Efficient oxidative chlorination of aromatics on saturated sodium chloride solution

Article abstract of DOI:10.1002/adsc.201300062

An efficient metal-free system using saturated aqueous sodium chloride/aqueous ammonium chloride solution as chlorine source and potassium persulfate as a cheap oxidant for the chlorination of various aromatic compounds including deactivated ones has been developed that proceeds without any acid additive in an excellent regioselective manner. The easy-to-handle aqueous solution/acetonitrile biphasic system as solvent and no need for precautionary measures make this process very practical. Copyright

Full text of DOI:10.1002/adsc.201300062

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DOI: 10.1002/adsc.201300062
Efficient Oxidative Chlorination of Aromatics on Saturated
Sodium Chloride Solution
Liuqun Gu,a Ting Lu,a Mingyun Zhang,a Lijuan Tou,a and Yugen Zhanga,*
a
Department of Pharmaceutical Synthesis and Green Chemistry, Institute of Bioengineering and Nanotechnology, 31
Biopolis Way, The Nanos, Singapore 138669
Fax : (+65)-6478-9080; e-mail: ygzhang@ibn.a-star.edu.sg
Received: January 23, 2013; Revised: March 18, 2013; Published online: April 9, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300062.
Abstract: An efficient metal-free system using satu-
rated aqueous sodium chloride/aqueous ammonium
chloride solution as chlorine source and potassium
persulfate as a cheap oxidant for the chlorination of
various aromatic compounds including deactivated
ones has been developed that proceeds without any
acid additive in an excellent regioselective manner.
The easy-to-handle aqueous solution/acetonitrile bi-
phasic system as solvent and no need for precau-
tionary measures make this process very practical.
fers from very low yield or even no reaction. Herein,
we report a metal-free oxidative chlorination on satu-
rated NaCl/NH4Cl aqueous solution with the cheap
oxidant potassium persulfate, which works well for
various aromatic compounds including deactivated
ones. In this work, both dichloro products and mono-
chloro products could be achieved in regioselective
manners by simply changing the reaction conditions.
Generally, chlorination reactions were more reactive
in the biphasic system of MeCN/saturated NaCl (pro-
ducing dichloro derivatives in most cases) than those
reactions in the system of MeCN/saturated NH4Cl
aqueous solution (producing mono chloro derivatives
in most cases) (Scheme 1).
Keywords: aromatic compounds; biphasic condi-
tions; chlorination; metal-free reaction; potassium
persulfate
Chlorinated aromatic compounds are very valuable
building blocks in pharmaceutical synthesis, when
considering the indispensable role of halogenated
compounds in transition metal-mediated coupling re-
actions.[1,2] Traditionally, molecular chlorine was com-
monly used with a metal catalyst for electrophilic
arene chlorination under relatively harsh conditions.[3]
Significant progress was achieved by using alternative
oxidized halogen reagents (N-chlorosuccinimide,
NCS), which is less toxic and easier to handle.[4] Olah
Scheme 1. Efficient combined systems for the chlorination
of aromatic compounds.
Peroxydisulfate has been extensively studied as an
and co-workers reported the acid-promoted NCS oxidant in Elbs and Boyland–Sims oxidations to intro-
chlorination of aromatic compoundss with an excess duce hydroxy groups into aromatic rings without
amount of BF3-H2O under heating conditions;[4] Re- cleavage of aromatic side chains,[8] it has not been
cently, the direct oxidative chlorination with chloride widely used in oxidative chlorination, probably due to
anions (sources such as HCl, KCl etc.) in the presence the poor selectivity and narrow substrate scope
of an oxidant has received more attention from the showed in the initial study.[9,10] Moreover, Ledwith et
green chemistry perspective.[5,6] To achieve excellent al. found that with Na2S2O8 and LiCl it was possible
regioselectivity, a selected metal catalyst is usually to achieve chlorinated hydrocarbons on the aromatic
a must in oxidative chlorination due to the high reac- ring rather than on the side chain in the presence of
tivity of those chlorinating reagents.[7] However, to CuCl2 and HCl.[10] However, the scope investigation
the best of our knowledge, in most of the cases, showed that only substrates more reactive (electron-
chlorination of deactivated aromatic compounds suf- rich) than benzene could give significant amounts of
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Table 1. Optimization of the reaction conditions.[a]
block the para position, the ortho-monochloro prod-
uct instead of the dichloro one was obtained (2e).
When R is electron-rich trimethyl or dimethyl groups,
dichloro (2f) and trichloro (2g) products were ach-
ieved, respectively. Simple electron-rich arenes such
as 1,3,5-trimethoxybenzene could be chlorinated with
only 1.1 equiv. K2S2O8 producing the monochloro
arene (2h). However, chlorination of mesitylene and
phenol gave messy products even in the presence of
1.1 equiv. K2S2O8, which suggested that the sulfona-
mide group on the aromatic ring is beneficial for the
high selectivity and the chlorination might proceed
via an N-chloro salt intermediate.[13]
Entry Solvent
Oxidant
Yield[b]
(4 equiv.)
1[c]
2[c]
3
MeCN
MeCN/water (v/v=1/1)
MeCN/sat. NaCl (v/v=1/1) K2S2O8
MeCN/sat. NaCl (v/v=1/1) K2S2O8
MeCN/sat. NaCl (v/v=1/1) PhIACTHNURTGNENUG(OAc)2
K2S2O8
K2S2O8
N.R.
complex
92%
78%
0
4[d]
5
To our delight, deactivated aromatic compounds
which were extremely difficult or even inert for
chlorination in systems of MeCN/HCl/Na2S2O8/LiCl/
[a]
The reaction was carried out at 1008C for 1 h in a sealed
vial with a combined solvent (1 mL) of MeCN/sat. NaCl
(v/v=1/1) using 1 (0.25 mmol) and K2S2O8 (1 mmol) as
an oxidant.
Isolated yield.
4 equiv. NaCl were used as chlorine source.
3 equiv. K2S2O8 were used.
[9]
CuCl2 or other oxidants/ClÀ[5,14] were also suitable
substrates for the system of MeCN/saturated NaCl/
K2S2O8. Chlorinations of 1,3-difluorobenzene and
fluorobenzene were completed in 1.5 h producing
para-chloro products quantitatively. And product 2i
could be a precursor for the synthesis of Diflunisal
(Dolobid, Merck & Co.), which is a non-opioid, non-
[b]
[c]
[d]
chlorinated products and the isomer distribution was steroidal anti-inflammatory drug.[15] Also, chlorination
similar to that of conventional electrophilic substitu- of benzene could be completed in 1 h, producing
tion.[10] In our exploration of oxidative coupling reac- chlorobenzene almost quantitatively. Interestingly, for
tions, we found that potassium persulfate was a much chlorobenzene and bromobenzene, chlorination reac-
more effective oxidant in the chlorination of aromatic tions gave the same product, namely dichlorobenzene
compoundss so that the reaction could occur even in with almost same 2/1 p/o ratio). And chlorination of
the absence of any acid additive under the combined iodobenzene gave an almost quantitative yield of
system of acetonitrile and saturated NaCl solution. chlorobenzene product in 1 h. It was known that in
Encouraged by this finding, various conditions were the HCl/H2O2 system, aryl iodide would be oxidized
optimized in the chlorination of sulfonamide 1a and to aryliodineACHTNUTGRNEUNG
(III) dichloride.[6] However, in our
we found that with 4 equiv. K2S2O8 the reaction could system, no similar intermediates were detected and
afford the dichloro product in 92% yield in MeCN/sa- we believe the product of chlorodeiodination is
turated NaCl (v/v=1/1, for details see Table S1 in the formed directly from the parent iodoarene. These re-
Supporting Information).[11] In the control experiment sults also indicate that the chlorination of bromoben-
without any water additive, the reaction did not zene may proceed via a radical halogen exchange and
occur, which indicated the important role of water in subsequent chlorination of a chlorobenzene inter-
this conversion (Table 1, entry 1). Increasing the mediate. For acetophenone, chlorination occurred on
water ratio in the mixed solvent system led to strong side chain instead of the aromatic ring (2m). Elec-
side reactions (entry 2). Saturated NaCl solution tron-deficient 2,2,2-trifluoroacetophenone is also
seems to be the perfect reaction medium in order to a suitable substrate yielding the p-chlorinated product
provide the water and chlorine source needed for (2p). Meanwhile, chlorination of methyl benzoate
ACTHNUTRGNEUNG
chlorination (entry 3).[12] The use of PhI(OAc)2 led to gave the chloromethyl ester (2n),[16] and chloromethyl
formation of carbazole (entry 5). And an excess esters are recognized as valuable intermediates for
amount of oxidant (4 equiv.) was necessary for high the preparation of prodrugs.[17]
yield (entry 2). MeCN proved to be the best co-sol-
vent in screening of other solvents including EtOAc, groups on the aromatic ring and ester part, methyl 4-
EtOH and methyl lactate. methylbenzoate was also examined in the presence of
In order to compare the reactivity of the methyl
Having thus found an efficient system for the 2 equiv. and 4 equiv. K2S2O8, respectively. methyl 4-
chlorination of aromatic compounds, we next investi- (chloromethyl)benzoate (2o) was obtained as major
gated its scope (Scheme 2). Upon replacement of product in 67% yield with 2 equiv. K2S2O8, and a mix-
phenyl with various other functional groups including ture of methyl 4-(chloromethyl)benzoate and chloro-
isopropyl, hydrogen on the aromatic ring, the chlori- methyl 4-(chloromethyl)benzoate was observed with
nation reactions all gave dichloro products in differ- 4 equiv. K2S2O8. This result indicated that the priority
ent reaction times (2a–d). With a 1,3-dioxole group to order for chlorination in methyl 4-methylbenzoate is
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Efficient Oxidative Chlorination of Aromatics on Saturated Sodium Chloride Solution
Scheme 2. Examination of various aromatic compounds in MeCN/saturated NaCl.
Mearomatic >Meester >Haromtic. Attempts with more elec- tained as major products regardless of an electron-do-
tron-deficient aromatic compounds including benzoni- nating functional group or electron-withdrawing
trile, 1,2,4,5-tetrafluorobenzene and nitrobenzene in group at the ortho-position of amino aromatic com-
this system were not successful and reaction afforded pounds (Scheme 3).[18] However, the meta-chloro
traces of or no chlorinated product.
product was observed in the chlorination of o/p
Further investigation proved that monochloro prod- blocked substrates with a methyl group. Chlorination
ucts could also be achieved in most cases in the pres- of the 3,5-dimethyl amino aromatic gave the dichloro
ence of potassium persulfate when saturated NH4Cl product in the presence of 4 equiv. oxidant, while
aqueous solution was used as co-solvent as well as chlorination of the 2,6-diethyl amino aromatic afford-
chlorine source instead of saturated NaCl. Mono- ed only the monochloro product at the meta position
chloro products at the para-position were usually ob- under the same conditions. Chlorinations of fluoro-
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Scheme 4. Possible pathways in chlorination.
Scheme 3. Examination of various aromatic compounds in
MeCN/NH4Cl (saturated solution.
Scheme 5. Control chlorination reactions on saturated NaCl
benzene, 1,3-difluorobenzene, bromobenzene and solution.
chlorobenzene gave the same products as those ob-
tained in MeCN/saturated NaCl solution system,
albeit with sharp decreases in reaction activity.
fluorobenzene was also studied in order to probe the
These facile and selective chlorination reactions in- reason for the high reactivity compared to the previ-
trigued us to explore more on how the chlorination ous oxone/KCl system[9] (see Table S2 in the Support-
reaction works in this biphasic system. In general, ing Information). In MeCN only, the combination of
there are two possible pathways: route A: oxidation K2S2O8 (4 equiv.)/NaCl (4 equiv.) was inert and 1,3-di-
of ClÀ by K2S2O8 (SO4À.) into more reactive chlorinat- fluorobenzene was recovered, which indicated the
ing species [“Cl+” (Cl2O) or “Cl2”] which can then critical role of water in the initiation of K2S2O8. In the
react with arenes in Àsitu.[14] Route B: oxidation of absence of NaCl, oxidation of 1,3-difluorobenzene oc-
arene by K2S2O8 (SO4 C) generates an aromatic cation curred in minutes and an insoluble yellow solid
radical, and then it reacts with ClÀ giving the chlori- formed under MeCN/deionized (DI) water (v/v=1/1)
nated aromatics (Scheme 4). Ledwith et al. demon- at 1008C. With a lower concentration of NaCl solu-
strated that the route B was more probably in MeCN/ tion (5 wt%), the oxidation pathway of aromatic com-
[10]
HCl/Na2S2O8/LiCl/CuCl2 although they did not rule pounds was remarkably prohibited and the chlorina-
out the other possibility. In order to gain more in- tion led to a mixture of various products and unreact-
sights on the mechanism in our system, a comparative ed 1,3-difluorobenzene. On increasing the concentra-
chlorination reaction of sulfonamide 1a in the pres- tion of NaCl solution to 10 wt%, a significant amount
ence of 4 equiv. NCS was performed and the reaction of over-oxidized by-product (tetrachlorobenzene, see
afforded the same dichloro product 2a in similar yield Table S2 in the Supporting Information) (11%) was
as that from the reaction with K2S2O8 [Scheme 5, Eq. observed. On further increases of the concentration
(1)]. And the observance of N-chloro salt 2r in the of NaCl solution to 15 wt% and 20 wt%, the over-oxi-
chlorination of electron-deficient arene 1r proved the dized by-product dropped dramatically, and the yields
existence of “Cl+”(Cl2O or Cl2) [Eq. (2)]. The rela- of chlorinated product 2i were increased to 95% and
tionship between the reactivity/selectivity and concen- 98%, respectively. And in MeCN/brine system
tration of NaCl solution in the chlorination of 1,3-di- (26 wt% of NaCl solution), the by-product was sup-
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Efficient Oxidative Chlorination of Aromatics on Saturated Sodium Chloride Solution
2002, 41, 4176; b) N. J. Whitcombe, K. K. (Mini) Hii,
pressed and only chlorinated product 2i was observed.
These results indicate that the chlorination might pro-
ceed via route A rather than route B in NaCl solution
although the process is not fully understood yet. How-
ever, we still could not rule out route B especially in
the chlorination of simple electron-rich arenes be-
cause of the higher reactivity observed in the chlori-
nation of 1s compared to that with iodobenzene [Eq.
(3)].
S. E. Gibson, Tetrahedron 2001, 57, 7449.
[3] A. Vigalok, A. W. Kaspi, Top. Organomet. Chem. 2010,
31, 19.
[4] G. K. S. Prakash, T. Mathew, D. Hoole, P. M. Esteves,
Q. Wang, G. Rasul, G. A. Olah, J. Am. Chem. Soc.
2004, 126, 15770.
ˇ
[5] A. PodgorSek, M. Zupan, J. Iskra, Angew. Chem. 2009,
121, 8576; Angew. Chem. Int. Ed. 2009, 48, 8424, and
references cited therein.
In summary, we have developed metal-free systems
for the chlorination of various aromatic compounds in
the absence of acids in an excellent regioselective
manner, even for deactivated ones. This method pro-
vides an efficient and practical way towards various
chlorinated aromatic compounds which are valuable
intermediates in industry due to the cheap reagents
and relatively mild conditions.
ˇ
[6] A. Podgorsek, J. Iskra, Molecules 2010, 15, 2857.
[7] Selected samples, see: a) C. U. Dinesh, R. Kumar, B.
Pandey, P. Kumar, J. Chem. Soc. Chem. Commun. 1995,
611; b) W. Adam, C. Mock-knoblauch, C. R. Saha-
Mçller, M. Herderich, J. Am. Chem. Soc. 2000, 122,
9685; c) X. Wan, Z. Ma, B. Li, K. Zhang, S. Cao, S.
Zhang, Z. Shi, J. Am. Chem. Soc. 2006, 128, 7416; d) D.
Kalyani, A. R. Dick, W. Q. Anani, M. S. Sanford, Org.
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Dong, J. Am. Chem. Soc. 2009, 131, 3466; f) F. Kakiu-
chi, T. Kochi, H. Mutsutani, N. Kobayashi, S. Urano,
M. Sato, S. Nishiyama, T. Tanabe, J. Am. Chem. Soc.
2009, 131, 11310; g) B. Song, X. Zheng, J. Mo, B. Xu,
Adv. Synth. Catal. 2010, 352, 329; h) R. B. Bedford,
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5524.
Experimental Section
General Procedure for Chlorination of Aromatic
Compounds
To
a
10-mL headspace vial were added substrate
(0.25 mmol) and MeCN (0.5 mL). Then brine (0.5 mL) and
K2S2O8 (4 equiv. or other amount) were added. After the re-
action vial had been sealed with PTFE/silicone septa, it was
placed in a heating block on a stirrer for 0.5 ~3 h at 1008C.
After the reaction had been completed, there were two
layers in the mixture. 5 mL Na2S2O3 solution (1M) (or
simply 5 mL deionized water) were added for quenching the
reaction, followed by extraction with EtOAc (5 mLꢁ3). The
combined organic layers were dried with anhydrous sodium
sulfate. Purification of crude products after concentration
with preparative TLC afforded the pure products. For halo-
benzene substrates, MeCN-d3 (0.5 mL) was used instead of
MeCN as solvent and the upper layer of the mixture was di-
rectly transferred to an NMR tube after simple filtration by
a glass dropper filled with anhydrous sodium sulfate for
measurement of the conversion yield.
[8] For selected reviews see: a) E. J. Behrman, Org. React.
1988, 35, 421; b) E. J. Behrman, Beilstein J. Org. Chem.
2006, 2, 22.
[9] Instead of potassium persulfate, Oxone (KHSO5) was
commonly used as an oxidizing reagent for the chlori-
nation of electron-rich arenes. See: a) N. Narender,
K. V. V. K. Mohan, P. Srinivasu, S. J. Kulkarni, K. V.
Raghavan, Indian J. Chem. Sect. B 2004, 43, 1335; b) N.
Narender, P. Srinivasu, S. J. Kulkarni, K. V. Raghavan,
Synth. Commun. 2002, 32, 279; c) R. Schmidt, A.
Stolle, B. Ondruschka, Green Chem. 2012, 14, 1673.
[10] a) A. Ledwith, P. J. Russell, J. Chem. Soc. Chem.
Commun. 1974, 291; b) A. Ledwith, P. J. Russell, J.
Chem. Soc. Perkin Trans. 2 1975, 1503.
[11] The regioselectivity of dichloro product 2a was con-
firmed by X-ray analysis, see the Supporting Informa-
tion. CCDC 928840 contains the supplementary crystal-
lographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
Acknowledgements
This work was supported by the Institute of Bioengineering
and Nanotechnology, Biomedical Research Council, Agency
for Science, Technology and Research, Singapore. We would
like to thank Dr. Thanh-Ha Nguyen (Bruker-AXS Ptd, Ltd,
Singapore) for X-ray analysis.
[12] In a recent study, the addition of NaCl was also found
to increase the yield of chlorinated product in aqueous
media with NCS as an oxidant. See: T. Mahajan, L.
Kumar, K. Dwivedi, D. D. Agarwal, In. Eng. Chem.
Res. 2012, 51, 3881.
[13] Some N-chloro derivatives are stable enough to be iso-
lated. See: a) R. R. Baxter, F. D. Chattaway, J. Chem.
Soc. Trans. 1915, 107, 1814; b) F. D. Chattaway, G. R.
Clemo, J. Chem. Soc. Trans. 1916, 109, 89.
[14] a) R. Ben-Daniel, S. P. Visser, S. Shaik, R. Neumann, J.
Am. Chem. Soc. 2003, 125, 12116; b) L. Yang, Z. Lu,
S. S. Stahl, Chem. Commun. 2009, 6460; c) C. G. Swain,
D. R. Crist, J. Am. Chem. Soc. 1972, 94, 3195.
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