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Specific Solvent Issues with Chlorination

Many radical and electrophilc chlorinations have traditionally been carried out in chlorinated solvents CCl4, CHCl3, C2H4Cl2 and CH2Cl2. If a chlorinated solvent is absolutely needed, CH2Cl2 should be used.

Radical chlorinations with Cl2 or NCS/DCDMH were traditionally carried out in CCl4, C6H6 and CHCl3. A range of alternative solvents for radial reactions has been reported. Some alternatives to the above solvents are listed below for radical bromination and may be suitable for radical chlorination.

Chlorobenzene, benzotrifluoride, n-hexane – less favored
Cyclohexane, heptane, Dimethyl carbonate, acetonitrile, methyl acetate, isopropyl acetate – favored

Cl2 , Cl+ reagents and higher oxidation state chlorine compounds are oxidizing reagents and can react violently with some organic solvents and  reagents. The use of DMSO in the presence of Cl2 / Cl+  reagents should be approached with caution. A number of incidents with brominating reagents and solvents have been reported – it is possible that analogous chlorine reagents may show similar behavior.

An explosion has been reported by an unexpected reaction of acetone with POCl3.

Brenek, S. J.; Am Ende, D. J.; Clifford, P. J. Phosphorus Oxychloride and Acetone: An Incompatibility Investigation Using ARC. Org. Process Res. Dev. 2000, 4(6), 585−586.

The decomposition of MTBE in the presence of SOCl2/HCl has been described.

Grimm, J. S.; Maryanoff, C. A.; Patel, M.; Palmer, D. C.; Sorgi, K. L.; Stefanik, S.; Webster, R. R. H.; Zhang, X. Reaction Safety: A Critical Parameter in the Development of a Scaleable Synthesis of 2,3-Bis-chloromethylpyridine Hydrochloride. Org. Process Res. Dev. 2002, 6(6), 938−942.

“For Reaction of NBS with THF”: Mauragis, M. A.; Veley, M. F.; Lipton, M. F. Evaluation and Rapid Scale-Up of the Synthesis of the Pyrrolopyrimidines U-101033E and U-104067F. Org. Process Res. Dev. 1997, 1(1), 39-44.

Unexpected reaction between NBS and NMP

Reaction between Br2 and TBME

DMSO Technical information package

Ionic liquid nitrate salts have been proposed as good reaction media/promoters for chlorination reactions.

Chiappe, C.; Leandri, E.; Tebano, M. [Hmim][NO3]—An Efficient Solvent and Promoter in the Oxidative Aromatic Chlorination. Green Chem. 2006, 8, 742-745.

Ionic liquids containing nitrate anion can be explosive, so caution needs to be exercised when using these materials.