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Chlorination

The inclusion of an article in this document does not give any indication of safety or operability. Anyone wishing to use any reaction or reagent must consult and follow their internal chemical safety and hazard procedures and local laws regarding handling chemicals

† Positioning on the grid depends on The impact of any oxidant/acid used. O2 or H2O2 are preferred oxidants.

General Overview

Chlorine is widely used in pharmaceutical synthesis as a reactive handle for FGI and is often incorporated in the final product. Typically, carbon-chlorine bonds are created through electrophilic attacks on substituted bonds or via radical reactions. Cl2 is a strong electrophile whose reactivity can be enhanced with strong acids/oxidizing agents. Oxidation can be a side reaction with electrophilic chlorination reactions. Another potential side reaction can be the displacement of Br+ or I+ by Cl+ in electron-rich aromatics. The high reactivity of chlorine often results in poly chlorination.

Chlorine can be introduced via SN2 type processes using chloride anion sources, or more commonly via deoxychlorination. Radical chlorination is also a common route to allyl and benzyl chlorides. Several chlorinating reagents can act as both electrophilic and radical sources of Cl depending on reaction conditions and the presence/absence of radical initiators – light or chemical initiators.

Green Criteria for Iodination

  1. Large molar excesses of reagents should be avoided if possible.
  2. For electrophilic chlorination, the least reactive Br+ reagent should be used.
  3. Reagents with lower mass intensity should be used if possible.
  4. High impact (re)oxidants like metals and hypervalent iodine materials should be avoided.
  5. Organochlorides/poly chlorinated organics can be persistent and bioaccummulative.
  6. Evaluate and control major safety issues and minimize the generation of hazardous waste.
  7. Solvent choice should minimize any potential safety and environmental impacts.
  8. See also: Adams, J. P.; Alder, C. M.; Andrews, I.; Bullion, A. M.; Campbell-Crawford, M.; Darcy, M. G.; Hayler, J. D.; Henderson, R. K.; Oare, C. A.; Pendrak, I.; et al. Development of GSK’s reagent guides – embedding sustainability into reagent selection. Green Chem. 2013, 15, 1542-1549.

 

General literature reviews on Chlorination

Smith, K.; Butters, M.; Paget, W. E.; Goubet, D.; Fromentin, E.; Nay, B. Selective mono-chlorination of aromatic compounds. Green Chem. 1999, 1,  83-90.

Sirovski, F. S. Some Examples of Phase-Transfer Catalysis Application in Organochlorine Chemistry. Org. Process Res. Dev. 1999,  3,  437–441.

Vyas, P. V.; Bhatt, A. K.; Ramachandraiah, G.; Bedekar, A. V. Environmentally Benign Chlorination and Bromination of Aromatic Amines, Hydrocarbons and Naphthols. ChemInform. 2003, 34.

Tilstam, U.; Weinmann, H. TrichloroisocyanuricAcid: A Safe and Efficient Oxidant. Org. Process Res. Dev. 2002, 6, 384-393.

Anilkumar, G.; Nambu, H.; Kita, Y. A Simple and Efficient Iodination of Alcohols on Polymer-Supported Triphenylphosphine. Org. Process Res. Dev. 2002, 6, 190–191.

Kandepi, V. V. K. M.; Narender, N. Ecofriendly Oxidative Nuclear Halogenation of Aromatic Compounds Using Potassium and Ammonium Halides. Synthesis. 2012, 44, 15-26.

Blaser, D.; Calmes, M.; Daunis, J.; Natt, F.; Tardy-Delassus, A.; Jacquier, R. Improvement Of The Vilsmeier-Haack Reaction. Org. Prep. Proceed.Int. 1993, 25, 338 -341.