Sodium Iodide1

NaI

[7681-82-5]  · INa  · Sodium Iodide  · (MW 149.89)

(source of iodide ion for nucleophilic displacement reactions in the preparation of alkyl iodides4-10 and aryl iodides11-13 from halides and sulfonates; in combination with Zn, reduces sulfonates;14,15 converts vic-dihalides and vic-disulfonates to alkenes;16-20 dehalogenates a-halo ketones21-23 and a-bromo enones;27 converts acyl chlorides to acyl iodides;24 cleaves aryl methyl25,26 and some dialkyl ethers;27-32 deoxygenates epoxides;31 in combination with TMSCl/MeCN, generates TMSI in situ;33-35 catalyzes phosphorylations;36 reduces ene dicarbonyl compounds;37 converts acetylenic ketones to vinyl iodides;38 in combination with TMSCl/MeCN/0.5 H2O, generates anhydrous HI;40 with various co-reagents, reduces sulfoxides41-43 and N-oxides;43a,44,45 with oxidizing agents, iodinates organoboranes,46 phenols,47,48 and aromatic compounds49)

Physical Data: mp 661 °C; bp 1304 °C; d 3.667 g cm-3.

Solubility: very sol cold H2O (184 g/100 mL, 25 °C), hot H2O (302 g/100 mL, 100 °C), alcohol (42.57 g/100 mL, 25 °C), acetone (39.9 g/100 mL, 25 °C); sol glycerin.2 Also sol acetic acid, acetonitrile, DMF, DMSO, formic acid, HMPA, methyl ethyl ketone.

Form Supplied in: white solid (crystalline, granular, or powder); widely available. Drying: can be dried under vacuum at 70 °C.3

Handling, Storage, and Precautions: deliquescent in moist air (gradually absorbs up to ca. 5% (0.5 mol) H2O in air), and upon long exposure to air will turn brown due to liberation of iodine; storage in a dry or inert atmosphere is recommended.

Introduction.

Sodium iodide and potassium iodide are used in organic synthesis as sources of iodide. NaI is more commonly used due to greater solubility in organic solvents and slightly lower cost. Tetraalkylammonium iodides have also been used as organic-soluble sources of iodide. See also Potassium Iodide and Tetra-n-butylammonium Iodide.

Displacement Reactions.

NaI reacts with alkyl chlorides, bromides, and sulfonates (e.g. mesylates and tosylates4) to provide the corresponding alkyl iodides.5 The conversion of alkyl halides to iodides using NaI in acetone is known as the Finkelstein reaction.6 Though usually an SN2 displacement, radicals have been implicated in some cases.6b Displacement reactions using NaI are numerous in the literature, and representative examples (eqs 1 and 2)7,8 are shown below. In some cases the iodo compound is not isolated but reacts with another nucleophile present (eq 3).9 NaI has been used catalytically in such reactions.10

NaI reacts with electron-deficient aryl halides in a formal SNAr reaction (e.g. with 2,4-dinitrochlorobenzene)11 to give aryl iodides; however, with aryl diazonium compounds the reaction proceeds via electron transfer and involves an aryl radical.12 The latter process has been applied to the Pschorr phenanthrene synthesis13 (eq 4).13b

Reductive Cleavage of Sulfonates.

NaI/Zinc has been used to reduce alkyl tosylates and mesylates to the corresponding alkanes (eq 5).14 This procedure complements Lithium Aluminum Hydride reductions of sulfonates since, in some cases, LiAlH4 produces both the alkane and the alcohol. However, with secondary mesylates and tosylates a large amount of the alkene elimination product is often obtained using NaI/Zn. NaI/Zn/D2O (or T2O) in dimethoxyethane has been used to replace primary and secondary hydroxyl groups with deuterium (or tritium).15

Conversion of vic-Halides and vic-Sulfonates to Alkenes.

NaI reacts with vic-dibromides, vic-bromochlorides, and vic-dichlorides to give the corresponding alkenes.16 This reaction can be utilized for alkene cis/trans isomerization (eq 6).17 vic-Bromochlorides and vic-dichlorides give predominantly cis-products while dibromides give predominantly trans-alkenes. vic-Dimesylates17 and vic-ditosylates18,19 also give alkenes when treated with sodium iodide, via initial displacement of one sulfonate group followed by attack of iodide on the iodine of the vic-iodosulfonate. This reaction has been carried out under phase-transfer conditions.20

Dehalogenation of a-Halo Ketones.

NaI will reductively dehalogenate some a-halo ketones in acidic aqueous THF or dioxane (eq 7)21 or in AcOH.22 This reaction may not be general for all a-halo ketones.21 NaI/Sulfur Trioxide-Pyridine in acetonitrile has also been used to carry out this transformation.23

Preparation of Acyl Iodides.

NaI reacts with acyl chlorides in anhydrous acetonitrile to give acyl iodides in high yield.24 Diacyl diiodides24b and iodoformates24c have also been prepared in this fashion.

Demethylation of Aryl Methyl Ethers.

NaI reacts with aryl methyl ethers in acetic or formic acid to give the corresponding phenolic derivatives and methyl iodide.25 In one study, KI was found to give slightly higher yields (eq 8).26 See also NaI/Me3SiCl/MeCN below.

Other Ether Cleavage Reactions.

NaI/Boron Trifluoride Etherate cleaves some alkyl ethers27 and acetals,27b and converts keto epoxides to enones.27c Some primary and secondary alkyl methyl ethers are cleaved by NaI/Boron Tribromide/15-Crown-5 in CH2Cl2.28 Cyclic (e.g. THF and THP) and acyclic dialkyl ethers are cleaved at the less substituted carbon by NaI in the presence of acyl chlorides.29 For example, 2-methyltetrahydrofuran gives the pivalate derivative of 5-iodo-2-pentanol when treated with NaI/t-BuCOCl in acetonitrile. Similarly, 2-iodoethyl esters are produced from acyl chlorides, Ethylene Oxide, and NaI (eq 9).30 NaI/Trifluoroacetic Anhydride has been used to deoxygenate epoxides with retention of configuration: trifluoroacetyl iodide is generated in situ and reacts with the epoxide in the presence of NaI to give a vic-iodo trifluoroacetate, which decomposes in the presence of excess NaI to give the alkene.31 NaI/NaOAc has been reported to reduce a,b-epoxy ketoses to b-hydroxy ketoses, presumably via the a-iodo-b-hydroxy ketone (eq 10).32

In Situ Generation of Trimethylsilyl Iodide.

NaI/Chlorotrimethylsilane/MeCN has been widely used as a convenient substitute for Iodotrimethylsilane.33-35 For example, this reagent removes benzylic hydroxyl groups,34 cleaves methoxyethoxymethyl (MEM),35 aryl methyl, and aryl ethyl ethers, deoxygenates sulfoxides (and N-oxides in the presence of zinc), converts some alcohols to iodides, and dehalogenates a-halo ketones.33a

Catalysis of Phosphorylation.

NaI catalyzes the phosphorylation of nucleosides by chlorophosphates, pyrophosphates, and triazolides.36 The rate of phosphorylation is greatly enhanced by addition of 1 or 2 equiv of NaI. For example, 3-O-benzoylthymidine is phosphorylated over 10 times faster with Diethyl Phosphorochloridate when 1 equiv of NaI is added, and over 300 times faster when 2 equiv of NaI are added.

1,4-Addition to a,b-Unsaturated Carbonyl Compounds.

NaI has been used to reduce the carbon-carbon double bond of 2-ene-1,4-dicarbonyl compounds, presumably via conjugate addition of iodide followed by reduction of the newly formed a-iodo carbonyl compound (eq 11).37 The reaction is specific to 1,4-diketones or keto aldehydes, and fails with 1,4-diacids, 1,4-diesters, and a,b-unsaturated monocarbonyl compounds. However, NaI apparently does add to enones under some conditions since NaI/BF3.OEt2 dehalogenates a-bromo enones (via the vic-bromoiodide).27c Furthermore, NaI in TFA reacts with a,b-acetylenic ketones to give (E)-b-iodovinyl ketones, while NaI in AcOH gives predominantly the (Z)-isomer (eq 12).38 The reaction tolerates both terminal and substituted alkynes.

Conversion of Allylic, Benzylic, and Tertiary Alcohols to Iodides.

NaI/BF3.OEt2 in acetonitrile converts allylic, benzylic, and tertiary alcohols to iodides in good yield.39,40 NaI/Me3SiCl/MeCN/0.5 H2O (anhydrous HI) has been used to convert allylic alcohols to allylic iodides, with allylic rearrangement if the alcohol is secondary or tertiary.40

Reduction of Sulfoxides.

NaI/(CF3CO)2O in acetone,41 NaI/BF3.OEt2 in acetonitrile,42 NaI/I2/Hexamethylphosphorous Triamide in acetonitrile,43a NaI/Oxalyl Chloride in acetonitrile,43b NaI/Me3SiCl in acetonitrile,43c NaI/I2/Me2NEt.SO3 in acetonitrile,43d and NaI/pyridine.SO3 in acetonitrile43d all reduce sulfoxides to sulfides in high yield.

Reduction of N-Oxides and Nitrones.

NaI/(CF3CO)2O in acetonitrile deoxygenates various heteroaromatic N-oxides and nitrones in very high yield.44 NaI/pyridine.SO3 deoxygenates di-N-oxides of quinoxalines and phenazines.45 NaI/I2/(Me2N)3P in acetonitrile deoxygenates azoxides.43a

Iodinations of Phenols and Organoboranes.

NaI/Chloramine-T has been used as an in situ source of Iodine Monochloride for iodinations of organoboranes46 and phenols.47 For example, methyl 5-iodosalicylate is prepared from methyl salicylate in 78% yield.47 Iodinated carbohydrates have been prepared via iodination of organoboranes (eq 13).46b Recently, NaI/Sodium Hypochlorite in methanol has been used to iodinate phenols in high yield with good regioselectivity.48 The yield and regioselectivity with phenol (80% para, 10% ortho, 4% ortho,para) are different than those obtained with ICl or NaI/Chloramine-T. Simple aromatic hydrocarbons are iodinated with NaI/O2/cat. Nitrosonium Tetrafluoroborate in CH2Cl2/TFA.49 This iodination fails with electron-deficient aromatics.

Related Reagents.

Sodium Iodide-Copper; Trifluoroacetic Anhydride-Sodium Iodide.


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James J. Kowalczyk

Eisai Research Institute of Boston, Andover, MA, USA



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