β-octamethoxyporphycenes

Article abstract of DOI:10.1021/ol403068j

Porphycene with eight methoxy substituents at its β-positions was synthesized for the first time in three steps from 3,4-dimethoxypyrrole. The presence of methoxy groups increases its hydrophilicity as evident from their increased solubility in methanol. Among its metallo-derivatives, the Pd(II)-complex displays efficient singlet oxygen quantum yield (73%) and hence can be a potentially good photosensitizer for photo-oxidation, DNA cleavage, and photodynamic therapy (PDT).

Full text of DOI:10.1021/ol403068j

Letter
pubs.acs.org/OrgLett
β‑Octamethoxyporphycenes
Anup Rana and Pradeepta K. Panda*
†School of Chemistry and Advance Centre of Research in High Energy Materials (ACRHEM), University of Hyderabad,
Hyderabad-500046, India
S
* Supporting Information
ABSTRACT: Porphycene with eight methoxy substituents at
its β-positions was synthesized for the first time in three steps
from 3,4-dimethoxypyrrole. The presence of methoxy groups
increases its hydrophilicity as evident from their increased
solubility in methanol. Among its metallo-derivatives, the
Pd(II)-complex displays efficient singlet oxygen quantum yield
(73%) and hence can be a potentially good photosensitizer for
photo-oxidation, DNA cleavage, and photodynamic therapy
(PDT).
orphycene is the first constitutional isomer of porphyrin to
1
Pbe synthesized. This is achieved by rearranging the meso-
methines of the porphyrin moiety, where two bipyrrolic
moieties are linked through two meso-like carbons on either
side through their α-positions. This rezigging of the meso-
methines led to a rectangular shaped macrocyclic core with
reduced molecular symmetry compared to porphyrin. Owing to
its unique structural feature, porphycene displays NH···N
hydrogen bonding stronger than that of its parent isomer.
Because of the structural similarities, both isomers display
similar photophysical properties and coordination behavior;
however, few subtle differences were also noticed.2 An
important attribute, in which porphycene scores over
porphyrin, is their relatively stronger absorption in the red
region, thereby making them a better candidate for PDT
application.3 In addition, porphycenes have also been explored
for possible applications in material chemistry,4 catalysis,5
photoinactivation of viruses and bacteria,6 protein mimicry,7
and nonlinear optical study.8
A general synthetic approach toward porphycenes includes
the McMurry coupling of diformyl-2,2′-bipyrroles employed
first by Vogel.1 However, owing to recent developments in
organic synthesis, the synthesis of the bipyrrole building block
has undergone several optimizations.9 Despite these develop-
ments, the functionalization of porphycene is mostly limited to
alkyl or aryl substituents at the periphery.10 In this regard, we
found that the presence of methoxy groups (3b) has significant
advantages over the nonmethoxylated analogues such as 3a;
first, it enhances cell localization, probably owing to the greater
hydrophilicity it imparts, and second, it can be subsequently
deprotected to hydroxy and further substituted with long alkyl,
alkoxy, or sugar moieties or different salts in order to modulate
the lipophilicity of the resultant macrocycle.11
Since Merz reported the synthesis of octamethoxyporphyrin
in 1993, 3,4-dimethoxypyrrole finds very little application in the
synthesis of porphyrinoids.12 This is ascribed to the difficulties
associated with this chemistry including a relatively less stable
nature, which was described in detail later by Merz himself.13
However, our recent interest in this chemistry14 led us to
explore the possible synthesis of β-octamethoxyporphycene,
which has potential application as a photosensitizer (PS) in
PDT. Another aspect of our interest is to see if the introduction
of oxygen atoms at the 3,6- and 13,16-positions can reduce the
nonbonding interaction and their consequence on its structure
and photophysical properties.
The key to our target was the precursor diformyl derivative
of tetramethoxy-2,2′-bipyrrole 5. Iodination of 2-formyl-3,4-
dimethoxypyrrole A1 using N-iodosuccinimide led to the
desired 5-iodo compound A2 (68%); however, subsequent
Ullmann coupling led to the formation of deiodinated
compound A1 (Supporting Information). Modified Pd-
catalyzed Ullmann coupling of A2, following Smith’s strategy,
led to desired bipyrrole 5 in poor yield (14%) (Supporting
Information).9c Therefore, we decided to explore the synthesis
Received: October 24, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol403068j | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of bipyrrole directly from the pyrrole itself using hypervalent
iodine mediated Lewis acid catalyzed coupling reactions with
[bis(trifluoroacetoxy)iodo]-benzene (PIFA) as an oxidant and
trimethylsilyl bromide (TMSBr) as a Lewis acid reported by
Kita’s group.9d Owing to the high reactivity of the 3,4-
dimethoxypyrrole 4,12b initially we used the corresponding N-
benzyl derivative A3 (which happens to be the precursor for
pyrrole 4), as our starting material. This led to the successful
isolation of the doubly N-protected 2,2′-bipyrrole A4 in good
yield (71%), whose structure was further confirmed by X-ray
diffraction (XRD) analysis (Supporting Information). Subse-
quent debenzylation using Na/liq NH3, however, led to
decomposition of the desired product (Supporting Informa-
tion). Therefore, we decided to explore the PIFA-TMSBr
coupling of 3,4-dimethoxypyrrole 4 itself. As expected, we
could notice the formation of the product at −45 °C; however,
the compound undergoes decomposition during the purifica-
tion. In order to avoid this, we subjected the reaction mixture to
Vilsmeier−Haack formylation, immediately after the workup
process. Finally this led us to the desired product 5 (two-step
yield 39%; Scheme 1), whose structure was confirmed by XRD
(0.65 ppm) is shifted upfield by about 0.3 ppm,10b which may
be attributed to the presence of eight electron-donating
methoxy groups at the porphycene periphery.
The UV−vis spectra of porphycene 1 and its metallo-
derivatives were recorded in chloroform (Figure 1). Porphy-
Figure 1. UV−vis spectra of 1, Zn1, Ni1, and Pd1 in chloroform at 25
°C.
cene 1 shows one characteristic intense Soret band at 382 nm
and three weaker Q-bands at 557, 599, and 636 nm. The lowest
energy band is 29 and 21 nm blue-shifted compared to
octaethylporphycene 2a and etioporphycene 2b, respective-
ly,10b which may be attributed to an increase in HOMO−
LUMO energy difference due to the presence of electron-rich
methoxy groups at its periphery. The UV−vis spectra of
metalloporphycenes Zn1, Ni1, and Pd1 show red-shifted Soret
bands at 388−390 nm compared to freebase porphycene 1 and
also display one Q-band between 590 and 618 nm. Further,
compound 1 displays very weak emission (ϕf < 10−4), whereas
insertion of zinc led to a substantial enhancement in the
emission (ϕf of Zn1 0.025; Supporting Information) with an
intense band at 632 nm accompanied by a weaker lower energy
band (689 nm). Both porphycene 1 and its Zn(II)-derivative
show relatively weaker emission compared to 2a and its Zn(II)-
complex (Zn2a), with Zn1 possessing a shorter fluorescence
lifetime (0.6 ns; Supporting Information) compared to
analogous Zn2a (3.2 ns).15a
Scheme 1. Synthesis of β-Octamethoxyporphycene and Its
M(II) Derivatives
Molecular structure of porphycenes 1, Pd1 and Zn1 were
unequivocally characterized in the solid state by X-ray
crystallographic analysis (Figure 2). All porphycenes display
planar macrocyclic core, and the observed planarity is more
compared to 2a. For example, the mean deviation of nitrogen
atoms from the mean plane of porphycene 1 (excluding the
methoxy substituents) is only 0.021 Å ( 0.27 Å for 2a).10b
This probably resulted from the reduced van der Waals
repulsion between 3,6- and 13,16-substituents, by replacing the
analysis (Supporting Information). McMurry coupling of the
dialdehyde 5 using TiCl4/Zn finally resulted in the formation of
the desired octamethoxyporphycene 1 in 14% yield (Scheme
1). Here the porphycene could be synthesized in only three
steps from the constituent pyrrole derivative, making it the
shortest route to β-substituted porphycenes. Further, this
strategy emerged as more efficient compared to the traditional
iodination and Ulmann coupling route (also not possible in this
case) to bipyrrole synthesis (where in many occasions BOC
protection is essential for enhanced yield). The freebase
porphycene could be further converted to its Zn(II)-, Ni(II)-
and Pd(II)-complexes. All of the porphycene derivatives were
characterized following standard spectroscopic techniques.
Further, the solid state structures of the freebase 1, Zn1, and
Pd1 could be ascertained by XRD analyses. All of these
porphycenes show good lipophilicity and hydrophilicity,
displaying good solubility in all organic solvents ranging from
hexane to methanol (Supporting Information).
1
The H NMR spectrum of 1 reveals the meso protons and
imino protons resonating at 9.66 and 0.36 ppm. In comparison
to analogous octaethylporphycene 2a, the meso protons (9.48
ppm) are shifted 0.18 ppm downfield, whereas the NH signal
Figure 2. X-ray crystal structure of (a) 1, (b) Zn1, and (c) Pd1 (above
front view and below side view) drawn in 35% probability level. Color
code: C, gray; N, blue; O, red; H, white; Zn, pink; Pd, green.
B
dx.doi.org/10.1021/ol403068j | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ethyl groups with less bulky methoxy groups in 2a. However,
these repulsive interactions are still strong enough to enforce a
square -type core for porphycene 1 (N1···N2 2.741 Å and N1···
N2′ 2.758 Å), as observed in case of 2a,b.10b
difference between the first oxidation and first reduction
potentials. The energy gap of 1 (ΔE = Eox1 − Ered1 = 1.89 V) is
slightly higher than that of 2a (1.81 V), which is increased due
to the presence of strong electron-donating methoxy groups
and again clearly reflected in the blue shift of Q-bands in the
absorption spectrum.
Among the metalloporphycenes, the deviation is relatively
more in the case of Zn1 ( 0.083 Å) than Pd1 ( 0.034 Å). As
expected, metal insertion led to a change in the macrocyclic
core geometry from square to rectangular type (Pd1 N1···N2
2.575 Å, N1···N2′ 3.009 Å and Zn1 N1···N2 2.613 Å, N1···N2′
3.024 Å).
In photodynamic therapy, an efficient photosensitizer is one
that converts molecular oxygen to singlet oxygen (1O2) most
effectively, in the presence of light, which is responsible for
subsequent death of the cancerous cells. So keeping this in
mind, we have measured steady state luminescence spectra of
singlet oxygen for 1 and its metallo-derivatives in aerated
toluene. Among them, Zn1 and Pd1 show emission bands
ranging from 1240 to 1320 nm with maxima at about 1274 nm,
when excited at 600 nm (Supporting Information). Singlet
oxygen quantum yield of Zn1 and Pd1 was evaluated by
comparative actinometry method by using tetraphenylporphyr-
in (H2TPP) as reference (ϕΔ 0.7) in aerated toluene.17 The
singlet oxygen quantum yields obtained for Zn1 and Pd1 are
0.12 and 0.73, respectively. Although not very high (up to 0.95)
as noticed in case of bromo-substituted porphycenes (owing to
expected heavy atom effect of bromine),17a still it is comparable
to that observed (0.78) in the case of 2,7,12,17-tetraphenylpor-
phycenato palladium(II).17c Analogous measurement for Zn2a
and Pd2a, synthesized following Kita’s procedure (for
bipyrrole)9d and subsequently the route of their methoxy
counterparts (Supporting Information), display singlet oxygen
quantum yields of 0.68 and 0.89, respectively. Interestingly, in
case of octaethylporphycene, the effect of the heavy atom is
marginal (Zn vs Pd), whereas that in case of their methoxy
analogues is quite substantial. This indicates the higher
intersystem crossing (ISC) noticed in the case of Zn2a15a is
not a general phenomenon in porphycenes. Further, like its
strong dependence on nature of substituents at the
periphery,15b it also depends on the nature of the metal ion
at the core, and further detailed photophysical study may
elaborate on this aspect. Free base 1 didn′t show any singlet
oxygen emission like 2a, probably due to lack of efficient
ISC.15a
Redox potentials of porphycene 1 and its metallo-derivatives
were determined by cyclic voltammetry (CV) and differential
pulse voltammetry (DPV) in dichloromethane (Figure 3 and
Figure 3. Cyclic voltammograms of 1, Zn1, Ni1, and Pd1 in
dichloromethane at 25 °C (scan rate 50 mV/s).
Supporting Information). These porphycenes display typical
two ring oxidation and two ring reduction potentials, except for
Pd1, which shows an additional reduction potential (confirmed
by DPV; the reason is not known at this stage). A closer
inspection of the voltammogram of 1 reveals reversibility for
the second ring reduction potential only, and further the
absence of the clear reduction waves in the oxidation half
indicates the unstable nature of both the cation radical and the
dication of porphycene 1. Oxidation and reduction potentials of
1 and its M(II) complexes are summarized vs SCE in Table 1.
Table 1. Comparative Oxidation and Reduction Potentials
(in V vs SCE) for Porphycenes and Their M(II) Complexes
In conclusion, PIFA-TMSBr coupling of 3,4-dimethoxypyr-
role to corresponding bipyrrole enabled us to synthesize
octamethoxyporphycene 1 for the first time, which happens to
be the most efficient route toward the synthesis of β-substituted
porphycenes. Further, the presence of methoxy groups led to
an increase in their hydrophilicity (these porphycenes display
good solubility in methanol). Photosensitizers based on the
Pd(II)-porphyrinoids display promising results in clinical
trials.3c In this regard, the Pd(II)-complex of porphycene 1
possesses efficient singlet oxygen quantum yield (73%), along
with its expected higher cell viability (owing to the presence of
eight methoxy groups), may emerge as a promising photo-
sensitizer for photo-oxidation, DNA cleavage, and PDT.
porphycenes
reduction
oxidation
a
a
a
1
−1.29, −1.11
−1.38, −1.13
−1.45, −1.19
+0.78, +1.15
a
Zn1
Ni1
Pd1
+0.60, +0.75
+0.71, +1.17
+0.77, +1.28
+0.87, +1.10
+0.64, +0.78
+0.81, +1.12
a
a
−1.36, −1.13, −1.03
−1.26, −0.94
b
2a
b
Zn2a
−1.38, −1.09
−1.46, −1.06
b
Ni2a
a
b
Measured by DPV. Taken from ref 16.
All of the metallo-porphycenes show two reversible ring
oxidation potentials (stabilized by the presence of Lewis acidic
metal ions) and two reduction potentials. The relatively
electron-rich character of the octamethoxyporphycene 1 and
its metal complexes, in comparison to their octaethyl analogue
2a and its metal complexes, is clearly reflected in their redox
potentials (Table 1), in particular in their corresponding first
oxidation (less positive potential) and reduction (more negative
potential) potentials.16 In addition, the evaluated HOMO−
LUMO energy gap of 1 and its M(II)-derivatives from the
ASSOCIATED CONTENT
■
S
* Supporting Information
Reaction scheme, detailed experimental procedures, NMR
spectra, electrochemical data, singlet oxygen luminiscence
spectra and crystal data CCDC 950087−950091. This material
is available free of charge via the Internet at http://pubs.acs.org.
C
dx.doi.org/10.1021/ol403068j | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Ramakrishnan, S.; Thomas, A. P.; Suresh, E.; Srinivasan, A. Org. Lett.
2008, 10, 5545. (j) Hayashi, T.; Nakashima, Y.; Ito, K.; Ikegami, T.;
Aritome, I.; Suzuki, A.; Hisaeda, Y. Org. Lett. 2003, 5, 2845.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: pkpsc@uohyd.ernet.in, predeepta.panda@uohyd.ac.in,
(11) (a) Richert, C.; Wessels, J. M.; Muller, M.; Kisters, M.;
̈
Benninghaus, T.; Goetz, A. E. J. Med. Chem. 1994, 37, 2797.
(b) Kessel, D.; Arroyo, A. S. Photochem. Photobiol. Sci. 2007, 6, 1290.
(12) (a) Merz, A.; Schropp, R.; Lex, J. Angew. Chem., Int. Ed. Engl.
1993, 32, 291. (b) Merz, A.; Scropp, R.; Dotterl, E. Synthesis 1995,
795. (c) Merz, A.; Meyer, T. Synthesis 1999, 94. (d) Shevchuk, V.;
Davis, J. M.; Sessler, J. L. Tetrahedron Lett. 2001, 42, 2447.
(13) Merz, A.; Anikin, S.; Lieser, B.; Heinze, J.; John, H. Chem.Eur.
J. 2003, 9, 449.
(14) (a) Rana, A.; Panda, P. K. Tetrahedron Lett. 2011, 52, 2697.
(b) Rana, A.; Panda, P. K. RSC Adv. 2012, 2, 12164.
(15) (a) Berman, A.; Michaeli, A.; Feitelson, J.; Bowman, M. K.;
Norris, J. R.; Levanon, H.; Vogel, E.; Koch, P. J. Phys. Chem. 1992, 96,
3041. (b) Levanon, H.; Toporowicz, M.; Ofir, H.; Fessenden, R. W.;
predeepta.panda@gmail.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by Council of Scientific & Industrial
Research (CSIR), India and Defence Research & Development
Organization (DRDO), India through ACRHEM, University of
Hyderabad. A.R. thanks CSIR for fellowship. The authors also
thank Dr. K. Santhosh, School of Chemistry, University of
Hyderabad for the fluorescence lifetime studies.
Das, P. K.; Vogel, E.; Kocher, M.; Promod, K. J. Phys. Chem. 1988, 92,
̈
2429.
REFERENCES
■
(16) Gisselbrecht, J. P.; Gross, M.; Kocher, M.; Lausmann, M.; Vogel,
̈
(1) Vogel, E.; Kocher, M.; Schmickler, H.; Lex, J. Angew. Chem., Int.
Ed. Engl. 1986, 25, 257.
E. J. Am. Chem. Soc. 1990, 112, 8618.
(17) (a) Shimakoshi, H.; Baba, T.; Iseki, Y.; Aritome, I.; Endo, A.;
Adachi, C.; Hisaeda, Y. Chem. Commun. 2008, 2882. (b) Shao, W.;
Wang, H.; He, S.; Shi, L.; Peng, K.; Lin, Y.; Zhang, L.; Ji, L.; Liu, H. J.
Phys. Chem. B 2012, 116, 14228. (c) Rubio, N.; Prat, F.; Bou, N.;
(2) (a) Sessler, J. L.; Gebauer, A.; Vogel, E. Porphyrin Handb. 2000,
2, 1. (b) San
215.
(3) (a) Stockert, J. C.; Canete, M.; Juarranz, A.; Villanueva, A.;
́
chez-García, D.; Sessler, J. L. Chem. Soc. Rev. 2008, 37,
̃
́ ́
́
J.; Vollanueva, A.; Juarranz, A.; Canete, M.;
̃
Borrell, J. I.; Teixido,
Stockert, J. C.; Nonell, S. New J. Chem. 2005, 29, 378.
́
Horobin, R. W.; Borrell, J. I.; Teixido, J.; Nonell, S. Curr. Med. Chem.
2007, 14, 997. (b) Bonnett, R. Chem. Soc. Rev. 1995, 24, 19.
(c) Ethirajan, M.; Chen, Y.; Joshi, P.; Pandey, R. K. Chem. Soc. Rev.
2011, 40, 340.
(4) (a) Barbe, J.-M.; Richard, P.; Aukauloo, M. A.; Lecomte, C.; Petit,
P.; Guilard, R. J. Chem. Soc., Chem. Commun. 1994, 2757. (b) Brenner,
W.; Malig, J.; Costa, R. D.; Guldi, D. M.; Jux, N. Adv. Mater. 2013, 25,
2314. (c) Costa, R. D.; Malig, J.; Brenner, W.; Jux, N.; Guldi, D. M.
Adv. Mater. 2013, 25, 2600.
(5) (a) Hayashi, T.; Okazaki, K.; Urakawa, N.; Shimakoshi, H.;
Sessler, J. L.; Vogel, E.; Hisaeda, Y. Organometallics 2001, 20, 3074.
(b) Lo, W.-C.; Che, C.-M.; Cheng, K.-F.; Mak, T. C. W. Chem.
Commun. 1997, 1205.
(6) Lauro, F. M.; Pretto, P.; Covolo, L.; Jori, G.; Bertoloni, G.
Photochem. Photobiol. Sci. 2002, 1, 468.
(7) (a) Matsuo, T.; Dejima, H.; Hirota, S.; Murata, D.; Sato, H.;
Ikegami, T.; Hori, H.; Hisaeda, Y.; Hayashi, T. J. Am. Chem. Soc. 2004,
126, 16007. (b) Hayashi, T.; Murata, D.; Makino, M.; Sugimoto, H.;
Matsuo, T.; Sato, H.; Shiro, Y.; Hisaeda, Y. Inorg. Chem. 2006, 45,
10530.
́
(8) (a) Arnbjerg, J.; Jimenez-Banzo, A.; Paterson, M. J.; Nonell, S.;
Borrell, J. I.; Christiansen, O.; Ogliby, P. R. J. Am. Chem. Soc. 2007,
129, 5188. (b) Sarma, T.; Panda, P. K.; Anusha, P. T.; Rao, S. V. Org.
Lett. 2011, 13, 188. (c) Rao, S. V.; Prashant, T. S.; Swine, D.; Sarma,
T.; Panda, P. K.; Tewari, S. P. Chem. Phys. Lett. 2011, 514, 98.
(9) (a) Arad, O.; Morros, J.; Batllori, X.; Teixido,
́
J.; Nonell, S.;
Borrell, J. I. Org. Lett. 2006, 8, 847. (b) Sanchez-García, D.; Borrell, J.
́
I.; Nonell, S. Org. Lett. 2009, 11, 77. (c) Jiao, L.; Hao, E.; Vincente, G.
H.; Smith, K. M. J. Org. Chem. 2007, 72, 8119. (d) Dohi, T.;
Morimoto, K.; Maruyama, A.; Kita, Y. Org. Lett. 2006, 8, 2007.
(10) (a) Vogel, E.; Balci, M.; Pramod, K.; Koch, P.; Lex, J.; Ermer, O.
Angew. Chem., Int. Ed. Engl. 1987, 26, 928. (b) Vogel, E.; Koch, P.;
Hou, X.-L.; Lex, J.; Lausmann, M.; Kisters, M.; Aukauloo, M. A.;
Richard, P.; Guilard, R. Angew. Chem., Int. Ed. Engl. 1993, 32, 1600.
̀ ́ ́
(c) Ragas, X.; Sanchez-García, D.; Ruiz-Gonzalez, R.; Dai, T.; Agut,
M.; Hamblin, M. R.; Nonell, S. J. Med. Chem. 2010, 53, 7796.
(d) Kuzuhara, D.; Mack, J.; Yamada, H.; Okujima, T.; Ono, N.;
Kobayashi, N. Chem.Eur. J. 2009, 15, 10060. (e) Roznyatovskiy, V.;
́
Lynch, V.; Sessler, J. L. Org. Lett. 2010, 12, 4424. (f) Stępien, M.;
Donnio, B.; Sessler, J. L. Chem.Eur. J. 2007, 13, 6853. (g) Kuzuhara,
D.; Yamada, H.; Yano, K.; Okujima, T.; Mori, S.; Uno, H. Chem.Eur.
́
J. 2011, 17, 3376. (h) García-Díaz, M.; Sanchez-García, D.; Soriano, J.;
Sagrista,
̀
M. L.; Mora, M.; Villanueva, A.; Stockert, J. C.; Canete, M.;
̃
Nonell, S. Med. Chem. Commun. 2011, 2, 616. (i) Anju, K. S.;
D
dx.doi.org/10.1021/ol403068j | Org. Lett. XXXX, XXX, XXX−XXX