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Nuclophilic I– Reagents

Mechanism + Description

Addition of I- through reaction with an electrophile with appropriate leaving group (SN2) or activated by protonation. Alcohols can be activated in situ (e.g., Ph3PI2)

General comments

Iodine can be introduced by the reaction of iodide with appropriate nucleopiles like alkyl halides or sulphonates. With Cl- and Br- leaving groups, the reaction often has to be driven in the direction of the iodide by using the preferential solubility of NaI in ketones, acetone, (Finkelstein reaction) since I- is the best leaving group.

I- can also be inserted via metal-catalyzed halogen exchange or the classical decomposition of aryl diazonium salts (Sandmeyer reaction) in the presence of Cuprous iodide and HI.

Key references

Klein, S. M.; Zhang, C.; Jiang, Y. L. Simple synthesis of fresh alkyl iodides using alcohols and hydriodicacid. Tetrahedron Lett. 2008, 49(16), 2638–2641.

Klapars, A.; Buchwald, S. L. Copper-CatalyzedHalogen Exchange in Aryl Halides: An Aromatic Finkelstein Reaction. J. Am. Chem. Soc. 2002, 124(50), 14844-14845.

“For Example of Finkelstein reaction with alkyl chloride”:  Baughman, T. W.; Sworen, J. C.; Wagener, K. B. The facile preparation of alkenyl metathesis synthons. Tetrahedron. 2004, 60(48), 10943-10948.

Liu, Y.; Xu, Y.; Jung, S. H.; Chae, J. A Facile and Green Protocol for Nucleophilic Substitution Reactions of Sulfonate Esters by Recyclable Ionic Liquids [bmim][X]. Synlett. 2012, 23(18), 2663-2666.

Masada, H.; Murotani, Y. A Convenient Method for the Preparation of Highly Pure t-Alkyl Bromides and Iodides. Bull. Chem. Soc. Jpn. 1980, 53(4), 1181-1182.

Maloney, K. M.; Nwakpuda, E.; Kuethe, J. T.; Yin, J. One-Pot Iodination of Hydroxypyridines. J. Org. Chem. 2009, 74(14), 5111–5114.

Kim, D. W.; Song, C. E.; Chi, D. Y. Significantly Enhanced Reactivities of the Nucleophilic Substitution Reactions in Ionic Liquid. J. Org. Chem. 2003, 68(11), 4281-4285.

Ellwood, A. R.; Porter, M. J. Selective Conversion of Alcohols into Alkyl Iodides Using a Thioiminium Salt. J. Org. Chem. 2009, 74(20), 7982-7985.

Skaanderup, P. R.; Poulsen, C. S.; Hyldtoft, L.; Jørgensen, M. R.; Madsen, R. RegioselectiveConversion of Primary Alcohols into Iodides in Unprotected Methyl Furanosidesand Pyranosides. Synthesis. 2002, 12, 1721-1727.

Filimonov, V. D.; Semenischeva, N. I.; Krasnokutskaya, E. A.; Tretyakov, A. N.; Hwang, H. Y.; Chi, K. Sulfonic Acid Based Cation-Exchange Resin: A Novel Proton Source for One-Pot Diazotization-Iodination of Aromatic Amines in Water. Synthesis. 2008, 2, 185-187.

Krasnokutskaya, E. A.; Semenischeva, N. I.; Filimonov, V. D.; Knochel, P. A New, One-Step, Effective Protocol for the Iodination of Aromatic and Heterocyclic Compounds via Aprotic Diazotization of Amines. Synthesis. 2007, 1, 81-84.

Tajbakhsh, M.; Hosseinzadeh, R.; Lasemi, Z. Selective Iodination of Alcohols with NaI/Amberlyst 15 in Acetonitrile. Synlett. 2004, 4, 635-638. 

Sarmah, P.; Barua, N. C. Regioselectivetransformation of allylic, benzylic and tertiary alcohols into the corresponding iodides wrih aluminium triiodide: deoxygenation of vicinal diols. Tetrahedron. 1989, 45(11), 3569-3574.

Bandgar, B. P.; Sadavarte, V. S.; Uppalla, L.S. An expedient and highly selective iodination of alcohols using a KI/BF3·Et2O system. Tetrahedron Lett. 2001, 42(5), 951–953.

 

Relevant scale up example

Org. Synth. 2005, 81, 121.
Experimental
20 g scale

Org. Synth. 2005, 81, 77.
Experimental
27 g scale

Org. Process Res. Dev. 2014, 18, 1728−1739.
Experimental
90 g scale

Green Review

  1. Atom efficiency (by-products Mwt)
    Optimal with simple leaving groups (Cl, Br, Mes) and salts like Na or KI. The use of Ph3P and related P reagents is very atom inefficient.
  2. Safety Concerns
    No general concerns; the unstable/explosive properties of aryl diazonium salts need consideration in use.
  3. Toxicity and environmental/aquatic impact
    High concentrations of I- reagents are toxic to aquatic organisms, especially freshwater organisms. Longer-term environmental effects will reflect organic materials associated with the reagent. Higher mol wt organic cations (quats, ionic liquids, etc.) can be inhibitory or toxic to certain aquatic life forms, so caution needs to be exercised with aqueous wastes. Ph3P and Ph3PO are of particular environmental concern and should not be discharged into aqueous waste streams.

    Iodinated organics can be persistent and bioaccumulate.

    Many examples use hazardous chlorinated solvents: Historically, these have been used, but greener alternatives aligned to solvent selection guides are encouraged.
  4. Cost, availability & sustainable feedstocks
    Most iodide reagents are available at scale with varying degrees of cost – the most economical being reagents based on HI and simple iodide salts. Na and K salts are preferred reagents.
  5. Sustainable implications
    Incineration of waste streams could be problematic (iodine content). Limited utility for waste by-products. Iodine is an element at medium-to-high risk of depletion. High LCA reagents, although it is possible to recover iodide from inorganic and organic waste streams.