Simple and catalyst-free synthesis of meso -O-, -S-, and -C-substituted porphyrins

Article abstract of DOI:10.1021/ol500191j

A simple and efficient method for the meso-functionalization of porphyrin has been developed. Kinetic studies of meso-fluoro-, -chloro-, -bromo-, -iodo-, and -nitro-substituted porphyrins (Ni) with phenol reveal that the reaction undergoes a typical aroma

Full text of DOI:10.1021/ol500191j

Letter
pubs.acs.org/OrgLett
Simple and Catalyst-Free Synthesis of meso-O‑, -S‑, and
-C‑Substituted Porphyrins
Qiang Chen, Yi-Zhou Zhu,* Qiao-Jun Fan, Shao-Chun Zhang, and Jian-Yu Zheng*
State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A simple and efficient method for the meso-
functionalization of porphyrin has been developed. Kinetic
studies of meso-fluoro-, -chloro-, -bromo-, -iodo-, and -nitro-
substituted porphyrins (Ni) with phenol reveal that the
reaction undergoes a typical aromatic nucleophilic substitution
(SNAr) process. This catalyst-free method can be performed
with meso-brominated porphyrins and oxygen-, sulfur-, and
carbon-based nucleophiles to achieve a wide variety of meso-
substituted porphyrins.
orphyrins are an important class of functional molecules in
nature and have shown diverse potential applications in
P
catalysis, material science, medicine, and so forth.1 The
performance of porphyrins in these areas has often been
found to be intimately dependent on their peripheral
substituents.2 Considerable efforts have therefore been devoted
to the synthesis of such structures, especially on the
unsymmetrically substituted porphyrins.2 The outer rim
substituents, until now, have been mostly introduced into the
pyrrole and aldehyde precursors before the porphyrin-forming
procedure.3 However, this method often results in mixed
condensation products and needs a tedious chromatographic
workup. Likewise, use of acid-labile groups and sterically
hindered residues is problematic.4 Thus, interest has shifted
toward the use of a postmodification strategy to obtain
unsymmetrically substituted porphyrins via direct derivatization
of easily accessible porphyrin synthons such as haloporphyrin,
formylporphyrin, and nitroporphyrin synthesized by classic but
still useful electrophilic substitutions.5 Recently, efforts have
mainly been focused on the nucleophilic reactions of meso-
unsubstituted porphyrins with organometallic reagents followed
by oxidation6 and transition-metal-catalyzed C−heteroatom7 or
C−C bond formation reactions.8 But the metal reagents and
specific ligands involved in these methods will hamper their
widespread applications. Thus, there remains a need to develop
an alternative way to achieve these unsymmetrically substituted
porphyrins with improved generality and practicality.
Figure 1. SNAr reactions of meso-substituted porphyrins (Ni) with
various nucleophilic substrates.
The meso-brominated porphyrin 5-bromo-10,20-di(3,5-di-
tert-butylphenyl)-15-phenylporphyrin (1a), which can be
readily prepared via convenient bromination, and its metal
complexes (1b, 1c, and 1d) have been initially used as
representative halogenated porphyrin precursors to evaluate the
reaction conditions. As shown in Table 1, the solvent is found
to be critical for the transformation. The reaction went
smoothly in DMF (entry 1), while no reaction occurred in
toluene or 1,4-dioxane (entries 2 and 3). That can be ascribed
to the effective transition-state stabilization by amide solvent.11
Further screening of bases indicated that Cs2CO3 worked best
for the synthesis, and partial decomposition of starting material
was observed when a stronger base such as t-BuOK was used
(entries 4−7).
The reactivity of porphyrin substrates was also dependent on
the central metal ion. When Cu(II) and Ni(II) were inserted
into the porphyrin core, the reactivity of the resultant
metalloporphyrin was obviously enhanced (entries 9 and
10).12 In sharp contrast, Zn(II) porphyrin (1b) can hardly
react with phenol (entry 8). That can be attributed to the
Aromatic nucleophilic substitution (SNAr) reaction of aryl
halides is an important method for the modification of electron-
deficient aromatic compounds, but it has rarely been applied in
the synthesis of porphyrin derivatives except for several
examples reported.9 Herein, we report a facile SNAr reaction
of easily accessible meso-halo- or -nitro-substituted porphyrins
with oxygen-, sulfur-, and carbon-based nucleophiles under
mild conditions to give the corresponding meso-derivatives in
high yield (Figure 1).10
Received: January 19, 2014
Published: March 5, 2014
© 2014 American Chemical Society
1590
dx.doi.org/10.1021/ol500191j | Org. Lett. 2014, 16, 1590−1593

Organic Letters
Letter
Table 1. SNAr Reaction of meso-Bromoporphyrin (M = 2H/
Zn/Cu/Ni) with Phenol under Various Conditions
Table 2. SNAr Reaction of 1d with Phenol Derivatives and
Alcohols
a
a
e
entry
1
M
base
solvent
DMF
product temp (°C) yield (%)
2H
2H
2H
2H
2H
2H
2H
Zn
Cu
Ni
K2CO3
K2CO3
K2CO3
2H2a
100
100
100
100
100
100
100
100
100
100
100
120
80
74
0
b
2
1,4-dioxane
toluene
DMF
b
3
0
b
4
0
b
5
Na3PO4
t-BuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
2H2a
2H2a
7
c
6
DMF
0
7
DMF
84
0
b
8
DMF
9
DMF
Cu2a
2a
89
99
99
99
80
45
10
DMF
d
11
Ni
DMF
2a
12
13
14
Ni
DMF
2a
Ni
DMF
2a
Ni
DMF
2a
60
a
Reactions were carried out in the indicated solvent (3.0 mL) with
porphyrin (30.0 mg, 1.0 equiv), phenol (1.4 equiv), and indicated base
b
(2.0 equiv) under N2 atmosphere for 1 h. Recovery of starting
c
d
materials. Decomposition of porphyrin was observed. Compound 1d
was dissolved in dichloromethane (50 mL) and washed with edetate
disodium (0.1 N, 50 mL) to remove possible free nickel(II) ions
a
For entries 1−9, reactions were carried out in DMF (3.0 mL) under
e
N2 atmosphere with 1d (30.0 mg, 1.0 equiv), phenol derivatives (1.4
equiv), and Cs2CO3 (2.0 equiv). Entries 10−12, 10.0 equiv of NaH,
and alcohols were used. Partial decomposition of porphyrin was
before use. Isolated yield.
b
c
observed. Isolated yield.
relative electropositivity for zinc(II) (Pauling electronegativity
1.65) in comparison to copper(II) and nickel(II) (Pauling
electronegativity 1.90 and 1.91, respectively). Thus, zinc
porphyrin will have greater electron density on the periphery
and show lower activity in the SNAr reaction.13 Temperature is
another factor that affects the conversion and yield. An elevated
temperature was needed for effective transformation, as
decreased reactivity was observed when the reaction temper-
ature was below 100 °C (entries 13 and 14). In addition,
treating the Ni(II) porphyrin with edetate disodium before use,
in order to remove any free metal ions that may exist, resulted
in no change for the conversion (entries 10 and 11). That is
quite different from the reported nickel(II) catalyzed cross-
coupling reaction, and in that case the nickel(II) catalyst is
essential.14
Under the optimized conditions, compound 1d was further
employed to react with substituted phenol and aliphatic alcohol
(Table 2). Electron-rich and -poor phenol derivatives, as well as
more sterically hindered 2-acetylaminophenol, could all be
transformed to the corresponding meso-substituted porphyrins
in high yield (entries 2−6). Substrates with an amino group
(entry 7) also worked smoothly with good selectivity, and no
N-substituted product was observed. When it came to the
fused-ring aromatic compounds or heterocycle substrates
(entries 8 and 9), meso-aryloxy-substituted products could be
obtained efficiently. Aliphatic alcohols were also employed in
the reaction, but they did not work under the same conditions.
A stronger base such as NaH must be used to promote this
transformation, and the meso-alkoxy-substituted porphyrins
were obtained at room temperature in moderate yield (entries
10−12).
To our delight, the reaction was not limited to oxygen-based
nucleophiles. Multiple kinds of sulfur-based nucleophiles were
found to be suitable for this process. As shown in Table 3, in
addition to 4-methylbenzenethiol (entry 1), 1d could be
coupled smoothly to other electron-rich or -poor aromatic
thiols, such as 4-methoxythiophenol and 4-fluorothiophenol,
affording meso-sulfanyl-substituted porphyrins (entries 2 and
3). 2-Naphthalenethiol could also participate as a suitable
substrate, furnishing the desired product in 71% yield (entry 4).
When aliphatic thiols 1-propanethiol and benzylmercaptan
were used, meso-alkylsulfanyl-substituted porphyrins could also
be easily obtained (entries 5 and 6). It is worthwhile to point
out that dithiol substrate could react with 1d to afford
diporphyrin 3g in 79% yield (entry 7). That should be a
practical way to construct some functional face-to-face
diporphyrins.
The results mentioned above encouraged us further to
extend the scope of substrates to carbon-based nucleophiles
(Table 4). For example, 1d reacted with malononitrile and
ethylcyanacetate to afford cyano-contained porphyrins 4a and
4b in 89 and 91% yields, respectively (entries 1 and 2). The
cyano-substituted porphyrins are thought to be one of the most
important precursors for their valuable transformation to some
functional groups such as aldehydes, amines, amides, and acid
derivatives. 1,3-Diketones and malonate-type nucleophiles
could also react with 1d successfully to provide the
1591
dx.doi.org/10.1021/ol500191j | Org. Lett. 2014, 16, 1590−1593

Organic Letters
Letter
fluoroporphyrin(Ni) was too fast to be measured, we finally
obtained four sets of reactivity data. As shown in Figure 2,
Table 3. SNAr Reaction of 1d with Sulfur-Based
Nucleophiles
a
a
Reactions were carried out in DMF (3.0 mL) under N2 atmosphere
with 1d (30.0 mg, 1.0 equiv), RSH (1.4 equiv), and Cs2CO3 (2.0
b
equiv) at 100 °C for 1 h. The product was purified by recrystallization
Figure 2. Kinetic plots for the reaction of meso-Cl, -Br-, -I-, and -NO2-
substituted porphyrins (Ni) with phenols.
c
since it easily decomposed on silica gel. 0.5 equiv of 1,5-
d
pentanedithiol was used. Isolated yield.
Table 4. SNAr Reaction of 1d with Carbon-Based
a
Nucleophiles
reactivity of the substituted porphyrins(Ni) was measured in
the order Cl > NO2 > Br > I (known as the “element effect”,
Figures S1−S5 and Tables S1−S5 in the Supporting
Information), which is consistent with the reported classic
SNAr reaction.16 Most aromatic nucleophilic substitution
reactions were thought to proceed via a Meisenheimer complex
or a σ-complex intermediate procedure,17 and the rate-
determining step18 might be the formation or decomposition
of Meisenheimer complex. Based on the results measured
above, we propose the reaction may proceed through an
addition−elimination process with the addition of nucleophiles
being rate-determining step.
In conclusion, we have developed a facile and effective
catalyst-free method for the preparation of meso-O, -S-, and -C-
substituted porphyrins from meso-brominated porphyrin. Most
of the reactions can be completed within 1 h and in high yield
except that relatively long reaction times were needed for the
carbon-based nucleophiles. Kinetic investigation shows that the
reaction adopts a typical nucleophilic aromatic substitution
(SNAr) procedure. The general simple methodology will grant
access to a variety of meso-functionalization of porphyrins that
could be applied in catalysts, photodynamic therapy agents, and
nonlinear optical materials.
a
Reactions were carried out in DMF (3.0 mL) under N2 atmosphere
with 1d (30 mg, 1.0 equiv), CH2R1R2 (1.4 equiv), and Cs2CO3 (2.0
equiv) at 100 °C for 1−6 h. The product was separated by
recrystallization from CH2Cl2/MeOH since it strongly absorbed and
b
c
decomposed on silica gel. Enantiomers were not separated, and keto−
enol tautomeriztion was observed for compounds 4c, 4d, 4f, and 4e.
d
e
Partial decomposition of porphyrins was observed. Isolated yield.
corresponding meso-carbon-based products in moderate to high
yields (entries 3−7).
ASSOCIATED CONTENT
■
S
* Supporting Information
In order to obtain deeper insights into the mechanism, meso-
F- (1h), -Cl- (1e), -I- (1f), and -nitro- (1g) substituted
porphyrins(Ni) were also prepared. Reaction rate constants of
meso-F-, -Cl-, -Br-, -I-, and -NO2-substituted porphyrins(Ni)
with phenol were further measured and ranked.15
All kinetic measurements (in triplicate) were conducted
under pseudo-first-order conditions
Experimental procedures and characteristic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: zhuyizhou@nankai.edu.cn.
*E-mail: jyzheng@nankai.edu.cn.
kt = −2.303 log(C/C0) + b
where C/C0 is the ratio of 5-substituted porphyrins(Ni) in the
mixture at time t to the initial concentration. Values of the term
[−log(C/C0)] were plotted against t. Since the reaction of 5-
Notes
The authors declare no competing financial interest.
1592
dx.doi.org/10.1021/ol500191j | Org. Lett. 2014, 16, 1590−1593

Organic Letters
Letter
(12) (a) Chen, Q.-Y.; Guo, C.-C.; Jin, L.-M.; Yin, J.-J.; Chen, L.
Synlett 2005, 2893. (b) Ouyang, Q.; Zhu, Y.-Z.; Zhang, C.-H.; Yan, K.-
Q.; Li, Y.-C.; Zheng, J.-Y. Org. Lett. 2009, 11, 5266.
(13) Crossley, M. J.; King, L. G. J. Chem. Soc., Perkin Trans. 1 1996,
1251.
ACKNOWLEDGMENTS
■
We thank the 973 Program (2011CB932502) and NSFC (Nos.
21172126 and 21272123) for their generous financial support.
(14) Liu, C.; Shen, D.-M.; Chen, Q.-Y. J. Org. Chem. 2007, 72, 2732.
(15) Details about the experimental procedure and principle are
described in the Supporting Information.
(16) (a) Liu, J.; Robins, M. J. J. Am. Chem. Soc. 2007, 129, 5962.
(b) Okamura, T.; Kikuchi, T.; Fukushi, K.; Irie, T. J. Med. Chem. 2009,
52, 7284. (c) Senger, N. A.; Bo, B.; Cheng, Q.; Keeffe, J. R.; Gronert,
S.; Wu, W. J. Org. Chem. 2012, 77, 9535.
(17) Miller, J. Variation of Leaving Groups. In Reaction Mechanisms in
Organic Chemistry; Eaborn, C., Chapman, N. B., Eds.; Elsevier:
NewYork, 1968; pp 137.
REFERENCES
■
(1) (a) Handbook of Porphyrin Science; Kadish, K. M., Smith, K. M.,
Guilard, R., Eds.; World Scientific Publishing: Singapore, 2010; Vol. 4.
(b) Handbook of Porphyrin Science; Kadish, K. M., Smith, K. M.,
Guilard, R., Eds.; World Scientific Publishing: Singapore, 2011; Vol.
12.
(2) (a) Senge, M. O. In The Porphyrin Handbook; Kadish, K. M.,
Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000;
Vol. 1, pp 239−347. (b) Mack, J.; Shen, Z.; Kobayashi, N. In
Handbook of Porphyrin Science; Kadish, K. M., Smith, K. M., Guilard,
R., Eds.; World Scientific Publishing: Singapore, 2012; Vol. 23, pp
281−373.
(18) Bunnett, J. F.; Garbisch, E. W.; Pruitt, K. M. J. Am. Chem. Soc.
1957, 79, 385.
(3) Lukyanets, E. A.; Nemykin, V. N. In Handbook of Porphyrin
Science; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; World Scientific
Publishing: Singapore, 2010; Vol. 3, pp 3−54.
(4) Beyzavi, M. H.; Nietzold, C.; Reissig, H.-U.; Wiehe, A. Adv. Synth.
Catal. 2013, 355, 1409.
(5) (a) Jin, L.-M.; Chen, L.; Yin, J.-J.; Zhou, J.-M.; Guo, C.-C.; Chen,
Q.-Y. J. Org. Chem. 2006, 71, 527. (b) Chumakov, D. E.; Khoroshutin,
A. V.; Anisimov, A. V.; Kobrakov, K. I. Chem. Heterocycl. Compd. 2009,
45, 259.
(6) (a) Baldwin, J. E.; Crossley, M. J.; Debernardis, J. Tetrahedron
1982, 38, 685. (b) Krattinger, B.; Callot, H. J. Eur. J. Org. Chem. 1999,
1857. (c) Senge, M. O. Acc. Chem. Res. 2005, 38, 733. (d) Takanami,
T.; Wakita, A.; Sawaizumi, A.; Iso, K.; Onodera, H.; Suda, K. Org. Lett.
2008, 10, 685. (e) Takanami, T.; Wakita, A.; Matsumoto, J.; Sekine, S.;
Suda, K. Chem. Commun. 2009, 1011. (f) Senge, M. O. Chem.
Commun. 2011, 47, 1943.
(7) (a) Gao, G.-Y.; Colvin, A. J.; Chen, Y.; Zhang, X. P. Org. Lett.
2003, 5, 3261. (b) Chen, Y.; Zhang, X. P. J. Org. Chem. 2003, 68, 4432.
(c) Gao, G.-Y.; Chen, Y.; Zhang, X. P. Org. Lett. 2004, 6, 1837.
(d) Gao, G.-Y.; Colvin, A. J.; Chen, Y.; Zhang, X. P. J. Org. Chem.
2004, 69, 8886. (e) Atefi, F.; McMurtrie, J. C.; Turner, P.; Duriska, M.;
Arnold, D. P. Inorg. Chem. 2006, 45, 6479. (f) Esdaile, L. J.; Senge, M.
O.; Arnold, D. P. Chem. Commun. 2006, 4192. (g) Matano, Y.;
Shinokura, T.; Matsumoto, K.; Imahori, H.; Nakano, H. Chem.Asian
J. 2007, 2, 1417. (h) Gao, G.-Y.; Ruppel, J. V.; Allen, D. B.; Chen, Y.;
Zhang, X. P. J. Org. Chem. 2007, 72, 9060. (i) Enakieva, Y. Y.;
Bessmertnykh, A. G.; Gorbunova, Y. G.; Stern, C.; Rousselin, Y.;
Tsivadze, A. Y.; Guilard, R. Org. Lett. 2009, 11, 3842. (j) Ladomenou,
K.; Lazarides, T.; Panda, M. K.; Charalambidis, G.; Daphnomili, D.;
Coutsolelos, A. G. Inorg. Chem. 2012, 51, 10548.
(8) For reviews, see: (a) Ren, T. Chem. Rev. 2008, 108, 4185.
(b) Shinokubo, H.; Osuka, A. Chem. Commun. 2009, 1011. For
examples, see: (c) Kurotobi, K.; Osuka, A. Org. Lett. 2005, 7, 1055.
(d) Fortage, J.; Scarpaci, A.; Viau, L.; Pellegrin, Y.; Blart, E.;
Falkenstrom, M.; Hammarstrom, L.; Asselberghs, I.; Kellens, R.;
Libaers, W.; Clays, K.; Eng, M. P.; Odobel, F. Chem.Eur. J. 2009, 15,
9058. (e) Ouyang, Q.; Yan, K.-Q.; Zhu, Y.-Z.; Zhang, C.-H.; Liu, J.-Z.;
Chen, C.; Zheng, J.-Y. Org. Lett. 2012, 14, 2746. (f) Carcel, C. M.;
Laha, J. K.; Loewe, R. S.; Thamyongkit, P.; Schweikart, K.-H.; Misra,
V.; Bocian, D. F.; Lindsey, J. S. J. Org. Chem. 2004, 69, 6739.
(9) (a) Gong, L.-C.; Dolphin, D. Can. J. Chem. 1985, 63, 406.
(b) Balaban, M. C.; Eichhofer, A.; Buth, G.; Hauschild, R.;
̈
Szmytkowski, J.; Kalt, H.; Balaban, T. S. J. Phys. Chem. B 2008, 112,
5512. (c) Balaban, M. C.; Chappaz-Gillot, C.; Canard, G.; Fuhr, O.;
Roussel, C.; Balaban, T. S. Tetrahedron 2009, 65, 3733. (d) Yamashita,
K.-I.; Kataoka, K.; Asano, M. S.; Sugiura, K.-I. Org. Lett. 2012, 14, 190.
(e) Ryan, A. A.; Plunkett, S.; Casey, A.; McCabe, T.; Senge, M. O.
Chem. Commun. 2014, 50, 353.
(10) Direct phenoxylation of OEP was once reported by Senge:
Senge, M. O.; Bischoff, I. Eur. J. Org. Chem. 2001, 2001, 1735.
(11) Yap, J. L.; Horn, K.; Fletcher, S. Tetrahedron Lett. 2011, 52,
4172.
1593
dx.doi.org/10.1021/ol500191j | Org. Lett. 2014, 16, 1590−1593