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.