Selective halogenation of CH bonds on porphyrin rings using NaX/H2O2

Article abstract of DOI:10.1246/cl.150604

The selective oxidative halogenation of CH bonds on porphyrins by halides/H₂O₂ is achieved. Different activities are observed for the three types of aromatic CH bonds on porphyrin ring: meso-H is halogenated preferentially, the β'-H

Full text of DOI:10.1246/cl.150604

Received: June 22, 2015 | Accepted: July 2, 2015 | Web Released: July 11, 2015
CL-150604
Selective Halogenation of C-H Bonds on Porphyrin Rings Using NaX/H2O2
Mi Tian,1 Shi Chen,1 Wenbing Sheng,1,2 Hui Huang,1 and Cancheng Guo*1
1College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China
2College of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, P. R. China
(E-mail: ccguo@hnu.edu.cn)
Table 1. Halogenation of tetraphenylporphyrin
The selective oxidative halogenation of C-H bonds on
porphyrins by halides/H2O2 is achieved. Different activities are
observed for the three types of aromatic C-H bonds on
porphyrin ring: meso-H is halogenated preferentially, the ¢-H
could be substituted by Br or I, whereas benzo-C-H bonds
remain intact. The reaction proceeds smoothly in a pseudo
heterogeneous system and provides an alternative eco-friendly
and efficient protocol for the synthesis of haloporphyrins.
Ph
Ph
X
NH
N
N
NH
N
N
H2O2/NaX
HOAc r.t.
Ph
Ph
Ph
Ph
HN
HN
Ph
Ph
2a X = Br 28%
1
2b
X = I 11%
Porphyrins, one type of important aromatic macrocycles,
have been widely applied in catalysis, material sciences, and
biology.1 The performance of porphyrins in these fields
generally depends on their peripheral substituents. Haloporphy-
rins are usually found to serve as the best organic synthetic
intermediates for the synthesis of such substituted porphyrins,
particularly unsymmetrical porphyrins, by aromatic nucleophilic
substitution (SNAr) reactions and transition-metal-catalyzed
cross-coupling reactions,2 thus the selective direct halogenation
of distinct C-H bonds on porphyrin ring have been widely
investigated. Previous halogenation of porphyrin strongly
depends on the toxic molecular halogen or organohalides
generated from X2. For example, Krishnan synthesized ¢-
octabromotetraphenylporphyrin by reacting copper tetraphenyl-
porphyrin with excess Br2.3 Burn achieved ¢-position chlorina-
tion of free-base porphyrins by pseudohalogens.4 Nudy realized
bromination of meso-C-H bonds of porphine by dibromoiso-
cyanuric acid or PyHBr/Br2.5 Chen et al. also chlorinated
porphyrins at meso positions using PhICl2 as the halogen
source.6 In addition, halogenated amides were used widely to
prepare meso-chloro/bromoporphyrins or ¢-bromotetraphenyl-
porphyrins.7
Halide
(equiv)
Yieldb
/%
Entrya
Solvent
1
2
3
HOAc
HOAc
HOAc
NaCl (5)
NaBr (5)
NaI (5)
®
28
11
a2.5 mmol L¹1 prophyrin, 5 equiv of 30% H2O2 stirred for 24 h
at room temperature. Measured by HPLC.
b
present, the ¢-H could be substituted by Br or I, whereas benzo-
C-H bonds were unreactive. The substituent porphyrins or metal
porphyrins showed similar reactivity.
Initially, 5,10,15,20-tetraphenylporphyrin (1) was selected
as the model substrate to react with NaX/H2O2 (Table 1).13
Although the chlorination of 1 failed, the bromination and
iodination afforded the corresponding ¢-halogenated products
selectively in 28% and 11% yields, respectively, indicating that
the ¢-C-H bonds on a porphyrin ring can be halogenated by
such a system and the C-H bonds on the benzene ring are
unreactive. Obviously, the activity of halogens increased as
Cl < Br < I . However, the lower yield of iodoporphyrin was
unexpected. This is probably ascribed to the formation of the
labile hypoiodous which easily decomposes to unreactive I2.7a
This hypothesis was proved by heating the reaction mixture and
recovering 72% sublimated I2.
Subsequently, 5,10,15-triphenylporphyrin (3) was synthe-
sized following a literature method14 to investigate the reactivity
of meso-C-H bonds and ¢-C-H bonds. The results summarized
in Table 2 showed that the halogenation of meso-C-H bonds
proceeded preferentially. All the chlorination reactions were
successful, and the meso-chloroporphyrins were obtained regio-
selectively. The Lewis acids, TiCl4 and AlX3, which were first
used as the halogen source, afforded chloroporphyrin in 99%
and 38% yields, respectively (Entries 1 and 2). Considering the
generation of HCl from the hydrolysis of Lewis acids in the
presence of water, equivalent HCl was loaded as the chlorinated
reagent and also gave 4a in a moderate yield under similar
conditions (68%, Entry 3). The excellent reactivity of TiCl4 may
be partially ascribed to the catalytic capability of Ti cation.15
Using the combination of NaCl/H2SO4 instead of HCl solution,
this chlorination also proceeded smoothly (65%, Entry 4). The
¹
¹
¹
¹
The combination of H2O2/X /H+ is a green oxidative
halogenative system that is capable of selectively halogenating
C-H bonds of simple arenes,8 e.g. aniline and toluene were
chlorinated at the ortho position of substituents by using an
excess of HCl/H2O2 in hot alcohol.9 The bromination at ortho-/
para-positions of anilines and anisoles was achieved by using
NH4Br/H2O2/HOAc at room temperature.10 Ortho-/para-C-H
bonds of aniline were also iodinated quantitatively in a H2SO4/
KI/H2O2 system.11 Under microwave-assistant reaction condi-
tions, the polycyclic aromatic hydrocarbons like anthraquinone
also were halogenated by HX/H2O2.12 However, to the best
of our knowledge, the oxidative halogenation of macrocycle
molecules has not been reported. Porphyrin is a special
macrocycle with three types of special aromatic C-H bonds
(meso-, ¢-, and potential benzo-). Herein, we report the selective
oxidative halogenation of C-H bonds on porphyrin ring by using
the combination of H2O2 and an inorganic halogen. It is shown
that oxidative halogenation works smoothly and selectively:
meso-H was substituted preferentially, when meso-H was not
Chem. Lett. 2015, 44, 1383–1385 | doi:10.1246/cl.150604
© 2015 The Chemical Society of Japan | 1383

Table 2. Halogenation of 5,10,15-triphenylporphyrin
Ph
Ph
NH
N
N
NH
N
N
H2O2/X-/acid
Solvent
X
H
Ph
Ph
HN
HN
Ph
Ph
4a
4b
X = Br
X = Cl,
3
Prophyrin
/mmol L
Temp.
/°C
Time
/h
Yielda
/%
Entry
Solvent
H2O2 (equiv)
Halide (equiv)
¹1
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
HOAc
HOAc
HOAc
CH2Cl2
HOAc
HOAc
HOAc
2.5
2.5
2.5
2.5
1
1
10
1
H2O2 (5)
H2O2 (5)
H2O2 (5)
H2O2 (5)
H2O2 (5)
H2O2 (5)
H2O2 (10)
H2O2 (5)
H2O2 (5)
H2O2 (10)
H2O2 (5)
TiCl4 (0.5)
AlCl3 (0.66)
HCl (2)b
25
25
25
25
25
25
60
25
25
60
25
24
24
24
24
24
24
4
24
24
4
99
38
68
65
74
99
99
99
H2SO4 (2.5); NaCl (2)b
NaCl (2)
NaCl (5)
NaCl (2)
AlBr3 (2)
NaBr (2)
NaBr (2)
NaI (2)
1
10
1
99
99
10
11
24
complicated
b
aMeasured by HPLC. Dissolved in 1:5 H2O-MeOH.
Table 3. Halogenation of 5,15-disubstituted porphyrina
present oxidative halogenation was also achieved in the weak
acidic system (HOAc/NaCl) to give the desired product 4a in
good yield (74%, Entry 5). Interestingly, almost quantitative
yield was obtained under similar reaction conditions when the
R
R
N
N
N
N
N
N
N
N
¹1
concentration was increased to 10 mmol L (Entry 7).16 This
H2O2/NaX
HOAc
M
X
M
X
result probably was attributed to the poor solubility of
haloporphyrin in HOAc, which precipitated during the reaction.
This result also indicated more amount of substrate could be
employed under the reaction conditions.
R
R
6
Similar results were obtained in the bromination of 3.
Although Br can substitute the ¢-H on porphyrin, no ¢-
bromoporphyrin was detected under the reaction conditions
indicating much higher reactivity of meso-C-H bonds than ¢-
C-H bonds (Entries 8-10). Unfortunately, the iodination failed
and a mixture was afforded. As indicated from the MS and
1H NMR spectrum, both ¢-iodinated porphyrins and meso-
iodinated porphyrins were generated. (Entry 11, for MS and
1H NMR spectrum, see pages 4-6 in SI).
Then, 5,15-diphenylporphyrin bearing two meso-C-H
bonds was synthesized17 and treated with NaX/H2O2 under
the optimal conditions. Both of meso-C-H bonds on porphyrin
ring were chlorinated or brominated regioselectively to produce
the dihalogenated products 6a and 6b in high yields (Table 3,
Entries 1 and 2). Other selected 5,15-diaryl-substituted porphy-
rins with electron-withdrawing group or electron-donating
groups on the benzene rings, 5,15-dialkyl-substituted porphrins
and metal prophyrins were tested under the same conditions and
gave similar results (Table 3, Entries 3-8).
5
Halide
(equiv)
Isolated yield
/%
Entry
R
M
1
2
3
4
5
6
7
8
Ph
Ph
2H
2H
2H
2H
2H
2H
Ni
NaCl (5)
NaBr (5)
NaCl (5)
NaCl (5)
NaCl (5)
NaCl (5)
NaCl (5)
NaCl (5)
6a, 96
6b, 97
6c, 97
6d, 96
6e, 94
6f, 91
6g, 93
6h, 86
p-ClC6H4
p-MeC6H4
p-MeOC6H4
n-C6H13
Ph
Ph
Cu
a10 mmol L porphyrin, 10 equiv of 30 wt % H2O2, 60 °C
¹1
stirred for 5.5 h.
reagent replacing the combination of H2O2/NaCl, indicating
that NaClO would be the active intermediate (Entry 2). In the
presence of radical scavenger 2,2,6,6-tetramethylpiperidinyloxy
(TEMPO) or 2,6-dibutylhydroxyltoluene (BHT), 3 could also be
chlorinated readily, implying that this reaction would not be a
radical process (Entries 3 and 4). Thus, this reaction probably
In an effort to get some information on the mechanism,
several control experiments were performed (Table 4). In the
absence of chlorinated reagent, 3 did not decompose and was
recovered quantitatively (Entry 1). This chlorination also occur-
red when 2 equiv NaClO was employed as the chlorinated
¹
takes place via a reaction path involving the oxidation of X
by H2O2 to generate hypohalous species, which subsequently
1384 | Chem. Lett. 2015, 44, 1383–1385 | doi:10.1246/cl.150604
© 2015 The Chemical Society of Japan

Table 4. Control experimentsa
3
4
P. Bhyrappa, V. Krishnan, Inorg. Chem. 1991, 30, 239.
W. Zhang, M. N. Wicks, P. L. Burn, Org. Biomol. Chem.
2008, 6, 879.
L. R. Nudy, C. Schieber, F. R. Longo, V. S. Agarwala,
Heterocycles 1987, 26, 1797.
4a
3
H2O2
/equiv
Yieldb
/%
5
6
7
Entry
Halide (equiv)
1
2c
10
5
®
®
66
L.-M. Jin, J.-J. Yin, L. Chen, C.-C. Guo, Q.-Y. Chen, Synlett
2005, 2893.
NaClO (2)
NaCl (2)
BHT (11)
NaCl (2)
TEMPO (11)
a) P. Bhyrappa, V. Velkannan, Tetrahedron Lett. 2010, 51,
40. b) G.-Y. Gao, J. V. Ruppel, D. B. Allen, Y. Chen, X. P.
Zhang, J. Org. Chem. 2007, 72, 9060. c) S. Ito, L. T. Phong,
T. Komatsu, N. Igarashi, S. Otsubo, Y. Sakai, A. Ohno, S.
Aramaki, Y. Tanaka, H. Uno, T. Oba, K. Hiratani, Eur. J.
Org. Chem. 2009, 5373.
a) V. V. K. M. Kandepi, N. Narender, Synthesis 2012, 44, 15.
b) A. Podgoršek, M. Zupan, J. Iskra, Angew. Chem., Int. Ed.
2009, 48, 8424.
3
4
10
10
95
89
a10 mmol L porphyrin, 10 equiv 30 wt % H2O2, 60 °C stirred
¹1
b
c
¹1
for 4 h. Measured by HPLC. 1 mmol L porphyrin, 5 equiv
30 wt % H2O2, 25 °C stirred for 24 h.
8
9
reacts with porphyrins to produce the corresponding halopor-
phyrins.18
a) S. Mukhopadhyay, S. B. Chandalia, Org. Process Res.
Dev. 1999, 3, 10. b) S. Mukhopadhyay, K. H. Chandnani,
S. B. Chandalia, Org. Process Res. Dev. 1999, 3, 196.
In summary, C-H bonds on porphyrin ring can be
selectively halogenated by using the combination of H+/X /
10 K. V. V. Krishna Mohan, N. Narender, P. Srinivasu, S. J.
Kulkarni, K. V. Raghavan, Synth. Commun. 2004, 34, 2143.
11 J. Iskra, S. Stavber, M. Zupan, Synthesis 2004, 1869.
12 a) P. V. Vyas, A. K. Bhatt, G. Ramachandraiah, A. V.
Bedekar, Tetrahedron Lett. 2003, 44, 4085. b) D. Bogdal, M.
Lukasiewicz, J. Pielichowski, Green Chem. 2004, 6, 110.
13 Typical procedure: 30.7 mg of 1 was dissolved in 50 mL of
acetic acid, and then 5 equiv of H2O2 and sodium halide
were added. The mixture was stirred at room temperature for
24 h and then neutralized with a sodium carbonate solution
and extracted with dichloromethane. The crude product was
purified by flash column chromatography on silica gel eluted
with methylene chloride/hexane (1:3) to give the product.
14 J. Wojaczyński, L. Latos-Grażyński, P. J. Chmielewski, P.
Van Calcar, A. L. Balch, Inorg. Chem. 1999, 38, 3040.
15 J. V. Walker, M. Morey, H. Carlsson, A. Davidson, G. D.
Stucky, A. Butler, J. Am. Chem. Soc. 1997, 119, 6921.
16 The starting material porphyrin did not dissolve completely
in the acetic acid.
¹
H2O2. The chlorination and bromination reactions of porphyrin
exhibited the regioselectivity to meso-C-H bond, the bromina-
tion and iodination reactions also occurred at the ¢-position
when the meso-C-H was absent. This transformation represents
the first selective oxidative halogenation of aromatic macro-
¹
cyclic compounds in the green H+/X /H2O2 system, and also
provides an alternative eco-friendly and efficient strategy for the
synthesis of haloporphyrins under mild reaction conditions.
This work was supported by NSFC (No. 21372068).
Supporting Information is available electronically on J-STAGE.
References and Notes
1
a) A. V. Solomonov, E. V. Rumyantsev, E. V. Antina,
Monatsh. Chem. 2013, 144, 1743. b) M. Zhao, S. Ou, C.-D.
Wu, Acc. Chem. Res. 2014, 47, 1199. c) L.-L. Li, E. W.-G.
Diau, Chem. Soc. Rev. 2013, 42, 291.
2
a) Q. Chen, Y.-Z. Zhu, Q.-J. Fan, S.-C. Zhang, J.-Y. Zheng,
Org. Lett. 2014, 16, 1590. b) T. Takanami, Heterocycles
2013, 87, 1659. c) K. Fujimoto, H. Yorimitsu, A. Osuka,
Org. Lett. 2014, 16, 972.
17 J. S. Manka, D. S. Lawrence, Tetrahedron Lett. 1989, 30,
6989.
18 N. Narender, K. S. K. Reddy, K. V. V. Krishna Mohan, S. J.
Kulkarni, Tetrahedron Lett. 2007, 48, 6124.
Chem. Lett. 2015, 44, 1383–1385 | doi:10.1246/cl.150604
© 2015 The Chemical Society of Japan | 1385