Bromination

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General Overview

Bromine is widely used in pharmaceutical synthesis as a reactive handle for FGI, and is occasionally carried through to the final product. Typically carbon-bromine bonds are created through electrophilic attack on substituted bonds. Br2 is a moderately strong electrophile whose reactivity can be enhanced with strong acids/oxidising agents. Oxidation can be a side reaction with electrophilic bromination reactions. Bromine can be introduced via an SN2 type processes using bromide anion sources, or more commonly via deoxybromination. Radical bromination is also a common route to allyl and benzyl bromides. Several brominating reagents can act as both an electrophilic and radical sources of “Br” depending on the reaction conditions and the presence/absence of radical initiators (either light or chemical based radical initiators).

 

Green Criteria for Bromination

  1. Large molar excesses of reagents should be avoided.
  2. For electrophilic bromination, the least reactive Br+ source should be used.
  3. Reagents with lower mass intensity should be used.
  4. High impact (re)oxidants like metals, hypervalent iodine materials should be avoided.
  5. Note that organobromides and polybrominated organics can be persistent and bio-accummulative.
  6. Process has no major safety issues, and the generation of hazardous waste is minimised and controlled.
  7. Solvents should be chosen to minimise any potential safety and environmental impact.

See also : Green Chem., 2013, 15, 1542-1549 - Development of GSK's reagent guides – embedding sustainability into reagent selection

 

General literature reviews on Bromination

Eissen and  Lenoir published a comprehensive review Chem. Eur. J. 2008, 14, 9830–9841 - Electrophilic Bromination of Alkenes: Environmental Health and Safety on reagents used to brominate alkenes.The key focus of many new methods sought to avoid hazards of handling molecular Br2. They found that many methods resulted in considerably higher environmental impact than using Br2, HBr or Bromide salts with simple oxidants.

Angew. Chem.  Int.  Ed., 200948,  8424-8450 - Oxidative Halogenation with “Green” Oxidants: Oxygen and Hydrogen Peroxide

Tetrahedron Lett., 2003, 44, 4085–4088 - Environmentally benign chlorination and bromination of aromatic amines, hydrocarbons and naphthols

Russian Chemical Rev., 2011, 80, 421-428 - Bromination of Deactivated Aromatic Compounds

Topics in Heterocyclic Chemistry, 2012, 27 (Halogenated Heterocycles), 269-308 - Green methods in halogenation of heterocycles.

Current Organic Synthesis, 201310 (6), 837-863 - Alternative Methodologies for Halogenation of Organic Compounds

Molecules, 2014, 19, 3401-3416 - Regioselective Electrophilic Aromatic Bromination: Theoretical Analysis and Experimental Verification

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