I2 and Electrophilic I+ reagents

Mechanism + Description

I2 and I+ equivalents are electrophilic reagents normally used to add to unsaturated C-C bonds, take part in electrophilic substitution reactions with aromatics/heteroaromatics, or react with acidic C-H bonds. The attacking species is often written as I2 or I+, but may be more complex than these simple species.

General comments

I2 is the weakest electrophile of the molecular halogens, but will react directly with electron-rich double bonds. It is often activated by strong acids, Lewis acids, and oxidants. Oxidants can boost the iodination power of the reagent and can also generate I2 / I+ in situ from HI or simple iodide salts. Oxidants can also reoxidize any I- produced and maximize the use of iodine. Electrophilic iodination in the presence of chlorine reagents/chloride can occasionally result in chlorinated materials as by-products. Common oxidants and acid activators are listed below.

Common (re)oxidants for iodination: H2O2 or urea H2O2 complex AgNO3/Ag2SO4 NaBrO3 Ammonium peroxodisulfate (NH4)2S2O8 Tetrabutylammonium peroxydisulfate (nBu4N)2S2O8 Oxone KHSO5 0.5KHSO4 0.5K2SO4 Chloramine T Selectfluor F−TEDA−BF4 NaOCl KIO3/NaIO4

Common acid activators for iodination: H2SO4 p-Tosic acid CF3SO3H MeSO3H CF3CO2H

Other electrophilic iodination reagents are N-I reagents like NIS and DIDMH (1,3-diiodo-5,5-dimethylhydantoin). N-iodosuccinimide (NIS) is an expensive reagent and is often replaced by N-chlorosuccinimide (NCS), plus an iodine source. Other common reagents are ICl and related complexes, and anionic ICl2- reagents.

Less reactive (electrophilic) substrates may need conversion to anions prior to reaction with I+ reagent. The choice of which I+ reagent to use comes down to screening for yield and required selectivity, avoiding polyiodination and unwanted oxidation side reactions.

Key references

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Castanet, A.; Colobert, F.; Broutin, P. Mild and regioselective iodination of electron-rich aromatics with N-iodosuccinimideand catalytic trifluoroaceticacid. Tetrahedron Lett. 2002, 43(29), 5047-5048.

Mohanakrishnan, A. K.; Prakash, C.; Ramesh, N. A simple iodination protocol via in situ generated ICl using NaI/FeCl3. Tetrahedron. 2006, 62(14), 3242-3247.

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D’Auria, M.; Mauriello, G. Reevaluationof BenzyltrimethylammoniumDichloroiodide, Previously Reported to be a Selective Iodinating Agent. Synthesis. 1995, No. 3, 248-250.

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Garden, S. J.; Torres, J. C.; De Souza Melo, S. C.; Lima, A. S.; Pinto, A. C.; Lima, E. L. S. Aromatic iodination in aqueous solution. A new lease of life for aqueous potassium dichloroiodate. Tetrahedron Lett. 2001, 42(11), 2089-2092.

Kosynkin, D. V.; Tour, J. M. BenzyltriethylammoniumDichloroiodate/Sodium Bicarbonate Combination as an Inexpensive, Environmentally Friendly, and Mild Iodinating Reagent for Anilines. Org. Lett. 2001, 3(7), 991-992.

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Reddy, K. S. K.; Narender, N.; Rohitha, C. N.; Kulkarni, S. J. Iodination of Aromatic Compounds Using Potassium Iodide and Hydrogen Peroxide. Synthetic Communications. 2008, 38(22), 3894-3902.

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Castanet, A.; Colobert, F.; Broutin, P. Mild and regioselective iodination of electron-rich aromatics with N-iodosuccinimide and catalytic trifluoroaceticacid. Tetrahedron Lett. 2002, 43(29), 5047-5048.

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Relevant scale up example

Org. Process Res. Dev. 2011, 15, 449-454. Experimental 100 g scale

Org. Process Res. Dev. 2007, 11, 237-240. Experimental 100 g scale

Org. Process Res. Dev. 2001, 5, 80-83. Experimental 2.2 kg scale

Org. Process Res. Dev. 2001, 5, 80-83. Experimental 50 g scale

Org. Process Res. Dev. 2012, 16, 561−566. Experimental 400 g scale

Org. Process Res. Dev. 2014, 18, 528−538. Experimental 27 kg scale

Org. Process Res. Dev. 2012, 16, 1953−1966. Experimental 68 kg scale

Org. Process Res. Dev. 2010, 14, 1248-1253. Experimental 80 g scale

Org. Process Res. Dev. 2013, 17, 940−945. Experimental 80 g scale

Org. Process Res. Dev. 2004, 8, 353-359. Experimental 50 g scale

Org. Process Res. Dev. 2013, 17, 138−144. Experimental 120 g scale

Org. Process Res. Dev. 2003, 7, 663-675. Experimental 120 kg scale

Org. Process Res. Dev. 2012, 16, 1329−1337. Experimental 7 kg scale

Org. Process Res. Dev. 2011, 15, 1149-1162. Experimental 125g scale

Green Review

1. Atom efficiency (by-products Mwt) HI and I2 with activators/(re)oxidants are the most atom-efficient and maximize the use of Iodine.
2. Safety Concerns N-I and hypervalent Iodine reagents can be explosive, and many iodination reactions run with iodide and oxidants can be highly exothermic and evolve gas (O2).
3. Toxicity and environmental/aquatic impact High concentrations of I+ reagents will be extremely toxic to aquatic organisms, but are probably too reactive to be persistent in the environment. Longer-term environmental effects will reflect organic materials associated with the reagent. Higher Mwt organic cations can be inhibitory or toxic to certain aquatic life forms, so caution needs to be exercised with aqueous wastes. Iodinated organics can be persistent and bioaccumulate. The quaternary salts mentioned are generally tetra n-butyl; given the alkyl substituent is not directly involved, it may be assumed that this could alter. Care should be taken if substitution to lower order groups - particularly the tetra-methyl (Me4N+) moiety - given high reported toxicity. The cation is a neurotoxin akin to paraquat and banned in the EU since 2007: Tetramethylammoniumhydroxide poisoning. Lin, C. C.; Yang, C. C,; Ger, J.; Deng, J.; Hung, D. Clin. Toxicol (Phila). 2010, 48(3), 213-217.
4. Cost, availability & sustainable feedstocks Most iodination reagents are available at scale with varying degrees of cost, the most economical being reagents based on HI, I2, or simple Iodide salts with oxidants/activators.
5. Sustainable implications Incineration of waste streams can 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.