Synthesis of a highly soluble superstructured phenanthroline strapped porphyrin

Article abstract of DOI:10.1016/j.tetlet.2004.10.167

A highly soluble phenanthroline strapped porphyrin is prepared on multigram scale by appropriate functionalization with C₁₂ chains a posteriori to the efficient cyclization of the tetrapyrrolic macrocycle. A highly soluble phenanthroline strapp

Full text of DOI:10.1016/j.tetlet.2004.10.167

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 139–142
Synthesis of a highly soluble superstructured
phenanthroline strapped porphyrin
*
´ ´ ´ ˆ
Matthieu Koepf, Frederic Melin, Jerome Jaillard and Jean Weiss
´
Institut de Chimie, Universite Louis Pasteur, UMR 7512 au CNRS, 4 rue Blaise Pascal, 67070 Strasbourg, France
Received 4 October 2004; revised 28 October 2004; accepted 29 October 2004
Available online 21 November 2004
Abstract—A highly soluble phenanthroline strapped porphyrin is prepared on multigram scale by appropriate functionalization
with C12 chains after the cyclization of the tetrapyrrolic macrocycle.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
increase, but attempts to use more soluble intermediates
such as m-xylyl dipyrrylmethane to obtain the derivative
2 were unsuccessful. Compound 2 had to be prepared
from 1 in two steps in 60% yield (overall) by functional-
ization of the free meso positions (10,20).9 In addition,
because the most interesting features of 1 and 2 lie in
the use of the cavity defined by the phenanthroline
strap,10 functionalization of these structures requires
that the meso positions remain unhindered, thus forbid-
ding solubility increase involving their substitution (Fig.
1). All attempts to use more soluble phenanthroline
intermediates resulted in extremely poor cyclization
yields and inextricable mixtures of porphyrin deriva-
tives. Previous failure of cyclizations using alkyl dipyr-
rylmethanes strongly suggested that poor solubility of
the porphyrinogen intermediate was a thermodynamic
well essential to the high cyclization yield. However,
no other successful cyclization experiments were avail-
able to support this hypothesis. We were thus prompted
to perform the condensation reaction with a poorly
The design and preparation of 5,15-diaryl and
5,10,15,20-tetraaryl porphyrin architectures to be used
either as enzyme models, or in the preparation of new
materials often faces the challenge of the tetrapyrrolic
macrocycleÕs poor solubility.1 Sulfonation of the aryl
groups,2 quaternization of pyridine substituents,3 or
introduction of neutral hydrophilic groups4,5 performed
a posteriori to the formation of the tetrapyrrolic macro-
cycle have provided nice ways to access water soluble
material.6 The preparation of sophisticated porphyrin
derivatives soluble in organic solvents is usually
achieved by the use of aldehydes bearing long alkyl
chains or substituted dipyrrylmethanes in LindseyÕs
modern version of AdlerÕs condensation.7 Such an
approach has the advantage of limiting the number of
synthetic steps performed on the porphyrin itself.
For the last decade, we have made extensive use of a
phenanthroline strapped porphyrin 1, which was pre-
pared by cyclization, at low concentration in dichloro-
methane, of a phenanthroline dialdehyde derivative
with an unsubstituted dipyrrylmethane in the presence
of trifluoroacetic acid.8 The efficiency of the condensa-
tion (45–60%) has turned 1 into a starting material for
several ongoing projects in our group, however its low
solubility in dichloromethane (4mg/mL) has always
been a drawback for further functionalization. The
introduction of xylyl groups provided a slight solubility
N
N
N
N
N
20
5
N
N
H
N
H
NH
N
N
10
NH
15
2
1
Keywords: Porphyrins; Solubility; Cyclization; Phenanthroline.
*
Figure 1. Two phenanthroline strapped porphyrin derivatives poorly
soluble in organic solvents.
Corresponding author. Tel.: +33 390241419; fax: +33 390241431;
e-mail: jweiss@chimie.u-strasbg.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.167

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M. Koepf et al. / Tetrahedron Letters 46 (2005) 139–142
soluble phenanthroline aldehyde derivative, which
incorporated two sites that could be used to add solu-
bilizing alkyl chains after porphyrin formation.
N
N
N
The 2,9-di-(4-bromophenyl)-1,10-phenanthroline deriv-
ative 4 has been prepared as previously described in
the literature.11 Dioxolane formation on the 2-bromo-
5-methoxy benzaldehyde was achieved in 89% in the
presence of ethylene glycol in toluene containing p-tolu-
ene sulfonic acid as a catalyst. Further lithiation at low
temperature (ꢀ78°C) with n-butyllithium, and quench-
ing of the intermediate with tri-n-butylborate afforded
the boronic acid 5 in 81% after acidic treatment. Suzuki
coupling (2M K2CO3, toluene, MeOH, Pd(PPh3)4,
90°C, 1day) of the dibromide 3 and 2equiv of boronic
acid 5 afforded the dialdehyde 6 in 71% yield (Scheme 1).
6 (0.5 eq.)
RO
N
H
NH
NH
HN
i)
N
7
8: R=CH3
9: R=H
OR
ii)
iii)
10: R=CH2-(-CH2)10-CH3
The dipyrrylmethane 7 was prepared by reported meth-
ods12 and condensed under dilute conditions in a 2/1
stoichiometry with the dialdehyde 6 to afford a unique
porphyrin derivative 8 in 60% yield. Interestingly, over
repeated cyclization reactions, the average yield for 8
tends to be 5–10% higher than for 1 under identical con-
ditions. The dimethoxy derivative 8 is slightly less solu-
ble than the unsubstituted 1, and the high yields
obtained at this stage tend to confirm our hypothesis
regarding the thermodynamically favored formation of
insoluble cyclic material. After drying by repeated evap-
oration with toluene, the poorly soluble porphyrin 8
(3mg/mL) was then treated with BBr3 (1M in CH2Cl2)
in refluxing CH2Cl2 for 4h to cleave the methoxy
groups. The corresponding dihydroxy derivative 9 is
insoluble in most organic solvents, except for hot
dimethylformamide. Alkylation of 9 with 1-bromodode-
cane was performed in DMF in the presence of K2CO3,
to afford the porphyrin derivative 10 in 90% yield
(two steps) (Scheme 2). The high solubility of 10
(40mg/mL), combined with its gram scale availability
certainly opens new possibilities regarding further func-
tionalization of the unsubstituted 10, and 20 (meso)
positions.
Scheme 2. Porphyrin 8 formation. Reagents and conditions: (i) a.
TFA, CH2Cl2, 25°C, 20h, b. 10equiv DDQ, 25°C, 2h; (ii) 50equiv
BBr3, CH2Cl2, 40°C, 4h; (iii) 7.3equiv Br–(–CH2)11–CH3, K2CO3,
DMF, 80°C, 20h.
2. Experimental
2.1. 2-(2-Bromo-5-methoxy-phenyl)-[1,3]dioxolane (4)
A mixture of 2-bromo-5-methoxybenzaldehyde (14.5g,
68mmol), ethylene glycol (5mL, 88mmol), and p-tolu-
enesulfonic acid (380mg, 2mmol) in 230mL of toluene
was heated to reflux. The water formed during the reac-
tion was eliminated with a ÔDean StarkÕ apparatus. After
15h the solution was washed twice with a 2M solution
of aqueous K2CO3, dried over anhydrous Na2SO4, and
the solvent was evaporated. Column chromatography
(60–200lm SiO2, cyclohexane/ethyl acetate 4:1, diame-
ter 4.5cm, h = 30cm) afforded 15.5g (60mmol, 89%) of
4 as a yellow-brown oil that was used without further
purification. 1H NMR (CDCl3, 300MHz): 7.45 (d,
J = 8.7Hz, 1H), 7.16 (d, J = 3.1Hz, 1H), 6.79 (dd,
J1 = 8.7Hz, J2 = 3.1Hz, 1H), 6.05 (s, 1H), 4.21–4.03
(m, 4H), 3.81 (s, 3H).
In conclusion, the porphyrin 10 is available on gram
scale, is highly soluble in organic solvents, and bears
two meso positions available for further functionaliza-
tion. This is a rare combination in the area of strapped
porphyrins. Development of soluble self-assembled pho-
tonic devices incorporating 10 as a building block is
under progress.
2.2. 2-Formyl-4-methoxy-phenylboronic acid (5)
An argon flushed solution of dioxolane 4 (15.5g,
60mmol) in 200mL of freshly distilled diethyl ether
was cooled to ꢀ78°C. n-Butyl lithium (1.6M in
N
N
N
N
Br
B(OH)2
CHO
3
Br
Br
O
O
i)
ii)
MeO
MeO
CHO
OHC
4
5
6
MeO
OMe
Scheme 1. Synthesis of 6. Reagents and conditions: (i) a. 1.1equiv n-BuLi, Et2O, ꢀ78°C, 45min, b. 1.3equiv B(OBu)3, ꢀ78°C, 30min, 25°C, 2h, c.
H3O+, H2O; (ii) Pd[P(Ph3)4], K2CO3, toluene/MeOH/H2O, 90°C, 24h.

M. Koepf et al. / Tetrahedron Letters 46 (2005) 139–142
141
hexane, 42mL, 66mmol) was added dropwise while
2.5. Dihydroxy-phenanthroline strapped porphyrin (9)
maintaining the temperature below ꢀ70°C. After
stirring the mixture for 45min at ꢀ78°C, tributyl borate
(22mL, 79mmol) was added dropwise, keeping the
temperature below ꢀ55°C. After stirring for 30min
at ꢀ78°C, the solution was warmed to room
temperature over 2h. Acid–base extraction of the reac-
tion mixture afforded 8.7g (48mmol, 81%) of 5 as a
grayish solid. This product was also used without
1M boron tribromide solution (30mL, 30mmol) in dry
dichloromethane was added dropwise under argon to a
solution of porphyrin 8 (880mg, 0.59mmol) in 100mL
of dry dichloromethane. The mixture was refluxed for
4h under argon and then a portion of 20mL of metha-
nol was added. The solvent was removed and the crude
product was dissolved in CH2Cl2/EtOH (10:4). The solu-
tion was washed once with water and twice with a 2M
solution of aqueous K2CO3, and then dried over
Na2SO4. Evaporation of the solvent afforded crude 9
as a dark-red powder. Due to its insolubility this prod-
uct was used without further purification.
1
further purification. H NMR (CDCl3, 300MHz): 9.88
(s, 1H), 8.23 (d, J = 8.5Hz, 1H), 7.44 (d, J = 2.7Hz,
1H), 7.20 (dd, J = 8.5Hz, J0 = 2.7Hz, 1H), 6.96 (s,
2H), 3.93 (s, 3H).
2.3. Dialdehyde (6)
2.6. Didodecanoxy-phenanthroline strapped porphyrin
(10)
To a suspension of 2,9-bis(4-bromophenyl)-1,10-phen-
anthroline (7.7g, 15.7mmol), boronic acid 5 (7g,
39mmol), and K2CO3 (43g, 311mmol) in 250mL of tolu-
ene, was added 80mL of water and 80mL of methanol.
The mixture was Ar flushed and Pd(PPh3)4 (200mg,
0.17mmol) was added. After stirring at 85°C for 20h,
200mL of a solution of 15% ethyl acetate in CH2Cl2
was added to the reaction mixture and the organic sus-
pension was washed three times with brine, then dried
with toluene (azeotropic distillation of residual water).
The crude product was recrystallized in boiling toluene
to yield 6.6g (16mmol, 71%) of 6 as a brown solid. Melt-
ing point: 239–241°C. 1H NMR (CDCl3, 300MHz):
10.12 (s, 2H), 8.61–8.58 (m, 4H), 8.46 (d, J = 8.5Hz,
2H), 8.29 (d, J = 8.5Hz, 2H), 7.92 (s, 2H), 7.68–7.65
(m, 4H), 7.58–7.55 (m, 4H), 7.31 (dd, J = 8.6Hz,
J0 = 3Hz, 2H), 3.97 (s, 6H). Elemental analysis: % calcu-
lated for C40H28N2O4 + 0.5C7H8 + 0.5CH3COOCH2-
CH3: C, 79.11; H, 5.25; N, 4.06; found: C, 78.74; H,
5.53; N, 4.06.
Crude porphyrin 9 (0.59mmol) was reacted with an ex-
cess of 1-bromo-dodecane (588mg, 4.4mmol) in 200mL
of DMF with K2CO3 (815mg). After stirring the mix-
ture at 80°C for 20h, the solvent was partially removed.
Water (200mL) was added, and the product was filtered
over Celite. The crude porphyrin 10 was taken in dichlo-
romethane and the solution was dried over Na2SO4. The
solvent and the excess of 1-bromododecane were dis-
tilled under reduced pressure (10mmHg). Porphyrin
10 was then purified by chromatography over Al2O3
(neutral, activities II–III, diameter 2cm, h = 20cm). Elu-
tion with dichloromethane and evaporation of the sol-
vent afforded 1.08g of 10 (91% yield for the last two
steps) as a purple powder. Melting point: 255–265°C.
1H NMR (CDCl3, 300MHz): 10.14 (s, 2H), 9.24 (d,
J = 4.7Hz, 4H), 8.98 (d, J = 4.7Hz, 4H), 8.33 (d, J =
2.7Hz, 2H), 7.95 (d, J = 8.4Hz, 2H), 7.80 (d,
J = 8.6Hz, 2H), 7.51 (m, 6H), 6.69 (d, J = 8.6Hz, 4H),
6.35 (d, J = 8.6Hz, 4H), 4.32 (t, J = 6.8Hz, 4H), 1.99
(m, 4H), 1.5–1.2 (m, 18H), 0.88 (m, 6H), ꢀ2.91 (s,
2H). UV–visible in CH2Cl2 kmax (e in Mꢀ1 cmꢀ1): 302
(64,000), 338 shoulder (56,000), 416 (233,000), 507
(14,000), 541 (4000), 579 (5000), 635 (1000). Elemental
analysis: % calculated for C82H88N6O2 + 0.5CH2Cl2:
C, 80.44; H, 6.96; N, 6.99; found: C, 80.78; H, 7.07;
N, 6.66. Mass spectrometry (MALDI TOF): mass calcu-
lated for M+H+: 1159; found: 1159.23.
2.4. Dimethoxy-phenanthroline strapped porphyrin (8)
A solution of dialdehyde 6 (278mg, 0.46mmol), dipyr-
rylmethane (140mg, 0.46mmol) and trifluoroacetic acid
(1mL) in 1.6L of dichloromethane was stirred for 20h
under argon. Dichloro-dicyano-quinone (900mg), was
added and the mixture was refluxed for 2h. The solution
was neutralized with 20mL of triethylamine, washed
three times with water, and dried over Na2SO4 prior
to the evaporation of the solvent. The porphyrin was
purified by chromatography over Al2O3 (neutral, activi-
ties II–III, diameter 4cm, h = 10cm). Elution with
CH2Cl2 and evaporation of the solvent afforded
243mg (62% yield) of 8 as a red-brownish powder. Melt-
Acknowledgements
´
The CNRS and the Universite Louis Pasteur de Stras-
bourg are acknowledged for financial support. M.K.
´
thanks the Region Alsace and the CNRS for a BDI
fellowship.
1
ing point: >300°C; H NMR (CDCl3, 300MHz): 10.21
(s, 2H), 9.34 (d, J = 4.5Hz, 4H), 9.07 (d, J = 4.5Hz,
4H), 8.34 (d, J = 2.8Hz, 2H), 8.02 (d, J = 8.4Hz, 2H),
7.87 (d, J = 8.8Hz, 2H), 7.58 (dd, J = 8.8Hz,
J0 = 2.8Hz, 2H), 7.55 (d, J = 8.4Hz, 2H), 7.54 (s, 2H),
6.71 (d, J = 8.6Hz, 4H), 6.52 (d, J = 8.6Hz, 4H), 4.18
(s, 6H), ꢀ3.12 (s, 2H). UV–visible in CH2Cl2 kmax (e in
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