IRON(II) CHLORIDE 1
NaBH4, lipoamide, FeCl2
Iron(II) Chloride1
EtOH
Ph Ph
Ph Ph (3)
75%
FeCl2
Amination of the C H Bond. Reaction of Chloramine-T
with rigorously dry FeCl2 and adamantane in dichloromethane
[7758-94-3] Cl2Fe (MW 126.75)
under nitrogen, and column chromatography of the crude reaction
InChI = 1/2ClH.Fe/h2*1H;/q;;+2/p-2/f2Cl.Fe/h2*1h;/q2*-1;m
mixture after 2 h, gives a 63% yield of the tertiary sulfonamide
InChIKey = NMCUIPGRVMDVDB-AXRWJRPMCC
(eq 4).6
(synthesis of ferrocene2 and derivatives;3 Sandmeyer reaction;4
TsNClNa
alkane C H functionalizations;6,7 alkyne reductions;5 catalytic FeCl2
(4)
NHTs
additive8)
63%
Alternate Name: ferrous chloride.
ć%
IV
IV
Physical Data: mp 670 674 C; sublimes; d 3.16 g cm-3.
GifIV Oxidation Catalyst. FeCl2·4H2O is one of the cata-
ć%
Solubility: 64.4 g/100 mL cold water (10 C), 105.7 g/100 mL
lysts used in the GifIV oxidation of saturated hydrocarbons using
ć%
hot water (100 C); 100 g/100 mL alcohol; sol acetone; insol
molecular oxygen. However, many iron catalysts have been used
ether.
with varying results. FeCl2 provides a good ratio of secondary to
Form Supplied in: green to yellow solid; widely available, can
tertiary hydroxylation with a reasonable turnover (30). A com-
be obtained as 99.999% ultra dry material.
bination of adamantane (2 mmol), Zinc (20 mmol), and FeCl2
Preparative Methods: chlorobenzene (1 kg) and sublimed
(7 mol) in pyridine acetic acid is stirred for 18 h, open to the
(anhydrous) Iron(III) Chloride is refluxed for 3.5 h. The
atmosphere, to yield oxidation products (eq 5).7
iron(II) chloride is filtered and washed with anhydrous benzene
Zn, AcOH, py, H2O
(97% yield).1
FeCl2·4H2O, O2
Handling, Storage, and Precautions: incompatible with strong
30 °C, 18 h
oxidizing agents; hygroscopic; may decompose on exposure to
air, HCl being produced. It is an irritant. Use in a fume hood.
OH
OH O
++(5)
Original Commentary
Andrew D. White
Parke-Davis Pharmaceutical Research, Ann Arbor, MI, USA 0.5% 6.8%
Ferrocene Synthesis. Iron(II) chloride reacts with sodium cy-
Raney Cobalt Catalyst Additive. Unsaturated alcohols can
clopentadienide in THF to give ferrocene (eq 1). This method
be obtained from Ä…,²-unsaturated aldehydes via hydrogenation
has been described in detail2 and is applicable to many ferrocene
with Raney cobalt catalyst. FeCl2 addition to the catalyst increases
derivatives.3
yields.8

(1)
2 Na+ + FeCl2 73% Fe
First Update
David G. Hilmey
Sandmeyer Reaction. The Sandmeyer reaction has been
Cornell University, Ithaca, NY, USA
performed with iron(II) chloride, in place of Copper(II) Chlo-
ride. The reactions proceed in good yield, except with methyl
Fenton-type Chemistry. The Fenton reaction involves FeII
substituents, where phenols are obtained (eq 2).4
acting as a catalyst in the generation of two hydroxyl radicals
from hydrogen peroxide, and the subsequent oxidation of organic
OMe OMe
molecules. Fenton-type chemistry is critical to the understanding
N2+ Cl
of biological systems, their oxidative damage, and detoxification
(2)
+ FeCl2 80%
processes.9 Iron(II) chloride has been used in Fenton-type reac-
O2N O2N
tions with organic peroxides in a more controlled fashion to effect
oxidations and ring contractions, and to study the mechanisms of
FeCl2 Lipoamide NaH Reductions. Iron(II) chloride in action of antimicrobial therapeutics.
combination with simple dithiols are effective catalysts for the Artemisinin (1) contains a 1,2,4-trioxane ring and is the only
reduction of alkynes to alkenes with Sodium Borohydride antimalarial agent with no known resistance mechanism. It is be-
(22 93% yields) (eq 3).5 The best reaction conditions employ lieved that the drug functions through radical formation upon in-
5 equiv NaBH4, 7.5 mol% lipoamide, and 10 mol% FeCl2 stirred teraction with FeII heme. To model this chemistry, ferrous chloride
at rt for 8 h. 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- Benzylic Oxidations. Iron(II) chloride has been employed in
bridged product (4), and the alcohol (3). Ferric chloride and ferric the GifIV oxidation of benzylic methyl groups to aldehydes in the
triflate produced similar results, although they did not convert presence of molecular oxygen with or without zinc.13,14 Another
artemisinin to the bridged ether (4). Other Lewis and protic acids protocol uses iodine, t-butyl iodide, and trifluoroacetic acid along
such as trifluoromethanesulfonic acid, zinc bromide, and ferrous with a ferrous salt.15 This procedure oxidized the quinoline (9) to
perchlorate were unreactive in this fashion.10 Treatment of the tri- the aldehyde (10), which served as an intermediate in the formal
cyclic peroxide (5) with FeCl2 in the presence of CuII resulted in total synthesis of the natural alkaloid, batzelline C (eq 9).16
a ring-opened primary chloride, which upon basic treatment pro-
vided the ring-contracted tetrahydrofuranyl tricycle (6) in good
NO2 CH3
yield (eq 7).11 The bis-steroidal tetraoxane (7) was also cleaved
I2, DMSO, TFA, t-BuI
MeO
FeCl2, 80 °C
in the presence of FeCl2 to produce two equivalents of the ketone
(8) in 95% yield (eq 8). EPR experiments indicated an oxygen rad-
(76%)
N
ical as an intermediate with generation of an FeIV=O species.12 MeO
Cl
NO2 CHO
H
MeO
H
9
O
(9)
FeCl2, imidazole O
O
O
MeO N
CH3CN
AcO
H H
Cl
H H
O
O
10
O
O
1 2
78%
N O Bond Cleavage. Many procedures have been developed
HO
H for the reduction of nitro compounds to amines.17 Several of these
H
use FeCl2 with additives, such as hydrochloric acid18 and Fe0.19
O
O
In buffered aqueous media, the aniline product (12) was obtained
(6)
O
O
+
+
in 89% yield from nitrobenzene (11) en route toward antagonists
H H
H H
O
O
to G-protein-coupled receptors (eq 10).20
O
O
SO3Na
3
4
NaO3S
16%
6%
FeCl2·4H2O, pH 7.5
OOH
(89%)
HN O
NaO3S
1. FeCl2, CuCl2
O
O
2. KOH
(57%)
(7)
HH
SO3Na
NO2
56
NaO3S
Cl
11
HN O
CONH2
NaO3S
O
H O
AcO
OAc
O H
NH2
O
Cl
O
H2N 12
(10)
7
OAc
Iron(II) chloride has been used to cleave the nitrogen oxygen
bond of secondary hydroxylamines as well. For instance, when
CONH2
FeCl2 · 4H2O treated with an aryl Grignard reagent, exemplary nitrobenzenes
CH3CN
produced nitrosobenzene intermediates, which were alkylated by
2
a second Grignard equivalent (eq 11).21 The resulting hydroxy-
(95%)
(8)
lamine salts were reduced to secondary anilines in the presence
O OAc
H
of sodium borohydride and FeII to give products such as 14 in
8
63 86% yield.
A list of General Abbreviations appears on the front Endpapers
IRON(II) CHLORIDE 3
been generated from pyrazolines by treatment with iron(II) chlo-
CN
ride and hydrogen peroxide.27
1. iPrMgCl (2 equiv)
N
THF,  20 °C FeCl2, 80 °C
N Cl dimethoxyethane
2. 4-nitrobromo- N
ICN OAr
benzene (68%)
F
F
Br
17
13
Cl
N
N
CN (14)
18
3. FeCl2, NaBH4
EtOH
nBu 1. pyrrolidine, 80 °C
(11)
NH
2. Fe, FeCl2, EtOH
(78%)
80 °C, 10 h
nBu
Br
(91%)
N
Cl
Cl NO2
H
14
(15)
Kociolek and coworkers have used the N O bond cleav-
ing capabilities of iron(II) chloride to form ²-ketonitriles from
Reductions. Iron(II) chloride was shown to reduce car-
3-bromoisoxazoles (eq 12). Molybdenum hexacarbonyl, known
bonyl and imine compounds on a number of different systems.28
to cleave the nitrogen oxygen bond, resulted in product formation
FeCl2·4H2O in the presence of lithium metal and catalytic 4,4 -
as well.22 This same heterocyclic moiety in (15) was also treated
di-tert-butylbiphenyl reduced a number of aryl and alkyl imines,
with FeCl2 and underwent a tandem ring-opening/cyclization to
aldehydes, and ketones. This mild active-iron species was as
give 1-benzoxepine (16) in very good yield (eq 13).23 Substitution
effective as many of the standard hydride conditions employed
of Mo(CO)6 for ferrous chloride in this case resulted in no product
for such reactions. When nickel(II) chloride or copper(II) chloride
formation.
FeCl2·4H2O was used in place of the ferrous salt, lower yields and selectivity
AcO
O
O
CH3CN
were observed. This reducing system can convert a cyclohexenone
N
CN (12)
(72%) to the corresponding saturated alcohol in very good yield and ex-
cellent diastereoselectivity (eq 16). A similar reducing system,
OAc
Br
based on iron(II) chloride and methyllithium, can result in 1,4-
O alkylation without any 1,2-alkylation in excellent yields.29 Iron(II)
CN
chloride can also reduce Å‚-hydroxy-²-ketoesters in the presence
FeCl2·4H2O
H
CH3CN, rt of hydrogen gas to give syn-1,3-diol ester (19) and anti-diol es-
O
(13)
O
ter (20) (eq 17).30 This reduction was performed without iron(II)
O (76%)
N
O
chloride, but proceeded much slower. Other reagents capable of
this reductive transformation are zinc borohydride and triethylb-
Br
16
15
orane/oxygen, giving similar yields and stereoselectivity.
OH
O
FeCl2·4H2O, THF
Heteroaromatic Formation. Iron(II) chloride has been lithium powder
di-tert-butylbiphenyl
employed in the synthesis of various heteroaromatics. Azirines
(16)
were used to generate several nitrogen heterocycles in the pres- (78%)
ence of FeCl2. Treatment of aryl azirines with FeCl2 resulted
99:1
in dimerization to give 2H-imidazoles, pyridazines, and pyrro-
syn:anti
lines, believed to result from FeII-induced single-electron cleav-
age of the azirine ring.24 In one example, when azirine (17) was
FeCl2, H2 (50 psi)
ć%
MeOH
heated to 180 C, thermal rearrangement resulted in the pyrazole
OEt
(18) in low yield with significant decomposition. The reactive (74%)
2-chloropyridine moiety was thought to be unstable at these high OH O O
temperatures. Switching to the milder iron(II) chloride method
OEt
OEt
resulted in the same pyrazole in very good yield (eq 14).25 For
+
the synthesis of indoles, when several 2-nitro-aryl alkynes were
OH OH O
OH OH O
subjected to pyrrolidine at higher temperatures, a 1,4-conjugate
78 : 22
addition took place. The nitro group was then reduced by Fe0/FeII (17)
19 20
chloride, or palladium on carbon in a hydrogen atmosphere,
followed by spontaneous cyclization to give the indole hetero- Iron(II) chloride may also be employed in the electrolytic
cycle. The chloroindole product in eq 15 was synthesized using reductive coupling of ketones producing pinacol products.31
only the ferrous chloride reducing method to avoid dehalogena- Aromatic epoxides are also reduced to the corresponding alcohols
tion of the chlorobenzene starting material.26 Pyrazoles have also and olefins by sodium borohydride in the presence of FeCl2 and
Avoid Skin Contact with All Reagents
4 IRON(II) CHLORIDE
elemental selenium.32 Ä…-Haloketones have been dehalogenated by tetrafluoroborate or perchlorate resulted in slightly higher yields,
FeCl2 and a sulfur source.33 Finally, trichloromethylaryl deriva- but lower enantioselectivity, and iron(III) chloride gave only the
tives such as 21 can be reductively dehalocoupled and dehalo- racemate.43 Finally, FeCl2 served as a reagent in the enzymatic
genated using iron(II) chloride to give dimers such as 22 (eq 18).34 resolution of sulfate esters through hydrolysis. However, FeIII ap-
peared to be a superior metal additive.44
Cl
R1
Cl
FeCl2·4H2O, CH3CN, rt
CCl3
N
(93%) N
Cl
N
Cl
R1
FeCl2
(18)
2,6-lutidine, DMF
21 22 HN
NH
NH
(68%)
N
Nitrene Generation. Acyl azides undergo thermolysis at
O
elevated temperatures to generate acylnitrene species.35 In the
presence of iron(II) chloride, N-tert-butyloxycarbonyl azide was
R2
ć%
converted to an intermediate nitrene even at 0 C. The nitrene
R1
O
then added to sulfoxides or sulfones to give sulfoxamines and sul-
fimines, respectively (eq 19). Substitution of other transition metal N
N
salts for iron(II) chloride resulted in poor to no yield.36 An acyl-
N
R1
nitrene species, generated by treatment of (23) with FeCl2, added
N Fe N
to an intramolecular olefin, which was then attacked by chloride
NH
to generate 24 (eq 20).37 The lack of stereospecificity implicates
N
an open radical intermediate as opposed to a concerted aziridina-
O
tion. This same tandem nitrene formation/cyclization/chlorination
strategy also provided 3-amino-2-chloro-D-gylcopyranosides.38
R2 (21)
O
O
BocN3, FeCl2 O
NHBoc
CH2Cl2
S+
S+
(84% ee)
(74%)
(19)
O
O
FeCl2 (0.5 equiv)
O
O N3 FeCl2, TMSCl, CH3CN
N
CH3CN:CHCl3
NH
(70%) N
(quant)
Cl
O
O
24
23
O
O
O O
trans:cis
(20)
O O
(90:10)
O
O
O
O
Coordination Chemistry. Ferrous chloride, as well as other
O O
FeII salts, has been used to generate many supramolecular com-
plexes. In one example, protoheme IX was generated from a pory-
O
phyrin and proved capable of binding oxygen through addition of
O
O
a covalently bound proximal base (eq 21).39 Terpyridines have
O
also been treated with FeCl2 in water to generate ferrous-bound
O
O
dimers. In the presence of LiI and FeII cations, these bifunctional
O
O
O
metal receptors coordinate iron(II) exclusively at the terpyridine
O
O
subunit (eq 22).40
O
O
N O
Miscellaneous. Ferrous chloride has been used increasingly
N
(22)
in a variety of organic transformations due to its lower toxicity
N
N-Fe2+
and cost relative to more traditional transition metal reagents. For
example, it was used as a Lewis acid in the Friedel Crafts acyla-
N
2Cl
O
N
tion of the diacyl chloride (25) to furnish the tricyclic pyrone (26)
O
O
in very good yield (eq 23).41 Iron(II) chloride was also useful as
O O
O
a Lewis acid in the TMS deprotection of sugar (27) (eq 24).42
O
O
Iron(II) chloride tetrahydrate and the pybox ligand (28) gener-
O
O
O
ated a FeII-based asymmetric catalyst in situ capable of perform-
OO
O
ing a Mukaiyama aldol reaction in aqueous media in good yields
and reasonable enantioselectivity (eq 25). Switching to iron(II)
A list of General Abbreviations appears on the front Endpapers
IRON(II) CHLORIDE 5
O
12. Opsenica, I.; Terzic, N.; Opsenica, D.; Angelovski, G.; Lehnig, M.;
Eilbracht, P.; Tinant, B.; Juranic, Z.; Smith, K. S.; Yang, Y. S.; Diaz,
Cl
D. S.; Smith, P. L.; Milhous, W. K.; Dokovic, D.; Solaja, B. A., J. Med.
Chem. 2006, 49, 3790.
1. FeCl2, toluene, 50 °C
O
13. Barton, D. H. R.; Lee, K. W.; Mehl, W.; Ozbalik, N.; Zhang, L.,
2. MeNHOH·HCl
Cl
Tetrahedron 1990, 46, 3753.
KHCO3, EtOAC
(75%) 14. Li, K.-T.; Liu, P.-Y., Appl. Catal. A 2004, 272, 167.
O
15. Vismara, E.; Fontana, F.; Minisci, F., Gazz. Chim. Ital. 1987, 117, 135.
O O
25
OH 16. Roberts, D.; Joule, J. A., Bros, M. A.; Alvarez, M., J. Org. Chem. 1997,
62, 568.
N
17. For reviews, see Rylander, P. N., Hydrogenation Methods; Academic
Press: New York, 1985, p 104.
(23)
O
18. Bjoerk, P.; Malm, J.; Hoernfeldt, A.-B.; Gronowitz, S., Heterocycles
26
1997, 44, 237.
19. Yamada, K.; Kurokawa, T.; Tokuyama, H.; Fukuyama, T., J. Am. Chem.
CN
CN
Soc. 2003, 125, 6630.
OBn
OBn
20. Ullmann, H.; Meis, S.; Hongwiset, D.; Marzian, C.; Wiese, M.; Nickel, P.;
FeCl2
OBn
OBn
Communi, D.; Boeynaems, J.-M.; Wolf, C.; Hausmann, R.; Schmalzing,
(24)
OBn
(77%) OBn
G.; Kassack, M. U., J. Med. Chem. 2005, 48, 7040.
OTMS
OH 21. Sapountzis, I.; Knochel, P., J. Am. Chem. Soc. 2002, 124, 9390.
OBn
OBn 22. Kociolek, M. G.; Straub, N. G.; Menton, E. J., Lett. Org. Chem. 2005, 2,
280.
(27)
23. Kociolek, M. G.; Straub, N. G.; Schuster, J. V., Synlett 2005, 259.
24. Auricchio, S.; Grassi, S.; Malpezzi, L.; Sartori, A. S.; Truscello, A. M.,
Eur. J. Org. Chem. 2001, 1183.
O O
N
25. Johns, B. A.; Gudmundsson, K. S.; Turner, E. M.; Allen, S. H.; Jung,
O
N N
OTMS
10 mol %
D. K.; Sexton, C. J.; Boyd, F. L., Jr.; Peel, M. R., Tetrahedron 2003, 59,
28
9001.
OH HO
+
26. Tokuyama, H.; Makido, T.; Han-ya, Y.; Fukuyama, T., Heterocycles
FeCl2·4H2O
MeO
2007, 72, 191.
EtOH/H2O, 0 °C
(65%) 27. Kamitori, Y.; Hojo, M.; Masuda, R.; Fujishiro, M.; Wada, M.,
Heterocycles 1994, 38, 21.
O OH 28. Moglie, Y.; Alonso, F.; Vitale, C.; Yus, M.; Radivoy, G., Tetrahedron
2006, 62, 2812.
(25)
29. Kauffmann, T.; Huelsduenker, A.; Menges, D.; Nienaber, H.; Rethmeier,
L.; Robbe, S.; Scherler, D.; Schricke, J.; Wingbermeuhle, D.,
OMe
Tetrahedron Lett. 1990, 31, 1553.
dr: 93:7
30. Kathawala, F. G.; Prager, B.; Prasad, K.; Repic, O.; Shapiro, M. J.;
ee: 75%
Stabler, R. S.; Widler, L., Helv. Chim. Acta 1986, 69, 803.
31. Fournier, F.; Fournier, M., Can. J. Chem. 1986, 64, 881.
Related Reagents. Sodium Triethylborohydride Iron(II)
32. Yanada, K.; Yanada, R.; Meguri, H., Chem. Pharm. Bull. 1989, 37, 3423.
Chloride.
33. Ono, A.; Maruyama, T.; Kamimura, J., Synthesis 1987, 1093.
34. Folli, U.; Goldoni, F.; Iarossi, D.; Sbardellati, S.; Taddei, F., J. Chem.
Soc., Perkin Trans. 2 1995, 1017.
1. Fieser & Fieser 1967, 1, 145.
35. Bach, T.; Körber, C., Eur. J. Org. Chem. 1999, 1033.
2. Wilkinson, G., Org. Synth., Coll. Vol. 1963, 4, 473.
36. Bergmeier, S. C.; Stanchina, D. M., J. Org. Chem. 1997, 62, 4449.
3. Wilkinson, G.; Birmingham, J. M., J. Am. Chem. Soc. 1954, 76, 4281.
37. Bach, T.; Schlummer, B.; Harms, K., Chem. Commun. 2000, 287.
4. Nakatani, Y., Tetrahedron Lett. 1970, 4455 (Chem. Abstr. 1971, 74, 31
38. Chung, H. W.; Lee, G. S.; Chung, B. Y., Bull. Korean Chem. Soc. 2002,
594d).
23, 1325.
5. Kijima, M.; Nambu, Y.; Endo, T., Chem. Lett. 1985, 1851.
39. Nakagawa, A.; Ohmichi, N.; Komatsu, T.; Tsuchida, E., Org. Biol. Chem.
6. Barton, D. H. R.; Hay-Motherwell, R. S.; Motherwell, W. B., J. Chem.
2004, 2, 3108.
Soc., Perkin Trans. 1 1983, 445.
40. Hilmey, D. G.; Paquette, L. A., J. Org. Chem. 2004, 69, 3262.
7. Barton, D. H. R.; Boivin, J.; Gastiger, M.; Morzycki, J.; Hay-Motherwell,
41. Lee, T. B. K.; Tebben, A. J.; Weiberth, F. J.; Wang, G. S. K., Synth.
R. S.; Motherwell, W. B.; Ozbalik, N.; Schwartzentruber, K. M., J. Chem.
Commun. 1998, 28, 747.
Soc., Perkin Trans. 1 1986, 947.
42. Hashimoto, H.; Hayakawa, M., Chem. Lett. 1989, 1881.
8. Hotta, K.; Kubomatsu, T., Bull. Chem. Soc. Jpn. 1969, 42, 1447.
43. Jankowska, J.; Paradowska, J.; Mlynarski, J., Tetrahedron Lett. 2006, 47,
9. Pignatello, J. J.; Oliveros, E.; MacKay, A., Crit. Rev. Environ. Sci.
5281.
Technol. 2006, 36, 1.
44. Pogorevc, M.; Strauss, U. T.; Riermeier, T.; Faber, K., Tetrahedron 2002,
10. Haynes, R. K.; Vonwiller, S. C., Tetrahedron Lett. 1996, 37, 257.
13, 1443.
11. Christenson, P. A., Tetrahedron 1988, 44, 1925.
Avoid Skin Contact with All Reagents