IRON(II) CHLORIDE

1

Iron(II) Chloride

1

FeCl

2

[7758-94-3]

Cl

2

Fe

(MW 126.75)

InChI = 1/2ClH.Fe/h2*1H;/q;;+2/p-2/f2Cl.Fe/h2*1h;/q2*-1;m
InChIKey = NMCUIPGRVMDVDB-AXRWJRPMCC

(synthesis of ferrocene

2

and derivatives;

3

Sandmeyer reaction;

4

alkane C–H functionalizations;

6,7

alkyne reductions;

5

catalytic

additive

8

)

Alternate Name:

ferrous chloride.

Physical Data:

mp 670–674

◦

C; sublimes; d 3.16 g cm

−3

.

Solubility:

64.4 g/100 mL cold water (10

◦

C), 105.7 g/100 mL

hot water (100

◦

C); 100 g/100 mL alcohol; sol acetone; insol

ether.

Form Supplied in:

green to yellow solid; widely available, can

be obtained as 99.999% ultra dry material.

Preparative Methods:

chlorobenzene (1 kg) and sublimed

(anhydrous) Iron(III) Chloride is refluxed for 3.5 h. The
iron(II) chloride is filtered and washed with anhydrous benzene
(97% yield).

1

Handling, Storage, and Precautions:

incompatible with strong

oxidizing agents; hygroscopic; may decompose on exposure to
air, HCl being produced. It is an irritant. Use in a fume hood.

Original Commentary

Andrew D. White
Parke-Davis Pharmaceutical Research, Ann Arbor, MI, USA

Ferrocene Synthesis. Iron(II) chloride reacts with sodium cy-

clopentadienide in THF to give ferrocene (eq 1). This method
has been described in detail

2

and is applicable to many ferrocene

derivatives.

3

2

–

+ FeCl

2

Fe

73%

(1)

Na

+

Sandmeyer Reaction.

The Sandmeyer reaction has been

performed with iron(II) chloride, in place of Copper(II) Chlo-
ride. The reactions proceed in good yield, except with methyl
substituents, where phenols are obtained (eq 2).

4

OMe

N

2

+

O

2

N

OMe

Cl

O

2

N

+ FeCl

2

80%

(2)

FeCl

2

–Lipoamide–NaH Reductions.

Iron(II) chloride in

combination with simple dithiols are effective catalysts for the
reduction of alkynes to alkenes with Sodium Borohydride
(22–93% yields) (eq 3).

5

The best reaction conditions employ

5 equiv NaBH

4

, 7.5 mol% lipoamide, and 10 mol% FeCl

2

stirred

at rt for 8 h.

(3)

Ph

Ph

Ph

Ph

NaBH

4

, lipoamide, FeCl

2

EtOH

75%

Amination of the C–H Bond.

Reaction of Chloramine-T

with rigorously dry FeCl

2

and adamantane in dichloromethane

under nitrogen, and column chromatography of the crude reaction
mixture after 2 h, gives a 63% yield of the tertiary sulfonamide
(eq 4).

6

TsNClNa

FeCl

2

NHTs

(4)

63%

Gif

IV

IV

IV

Oxidation Catalyst. FeCl

2

·4H

2

O is one of the cata-

lysts used in the Gif

IV

oxidation of saturated hydrocarbons using

molecular oxygen. However, many iron catalysts have been used
with varying results. FeCl

2

provides a good ratio of secondary to

tertiary hydroxylation with a reasonable turnover (30). A com-
bination of adamantane (2 mmol), Zinc (20 mmol), and FeCl

2

(7 ␮mol) in pyridine–acetic acid is stirred for 18 h, open to the
atmosphere, to yield oxidation products (eq 5).

7

(5)

Zn, AcOH, py, H

2

O

FeCl

2

·4H

2

O, O

2

OH

OH

O

+

+

0.5%

6.8%

30

°C, 18 h

Raney Cobalt Catalyst Additive. Unsaturated alcohols can

be obtained from α,β-unsaturated aldehydes via hydrogenation
with Raney cobalt catalyst. FeCl

2

addition to the catalyst increases

yields.

8

First Update

David G. Hilmey
Cornell University, Ithaca, NY, USA

Fenton-type Chemistry. The Fenton reaction involves Fe

II

acting as a catalyst in the generation of two hydroxyl radicals
from hydrogen peroxide, and the subsequent oxidation of organic
molecules. Fenton-type chemistry is critical to the understanding
of biological systems, their oxidative damage, and detoxification
processes.

9

Iron(II) chloride has been used in Fenton-type reac-

tions with organic peroxides in a more controlled fashion to effect
oxidations and ring contractions, and to study the mechanisms of
action of antimicrobial therapeutics.

Artemisinin (1) contains a 1,2,4-trioxane ring and is the only

antimalarial agent with no known resistance mechanism. It is be-
lieved that the drug functions through radical formation upon in-
teraction with Fe

II

heme. To model this chemistry, ferrous chloride

was added to artemisinin (eq 6). The resulting products included

Avoid Skin Contact with All Reagents

2

IRON(II) CHLORIDE

the tetrahydrofuran (2) as the major product, the reduced ether-
bridged product (4), and the alcohol (3). Ferric chloride and ferric
triflate produced similar results, although they did not convert
artemisinin to the bridged ether (4). Other Lewis and protic acids
such as trifluoromethanesulfonic acid, zinc bromide, and ferrous
perchlorate were unreactive in this fashion.

10

Treatment of the tri-

cyclic peroxide (5) with FeCl

2

in the presence of Cu

II

resulted in

a ring-opened primary chloride, which upon basic treatment pro-
vided the ring-contracted tetrahydrofuranyl tricycle (6) in good
yield (eq 7).

11

The bis-steroidal tetraoxane (7) was also cleaved

in the presence of FeCl

2

to produce two equivalents of the ketone

(8) in 95% yield (eq 8). EPR experiments indicated an oxygen rad-
ical as an intermediate with generation of an Fe

IV

=O species.

12

O

O

O

O

HO

H

H

H

O

O

H

H

H

O

AcO

O

O

O

O

H

H

H

O

O

O

H

H

H

O

O

78%

16%

6%

FeCl

2

, imidazole

CH

3

CN

(6)

1

+

+

2

3

4

O

OOH

H

H

O

1. FeCl

2

, CuCl

2

2. KOH

5

6

(57%)

(7)

O

O

O

O

OAc

AcO

H

H

OAc

CONH

2

O

H

2

N

H

OAc

CONH

2

O

2

7

8

(95%)

(8)

FeCl

2

·

4H

2

O

CH

3

CN

Benzylic Oxidations. Iron(II) chloride has been employed in

the Gif

IV

oxidation of benzylic methyl groups to aldehydes in the

presence of molecular oxygen with or without zinc.

13,14

Another

protocol uses iodine, t-butyl iodide, and trifluoroacetic acid along
with a ferrous salt.

15

This procedure oxidized the quinoline (9) to

the aldehyde (10), which served as an intermediate in the formal
total synthesis of the natural alkaloid, batzelline C (eq 9).

16

N

NO

2

Cl

MeO

MeO

CH

3

N

NO

2

Cl

MeO

MeO

CHO

I

2

, DMSO, TFA, t-BuI

FeCl

2

, 80

°C

(9)

9

10

(76%)

N–O Bond Cleavage. Many procedures have been developed

for the reduction of nitro compounds to amines.

17

Several of these

use FeCl

2

with additives, such as hydrochloric acid

18

and Fe

0

.

19

In buffered aqueous media, the aniline product (12) was obtained
in 89% yield from nitrobenzene (11) en route toward antagonists
to G-protein-coupled receptors (eq 10).

20

NaO

3

S

NaO

3

S

SO

3

Na

HN

O

Cl

NO

2

NaO

3

S

NaO

3

S

SO

3

Na

HN

O

Cl

NH

2

FeCl

2

·4H

2

O, pH 7.5

(10)

11

12

(89%)

Iron(II) chloride has been used to cleave the nitrogen–oxygen

bond of secondary hydroxylamines as well. For instance, when
treated with an aryl Grignard reagent, exemplary nitrobenzenes
produced nitrosobenzene intermediates, which were alkylated by
a second Grignard equivalent (eq 11).

21

The resulting hydroxy-

lamine salts were reduced to secondary anilines in the presence
of sodium borohydride and Fe

II

to give products such as 14 in

63–86% yield.

A list of General Abbreviations appears on the front Endpapers

IRON(II) CHLORIDE

3

I

CN

NH

CN

Br

N

CN

Br

OAr

1. iPrMgCl (2 equiv)
THF, –20

°C

(11)

14

3. FeCl

2

, NaBH

4

EtOH

13

2. 4-nitrobromo-
benzene

(78%)

Kociolek and coworkers have used the N–O bond cleav-

ing capabilities of iron(II) chloride to form β-ketonitriles from
3-bromoisoxazoles (eq 12). Molybdenum hexacarbonyl, known
to cleave the nitrogen–oxygen bond, resulted in product formation
as well.

22

This same heterocyclic moiety in (15) was also treated

with FeCl

2

and underwent a tandem ring-opening/cyclization to

give 1-benzoxepine (16) in very good yield (eq 13).

23

Substitution

of Mo(CO)

6

for ferrous chloride in this case resulted in no product

formation.

N

O

AcO

Br

OAc

O

CN

(12)

(72%)

FeCl

2

·4H

2

O

CH

3

CN

O

N

O

Br

O

H

O

O

CN

FeCl

2

·4H

2

O

CH

3

CN, rt

15

16

(13)

(76%)

Heteroaromatic Formation.

Iron(II) chloride has been

employed in the synthesis of various heteroaromatics. Azirines
were used to generate several nitrogen heterocycles in the pres-
ence of FeCl

2

. Treatment of aryl azirines with FeCl

2

resulted

in dimerization to give 2H-imidazoles, pyridazines, and pyrro-
lines, believed to result from Fe

II

-induced single-electron cleav-

age of the azirine ring.

24

In one example, when azirine (17) was

heated to 180

◦

C, thermal rearrangement resulted in the pyrazole

(18) in low yield with significant decomposition. The reactive
2-chloropyridine moiety was thought to be unstable at these high
temperatures. Switching to the milder iron(II) chloride method
resulted in the same pyrazole in very good yield (eq 14).

25

For

the synthesis of indoles, when several 2-nitro-aryl alkynes were
subjected to pyrrolidine at higher temperatures, a 1,4-conjugate
addition took place. The nitro group was then reduced by Fe

0

/Fe

II

chloride, or palladium on carbon in a hydrogen atmosphere,
followed by spontaneous cyclization to give the indole hetero-
cycle. The chloroindole product in eq 15 was synthesized using
only the ferrous chloride reducing method to avoid dehalogena-
tion of the chlorobenzene starting material.

26

Pyrazoles have also

been generated from pyrazolines by treatment with iron(II) chlo-
ride and hydrogen peroxide.

27

N

N

F

Cl

N

N

Cl

F

17

18

FeCl

2

, 80

°C

dimethoxyethane

(68%)

(14)

Cl

NO

2

n

Bu

n

Bu

N
H

Cl

(15)

1. pyrrolidine, 80

°C

2. Fe, FeCl

2

, EtOH

80

°C, 10 h

(91%)

Reductions.

Iron(II) chloride was shown to reduce car-

bonyl and imine compounds on a number of different systems.

28

FeCl

2

·4H

2

O in the presence of lithium metal and catalytic 4,4

′

-

di-tert-butylbiphenyl reduced a number of aryl and alkyl imines,
aldehydes, and ketones. This mild active-iron species was as
effective as many of the standard hydride conditions employed
for such reactions. When nickel(II) chloride or copper(II) chloride
was used in place of the ferrous salt, lower yields and selectivity
were observed. This reducing system can convert a cyclohexenone
to the corresponding saturated alcohol in very good yield and ex-
cellent diastereoselectivity (eq 16). A similar reducing system,
based on iron(II) chloride and methyllithium, can result in 1,4-
alkylation without any 1,2-alkylation in excellent yields.

29

Iron(II)

chloride can also reduce γ-hydroxy-β-ketoesters in the presence
of hydrogen gas to give syn-1,3-diol ester (19) and anti-diol es-
ter (20) (eq 17).

30

This reduction was performed without iron(II)

chloride, but proceeded much slower. Other reagents capable of
this reductive transformation are zinc borohydride and triethylb-
orane/oxygen, giving similar yields and stereoselectivity.

O

OH

FeCl

2

·4H

2

O, THF

lithium powder

di-tert-butylbiphenyl

99:1
syn

:anti

(78%)

(16)

O

O

OEt

OH

OH

O

OEt

OH

OH

O

OEt

OH

78 : 22
19 20

+

(17)

(74%)

FeCl

2

, H

2

(50 psi)

MeOH

Iron(II) chloride may also be employed in the electrolytic

reductive coupling of ketones producing pinacol products.

31

Aromatic epoxides are also reduced to the corresponding alcohols
and olefins by sodium borohydride in the presence of FeCl

2

and

Avoid Skin Contact with All Reagents

4

IRON(II) CHLORIDE

elemental selenium.

32

α

-Haloketones have been dehalogenated by

FeCl

2

and a sulfur source.

33

Finally, trichloromethylaryl deriva-

tives such as 21 can be reductively dehalocoupled and dehalo-
genated using iron(II) chloride to give dimers such as 22 (eq 18).

34

CCl

3

Cl

Cl

Cl

Cl

FeCl

2

·4H

2

O, CH

3

CN, rt

21

22

(93%)

(18)

Nitrene Generation.

Acyl azides undergo thermolysis at

elevated temperatures to generate acylnitrene species.

35

In the

presence of iron(II) chloride, N-tert-butyloxycarbonyl azide was
converted to an intermediate nitrene even at 0

◦

C. The nitrene

then added to sulfoxides or sulfones to give sulfoxamines and sul-
fimines, respectively (eq 19). Substitution of other transition metal
salts for iron(II) chloride resulted in poor to no yield.

36

An acyl-

nitrene species, generated by treatment of (23) with FeCl

2

, added

to an intramolecular olefin, which was then attacked by chloride
to generate 24 (eq 20).

37

The lack of stereospecificity implicates

an open radical intermediate as opposed to a concerted aziridina-
tion. This same tandem nitrene formation/cyclization/chlorination
strategy also provided 3-amino-2-chloro-

D

-gylcopyranosides.

38

S

+

O

–

S

+

O

–

NHBoc

BocN

3

, FeCl

2

CH

2

Cl

2

(84% ee)

(74%)

(19)

O

O

N

3

NH

O

O

Cl

FeCl

2

, TMSCl, CH

3

CN

trans:cis
(90:10)

23

24

(70%)

(20)

Coordination Chemistry. Ferrous chloride, as well as other

Fe

II

salts, has been used to generate many supramolecular com-

plexes. In one example, protoheme IX was generated from a pory-
phyrin and proved capable of binding oxygen through addition of
a covalently bound proximal base (eq 21).

39

Terpyridines have

also been treated with FeCl

2

in water to generate ferrous-bound

dimers. In the presence of Li

I

and Fe

II

cations, these bifunctional

metal receptors coordinate iron(II) exclusively at the terpyridine
subunit (eq 22).

40

Miscellaneous. Ferrous chloride has been used increasingly

in a variety of organic transformations due to its lower toxicity
and cost relative to more traditional transition metal reagents. For
example, it was used as a Lewis acid in the Friedel–Crafts acyla-
tion of the diacyl chloride (25) to furnish the tricyclic pyrone (26)
in very good yield (eq 23).

41

Iron(II) chloride was also useful as

a Lewis acid in the TMS deprotection of sugar (27) (eq 24).

42

Iron(II) chloride tetrahydrate and the pybox ligand (28) gener-
ated a Fe

II

-based asymmetric catalyst in situ capable of perform-

ing a Mukaiyama aldol reaction in aqueous media in good yields
and reasonable enantioselectivity (eq 25). Switching to iron(II)

tetrafluoroborate or perchlorate resulted in slightly higher yields,
but lower enantioselectivity, and iron(III) chloride gave only the
racemate.

43

Finally, FeCl

2

served as a reagent in the enzymatic

resolution of sulfate esters through hydrolysis. However, Fe

III

ap-

peared to be a superior metal additive.

44

N

HN

N

NH

R

1

R

1

O

R

2

O

NH

N

N

N

N

N

N

R

1

R

1

O

R

2

O

NH

N

N

Fe

FeCl

2

2,6-lutidine, DMF

(21)

(68%)

N

N

O

O

O

O

O

O

O

O

O

O

O

O

O

O

N-

N

N

N

N

N

Fe

2+

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O O

O

O

O

O

O

O

O

O

O

2Cl

–

FeCl

2

(0.5 equiv)

CH

3

CN:CHCl

3

(22)

(quant)

A list of General Abbreviations appears on the front Endpapers

IRON(II) CHLORIDE

5

O

O

Cl

O

Cl

O

N

OH

O

O

1. FeCl

2

, toluene, 50

°C

25

26

2. MeNHOH·HCl
KHCO

3

, EtOAC

(75%)

(23)

OBn

OBn

OBn

OTMS

OBn

CN

OBn

OBn

OBn

OH

OBn

CN

(24)

(77%)

FeCl

2

(27)

OTMS

MeO

O

OH

OMe

O

N

N

O

O

N

HO

OH

+

FeCl

2

·4H

2

O

EtOH/H

2

O, 0

°C

(65%)

10 mol %

dr: 93:7
ee: 75%

(25)

28

Related

Reagents. Sodium

Triethylborohydride–Iron(II)

Chloride.

1.

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Avoid Skin Contact with All Reagents