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.
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ˇ
[5] A. PodgorSek, M. Zupan, J. Iskra, Angew. Chem. 2009,
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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.
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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-
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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