Synthetic strategies and porphyrin building blocks for unsymmetrical multichromophores

Article abstract of DOI:10.1016/j.tetlet.2008.02.029

A sequential use of halogenation, S_NAr, Sonogashira and/or Suzuki couplings together with the use of either mono-5-, 5,15- or 5,10-di-meso-substituted porphyrins allows the facile construction of unsymmetrical porphyrin dimers and trimers with

Full text of DOI:10.1016/j.tetlet.2008.02.029

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2236–2239
Synthetic strategies and porphyrin building blocks
for unsymmetrical multichromophores
Marijana Fazekas , Monica Pintea , Mathias O. Senge a,b,*, Monika Zawadzka a
a
a
a
School of Chemistry, SFI Tetrapyrrole Laboratory, Trinity College Dublin, Dublin 2, Ireland
Institute for Molecular Medicine, Medicinal Chemistry, Trinity Centre for Health Sciences, Trinity College Dublin,
St. James’s Hospital, Dublin 8, Ireland
b
Received 22 November 2007; revised 5 February 2008; accepted 7 February 2008
Available online 10 February 2008
Abstract
A sequential use of halogenation, S
N
Ar, Sonogashira and/or Suzuki couplings together with the use of either mono-5-, 5,15- or 5,10-
di-meso-substituted porphyrins allows the facile construction of unsymmetrical porphyrin dimers and trimers with different spatial ori-
entation. The protocols established allow a convenient entry into multichromophores suitable for application in nonlinear optics and
biomedicine.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Pd-catalyzed coupling; Porphyrins; Tetrapyrroles; Halogenation; Nonlinear optical limiting
Current advances in the use of porphyrins for photo-
dynamic cancer therapy, solar energy conversion and as
optical limiters and sensors necessitate the development
results on the development of appropriate building blocks
and synthetic sequences for the general preparation of di-
and trimeric porphyrin systems with unsymmetrical substi-
tuent patterns and linker groups.
1
of synthetic strategies. Most of the applications mentioned
require chromophores with a strong intramolecular dipole
moment (e.g., push–pull systems) and long wavelength
absorption. Suitable target compounds are multi-chromo-
phore systems with appropriate functional groups. From
a synthetic viewpoint, this necessitates the use of unsym-
metrically substituted porphyrin building blocks in conver-
gent or linear syntheses to construct porphyrin dimers or
trimers with fine-tuned photophysical properties.
As several methods are available for the functionali-
zation of the meso position of porphyrins, we chose porp-
hyrins with free meso positions as starting materials.
In order to allow for subsequent asymmetrization and
5
a
to access different linker strategies, we used mono-,
5
a
5b
5,10-di- and 5,15-disubstituted porphyrins. These have
been shown to be useful starting materials for the prepara-
tion of various so-called ABCD porphyrins (Fig. 1).
The last two decades have seen many advances in the
synthesis of unsymmetrically substituted porphyrins, both
R1
2
a
through total synthesis and the use of organometallic
2
b,c
R1
reactions.
Likewise, many di-, tri- and oligomeric por-
3
N
NH
N
phyrin systems have been synthesized. However, only a
few methodological studies have targeted unsymmetrical
multiporphyrin systems. Here, we present preliminary
R4
R2
R4
R2
HN
4
R3
R3
*
Corresponding author. Tel.: +353 1 896 8537; fax: +353 1 896 8536.
E-mail address: sengem@tcd.ie (M. O. Senge).
Fig. 1. ABCD–type porphyrin and the simplified formula used in other
schemes.
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.029

M. Fazekas et al. / Tetrahedron Letters 49 (2008) 2236–2239
2237
R1
R1
R1
R1
R1
R1
(
b)
(a)
(b)
Br
Br
+
Br
Br
R1
2a 60%
R1
R1
11a 84%
R1
12a 92%
(d)
(
f)
e)
3a 37%
1a R1 = Ph
1
(
3b 80%
1
b R = 1-Naphthyl
c)
(
d)
(
R1
R1
R1
R1
O2N
NO2
(
e)
R1
13a 40%
R1
R1
7a 85%
R1 14a 42%
14b 55%
4b 50%
(
b)
(b)
Br
R1
R1
R1
Br
NO2
R1 15a 88%
15b 92%
R1
a 92%
TMS
(
e)
8
R1
a 60%
R1
R1
R1
(
f)
R1
5
TMS
NO2
(
f)
NO2
R1
9a 65%
R1
0a 90%
6
a 92%
1
Scheme 1. Synthesis of monomeric porphyrin building blocks. Reagents and conditions: (a) 1-bromo-4-ethynylbenzene (15 equiv), Et
2
O, n-BuLi
(
(
30 equiv), H
6 equiv), THF (40 mL), À78 °C; (d) 4-nitrophenylboronic acid pinacol ester (12 equiv), K
Cl (0.1 equiv); (f) 0.3 mL TBAF 1 M solution in THF, CH
2
O (2 mL), DDQ (15 equiv), À78 °C; (b) NBS (1.1 equiv), pyridine (1 mL), CHCl
3
(40 mL), 0 °C; (c) n-BuLi (6 equiv), H
2
O (1 mL), DDQ
PO (25 equiv), Pd(PPh (0.1 equiv); (e) ethynyltri-
3
4
3 4
)
methylsilane (1.1 equiv), CuI (0.25 equiv), Pd(PPh
3
)
2
2
2
2
Cl .
1
c
Due to their utility in nonlinear optical porphyrins, for
the present study, we concentrated on alkynyl-linked sys-
tems. These are conveniently prepared via Pd-catalyzed
coupling reactions and require appropriate bromo and
alkynyl precursors. Thus, the initial step involved either
1
6
NBS, CHCl3, 0 ºC
6
2c,7
bromination with NBS or arylation with RLi
of the
free base porphyrins. meso Halo- and alkyne-substituted
+
+
+
Br
Br + Br
Br
Br
Br
porphyrins are important precursors for multiporphyrin
chromophores. A large number of conjugated porphyrins
8
Br
Br
19
Br
20
17
18
21
have been prepared using simple synthetic tools and easily
accessible porphyrins (1a, 1b) in good yields (Scheme 1).
The ethynylphenyl motif was smoothly inserted in a one-
eq. NBS 16
17
18+19 20
21
3
1.5
1
-
93%
-
-
-
8
a
-
2%
5%
4%
4%
31%
60%
41%
1
6%
step reaction by treatment with aryllithium reagents.
5%
10%
-
-
21%
14%
Sequences of reactions were used to introduce the acetylene
moiety, for example, bromination (affording 8a), the intro-
duction of TMS protected acetylene via a Sonogashira cou-
0.8
Scheme 2. Bromination of 16 and product distribution based on the
8
c
equivalence of NBS.
pling reaction (giving 9a) followed by the removal of the
TMS group to afford precursor 10a. Similarly, monobro-
mination of 1a to afford compound 2a in good yield and
chemical arrangements of meso bromo substituents. As
shown in Scheme 2, with smaller amounts of NBS the yield
of tribrominated porphyrin 17 decreased in favour of the
less brominated porphyrins 20 and 21. Thus, depending
on the conditions, an entry into mono- to tribrominated
porphyrins is possible; with a preference for bromination
in the ‘trans’ 15-position relative to the alkyl residue. Com-
pound 17, obtained easily with 3 equiv of NBS, can be used
to quickly construct porphyrin tetramers with two different
8
b
subsequent Suzuki coupling enabled the introduction
of, for example, a 4-nitrophenyl residue for the preparation
8
g
of push–pull systems. Alternatively, alkyl substituted
compounds 14 are accessible via reaction with n-BuLi
and can then be brominated to 15 to serve as precursors
for subsequent couplings.
5
-Monosubstituted porphyrins with three free meso
positions available for further asymmetric functionali-
zation are important precursors for multiporphyrin sys-
9
porphyrin units in a unique 10, 15, 20 orientation.
Our approach to porphyrin dimers linked by acetylene
and ethynylphenyl bridges involved optimized Pd-mediated
5
a
5a
tems. We used the soluble porphyrin 16 to elaborate
an entry into substituted porphyrins with different regio-

2238
M. Fazekas et al. / Tetrahedron Letters 49 (2008) 2236–2239
Ph
R1
Ph
Ph
R1
R1
1
2
2
2 R =Ph, R = H 46%
1 2
R2
R2
23 R =1-Naphthyl, R = butyl 42%
1 2
+
+
Br
Br
2
4 R =Ph, R = 4-nitrophenyl
1
1
2
R1
R1
2a R =Ph, R = H
43%
Ph
Ph
2
1
5a R =1-Naphthyl, R = butyl
1 2
1
1a
8
a R =Ph, R = 4-nitrophenyl
Ph
R1
R1
O N
O2N
2
25a R1 = Ph 42%
5b R1 = 1-Naphthyl 21%
1
5a R1 = Ph
Ph
Ph
R1
R1
1
Ph
Ph
13a
15b R = 1-Naphthyl
2
R1
O N
+
+
+
Br
Br
O2N
1
2
26a R = Ph 31%
2
6b R1 = 1-Naphthyl 25%
R1 15a R1 = Ph
R1
Ph
Ph
Ph
Ph
15b R1 = 1-Naphthyl
1
0a
2
7 29%
Ph
Ph
Ph
Ph
6
a
20
28 20%
Ph
Ph
Br
Ph
Ph
6a
21
2
9 8%
+
+
Br
Ph
Ph
Ph
Ph
1
1a
1a
20
30 26%
Ph
Br
Ph
1
21
3 2 3
Scheme 3. Synthesis of porphyrin dimers. Reagents and conditions: AsPh (2 equiv), Pd (dba) (0.1 equiv), THF (20 mL), TEA (4 mL), 65 °C, nitrogen.
coupling reactions in order to link the free base porphyrins
under mild conditions. For optical applications we targeted
the push–pull dimers 25a,b connected through an ethynyl-
phenyl linker and bearing either naphthyl or phenyl sub-
stituents. Their synthesis involved the coupling of 13a
with the appropriate meso-halogenated porphyrin (Scheme
R1
Ph
Ph
Ph
Ph
2
11a + 3b
R1
31 R1 = 1-Naphthyl 22%
Scheme 4. Synthesis of the linear porphyrin trimer 31. Reagents and
conditions: AsPh (2 equiv), Pd (dba) (0.1 equiv), THF (20 mL), TEA
4 mL), 65 °C, nitrogen.
3
). Using similar pathways, the more conjugated push–pull
3
2
3
dimers 26a,b were prepared in good yields. Furthermore,
porphyrins 20 and 21 were used for the synthesis of the
acetylene linked dimers 27 and 28 and the ethynylphenyl
linked dimers 29 and 30. Depending on which porphyrin
monomer carries the bromo or acetylenic group, dimers
with opposite orientations of the intramolecular dipole
are accessible (e.g., 24 vs 25a). These compounds allow
for further modifications as a wide range of reactions can
be performed at the free meso positions (e.g., linkage to
bioconjugates) and different metals can be inserted into
the dimers to further fine-tune their physical properties.
Similarly, linear porphyrin trimers are easily constructed
using 2 equiv of an alkylporphyrin and a dibromoporphy-
rin (Scheme 4). For example, the reaction of 11a with 3b
gave trimer 31 in 22% yield. Again, the terminal porphyrin
units contain a free meso position amenable for further syn-
thetic manipulations. As expected, the absorption spectrum
of 31 in CH Cl gives two sharp Soret bands at 413 nm and
(
451 nm, respectively, and the Q bands are red-shifted by
57 nm relative to that of 11a and by 23 nm relative to that
of dimer 23 indicating their potential for biomedical
applications.
Even more intriguing was the possibility of using 5,10-
disubstituted porphyrins for the construction of multi-
porphyrin systems with ‘rectangular’ geometry. They
have already been used as building blocks for the synthesis
of symmetric square shaped p-conjugated porphyrin oligo-
mers using Glaser couplings. Our recent results on the
potential of monomeric push–pull 5,10-A B porphyrins
for nonlinear optical applications encouraged us to expand
our studies to rectangular trimeric systems as NLO materi-
als. These were easily accessible by bromination of the
5,10-disubstituted porphyrins affording 32 followed by a
5
a
1
0
1
1
2
2
2
2

M. Fazekas et al. / Tetrahedron Letters 49 (2008) 2236–2239
2239
Acknowledgement
Ph
R1
+
2
This work was generously supported by the Science
Foundation Ireland (Research Professorship SFI 04/RP1/
B482 and SFI 06/RFP/CHO044).
Ph
11a R1 = H
1
Br
3a R1 = 4-nitrophenyl
Br
3
2
References and notes
Ph
1
. (a) Nyman, E. S.; Hynninen, P. H. J. Photochem. Photobiol., B 2004,
73, 1–28; (b) El-Khouly, M. E.; Ito, O.; Smith, P. M.; D’Souza, F. J.
Photochem. Photobiol., C 2004, 5, 79–104; (c) Senge, M. O.; Fazekas,
M.; Notaras, E. G. A.; Blau, W. J.; Zawadzka, M.; Locos, O. B.; Ni
Mhuircheartaigh, E. M. Adv. Mater. 2007, 19, 2737–2774.
R1
Ph
3
3
3a R1 = H 16%
2
. (a) Dogutan, D. K.; Zaidi, S. H. H.; Thamyongkit, P.; Lindsey, J. S.
J. Org. Chem. 2007, 72, 7701–7714; (b) Sharman, W. M.; Van Lier, J.
E. J. Porphyrins Phthalocyanines 2000, 4, 441–453; (c) Jun-ichiro, S. J.
Porphyrins Phthalocyanines 2004, 8, 93–102; (d) Senge, M. O. Acc.
Chem. Res. 2005, 38, 733–743.
3b R1 = 4-nitrophenyl 18%
Ph
Ph
R1
3. (a) Burrell, A. K.; Officer, D. L.; Plieger, P. G.; Reid, D. C. W. Chem.
Rev. 2001, 101, 2751–2796; (b) Iengo, E.; Zangrando, E.; Alessio, E.
Acc. Chem. Res. 2006, 39, 841–851.
Scheme 5. Synthesis of porphyrin trimers with rectangular geometry.
Reagents and conditions: AsPh (2 equiv), Pd (dba) (0.1 equiv), THF
20 mL), TEA (4 mL), 65 °C, nitrogen.
3
2
3
4
. (a) Paolesse, R.; Pandey, R. K.; Forsyth, T. P.; Jaquinod, L.;
Gerzevske, K. R.; Nurco, D. J.; Senge, M. O.; Licoccia, S.; Boschi, T.;
Smith, K. M. J. Am. Chem. Soc. 1996, 118, 3869–3882; (b) Vicente,
M. G. H.; Jaquinod, L.; Smith, K. M. Chem. Commun. 1999, 1771–
(
1
782.
. (a) Wiehe, A.; Ryppa, C.; Senge, M. O. Org. Lett. 2002, 4, 3807–3809;
b) Hatscher, S.; Senge, M. O. Tetrahedron Lett. 2003, 44, 157–160; (c)
Ryppa, C.; Senge, M. O.; Hatscher, S. S.; Kleinpeter, E.; Wacker, P.;
Schilde, U.; Wiehe, A. Chem. Eur. J. 2005, 11, 3427–3442; (d) Wiehe,
A.; Shaker, Y. M.; Brandt, J. C.; Mebs, S.; Senge, M. O. Tetrahedron
Pd-catalyzed coupling reaction with 2 equiv of precursors
5
1
1a and 13a, respectively, to yield dimers 33 (Scheme 5).
Similar to trimer 31, the absorption spectrum of the
(
rectangular trimers 33a,b exhibited a split Soret band and
a bathochromic shift of the Q bands due to the electronic
coupling of the subunits. The optical limiting (OL) proper-
ties of the multiporphyrins were investigated using the
open-aperture z-scan technique with 6 ns laser pulses at
2
005, 61, 5535–5564.
6
7
. Callot, H. J. Tetrahedron Lett. 1973, 50, 4890–4987.
. Senge, M. O.; Kalisch, W. W.; Bischoff, I. Chem. Eur. J. 2000, 6,
2721–2738.
1
2
8
. (a) Feng, X.; Senge, M. O. J. Chem. Soc., Perkin Trans. 1 2001, 1030–
5
32 nm. All the compounds examined exhibited reverse
1
038; (b) Baolu, S.; Boyle, W. R. J. Chem. Soc., Perkin Trans. 1 2002,
saturable absorption (RSA) under incident focal intensities
ranging from about 0.05 to approximately 0.10 GW cm
Preliminary studies showed the rectangular trimer 33a to
possess outstanding OL properties in comparison to the
linear compound 31 with the same number of porphyrin
units. The OL performances of the dimers examined (22,
1
397–1400; (c) Yeung, M.; Ng, A. C. H.; Drew, M. G. B.; Vorpagel,
À2
.
E.; Breitung, E. M.; McMahon, R. J.; Ng, D. K. P. J. Org. Chem.
998, 63, 7143–7150; (d) Boyle, R.; Johnson, C.K.; Dolphin, D. J.
1
Chem. Soc., Chem. Commun. 1995, 527–528; (e) Shediac, R.; Gray, M.
H. B.; Uyeda, T. H.; Johnson, R. C.; Hupp, J. T.; Anjiolillo, P. J.;
Therien, M. J. J. Am. Chem. Soc. 2000, 122, 7017–7033; (f) Berrzin,
D. B. Russ. J. Gen. Chem. 2005, 75, 854–858; (g) Compounds 1a,b, 2a,
2
3, 25a,b, 29 and 30) were better or comparable to the
8a,c–e
3
a,b, 4b and 5a were prepared according to the literature.
linear trimer 31 but did not exceed those of 33a.
9
. Initial studies showed that 17 can be converted to the 5-(1-ethyl-
propyl)-10,15,20-tri(2-trimethylsilylethynyl)porphyrin in 49% yield,
which subsequently was deprotected to 5,10,15-triethynyl-(20-(1-
ethylpropyl)porphyrin in 63% yield.
Currently, we are optimizing the reactions described
herein. The preliminary results indicate that judicious
choice of the starting materials and appropriate planning
of the sequence of coupling and functionalization reactions
allow the rapid generation of a variety of unsymmetrical
multichromophoric systems or precursors with enhanced
optical properties. The synthetic strategies are equally
amenable for the construction of amphiphilic porphyrin
dimers and trimers for use in photodynamic therapy and
will be useful precursors for the preparation of larger,
superstructured systems.
1
0. (a) Sugiura, K.; Fujimoto, Y.; Sakata, Y. Chem. Commun. 2000,
105–1106; (b) Kato, A.; Sugiura, K.; Miyasaka, H.; Tanaka, H.;
1
Kawai, T.; Sugimoto, M.; Yamashita, M. Chem. Lett. 2004, 33, 578–
579.
1
1. Notaras, E. G. A.; Fazekas, M.; Doyle, J. J.; Blau, W. J.; Senge, M.
O. Chem. Commun. 2007, 2166–2168.
1
2. z-Scans: Q-switched Nd:YAG laser with a pulse repetition rate of
À1
1
0 Hz; samples dissolved in DMF; c = 0.01 g L . The beam was
spatially filtered to remove the higher order modes and tightly focused
with a 9 cm focal length lens as described in Ref. 11.