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.
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
Ammonium peroxodisulfate (NH4)2S2O8
Tetrabutylammonium peroxydisulfate (nBu4N)2S2O8
Oxone KHSO5 0.5KHSO4 0.5K2SO4
Common acid activators for iodination:
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.
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Relevant scale up example
Org. Process Res. Dev. 2011, 15, 449–454.
100 g scale
Org. Process Res. Dev. 2007, 11, 237-240.
100 g scale
Org. Process Res. Dev. 2001, 5, 80-83.
2.2 kg scale
Org. Process Res. Dev. 2001, 5, 80-83.
50 g scale
Org. Process Res. Dev. 2012, 16, 561−566.
400 g scale
Org. Process Res. Dev. 2014, 18, 528−538.
27 kg scale
Org. Process Res. Dev. 2012, 16, 1953−1966.
68 kg scale
Org. Process Res. Dev. 2010, 14, 1248–1253.
80 g scale
Org. Process Res. Dev. 2013, 17, 940−945.
80 g scale
Org. Process Res. Dev. 2004, 8, 353-359.
50 g scale
Org. Process Res. Dev. 2013, 17, 138−144.
120 g scale
Org. Process Res. Dev. 2003, 7, 663-675.
120 kg scale
Org. Process Res. Dev. 2012, 16, 1329−1337.
7 kg scale
Org. Process Res. Dev. 2011, 15, 1149–1162.
Atom efficiency (by-products Mwt)
HI and I2 with activators/(re)oxidants are the most atom-efficient and maximize the use of Iodine.
- 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).
- 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.
- 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.
- 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.