IODINE

1

Iodine

I

2

[7553-56-2]

I

2

(MW 253.80)

InChI = 1/I2/c1-2
InChIKey = PNDPGZBMCMUPRI-UHFFFAOYAF

(electrophilic reagent that adds to alkenes

1

and alkynes

2

to give

diiodides; alkenyl carboxylic acids react to give iodolactones

3

and alkenyl amides lead to iodolactams;

4

dehydrogenates amines

5

and reacts with ketones, in the presence of base, to give
α

-iodo ketones;

6

carboxylic acids are converted to α-iodo acid

derivatives

7

and carbanions react to give the substituted iodides;

8

organoboranes can give alkyl iodides

9

and vinylboranes lead

to substituted alkenes;

10

important spotting reagent for TLC

analysis

11

)

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: H

2

O, 0.34; benzene, 164.0; CCl

4

, 19.2; CHCl

3

,

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

127

I. 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 va-
por. 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 pre-

pared 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

Purity:

vacuum sublimation.

Handling, Storage, and Precaution:

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.

Original Commentary

Michael B. Smith
University of Connecticut, Storrs, CT, USA

Introduction. Diatomic iodine (I

2

) is a member of the halo-

gen 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 suit-

able 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 for-
mation 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

I

2

I

I

(1)

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 pres-
ence of Cerium(IV) Ammonium Nitrate (CAN), a 92% yield of
2-methoxy-1-iodocyclohexane is obtained (eq 3).

21a

Similar re-

sults are obtained when iodine and Copper(II) Acetate are
used.

21b

Ph

I

I

Ph

I

I

Ph

Ph

(2)

I

2

+

neat

(3)

OMe

I

I

2

, CAN, MeOH

50 °C, 6 h

92%

Iodine reacts with dienes to form a mixture of 1,2-diiodoalkenes

and 1,4-diiodoalkenes. When done in the presence of Cop-
per(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,

Avoid Skin Contact with All Reagents

2

IODINE

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.

CN

CN

I

2

, CuCN, 85 °C

(4)

Parr reactor, heptane

84%

I

MeO

I

I

(5)

I

2

, MeOH

•

I

2

, CCl

4

There are two very interesting and useful variations of the

fundamental addition reactions to alkenes: iodolactonization

3

(to

form iodolactones) and iodolactamization (to produce iodolac-
tams). When an alkenyl acid reacts with iodine in the presence
of a base (such as sodium bicarbonate), the initially formed iodo-
nium ion reacts with the carboxylate anion (generated in situ) to
form the iodolactone (eq 6).

OH

O

O

–

O

I

O

O

(6)

I

+

I

2

, NaHCO

3

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-
δ

-butyrolactone is obtained (16% optical purity) (eq 7).

24

Simi-

larly, 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

HN

Ph

O

O

O

I

(7)

3 equiv I

2

, aq THF

(S)

77% (16% optical yield)

N

O

Ph

O

Me

O

N

I

O

(8)

Me

1. I

2

, rt, CH

2

Cl

2

2. Na

2

S

2

O

3

The more difficult lactam forming reaction (iodolactamization)

can be accomplished by treatment of primary alkenyl amides with
Trimethylsilyl Trifluoromethanesulfonate, followed by iodina-
tion, as in the conversion of 4-pentenamide to 5-iodomethyl-2-
pyrrolidinone in 68% yield (eq 9).

4

There are several other cy-

clization reactions that are initiated by the reaction of iodine with
an alkene, in the presence of a nucleophilic atom elsewhere in the
molecule.

26

1. Me

3

SiOTf, NEt

3

2. I

2

, THF

NH

2

O

NH

I

O

(9)

3. aq Na

2

SO

3

Addition to Alkynes.

Iodine undergoes addition reactions

with alkynes as well as alkenes, although the reaction is gen-
erally 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 iodo-
dienes. 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

Cl

Cl

Cl

Cl

I

I

I

I

Cl

(10)

I

2

, ClCH

2

CH

2

Cl

DBU, PhH

83 °C, 120 h

86%

20 °C, 71%

Cleavage of Cyclopropanes. Iodine also reacts with cyclo-

propanes, 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 avail-
able, such as trimethyltin, an alkenyl iodide is formed (eq 13).

I

I

O

I

I

I

I

MeOH

(11)

+

+

:

:

31

46

Bu

23

I

Bu

I

2

AgNO

3

89%

MeOH

(12)

I

I

I

2

, rt

(13)

SnMe

3

I

I

2

, CDCl

3

, 20 °C

Me

3

Sn–I

+

>90%

Conversion of Alcohols to Iodides. Alcohols react with io-

dine and red phosphorus to produce a phosphorus iodide, in situ.
Phosphorus iodides have poor shelf lives (they are unstable and

A list of General Abbreviations appears on the front Endpapers

IODINE

3

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.

C

15

H

31

OH

C

15

H

31

I

2 equiv P (red)

3 equiv I

2

(14)

150 °C

Reaction with Amines. Dehydrogenation is another impor-

tant reaction of iodine, and it is particularly useful for generation
of enamines. Reaction of nuciferine with iodine, in dioxane con-
taining 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

N

Me

MeO

MeO

N

Me

MeO

MeO

(15)

I

2

, dioxane

reflux, NaOAc

+

N

N

N

(16)

I

2

(17)

I

2

, 650 °C, O

2

molten LiI

flow apparatus

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 (CHI

3

) with

oxidative cleavage of the methyl group to produce a carboxylic
acid. The H

3

C–C bond of methyl carbinols [RCH(OH)Me] is also

cleaved with this reagent to give the corresponding acid and iod-
oform. 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, espe-

cially when sodium methoxide is substituted for sodium hydrox-
ide. Steroidal ketones react with iodine and sodium methoxide to
give a 58% yield of the α-iodo ketone, when air is excluded from
the reaction (eq 18).

6

When oxygen is introduced, an 85% yield

of the α,α-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

HO

O

I

HO

O

HO

O

I

I

(18)

2 equiv I

2

NaOMe, N

2

0 °C

0 °C, N

2

MeOH

I

2

NaOMe

MeOH

Ph

Ph

O

Ph

Ph

OH

O

Ph

Ph

O

Ph

Ph

O

(19)

I

2

, NaOMe

+

+

0.0071 M
0.2 M

99%
46%

trace

47%

trace

3%

PhCO

2

Me

25 °C

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 reac-
tion of ethyl 2-methylpropanoate with 2 equiv of LDA and subse-
quent reaction with iodine to give an 85% yield of diethyl 2,2,3,
3-tetramethyl-1,4-butanedioate (eq 21).

35

CO

2

H

CO

2

H

CO

2

H

CO

2

H

(20)

1. 2 equiv LDA

+

70%

I

12%

2. I

2

(21)

CO

2

Et

CO

2

Et

CO

2

Et

1. 2 equiv LDA, THF
–78 °C

2. I

2

, –78 °C

85%

Carboxylic acid derivatives can react with iodine without an

intermediary enolate anion to produce α-iodocarboxylic acids.
α

-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

Avoid Skin Contact with All Reagents

4

IODINE

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 mer-

cury(II) oxide is added, although the yield is lower.

OH

O

Cl

O

I

(22)

1. I

2

, SOCl

2

, 85 °C

90 min

2. Na

2

S

2

O

3

OH

O

Cl

O

I

(23)

0.5 equiv I

2

, ClSO

3

H

ClCH

2

CH

2

Cl, 80 °C

94%

(24)

CO

2

–

Ag

+

I

I

2

67%

I

2

, HgO 36%

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 Butyllithium and then with iodine,

to give a 41% yield of 2-iodo-N-tritylimidazole (eq 25).

8

N

N

Ph

Ph

Ph

N

N

Ph

Ph

Ph

I

(25)

1. BuLi

2. I

2

, THF

41%

Iodoindoles can also be produced by this approach. Reaction

of indole with n-butyllithium and quenching with iodine first pro-
duces an N-iodoindole, but this is unstable and rearranges un-
der 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

N
H

N
H

I

N

I

I

SO

2

Ph

(26)

1. BuLi

1. BuLi
PhSO

2

Cl

2. I

2

2. LDA, THF

–78 °C
3. I

2

Iodopyridine derivatives can also be generated with this tech-

nique. 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

N

F

N

I

F

(27)

1. LDA, THF, –78 °C

2. I

2

50%

N

N

I

1. t-BuLi, THF, –70 °C

Cl

Cl

(28)

2. I

2

, –70 °C

60%

Iodofuran derivatives can be formed, as in the reac-

tion 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

O

CO

2

H

TBDMS

O

CO

2

H

TBDMS

I

(29)

1. 2.2 equiv BuLi
–20 °C, 1 h

2. I

2

, THF, MgBr

2

3. 10% HCl
71%

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.

CN

CN

CN

CN

Li

CN

CN

I (30)

LDA, THF

I

2

–96 °C, 3 min

79%

Conversion of Organoboranes to Iodides. Another impor-

tant area of chemistry where iodine reactions are important in-
volves 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

(31)

I

1. Bu

3

B

2. I

2

, NaOH

65%

Substituted alkenes can also be prepared from vinylboranes

by reaction with iodine and sodium hydroxide. Reaction of dicy-
clohexylborane with 1-hexyne gives the vinylborane, and subse-
quent 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 mix-
ture is produced, but in only 13% yield.

10a

The poor yield

is probably due to the poor solubility of iodine in dichloro-
methane.

(32)

B

I

2

, NaOH

+

:

7

93

THF
85%

Miscellaneous Reactions. There are several specialized re-

actions of iodine that are useful in certain applications. Io-
dine induces coupling of sodium cyclopentadienide to form

A list of General Abbreviations appears on the front Endpapers

IODINE

5

9,10-dihydrofulvalene.

46

Iodine has also been used to cleave

iron–carbon bonds in organoiron species.

47

Iodine reacts with hy-

drazone derivatives to give vinyl iodides.

48

Reaction with Organic Halides. An important reaction of io-

dine is exchange with an alkyl iodide. The most common method
for exchanging an iodide is the Finkelstein reaction,

49

which in-

volves treatment of alkyl halides with Sodium Iodide to produce
alkyl iodides via an S

N

2 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 io-
dides 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 re-
action temperatures required are usually greater than 150

◦

C.

50

Aryl iodides undergo this exchange reaction at even higher tem-
peratures (150–190

◦

C).

51

α

-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 re-
actions of iodine involve the use of the natural abundance stable
isotope of iodine,

127

I. Radiolabeled molecules can be incorpo-

rated 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:

123

I,

125

I, and

131

I. If these isotopic

iodines are used in the preceding reactions, radiolabeled iodides
are produced. In the case of the Finkelstein reaction, sodium io-
dide 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

First Update

Michael B. Smith
University of Connecticut, Storrs, CT, USA

Iodine is known to form polyvalent I

2

compounds, and a variety

of chemical transformation are available from these compounds.

62

The focus of this review is on I

2

itself, sometimes in conjunction

with additives, to initiate chemical transformations.

Addition to Alkenes and Alkynes.

In the presence of an

electron-donating alkene or alkyne, I

2

reacts to form an inter-

mediate iodonium ion, which reacts with the iodide counterion
to give a vicinal diiodide. The addition of I

2

to cyclic alkenes

gives the trans-diiodide. Addition of I

2

to cyclohexene to give

trans

-1,2-diiodocyclohexane is a simple example (eq 1).

63

Such

iodination reactions can be used in conjunction with other reac-
tions. Alkenyl and alkynylmalonate derivatives undergoes reac-
tion with transition metal compounds, and subsequent reaction
with I

2

leads to iodocarbocyclization.

64

In eq 33, initial reaction

with tetrakis(isopropoxy)titanium in CH

2

Cl

2

, followed by reac-

tion with 1.5 equiv of I

2

at ambient temperatures gave a 74% yield

of the iodomethylcyclopentane derivative.

64

CO

2

Me

CO

2

Me

I

CO

2

Me

CO

2

Me

1. Ti(Oi-Pr)

4

, CH

2

Cl

2

2. 1.5 equiv I

2

, rt, 2 h

74%

(33)

Iodine reacts with an alkene and an alcohol, in the presence

of cupric acetate in dioxane, to give an iodohydrin.

65

In the

presence of Ce (IV) triflate, alkenes react with I

2

and an alco-

hol to give the iodohydrin.

66

Cyclohexene reacts with methanol

and iodine, for example eq 34, to give an 80% yield of trans-
methoxyiodocyclohexane. In the absence of Ce(OTf)

4

, the re-

action gave only 10% of product after 5 days. Iodohydrins
are also formed when alkenes react with a mixture of I

2

and

phenyliodine(III)–bis(trifluoroacetate) in aqueous acetonitrile at
−

15

◦

C.

67

I

OMe

0.75% I

2

, MeOH, rt

0.25% Ce(OTf)

4

, dixane

80%

(34)

Iodination of alkynes generally gives primarily the trans-diio-

dide,

68

but the reaction is sometimes slow, giving poor yields.

Iodination of terminal alkynes in methanol has been reported,

69

and Al

2

O

3

can catalyze the iodination of electron-rich alkynes

such as 1-hexyne.

70

This latter variation does not work well for

electron-deficient alkynes. Cuprous iodide is a good catalyst for
the iodination of terminal alkynes.

71

Treatment of 1-phenylethyne

with I

2

and CuI in eq 35, for example, gave a 95% yield of the

diiodide.

71

C

C

H

Ph

MeCN, 60

°C

Ph

I

H

I

I

2

, CuI, 3.5 h

95%

(35)

Iodine reacts with dienes to form a mixture of 1,2-diiodoalkenes

and 1,4-diiodoalkenes. Iodine adds to allenes to give iodomethyl
vinyl iodides, and addition to 1,1-disubstituted allenes gives
the more highly substituted and thermodynamically more stable
alkene.

72

This addition is solvent dependent, and equilibration

occurs to give the more stable product. In the example shown in
eq 36, addition of I

2

and equilibration over 3 h gave a 13:1 Z:E

mixture from a 0.8:1 Z:E mixture of the initial addition product.

73

C

7

H

15

TBDMSO

CDCl

3

C

7

H

15

I

TBDMSO

I

I

2

, 3 h

C

(36)

A variation of the iodination reaction generates an iodonium

intermediate in the presence of a nucleophilic atom, generating
five- and six-membered ring heterocyclic compounds. Alkene
precursors can be used as well as alkyne precursors. Iodopyrro-
lines,

74

iodopyrrolidines,

75

iodopyrrolidinones,

76

and iodote-

trahydrofuran derivatives

77

have been prepared by iodine-induced

cyclization. An example of the latter reaction is treatment of keto
esters, such as the one shown in eq 37, with I

2

in the presence

of sodium carbonate.

77

Cyclization via the enol or enolate form

Avoid Skin Contact with All Reagents

6

IODINE

of the keto ester in eq 37 gave the iodotetrahydrofuran in 84%
yield.

77

Similar cyclization of alkene acetals led to the transfor-

mation of 1,2-diols to the iodomethyltetrahydrofuran derivative
(86% yield) in eq 38.

78

Cyclization of 3-alkynyl-1,2-diols with

3 equiv of I

2

and NaHCO

3

gave good yields of 3-iodofurans.

79

Cyclization of o-acetoxy and o-benzyloxyalkynylpyridines with
I

2

and NaHCO

3

gave 2,3-disubstituted furopyridines.

80

The ap-

proach has been used to synthesize 4-iodoisoquinolines

81

via an

alkyne derivative. Reaction of the imine-alkyne in eq 39 with ex-
cess I

2

led to the vinyl diiodide. In the presence of the base, a 68%

yield of the isoquinoline was obtained.

81

Homopropargylic sul-

fonamides undergoes iodine-induced cyclization to give 4-iodo-
2,3-dihydropyrroles.

82

O

CO

2

Et

O

I

CO

2

Et

I

2

, Na

2

CO

3

, CH

2

Cl

2

rt, 9 h
84%

(37)

HO

OH

OBn

O

OBn

I

HO

I

2

, Na

2

CO

3

, MeCN

0

°C, 15 min

86%

(38)

N

Ph

N

I

Ph

8 equiv I

2

, MeCN

3 equiv NaOCO

2

Me

30 min, 25

°C

68%

(39)

Iodolactonization

83

is an often used variation of this ring-

forming protocol (eq 6) that continues to be important. In a synthe-
sis of (−)-cinatrin B,

84

alkene-acid (eq 40) formed an iodonium–

carboxylate during the course of the reaction with I

2

and NaHCO

3

,

leading to a 97% yield of the iodolactone with 88% ds. A vari-
ation of this cyclization reaction used an ester. In a synthesis of
( + )-epoxyquinol A,

85

the ester shown in eq 41 was treated with

iodine, and an 81% yield of the iodolactone was obtained (>99%
ee after crystallization). Iodolactonization of allene-acids leads
to β-iodobutenolides.

86

Another related reaction treated alkenyl

carbonates (OCO

2

t

-Bu) with I

2

to produce iodomethyl cyclic

carbonates.

87

O

C

9

H

19

OBn

MeO

BnO

O

OH

O

C

9

H

19

OBn

MeO

BnO

O

O

I

I

2

, NaHCO

3

ether-H

2

O

(40)

O

H

O

SO

2

Np

O

H

O

I

I

2

, MeCN, rt

(41)

Iodoaziridines can be prepared by a modification of the cy-

clization strategy just shown. Treatment of N-tosylallylamine with
potassium tert-butoxide and then iodine in toluene gave a 94%
yield of the iodoaziridine (eq 42).

88

Another aziridination reaction

involves the iodine-catalyzed reaction of alkenes with chloramine-
T.

89

In eq 43, 1-octene reacted with Chloramine-T and I

2

to give

a 67% yield of the N-tosylaziridine.

89

NHTs

t-

BuOK

NTs K

I

2

NTs

I

toluene

−

(42)

C

6

H

13

C

6

H

13

N

Ts

67%

MeCN, rt, 1 d

0.5 equiv Chloramine-T, 10% I

2

(43)

Yet another variation of this iodocyclization procedure prepared

phosphaisocoumarins.

90

Reaction of the alkynyl phosphonate in

eq 44 with 2 equiv of iodine in chloroform at ambient temperatures
gave an 83% yield of the phosphaisocoumarin.

90

Ph

P

OEt

OEt

P

O

OEt

I

Ph

2 equiv I

2

, CHCl

3

rt, 12 h

83%

O

(44)

Reaction with Arenes. Iodination of aromatic compounds is

possible (eqs 25–30). In some cases, direct iodination is possible
without the need for additives. In a synthesis of demethylaster-
riquinone B1 by Pirrung and co-workers,

91

the indole unit reacted

with I

2

faster than the trisubstituted alkene substituent to give a

69% yield of the iodoindole (eq 45) after Boc protection of the
nitrogen.

N

H

N

H

I

1. I

2

2. Boc

2

O, DMAP

69%

(45)

A list of General Abbreviations appears on the front Endpapers

IODINE

7

In most cases, an additive is required to convert arenes to the

corresponding aryl iodide. In combination with nitrogen diox-
ide, I

2

converts arenes to the aryl iodide.

92

As shown in eq 46,

toluene was converted to a 60:40 mixture of 4-iodotoluene and
2-iodotoluene with I

2

and NO

2

catalyzed by sulfuric acid in 60%

yield.

92

A mixture of I

2

and HgO can be used for the prepa-

ration of aryl iodides,

93

and mercuric nitrate can be used as

well.

94

Me

Me

I

Me

I

5% H

2

SO

4

, 60

°C, 4 h

0.5 equiv I

2

, excess NO

2

CHCl

3

+

60%

40%

(46)

In the presence of certain oxidants, I

2

reacts with arenes to

give the corresponding aryl iodide. Potassium permanganate and
manganese dioxide have been used

95

as well as tetrabutylammo-

nium peroxydisulfate.

96

In eq 47, this latter reagent converted

dimethoxybenzene to the 2-iodo derivative in 92% yield.

96

O

O

O

O

OMe

OMe

S

O

O

S

Bu

4

N

+

–

O

O

–

+

NBu

4

OMe

OMe

I

I

2

, MeCN, 3 h, 20

°C

92%

(47)

In combination with sodium periodate and sulfuric acid, I

2

re-

acts with arenes to form the corresponding aryl iodide. Benzene
reacted as shown in eq 48, for example, to give a 65% yield of
iodobenzene.

97

Similarly, carbazole reacted with I

2

under these

conditions to give a 75% yield of the aryl iodide (eq 49).

98

I

I

2

, NaIO

4

, H

2

SO

4

65%

AcOH, Ac

2

O

(48)

I

2

, NaIO

4

, cat H

2

SO

4

75%

EtOH, 65

°C, 1 h

N

H

N

H

I

(49)

Iodine has been shown to promote the decomposition of 1-

aryl-3,3-dialkyltriazenes.

99

Previous work reported the thermal

decomposition of triazines,

100

but there were problems associated

with the requisite high temperatures. The addition of I

2

diminished

the reaction temperature, and increased the yield of the aryl io-
dide. This protocol constitutes a mild procedure for the synthesis

of aryl iodides. When 1-phenyl-3-pyrrolidinetriazine reacted with
I

2

in diiodomethane at 8

◦

C, in eq 50, >98% of iodobenzene was

obtained.

99

Dialkyltriazenes of this type are prepared from the cor-

responding aryldiazonium salt.

101

Aniline derivatives and other

aromatic amines are treated with nitrous acid (typically formed
in situ with NaNO

2

and HCl) to give the aryldiazonium salt.

Subsequent reaction with a secondary amine gives the triazene.
The triazene used in eq 50 was prepared from benzenediazonium
chloride and pyrrolidine.

99,101

N N N

I

I

2

, CH

2

I

2

, 80

°C, 4 h

>98%

(50)

Cleavage of Epoxides.

The reaction of I

2

and an epoxide

in the presence of certain catalysts leads to the corresponding
iodohydrin. Iodine and a crown ether open epoxides to give the
iodohydrin.

102

Both phenylhydrazine

103

and 2,6-bis[2-o-amino-

phenoxy)methyl]-4-bromo-1-methoxybenzene

104

have been used

as catalyst. In eq 51, cyclohexene oxide reacted with I

2

in the

presence of 10% phenylhydrazine to give a 95% yield of the
iodohydrin.

103

Iodine also opens epoxides in combination with

manganese(salen) complexes.

105

O

OH

I

I

2

, 10% PhNHNH

2

CH

2

Cl

2

, 25

°C, 2.5 h

95%

(51)

Cleavage of Cyclopropanes.

Iodine reacts with cyclo-

propanes (eq 13), leading to ring opening and formation of a
diiodide.

106

An interesting example of this reaction involved I

2

with hexafluorocyclopropane.

107

As shown in eq 52, heating I

2

and hexafluorocyclopropane to 155

◦

C in a Shaker rube gave

an 80% yield of the mixed halide 1,1,2,2,3,3-hexafluoro-1,3-
diiodopropane.

107

F

F

I

F

F

F

F

I

F

F

F

F

F

F

I

2

, 155

°C

80%

(52)

The reaction is not restricted to simple cyclopropane deriva-

tives. Cyclopropylcarbene–chromium complexes react with I

2

to

form 1,4-diiodo-1-alkenes.

108

Two examples are shown that illus-

trate the diversity of the process. In eq 53, the bicyclo[4.1.0]hept-
anethiocarbene complexes were opened with I

2

to give the

diiodo compound shown in 87% yield as a 78:28 Z:E vinyl sul-
fide mixture.

108

In the second example (eq 54), opening the cy-

clopropyl(methoxy)carbene complex gave an intermediate that
generated methyl 4-iodobutanoate as the final product in 41%
yield.

108

Avoid Skin Contact with All Reagents

8

IODINE

SPh

Cr(CO)

5

H

H

I

I

SPh

I

2

, CH

2

Cl

2

, −20

°C

87% (78:28 Z:E)

(53)

OMe

Cr(CO)

5

I

OMe

O

I

2

, CH

2

Cl

2

, –20

°C

41%

(54)

Reaction of Alcohols with Iodine. Alcohols are converted

directly to the corresponding alkyl iodides in poor to moderate
yield by simply heating the alcohol with I

2

in an alkane solvent.

109

2(S)-Octanol was heated with I

2

(eq 55), but 2(R)-iodooctane was

obtained in only 25% yield. The reaction proceeds largely with
inversion of configuration, although the inversion does not appear
to be complete.

OH

I

I

2

, Pet. ether, reflux, 6 h

25%

(55)

Another useful protocol involves conversion of alcohols to

iodides with triphenylphosphine and iodine. In a synthesis of
( + )-discodermolide,

110

Smith and co-workers treated the alcohol

shown in eq 56 with triphenylphosphine, imidazole, and iodine in
1:2 benzene:ether and obtained a 95% yield of the primary iodide.

O

O

OH

OTBS

PMP

O

O

I

OTBS

PMP

PPh

3

, imidazole, I

2

PhH:ether (1:2)

95%

(56)

Modification of this procedure allows the formation of alkenes

from cyclopropylcarbinyl alcohols. In a synthesis of (−)-doli-
culide,

111

Ghosh and Liu treated the cyclopropylcarbinyl alco-

hol shown in eq 57 with triphenylphosphine, imidazole, and I

2

to give the corresponding iodide.

111

Subsequent treatment with

n-

butyllithium in the presence of TMEDA and molecular sieves

at −78

◦

C gave a 72% yield of the alkene. This protocol was

reported earlier by Charette and co-workers.

112

HO

BnO

BnO

1. PPh

3

, imidazole, I

2

2. BuLi, –78

°C

72%

(57)

A general application of this dehydration sequence treats sec-

ondary and tertiary alcohols with Ph

3

BiBr

2

and I

2

to give the

more stable alkene in good yield.

113

Reaction of the cyclohexanol

derivative in eq 58, for example, gave a 73% yield of the cyclo-
hexane derivative with only 8% of the cyclohexylidene derivative
being formed.

113

OH

Ph

Ph

3

BiBr

2

, I

2

Ph

Ph

+

45

°C, 3 h

73%

8%

(58)

A

related

reaction

converts

1,2-diols

to

the

corre-

sponding alkene. Pedro and co-workers, in a synthesis
of plagiochiline N,

114

reacted a diol unit (eq 59) with

chlorodiphenylphosphine–iodine

115

followed

by

hydrogen

peroxide–acetic acid/THF, and obtained a 70% yield of the
alkene.

H

H

OTBS

OH

OH

TBDMSO

H

H

OTBS

TBDMSO

1. Ph

2

PCl–I

2

2. H

2

O

2

, AcOH-THF

70%

(59)

Iodine and Amines. Iodine catalyzes the reduction of diaryl

alkenes in the presence of 50% aq H

3

PO

2

in acetic acid.

116

In

eq 60, dibenzosuberenone was reduced to dibenzocycloheptane,
and this reagent reduced both the alkene unit and also deoxy-
genated the ketone moiety.

117

The active reducing agent for this

system was reported to be hydrogen iodide.

117

This observation

was extended to include diaryl alkenes such as trans-stilbene,
which gave a 99% yield of 1,2-diphenylethane under these
reaction conditions.

116

O

H

3

PO

2

, AcOH, heat

cat I

2

(60)

Iodination Involving Carbonyl Compounds. Iodine reacts

with ketones to produce α-iodoketones. α-Iodoenones can be pre-
pared, but a catalytic amount of amine must be added,

118

although

ammonium salts can also be used. Solvent plays a significant role
in this reaction.

119

In the presence of the activating salt shown in eq

61, I

2

reacts with 4-hydroxyacetophenone to give the iodomethyl

compound in 78% yield when methanol was used as the solvent.
When the same reaction was performed in acetonitrile, however,
a 72% yield of 3-iodo-4-hydroxyacetophenone was recorded.

N

N

Cl

F

2 BF

4

–

HO

O

HO

O

I

I

2

, MeOH

78%

(61)

Iodination

has

been

accomplished

with

I

2

-(NH

4

)

2

Ce(NO

3

)

6

.

120

This reagent converted cyclohexanone to 2-

iodocyclohexanone in 94% yield as shown in eq 62.

120

α

-Iodo

A list of General Abbreviations appears on the front Endpapers

IODINE

9

aldehydes have been prepared in good yield by treatment of silyl
enol ethers with I

2

and AgOAc.

121

O

I

2

, 50

°C

O

I

CAN, AcOH/H

2

O

94%

(62)

In 1962, Barton and co-workers described reactions of hydra-

zones with iodine. Ketone hydrazones reacted with I

2

to give vinyl

iodides, but aldehyde hydrazones gave gem-diiodides.

122

A later

study by Pross and Sternhell showed that the relative amounts of
amine and ether solvents played a significant role in the product
distribution.

123

In 1983, Barton and co-workers introduced an im-

provement to this procedure that greatly improved the yield and
selectivity of the reaction.

124

The reaction of the ketone hydrazone

in eq 63 (from the reaction of the ketone with hydrazine) with the
azine base in ether gave an 89% yield of the vinyl iodide.

124

When

isobutyraldehyde was subjected to the same conditions, however,
a 70% yield of the gem-diiodide was obtained (eq 64).

124

These procedures have found their way into the synthesis of

natural products. In a synthesis of ( + )-norrisolide by Theodorakis
and co-workers,

125

the bicyclic ketone in eq 65 was treated with

hydrazine to give an 88% yield of the hydrazone, and then reaction
with I

2

and NEt

3

gave a 62% yield of the vinyl iodide.

Nt-Bu

Me

2

N

NMe

2

3.5 equiv

MeO

O

MeO

I

I

2

, ether, rt

89%

(63)

H

O

Me

2

N

NMe

2

Nt-Bu

I

I

3.5 equiv

I

2

, ether, rt

70%

(64)

Me O

H

Me

H

I

1. N

2

H

4

2. I

2

, NEt

3

62%

(65)

Formation of gem-diiodides has also been used in synthesis. In

a sphingosine synthesis by Griengl and co-workers,

126

tetrade-

canal was converted to the hydrazone with hydrazine hydrate
in eq 66, and subsequent treatment with I

2

and NEt

3

gave 1,

1-diiodotetradecane, but in only 25% yield.

C

12

H

25

H

O

C

12

H

25

I

I

1. N

2

H

4

hydrate

2. I

2

, NEt

3

25%

(66)

Iodination of Organometallic Compounds.

In a synthe-

sis of carerulomycin C, treatment of the pyridine amide shown
with lithium diisopropylamide generated the ortho-lithiated com-
pound, which reacted with I

2

to produce an 80% yield of

the 3-iodopyridine derivative.

127

This reaction is shown in

eq 67.

N

N(i-Pr)

2

O

N

N(i-Pr)

2

O

I

LiN(i-Pr)

2

, I

2

, −78

°C

80%

(67)

Another example, taken from a synthesis of caerulomycin E,

128

treated the pyridine oxide in eq 68 with LDA and then I

2

to give

a 70% yield of the 6-iodo compound.

N+

N

O

−

1. LDA, THF, −70 °C

2. I

2

N+

N

O

−

I

70%

(68)

Organoboranes are converted to the corresponding iodide with

iodine, as in the reaction of 1-decene with tri-n-butylborane and
then basic I

2

, to give a 65% yield of 1-iododecane (eq 31).

129

(2-Stannylalkenyl)boranes are similarly converted to the vinyl io-
dide by treatment with I

2

in THF and then with acetic acid.

130

When alkenylcatecholboranes are treated with a Grignard reagent,
subsequent treatment with iodine induces rearrangement and
oxidation to give Z-alkenes.

131

In eq 69, conversion of 1-decyne

to the vinyl catecholborane was followed by reaction with butyl-
magnesium bromide and then I

2

/NaOH to give a 60% yield of

Z-

5-tetradecene.

131

Substituted alkenes can also be prepared from

vinylboranes by reaction with I

2

and NaOH. Reaction of dicyclo-

hexylborane with 1-hexyne gives the vinylborane, and subsequent
reaction with basic I

2

in THF gives a 93:7 cis:trans mixture of

1-cyclohexyl-1-hexene in 85% yield.

132

C

8

H

17

O

B

O

H

C

8

H

17

B

O

O

C

8

H

17

Bu

1. BuMgBr, THF

2. I

2

, NaOH, THF

60%

(69)

Acyliron complexes are converted to esters upon treatment with

I

2

in alcohol solution.

133

In eq 70, addition of I

2

and benzyl alcohol

to the acyliron complex gave a 59% of the corresponding benzyl
ester.

133

Fe(CO)[(NO)dppe]

O

OCH

2

Ph

O

PhCH

2

OH, I

2

, MeCN

rt, 3 h

59% (66:34 E:Z)

(70)

Avoid Skin Contact with All Reagents

10

IODINE

Zirconacyclopentenes are converted to iodoalkenes upon treat-

ment with I

2

, in what is known as the Negishi zirconation–iodin-

ation protocol.

134

In a synthesis of furanocembranolides,

135

Pa-

quette and co-workers added a metal and a methyl group to the
alkyne in eq 71, using dichlorobis(cyclopentadienyl)zirconium
and trimethylaluminum, and then reacted the vinylzirconate with
I

2

to give the vinyl iodide.

Me

3

Si

Me

3

Si

Me

I

1. Cp

2

ZrCl

2

, AlMe

3

ClCH

2

CH

2

Cl, 0

°C

2. I

2

, THF, −30

°C

(71)

This sequence is highly selective for reaction of alkynes rather

than alkenes, as illustrated by a synthesis of curacin A,

136

in which

White and co-workers treated the terminal alkyne shown in eq
72 with dichlorobis(cyclopentadienyl)zirconium and trimethyl-
aluminum. Subsequent reaction with I

2

gave a 69% yield of the

vinyl iodide without disturbing the terminal alkene moiety.

OMe

OMe

Me

I

1. Cp

2

ZrCl

2

, AlMe

3

CH

2

Cl

2

2. I

2

, THF

69%

(72)

Iodine in the Protection/Deprotection of Various Functional

Groups. Alcohols are converted to the O-acetate with catalytic
I

2

,

137

and acetals are produced from aldehydes.

138

Acetals

139

and

dithioacetals

140

have been produced with this protocol. However,

dithioacetals are converted back to the carbonyl compound by
treatment with I

2

–silver nitrite.

141

Dithioacetals can be converted

to the corresponding dioxolane with I

2

in 1,2-ethanediol.

142

In ad-

dition, I

2

was shown to catalyze esterification of carboxylic acids

as well as transesterification of esters.

143

3-Methyl-2-butenyl es-

ters are converted to the carboxylic acid and alcohol precursors
with I

2

at ambient temperatures, although simple allylic esters

do not react.

144

Prenyl ethers can be cleaved to the correspond-

ing alcohol in the presence of I

2

,

145

as are trityl ethers with

I

2

in methanol.

146

In a similar manner, prenyl carbamates are

deprotected to regenerate the original amine compound.

147

p-

Methoxybenzyl ethers are cleaved with I

2

in methanol, but sim-

ple benzyl ethers are not.

148

Alkyl tert-butyldimethylsilyl ethers

are selectively cleaved in the presence of the analogous aryl silyl
ether by I

2

in methanol.

149

Iodine is used under microwave ir-

radiation to facilitate the reaction of 1,2-diols with dihydropyran
to give the monotetrahydropyranyl ether.

150

Iodine catalyzes the

formation of tetrahydropyranyl ethers from alcohols, as well as
the conversion (in methanol) to the original alcohol.

151

Oximes

are converted back to the carbonyl precursor by heating with I

2

in

acetonitrile.

152

Miscellaneous Reactions. Iodine is an oxidizing agent under

the proper conditons. Iodine, in conjunction with DMSO and hy-
drazine monohydrate in aqueous acetonitrile, efficiently oxidized
secondary alcohols to the corresponding ketone.

153

Photochem-

ical oxidative cleavage of styrenes gave carboxylic acids upon
treatment with mesoporous silica FSM-16–iodine.

154

Aldehydes

were produced from allylic and benzylic alcohols under simi-
lar conditions.

155

Iodine and NH

4

OH converted aldehydes into

nitriles.

156

Thiols were converted to disulfides by treatment with

I

2

and morpholine.

157

O

MeO

2

C

Me

I

OH

MeO

2

C

Me

6 equiv NaOEt, 2 equiv I

2

EtOH, –78

°C

66%

(73)

In the presence of an excess of sodium ethoxide and 2

equiv of iodine, 2-cyclohexenones that contain an electron-
withdrawing group undergoes aromatization to the corresponding
iodophenol.

158

In eq 73, the cyclohexenone derivative shown was

converted to the iodophenol in 66% yield.

158

In the presence of 2 equiv of indium, I

2

promoted radical cy-

clization of certain substrates.

159

In eq 74, the iodo allyl ether

reacted with I

2

and indium in methanol, via radical cyclization,

to give an 87% yield of benzofuran after a second step involving
reaction with 2 equiv of H

2

O

2

.

159

O

O

I

1. 2 equiv In, I

2

, DMF, rt, 4 h

I

2. 2 equiv H

2

O

2

, rt, 0.5 h

87%

(74)

Related Reagents. Dimethyl Sulfoxide–Iodine; Iodine– Alu-

minum(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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