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Iodination

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

Iodine is widely used in pharmaceutical synthesis as a reactive handle for Functional Group Interconversion (FGI). It is rarely carried through to the final product, although examples of iodine-containing APIs are slowly increasing. I can be used as a radioactive label.

Typically, carbon-iodine bonds are created through electrophilic attacks on substituted bonds. I2 is the weakest electrophile of all the molecular halogens, so is often activated, otherwise more reactive sources of I+  have to be generated. Electrophilic iodination is reversible under strongly acidic conditions. Oxidation can be a side reaction with electrophilic iodination reactions. Iodine can be introduced via SN2 type processes using the iodide anion. HI is a strong reducing agent, so care should be taken when using this reagent in the presence of  reducible functionality.

Green Criteria for Iodination

  1. Large molar excesses of reagents should be avoided if possible.
  2. For electrophilic iodination, the least reactive I+ reagent should be used.
  3. Reagents with lower mass intensity should be used if possible.
  4. Catalysis with Ag and Hg metals should be avoided if possible.
  5. The use of high impact (re)oxidants like Ag salts, Selectfluor, etc. should be avoided.
  6. Hypervalent iodine reagents (can be generated in situ) can be explosive.
  7. Organoiodides/poly iodinated organics can be persistant and bioaccummulative.
  8. Waste steams containing organoiodides/HI can be difficult to treat.
  9. Process has no major safety issues and the generation of hazardous waste is minimized and controlled
  10. Solvents should be chosen to minimize any potential safety and  environmental impact.
  11. 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. Development of GSK’s reagent guides – embedding sustainability into reagent selection. Green Chem. 2013, 15(6), 1542-1549.

General literature reviews on Iodination

Stavber, S.; Jereb, M.; Zupan, M. Electrophilic Iodination of Organic Compounds Using Elemental Iodine or Iodides. Synthesis. 2008, 10, 1487-1513.

Hanson, J. R. Advances in the Direct Iodination of Aromatic Compounds. Journal of chemical research. 2006, 277–280.

Merkushev, E. B. Advances in the Synthesis of IodoaromaticCompounds. Synthesis. 1988,12, 923-937.

Finkelstein Reaction. Comprehensive Organic Name Reactions and Reagents. 2010, 231, 1060-1063.

Pavlinac, J.; Zupan, M.; Laali, K. K.;Stavber, S. Halogenation of organic compounds in ionic liquids. Tetrahedron. 2009, 65,(29-30), 5625-5662.