an air atmosphere. The reaction was quenched with an excess of n-
hexane and precipitated catalyst and molecular sieves were separated by
filtration. The filtrate was evaporated under vacuum and the residue was
purified by flash chromatography (hexane, two parallel silica gel columns) to
afford pure product (6a–p).
6. (a) Evans, D. A.; Wood, M. R.; Trotter, B. W.; Richardson, T. I.; Barrow, J. C.; Katz,
J. L. Angew. Chem., Int. Ed. 1998, 37, 2700; (b) Deng, H.; Jung, J.-K.; Liu, T.; Kuntz,
K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 9032; (c)
Inaba, T.; Umezawa, I.; Yuasa, M.; Inoue, T.; Mihashi, S.; Itokawa, H.; Ogura, K. J.
Org. Chem. 2002, 52, 2957.
7. (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382; (b) Ullmann, F. Ber. Dtsch.
Chem. Ges. 1904, 37, 853; (c) Ullmann, F.; Sponagel, P. Ber. Dtsch. Chem. Ges.
1905, 38, 2211.
8. Gara, A.; Andersson, K.; Nilsson, C. A.; Norstrom, A. Chemosphere 1981, 10, 365.
9. Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998,
39, 2933.
14. (a) Kovats, E. Helv. Chim. Acta 1958, 41, 1915; (b) van der Dool, H.; Kratz, P. D. J.
Chromatogr. 1963, 11, 463.
15. Operating conditions for retention indices measurements: TR-5MS, 30 m/
10. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.;
Combs, A. Tetrahedron Lett. 1998, 39, 2941.
11. Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937.
0.25 mm/0.25 lm, N2, 8 °C/min, Tstart = 100 °C, Tend = 300 °C.
16. (a) Granoth, I. J. Chem. Soc., Perkin Trans. 2 1972, 1503; (b) Schwarz, H. Top. Curr.
Chem. 1978, 73, 231.