Iodine

I2

[7553-56-2]  · I2  · Iodine  · (MW 253.80)

(electrophilic reagent that adds to alkenes1 and alkynes2 to give diiodides; alkenyl carboxylic acids react to give iodolactones3 and alkenyl amides lead to iodolactams;4 dehydrogenates amines5 and reacts with ketones, in the presence of base, to give a-iodo ketones;6 carboxylic acids are converted to a-iodo acid derivatives7 and carbanions react to give the substituted iodides;8 organoboranes can give alkyl iodides9 and vinylboranes lead to substituted alkenes;10 important spotting reagent for TLC analysis11)

Physical Data: mp 113.6 °C; bp 185.24 °C; d 4.930 g cm-3; vapor pressure 0.31 mmHg at 25 °C.

Solubility: the solubility of iodine, expressed in g/kg of solvent at 25 °C is: H2O, 0.34; benzene, 164.0; CCl4, 19.2; CHCl3, 49.7; ethyl acetate, 157; ethanol, 271.7; diethyl ether, 337.3; n-hexane, 13.2; toluene, 1875.12 Soluble glacial acetic acid; relatively insol dichloromethane.

Form Supplied in: the natural abundance isotope is 127I. It is a massive bluish-black solid. When sublimed it forms near opaque, doubly refractory orthorhombic crystals that have a metallic luster. Heating iodine generates a violet-colored vapor. Commercially available in >99.5% purity, with bromine and chlorine the primary contaminants. Natural abundance iodine is diatomic, I-I.

Preparative Methods: commercially available but can be prepared by the reaction of potassium iodide and copper(II) sulfate.13 It is also prepared by chlorination of natural brines or by treatment of brine with silver nitrate and then iron(II) iodide, followed by addition of chloride to liberate iodine.14

Purification: vacuum sublimation.

Handling, Storage, and Precautions: somewhat corrosive.15 It is stored in a dark bottle or jar, at ambient temperatures. Iodine vapors have a sharp characteristic odor and they are irritating to eyes, skin, and mucous membranes (lachrymatory). Prolonged exposure should be avoided. Ingestion of large quantities can cause abdominal pain, nausea, vomiting, and diarrhea. If 2-3 g of iodine are ingested, death may occur.

Introduction.

Diatomic iodine (I2) is a member of the halogen family that is widely used in organic chemistry. Iodine is less electronegative than the other halogens, and iodides are generally less stable than other halides.16 Oxides of iodine and compounds where iodine is in a positive valence state are much more stable than the other halogens. Iodine forms binary compounds with all elements except sulfur, selenium, and the noble gases, although it does not react directly with carbon, nitrogen, or oxygen.15 Its applications in organic chemistry range from detection of organic molecules in TLC, to addition reactions with unsaturated molecules, to reactions as an electrophilic agent with nucleophilic species. Iodine is used not only as an agent for incorporating an iodine atom but also as an oxidizing agent, a dehydrogenation agent, and as a radiolabel in many biologically important systems.

One of the most common uses of iodine is as a spotting agent for the detection of organic molecules in TLC.11 Many organic molecules either adsorb iodine vapors or react with iodine vapor to produce a visible spot on the TLC plate. In general, basic compounds and reducing compounds pick up iodine vapors very well, but acidic compounds and oxidizing compounds do not.11 Many natural products can be detected via TLC, including steroids,17 phenolic compounds,18 and alkaloids.19

Addition to Alkenes.

Iodine is a highly polarizable molecule that behaves as electrophilic iodine (I+) in the presence of a suitable Lewis base, such as an alkene or an alkyne. When an alkene reacts with molecular iodine, a characteristic iodonium ion is formed, and subsequent reaction with the nucleophilic gegenion (I-) leads to the vicinal diiodide. There are many examples of this type of reaction. Addition of iodine to cyclohexene to give trans-1,2-diiodocyclohexane is a simple example (eq 1).1 The reaction is believed to involve a radical intermediate, evidenced by formation of dimeric coupling products in many alkene iodination reactions. Reaction of styrene with iodine (neat), for example, gives not only 1,2-diiodo-2-phenylethane but also 1,4-diiodo-2,3-diphenylbutane as a minor product (eq 2).20

The iodine reaction can be modified by addition of other reagents, such as methanol, to produce iodo ethers. When iodine in methanol is reacted with cyclohexene, in the presence of Cerium(IV) Ammonium Nitrate (CAN), a 92% yield of 2-methoxy-1-iodocyclohexane is obtained (eq 3).21a Similar results are obtained when iodine and Copper(II) Acetate are used.21b

Iodine reacts with dienes to form a mixture of 1,2-diiodoalkenes and 1,4-diiodoalkenes. When done in the presence of Copper(I) Cyanide, the 1,4-addition product predominates and 1,3-butadiene thus reacts to give an 84% yield of 1,4-dicyano-2-butene (eq 4).22 Allenes react with iodine to give diiodides. When 2,3-pentadiene reacts with iodine in carbon tetrachloride, 2,3-diiodo-3-pentene is formed (eq 5).23 When the reaction is done in methanol, however, 3-methoxy-2-iodo-3-pentene is the product.

There are two very interesting and useful variations of the fundamental addition reactions to alkenes: iodolactonization3 (to form iodolactones) and iodolactamization (to produce iodolactams). When an alkenyl acid reacts with iodine in the presence of a base (such as sodium bicarbonate), the initially formed iodonium ion reacts with the carboxylate anion (generated in situ) to form the iodolactone (eq 6).

Lactones are also formed when iodine reacts with alkenyl amides or alkenyl carbamates. In initial studies, amides led to the formation of lactones whereas carbamates gave oxazolidinones. When N-(S)-phenethyl-2-allyl-4-pentenamide reacts with 3 equiv of iodine in aqueous THF, a 77% yield of 2-allyl-5-iodomethyl-d-butyrolactone is obtained (16% optical purity) (eq 7).24 Similarly, reaction of N-Cbz-N-methyl-2-propenamine with iodine in dichloromethane leads to a 95% yield of N-methyl-4-iodomethyl-2-oxazolidinone (eq 8).25

The more difficult lactam forming reaction (iodolactamization) can be accomplished by treatment of primary alkenyl amides with Trimethylsilyl Trifluoromethanesulfonate, followed by iodination, as in the conversion of 4-pentenamide to 5-iodomethyl-2-pyrrolidinone in 68% yield (eq 9).4 There are several other cyclization reactions that are initiated by the reaction of iodine with an alkene, in the presence of a nucleophilic atom elsewhere in the molecule.26

Addition to Alkynes.

Iodine undergoes addition reactions with alkynes as well as alkenes, although the reaction is generally more sluggish. Reaction of 1,4-dichloro-2-butyne with iodine, for example, requires 1,2-dichloroethane as a solvent and heating to 83 °C for 120 h to give (E)-1,4-dichloro-2,3-diiodo-2-butene (eq 10).27 Treatment of this alkene with 1,8-Diazabicyclo[5.4.0]undec-7-ene leads to formation of iododienes. Another example is 1-hexyne, which reacts with iodine in methanol to produce (E)-1,2-diiodo-1-hexene (eq 11).2 When Silver(I) Nitrate is added to this mixture, however, a mixture of 1,1-diiodo-2-hexanone, 1-iodo-1-hexyne, and (E)-1,2-diiodo-1-hexene is formed (31%, 46%, 23% yields).15

Cleavage of Cyclopropanes.

Iodine also reacts with cyclopropanes, leading to ring opening and formation of a diiodide.28 The cyclopropane ring in benzocyclopropanes, for example, reacts with iodine to produce the diiodide (eq 12). Cyclopropylcarbinyl systems are opened by iodine, and when a leaving group is available, such as trimethyltin, an alkenyl iodide is formed (eq 13).

Conversion of Alcohols to Iodides.

Alcohols react with iodine and red phosphorus to produce a phosphorus iodide, in situ. Phosphorus iodides have poor shelf lives (they are unstable and decompose under mild conditions) and are prepared immediately prior to use. An example is the conversion of cetyl alcohol to cetyl iodide in 85% yield (eq 14).29 This is the most common method for the conversion of aliphatic alcohols to aliphatic iodides.

Reaction with Amines.

Dehydrogenation is another important reaction of iodine, and it is particularly useful for generation of enamines. Reaction of nuciferine with iodine, in dioxane containing sodium acetate, leads to an 87% yield of the enamine dehydronuciferine (eq 15).30 Amines in general lead to enamines, as in the conversion of triethylamine to N,N-diethylvinylamine (eq 16).5 This reaction can be applied to many systems.31 For systems that do not contain an amino moiety, e.g. arenes such as ethylbenzene, a flow reactor and high temperatures (650 °C) are required for dehydrogenation. This particular example uses a molten Lithium Iodide reactor to convert ethylbenzene to the alkene product, styrene, in 96% yield (eq 17).32

Reactions with Ketones, Aldehydes, and Carboxylic Acid Derivatives.

Iodine reacts with ketones as well as with alkenes. The reaction is usually done in the presence of base and proceeds via the enolate anion. This is the fundamental process that occurs in the Lieben iodoform reaction,33 in which a methyl ketone reacts with iodine and sodium hydroxide to give iodoform (CHI3) with oxidative cleavage of the methyl group to produce a carboxylic acid. The H3C-C bond of methyl carbinols [RCH(OH)Me] is also cleaved with this reagent to give the corresponding acid and iodoform. The iodoform reaction constitutes a classical test for the presence of a methyl ketone moiety or a methyl carbinol moiety in an unknown molecule.

Oxidative cleavage is not always the case in this reaction, especially when sodium methoxide is substituted for sodium hydroxide. Steroidal ketones react with iodine and sodium methoxide to give a 58% yield of the a-iodo ketone, when air is excluded from the reaction (eq 18).6 When oxygen is introduced, an 85% yield of the a,a-diiodo ketone is produced.6 Reaction of aryl ketones can lead to a different result. 1,2-Diphenyl-1-ethanone reacts with iodine and sodium methoxide at low concentrations to give a 99% yield of 1,2-diphenyl-2-hydroxy-2-ethanone (eq 19).34 When the concentration of the ketone substrate is increased, the yield of the hydroxy ketone is diminished and a dimer is formed, 1,2,3,4-tetraphenyl-1,4-butanedione (47% yield at 0.2 M).34

The iodoform reaction clearly shows that iodine behaves as an electrophile in the presence of enolate anions, particularly enolate anions of carboxylic acid derivatives. When 6-heptenoic acid is treated with 2 equiv of Lithium Diisopropylamide, and then quenched with iodine, a 70% yield of 2-iodo-6-heptenoic acid is obtained (eq 20).7 In this particular reaction, 12% of the dicarboxylic acid 2,3-di-4-pentenyl-1,4-butanedioic acid is also obtained, leading to the belief that radical anions are produced in this reaction.7 Such coupling reactions are also observed with esters which form succinic acid ester derivatives, as in the reaction of ethyl 2-methylpropanoate with 2 equiv of LDA and subsequent reaction with iodine to give an 85% yield of diethyl 2,2,3,3-tetramethyl-1,4-butanedioate (eq 21).35

Carboxylic acid derivatives can react with iodine without an intermediary enolate anion to produce a-iodocarboxylic acids. a-Iodocarboxylic acid chlorides can also be produced, as when hexanoic acid reacts with iodine and Thionyl Chloride, at 85 °C, to give an 80% yield of 2-iodohexanoyl chloride (eq 22).36 Similarly, butanoic acid reacts with Chlorosulfonic Acid and iodine to give a 94% yield of 2-iodobutanoic acid (eq 23).37 These examples are nothing more than the iodine analog of the Hell-Volhard-Zelinsky reaction.38 The silver salt of pentanoic acid reacts with iodine to produce 1-iodobutane in 67% yield, where decarboxylation occurs under the reaction conditions (eq 24).39 In general, alkyl iodides are formed from silver carboxylates. This is the iodine version of the Hunsdiecker reaction.40 Similar reaction occurs when mercury(II) oxide is added, although the yield is lower.

Iodination of Aromatic and Heteroaromatic Compounds.

Just as enolate anions react with the electrophilic iodine, so also other carbanions react. Iodoimidazoles can be formed, as when N-tritylimidazole reacts with n-Butyllithium and then with iodine, to give a 41% yield of 2-iodo-N-tritylimidazole (eq 25).8

Iodoindoles can also be produced by this approach. Reaction of indole with n-butyllithium and quenching with iodine first produces an N-iodoindole, but this is unstable and rearranges under the reaction conditions to 3-iodoindole, in near quantitative yield (eq 26).41 When this iodo derivative is converted to the N-phenylsulfonyl derivative, reaction with LDA and then iodine gives a 98% yield of 2,3-diiodo-N-phenylsulfonylindole.41

Iodopyridine derivatives can also be generated with this technique. 3-Fluoropyridine reacts with LDA and iodine to give a 50% yield of 4-iodo-3-fluoropyridine (eq 27),42 and 2-chloropyridine reacts with n-butyllithium and then iodine to give a 60% yield of 2-chloro-3-iodopyridine (eq 28).43

Iodofuran derivatives can be formed, as in the reaction of 2-(dimethyl-t-butylsilyl)furan-3-carboxylic acid with n-butyllithium and iodine, to give a 71% yield of the 4-iodofuran-3-carboxylic acid (eq 29).44

Simple aromatic derivatives can be iodinated to generate iodo-substituted aromatic compounds, if activating substituents are present on the aromatic ring. 1,3-Dicyanobenzene, for example, reacts with LDA and iodine to give a 79% yield of 2-iodo-1,3-dicyanobenzene (eq 30).45 In general, unactivated aromatics are less useful since formation of the requisite carbanion is somewhat more difficult.

Conversion of Organoboranes to Iodides.

Another important area of chemistry where iodine reactions are important involves organoboranes. When an alkene is reacted with a borane to produce a trialkylborane, subsequent reaction with iodine and sodium hydroxide leads to an iodoalkane. 1-Decene reacts with tri-n-butylborane and then basic iodine to give a 65% yield of 1-iododecane (eq 31).9

Substituted alkenes can also be prepared from vinylboranes by reaction with iodine and sodium hydroxide. Reaction of dicyclohexylborane with 1-hexyne gives the vinylborane, and subsequent reaction with basic iodine, in THF, gives a 93:7 cis:trans mixture of 1-cyclohexyl-1-hexene in 85% yield (eq 32).10 When the reaction is done in dichloromethane, a 77:23 cis:trans mixture is produced, but in only 13% yield.10a The poor yield is probably due to the poor solubility of iodine in dichloromethane.

Miscellaneous Reactions.

There are several specialized reactions of iodine that are useful in certain applications. Iodine induces coupling of sodium cyclopentadienide to form 9,10-dihydrofulvalene.46 Iodine has also been used to cleave iron-carbon bonds in organoiron species.47 Iodine reacts with hydrazone derivatives to give vinyl iodides.48

Reaction with Organic Halides.

An important reaction of iodine is exchange with an alkyl iodide. The most common method for exchanging an iodide is the Finkelstein reaction,49 which involves treatment of alkyl halides with Sodium Iodide to produce alkyl iodides via an SN2 reaction. Reaction of 1-bromobutane and sodium iodide in dry acetone, for example, gives 1-iodobutane. This exchange also occurs with alkyl iodides. The metal iodides used in this reaction are commercially available, but can be prepared from iodine.

Iodine itself is capable of exchanging the halide atom in alkyl halides, including alkyl iodides, to produce alkyl iodides. The reaction temperatures required are usually greater than 150 °C.50 Aryl iodides undergo this exchange reaction at even higher temperatures (150-190 °C).51 a-Iodo ketones also react with iodine, but this occurs at ambient temperatures.52 The product of these reactions is, of course, another iodide but this is very important in radiolabeling using radioactive iodine isotopes. All of the reactions of iodine involve the use of the natural abundance stable isotope of iodine, 127I. Radiolabeled molecules can be incorporated in a wide range of biological and mechanistic studies. There are at least 10 available isotopes of iodine, but only three are commonly used for labeling: 123I, 125I, and 131I. If these isotopic iodines are used in the preceding reactions, radiolabeled iodides are produced. In the case of the Finkelstein reaction, sodium iodide or Potassium Iodide can be produced by synthesizing those salts with radiolabeled iodine. A variety of organic molecules have been radiolabeled for use in biological studies. These include fatty acids,53 aniline derivatives,54 quinolines,55 nucleic acids,56 steroids,57 alkyl iodides,58 aryl iodides,59 carboxylic acids,60 and carbohydrates.61

Related Reagents.

Dimethyl Sulfoxide-Iodine; Iodine-Aluminum(III) Chloride-Copper(II) Chloride; Iodine-Cerium(IV) Ammonium Nitrate; Iodine-Copper(II) Acetate; Iodine-Copper(I) Chloride-Copper(II) Chloride; Iodine-Copper(II) Chloride; Iodine-Nitrogen Tetroxide; Iodine-Potassium Iodate; Iodine-Silver Acetate; Iodine-Silver Benzoate; Iodine-Silver(I) Fluoride; Iodine-Silver Trifluoroacetate; Lead(IV) Acetate-Iodine; Mercury(II) Oxide-Iodine; Thallium(I) Acetate-Iodine; Triphenylphosphine-Iodine.


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Michael B. Smith

University of Connecticut, Storrs, CT, USA



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