Catalytic electrophilic halogenations and haloalkoxylations by non-heme iron halides

Article abstract of DOI:10.1002/adsc.201400316

Synthetic non-heme iron halides promote sub-stoichiometric aliphatic halogenation reactions via a radical mechanism. Complementary to such activity, we have developed an electrophilic halogenation of arenes employing non-heme iron halides. A catalytic version of these reactions has also been developed using potassium halide as the source of halogen atom for arenes at room temperature. Efforts towards understanding the mechanism of these catalytic halogenation reactions led to the discovery of the haloalkoxylation of olefins by a non-heme iron complex. Implications of these findings with respect to natural transformations are also discussed.

Full text of DOI:10.1002/adsc.201400316

COMMUNICATIONS
DOI: 10.1002/adsc.201400316
Catalytic Electrophilic Halogenations and Haloalkoxylations by
Non-Heme Iron Halides
Sujoy Rana,a Sukdev Bag,a Tuhin Patra,a and Debabrata Maitia,*
a
Department of Chemistry, Indian Institute of Technology, Mumbai – 400076, India
E-mail: dmaiti@chem.iitb.ac.in
Received: March 27, 2014; Published online: August 1, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400316.
Abstract: Synthetic non-heme iron halides promote
sub-stoichiometric aliphatic halogenation reactions
via a radical mechanism. Complementary to such
activity, we have developed an electrophilic halo-
genation of arenes employing non-heme iron hal-
ides. A catalytic version of these reactions has also
been developed using potassium halide as the
source of halogen atom for arenes at room temper-
ature. Efforts towards understanding the mecha-
nism of these catalytic halogenation reactions led to
the discovery of the haloalkoxylation of olefins by
a non-heme iron complex. Implications of these
findings with respect to natural transformations are
also discussed.
Scheme 1. Electrophilic halogenation by non-heme iron
halide.
However, no reports of electrophilic halogenation of
arenes are known till date starting with non-heme
iron-halide complexes (Scheme 1).
Keywords: arenes; catalysis; haloalkoxylation; halo-
genation; non-heme iron; olefins
Fujii and co-workers developed an electrophilic
chlorination by employing ironACTHUNTGRNEUNG(III)isoporphyrin com-
plex via formation of ironACTHNURGTNE(UNG III)-meso-chloro-isopor-
phyrin species as active chlorinating source.[7] They
have also reported electrophilic chlorination from
Halogenating enzymes such as myeloperoxidase FeCAHTUNGTRENNUNG
(MPO), chloroperoxidase (CPO), bromoperoxidase formation of a hypochloritoironACHTNUGTRENNUNG
(BPO), a-ketoglutarate-dependent halogenase and Halogenation of electron-rich arenes was also report-
FADH2-dependent halogenase incorporate halogens ed with iron-hydroperoxo species.[8]
in natural products.[1] The majority of these enzymatic
Herein we report electrophilic halogenations reac-
halogenation reactions occurs either via a radical tions with non-heme iron halide complexes. Notably,
(ClC·) or via an electrophilic (hypohalide, e.g., ClOÀ) under the present reaction conditions, aliphatic sub-
mechanism.[2] Heme peroxidases (MPO, CPO, etc.) strates remain unreacted. Initially, we used crystallo-
catalyze oxidation of ClÀ to ClOÀ via formation of graphically characterized [(TPA)Fe(II)Cl2] (1)[6] and
a transient hypochloritoironACHTUNTRGNEUNG(III)porphyrin intermedi- [(TPA)Fe(II)Br2] (2) complexes [TPA=tris(2-pyridyl-
ate which is responsible for the electrophilic halogen- methyl)amine] for halogenation in ther presence of
ation reactions.[1c,e,3] In the case of non-heme iron en- iodosylbenzene (PhIO) as an oxidant in CH3CN/
zymes like a-ketoglutarate-dependent halogenase and MeOH at room temperature using 1,3,5-trimethoxy-
FADH2-dependent halogenase, a halide radical re- benzene as a model substrate under anaerobic condi-
bound mechanism has been proposed.[1d]
tions (Figure 1). A catalytic version of these halogena-
Halogenations of aliphatic substrates involving the tion reactions was subsequently developed with non-
synthetic non-heme iron halide complex, halide complexes [(TPA)Fe(II)(CH3CN)2](ClO4)2
[(TPA)Fe
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
(III)Cl2]+ were reported by Que and co- (3)[6] using an external halide (e.g., KCl and KBr) in
workers.[4] Such a halide radical-based reaction was the reaction mixture. Preliminary mechanistic investi-
further investigated by Comba and co-workers.[5] gations of these halogenation reactions led to the dis-
Adv. Synth. Catal. 2014, 356, 2453 – 2458
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2453

COMMUNICATIONS
Sujoy Rana et al.
Table 1. Substrate scope for chlorination and bromination.
Figure 1. ORTEP diagram of complex [(TPA)Fe(II)Cl2]
(1)[6] and [(TPA)Fe(II)Br2] (2). CCDC 964429 (2) contains
the supplementary crystallographic data for this
paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Scheme 3. Catalytic chlorination by non-heme iron species.
Scheme 2. Haloalkoxylation of olefins by non-heme iron.
Changes in the UV-vis spectra during halogenation
covery of the haloalkoxylation of olefins by a non- reactions were recorded at À708C. Complex 2 gave
heme iron complex (Scheme 2). absorption maxima at 402 nm in CH2Cl2. Upon addi-
A 90% yield (isolated) of 2-chloro-1,3,5-trimeth- tion of PhIO in methanol, the peak shifted towards
oxybenzene was obtained using optimized conditions the UV region and a shoulder was observed at
involving and PhIO. Other oxidants like 352 nm (Figure 2), which is suggestive of the forma-
PhI(OCOCH3)2, PhI(OCOCF3)2 and IBX can also be tion of iron(III) species under the reaction condi-
used for this reaction.[9] But H2O2 was found to be tions.[10]
less efficient for this reaction, whereas TBHP failed The choice of solvent was found to be crucial for
to give a halogenated product. Similar to chlorination these halogenation reactions. Chlorination reactions
from 1, bromination of TMB was achieved in 95% using [(TPA)Fe(II)(CH3CN)2] (ClO4)2 (3) and KCl in
ACHTUNGTRENNUNG
1
N
N
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
isolated yield with complex 2 (Table 1). Subsequently acetonitrile as solvent resulted in only a trace amount
we tested other arenes using the standard reaction (<5%) of 2-chloro-1,3,5-trimethoxybenzene. A com-
protocol. Naphthalene derivatives provided excellent bination of CH3CN/MeOH drastically increased the
yields for both chlorination and bromination. Anisole yield and even the halogenation reaction can be made
gave ortho/para regioisomeric halogenated products catalytic using KCl (Scheme 3) in this solvent mixture.
under the present reaction conditions (Table 1). En- Hence the generation of a methanol/methoxy-based
couraged by these findings, we developed the catalytic iron complex was hypothesized and formation of such
version (TON 5, Scheme 3) of this halogenation reac- a species (Scheme 4) was further verified by experi-
tion starting with non-halide containing complex mental observations (vide infra).
[(TPA)Fe(II)
G
G
We have detected the reactive intermediate by ESI-
external halides such as KCl and KBr.
MS at À788C. Upon addition of iodosylbenzene to
2454
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 2453 – 2458

COMMUNICATIONS
Catalytic Electrophilic Halogenations and Haloalkoxylations
(III)I
(OCH3)(Br)]+ (6), m/z=
ACHTUNGTRENNUNG
Figure 2. UV-vis spectra changes of 2 upon addition of
PhIO.
Figure 3. ESI-MS of [(TPA)Fe
456.0240 and [(TPA)Fe
ACTHNUGERTN(NUNG III)ACHTUGNTRENNNUG
(OCD3)(Br)]+ (6-d3), m/z=
459.0434.
a solution of 1 and 1,3,5-trimethoxybenzene, ESI-MS
showed the formation of [(TPA)Fe
A
C
The complex 2 produced [(TPA)Fe(IV)(O)Br]+ in
(5). clear mass pattern for [(TPA)FeACTHUNGTRENNNUG
A
(III)- acetonitrile at À408C upon addition of PhIO (ESI-
ACHTUNGTRENNUNG
(OCH3)(Br)]+ (6) was also observed by adding PhIO MS, Figure 4).[5] In order to investigate relevance of
to [(TPA)Fe(II)Br2] (2) in CH2Cl2/MeOH (2:3). La- XOÀ/X+ (X=Cl, Br) for the observed electrophilic
belling experiments using a CH2Cl2/CD3OD mixture halogenation of arenes, we have carried out a phenol
produced
[(TPA)Fe
G
G
(6-d3) red experiment. Oxidation of phenol red via electro-
(Figure 3). In the absence of exogenous arene sub- philic aromatic halogenation was confirmed by a UV-
strates, intermediate 5 or 6 can also be generated at vis study, which resulted in characteristics peak at
À788C. As expected, upon addition of 1,3,5-trime- 597 nm for bromophenol blue formation.[9,11] More-
thoxybenzene, these species were consumed with re- over chlorination of anisole with complex 1 (Table 1)
spect to time. We have also observed formation of gave only monochlorinated product. Such a product
these intermediates starting with non-halide com- formation can also rule out the possibility of a radical
plexes 3 and ironACHTUNGTRENNUNG(III)complex, [(TPA)FeACHTUNGTREN(NUGN III)Cl2]ClO4
(4). Similar to complexes 1–3, 4 produced chloroarene
under the standard reaction conditions. The complex
3 produced 5 in the presence of KCl as external
halide source. Deuterium labelling experiments with
CD3OD were also carried out successfully using 3 and
4.
Figure 4. ESI-MS of complex (TPA)Fe(II)(Br)+ (2), m/z=
425.0124 and complex [(TPA)Fe(IV)(O)Br]+ m/z=
,
Scheme 4. Halogenation by non-heme iron species.
441.0087.
Adv. Synth. Catal. 2014, 356, 2453 – 2458
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2455

COMMUNICATIONS
Sujoy Rana et al.
Figure 5. EPR spectrum upon addition of PhIO to
1 (MeOH).
Scheme 6. Proposed mechanism for observed halogenation.
generated during the reaction, halomethoxylation of
the olefin may be expected. Interestingly, styrene de-
rivatives produced 2-halo-1-methoxyethylbenzene de-
rivatives under the reaction conditions in excellent
Scheme 5. Catalytic chlorination by non-heme iron species.
halogenation since several isomeric chlorinated prod- yields (Table 2). Without an iron compound, such
ucts are expected for a radical mechanism.[8b]
a haloalkoxylation was not observed. Furthermore,
The EPR spectrum was recorded (liquid N2) upon a catalytic version of this reaction was also discovered
addition of PhIO to [(TPA)Fe(II)Cl2] (1) in CH3CN/ with TON 6 (Scheme 5).[9]
MeOH. We have qualitatively estimated the g tensors
which are at the values g1 =2.03, g2 =4.19, g3 =6.55 halogenation of alkyl substrate occur from
(Figure 5). This suggests a rhombic geometry with an (L)Fe
(III)(Cl)(OH) via radical mechanism,[1d,4,5] in
S=5/2 ground state arising from high-spin Fe(III) this present study we discovered that the in situ
species.[12] Busch and co-workers have reported very
similar EPR spectra for a Fe(III)-high-spin complex
Unlike non-heme iron halogenase enzymes where
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Table 2. Halomethoxylation of olefins by non-heme iron.
(g1 =2.0, g2 =4.3, g3 =6.0) with a tetradentate nitrogen
ligand which showed rhombic anisotropy.[12a] Similar
EPR spectra of high-spin iron complexes were ob-
tained when PhIO/KCl was added to a solution of 2
and 3.[9] Combining all the experimental observations
(UV-vis, EPR and ESI-MS, including labelling stud-
ies), high-spin iron
ACHTUNGTNER(NUNG III)-methoxy-halide complex
[(TPA)Fe(III)
N
ACHTUNGTRENNUNG
Scheme 4 and Scheme 6) was proposed under the re-
action conditions.
Compounds 5 and 6 can produce 8, which is the
key intermediate for electrophilic halogenation of
arenes upon reacting with PhIO. As depicted in
Scheme 6, formation of [(TPA)Fe(IV)ACTHNUTRGNEUNG
(OMe)(X)]2+
(7) can be envisioned from 1 and 2 in PhIO/
MeOH.[13] In spite of our best efforts, we failed to
detect such an intermediate by spectroscopic tech-
niques. However if such an intermediate is transiently
2456
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 2453 – 2458

COMMUNICATIONS
Catalytic Electrophilic Halogenations and Haloalkoxylations
(OCH3)(X)]+ (5 and 6) complex
formed [(L)FeACHTUNGTRENNUNG(III)ACHUTNGTRENNUGN
Br. J. Pharmacol. 2007, 152, 838–854; c) J. H. Dawson,
M. Sono, Chem. Rev. 1987, 87, 1255–1276; d) F. H. Vail-
lancourt, E. Yeh, D. A. Vosburg, S. Garneau-Tsodiko-
va, C. T. Walsh, Chem. Rev. 2006, 106, 3364–3378; e) R.
Rutter, L. P. Hager, J. Biol. Chem. 1982, 257, 7958–
7961; f) M. Hofrichter, R. Ullrich, Appl. Microbiol.
Biotechnol. 2006, 71, 276–288; g) A. Butler, M. Sandy,
Nature 2009, 460, 848–854; h) J. A. Manthey, L. P.
Hager, Biochemistry 1989, 28, 3052–3057; i) J. A. Man-
they, L. P. Hager, J. Biol. Chem. 1985, 260, 9654–9659;
j) M. P. Roach, Y. P. Chen, S. A. Woodin, D. E. Lincoln,
C. R. Lovell, J. H. Dawson, Biochemistry 1997, 36,
2197–2202.
can produce electrophilic aromatic halogenation reac-
tion of arenes. Aliphatic substrates remain unreactive.
Interestingly, complementary to Natureꢁs selective ali-
phatic halogenation over hydroxylation from the
(L)FeACHTUNGTRENNUNG
(III)(Cl)(OH) intermediate,[14] we observed
>99% selectivity for aromatic halogenation over me-
thoxylation (Scheme 4).[1d] Note that, only in case of
1,3,5-trimethoxybenzene and 2-methoxynaphthalene
as substrate (Table 1), we have detected ~1% arene
methoxylation product along with halogenation.
In summary, we have developed unprecedented
electrophilic halogenations of arenes starting with
non-heme iron halide complexes. A high-spin iron-
[2] a) K. H. van Pee, C. J. Dong, S. Flecks, J. Naismith,
E. P. Patallo, T. Wage, in: Advances in Applied Micro-
biology, Vol 59, Elsevier Academic Press Inc, San
Diego, 2006, pp 127–157; b) J. L. R. Anderson, S. K.
Chapman, Mol. Biosyst. 2006, 2, 350–357; c) D. G. Fuji-
mori, C. T. Walsh, Curr. Opin. Chem. Biol. 2007, 11,
553–560.
[3] a) Z. Q. Cong, S. Yanagisawa, T. Kurahashi, T. Ogura,
S. Nakashima, H. Fujii, J. Am. Chem. Soc. 2012, 134,
20617–20620; b) L. P. Hager, D. R. Morris, F. S. Brown,
H. Eberwein, J. Biol. Chem. 1966, 241, 1769–1777.
[4] T. Kojima, R. A. Leising, S. P. Yan, L. Que Jr, J. Am.
Chem. Soc. 1993, 115, 11328–11335.
ACHTUNGTRENNUNG(III)methoxy-halide complex, which generates iron
hypohalide upon addition of PhIO, was proposed to
be the active halogenating species. Also, haloalkoxy-
lation of olefins by the non-heme iron complex has
been discovered based on mechanistic understanding
of the halogenation reaction described herein. Both
the electrophilic halogenation and haloalkoxylation
reactions can be made catalytic using potassium
halide. Detailed mechanistic investigation of these re-
actions is currently undergoing in our laboratory.
[5] a) P. Comba, S. Wunderlich, Chem. Eur. J. 2010, 16,
7293–7299; b) J. Bautz, P. Comba, C. L. d. Laorden, M.
Menzel, G. Rajaraman, Angew. Chem. 2007, 119, 8213–
8216; Angew. Chem. Int. Ed. 2007, 46, 8067–8070; c) D.
Wang, K. Ray, M. J. Collins, E. R. Farquhar, J. R.
Frisch, L. Gomez, T. A. Jackson, M. Kerscher, A. Wale-
ska, P. Comba, M. Costas, L. Que Jr, Chem. Sci. 2013,
4, 282–291; d) W. N. Oloo, Y. Feng, S. Iyer, S. Parmelee,
G. Xue, L. Que Jr, New J. Chem. 2013, 37, 3411–3415;
e) J.-U. Rohde, A. Stubna, E. L. Bominaar, E. Munck,
W. Nam, L. Que Jr, Inorg. Chem. 2006, 45, 6435–6445.
[6] D. Mandon, A. Machkour, S. Goetz, R. Welter, Inorg.
Chem. 2002, 41, 5364–5372.
Experimental Section
General Procedure for halogenation and
halomethoxylation
In a 20-mL screw-cap reaction tube [Fe(II)
Cl, Br) (1, 2) or [Fe(II)(TPA)(CH3CN)2]
ACHTUNGTRENNUNG
N
G
ACHTUNGTRENNUNG
(0.125 mmol or 0.1 mmol) of the prepared non-heme com-
plexes were charged. Subsequently 0.125 mmol (0.25/
0.5 mmol of substrates for halomethoxylation) starting mate-
rial (1 mmol for catalytic reaction) and MeOH/DCM or
MeOH/MeCN (3:2) were added to the reaction tube. For
halomethoxylation MeOH (5 mL) was used. Then PhIO
(0.3 mmol) was added to the reaction mixture. The whole
reaction was set inside the glove box. The reaction mixture
was stirred for 24 h. After that the reaction tube was re-
moved from the glove box and the reaction mixture was fil-
tered through the celite and washed twice with ethyl acetate.
The filtrate was used for GC-MS, GC analysis and isolation.
[7] Z. Q. Cong, T. Kurahashi, H. Fujii, J. Am. Chem. Soc.
2012, 134, 4469–4472.
[8] a) A. K. Vardhaman, C. V. Sastri, D. Kumar, S. P. de
Visser, Chem. Commun. 2011, 47, 11044–11046;
b) A. K. Vardhaman, P. Barman, S. Kumar, C. V. Sastri,
D. Kumar, S. P. de Visser, Chem. Commun. 2013, 49,
10926–10928.
[9] See the Supporting Information for detailed descrip-
tions.
[10] a) F. S. Mei, C. P. Ou, G. L. Wu, L. Cao, F. Han, X. G.
Meng, J. Li, D. F. Li, Z. R. Liao, Dalton Trans. 2010, 39,
4267–4269; b) C. R. Goldsmith, R. T. Jonas, T. D. P.
Stack, J. Am. Chem. Soc. 2002, 124, 83–96.
Acknowledgements
[11] J. V. Walker, M. Morey, H. Carlsson, A. Davidson,
G. D. Stucky, A. Butler, J. Am. Chem. Soc. 1997, 119,
6921–6922.
[12] a) T. J. Hubin, J. M. McCormick, N. W. Alcock, D. H.
Busch, Inorg. Chem. 2001, 40, 435–444; b) F. Namuswe,
T. Hayashi, Y. B. Jiang, G. D. Kasper, A. A. N. Sarjeant,
P. Moenne-Loccoz, D. P. Goldberg, J. Am. Chem. Soc.
2010, 132, 157–167; c) Y. Zang, J. Kim, Y. H. Dong,
E. C. Wilkinson, E. H. Appelman, L. Que, J. Am.
Chem. Soc. 1997, 119, 4197–4205; d) N. Y. Oh, M. S.
This activity is supported by DST, India. Financial support
has been received from CSIR, India (fellowships to S.R. and
S.B.), UGC, India (fellowship to T.P.).
References
[1] a) S. J. Klebanoff, J. Leukoc. Biol. 2005, 77, 598–625;
b) E. Malle, P. G. Furtmuller, W. Sattler, C. Obinger,
Adv. Synth. Catal. 2014, 356, 2453 – 2458
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2457

COMMUNICATIONS
Sujoy Rana et al.
Seo, M. H. Lim, M. B. Consugar, M. J. Park, J. U.
Rohde, J. H. Han, K. M. Kim, J. Kim, L. Que, W. Nam,
Chem. Commun. 2005, 5644–5646; e) B. Chakraborty,
T. K. Paine, Angew. Chem. 2013, 125, 954–958; Angew.
Chem. Int. Ed. 2013, 52, 920–924.
[13] J. T. Groves, R. Quinn, T. J. McMurry, M. Nakamura,
G. Lang, B. Boso, J. Am. Chem. Soc. 1985, 107, 354–
360.
[14] M. G. Quesne, S. P. de Visser, J. Biol. Inorg. Chem.
2005, 17, 841–852.
2458
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 2453 – 2458