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35.3.1.5.6.2 Variation 2: Iodination with Hydriodic Acid

DOI: 10.1055/sos-SD-035-00503

Härtinger, S.Science of Synthesis, (200735636.

A wide range of alcohols can be converted into iodoalkanes by treatment with hydriodic acid under a variety of conditions. Early literature employing this synthesis method is reviewed in HoubenWeyl, Vol.5/4, pp611614. Anhydrous gaseous hydrogen iodide[‌391‌,‌392‌] and constant boiling 57% aqueous hydriodic acid with a specific gravity of 1.7 are the main reagents that have been used for the synthesis of primary,[‌389‌,‌391‌,‌393‌‌398‌] secondary,[‌391‌,‌399‌,‌400‌] tertiary,[‌401‌‌405‌] allylic,[‌406‌] and benzylic[‌407‌] iodides. Iodoalkanes with a short carbon chain are conveniently obtained as a mixture with azeotropic aqueous hydriodic acid from slow distillation over a period of 46 hours of the respective alcohol with constant boiling hydriodic acid.[‌408‌‌410‌] Allylic, benzylic, and simple tertiary alcohols may be converted by the same procedure, but their higher reactivity allows reaction already below room temperature with excess hydriodic acid.[‌406‌,‌407‌] Due to the instability in light and sensitivity toward oxygen, shortening of the reaction time by heating is recommended. Less-reactive aliphatic alcohols require prolonged heating with hydriodic acid under reflux. Early literature methods involve conducting the reaction in sealed tubes under heating. The reaction in 57% hydriodic acid can be accelerated by addition of up to equimolar amounts of a dehydrating agent, such as anhydrous magnesium sulfate, anhydrous calcium chloride, or calcium chloride dihydrate, and typically proceeds at temperatures below 40°C.[‌397‌] Fuming hydriodic acid with a specific gravity of 1.942.0,[‌393‌,‌411‌,‌412‌] optionally in the presence of red phosphorus,[‌413‌‌416‌] is used advantageously for the reaction with higher-molecular-weight alcohols and the conversion of dihydroxy and polyalcohol compounds. Occasionally, solutions of more dilute aqueous hydriodic acid[‌396‌,‌403‌] are used also in admixture with acetic anhydride,[‌417‌] acetic acid,[‌418‌] ethanol,[‌400‌] or benzene.[‌389‌,‌401‌,‌405‌,‌419‌] Anhydrous hydrogen iodide can be produced by the direct reaction of iodine vapor with hydrogen or hydrogen sulfide over a metal catalyst.[‌420‌,‌421‌] Other catalysts with surface-active hydroxy groups, such as dehydrated alumina and silica gels, have been used to generate hydrogen iodide from iodine.[‌422‌,‌423‌] The reaction between iodine, water, and carbon monoxide at a temperature of at least 75°C in the presence of a mineral acid and a rhodium- or iridium-containing catalyst also affords gaseous hydrogen iodide. Industrial processes for the synthesis of iodoalkanes involving reacting the hydriodic acid thus produced with an alcohol have been developed.[‌420‌,‌424‌] A related method of synthetic importance is the production of isotopically labeled iodoalkanes by way of an integrated process, which comprises as a key step the reduction of 11C-labeled carbon dioxide with lithium aluminum hydride and subsequent reaction with gaseous hydrogen iodide.[‌425‌‌427‌] By the use of alkylmagnesium bromide Grignard reagents, the synthesis of higher iodoalkanes is also achieved by reaction of the intermediate alkanols with hydrogen iodide.[‌428‌‌432‌] The hydroxy group in aliphatic alcohols is protonated in the reaction with hydriodic acid to give a species 88 with a latent leaving group (Scheme 32). Nucleophilic substitution of the neutral water leaving group proceeds by an SN2 mechanism in primary alcohols, whereas tertiary alcohols react in an SN1-type manner. Reactions of secondary alcohols may occur by both mechanisms and often lead to rearranged products paired with formation of alkenes due to elimination reactions. In general, isomerization of the carbon skeleton takes place if more stable carbenium ions can be formed. Primary alcohols do not rearrange even on prolonged heating with hydriodic acid unless sterically more demanding substituents are present at the β-carbon of the alcohol. 2,2-Dimethylpropan-1-ol and cycloalkylmethanol derivatives typically undergo WagnerMeerwein rearrangements[‌433‌] (see Section 35.3.1.5.3.2). Secondary alcohols, both straight-chain and branched, give rearranged iodide byproducts even at low temperatures.[‌434‌] Optically active alcohols undergo considerable racemization due to the carbenium ion mechanism.[‌377‌] With branching adjacent to the secondary hydroxy group bearing carbon atom, the corresponding tertiary iodoalkane almost invariably results. Hydriodic acid thus reacts with 3-methylbutan-2-ol to give 2-iodo-2-methylbutane as the sole reaction product.[‌435‌] Addition of catalytically active amounts of metal iodides formed with lithium,[‌404‌] calcium,[‌404‌] or zinc[‌399‌] accelerates the reaction and may suppress rearrangement of secondary alcohols. Use of hexamethylphosphoric triamide as a solvent can have the same effect.[‌436‌] Rearrangement of simple tertiary alcohols to secondary or primary iodides does not occur, but in more complex structures isomerization to alternative tertiary iodides may take place through formation of more stable carbenium ions. Addition of lithium iodide to hydriodic acid remarkably increases the yield and purity of tertiary iodoalkanes.[‌404‌] Further to the obvious incompatibility of the iodination method with acid-labile groups present in the molecule, tolerance of functional groups other than halogen and nitro groups is very low. Fission of the CO bond with iodofunctionalization may occur with certain ether (Section 35.3.1.5.4.1) and ester groups (Section 35.3.1.5.2.1).

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References


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