Controlled synthesis of meso-veratrylporphyrins under acid-catalyzed scrambling conditions

Article abstract of DOI:10.1080/00397910701356496

5,15-Bis(veratryl)porphyrin (1), 5,10,15-tris(veratryl)porphyrin (2), and 5,10,15,20-tetrakis(veratryl)porphyrin (3), C36H30N4O4, C44H38N4O6, and C52H46N4O8 were synthesized by an acid-catalyzed, one-pot reaction of meso-dipyrromethane, 3,4-di-OCH3-benzal

Full text of DOI:10.1080/00397910701356496

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Controlled Synthesis of
meso‐Veratrylporphyrins under
Acid‐Catalyzed Scrambling Conditions
a
a
a
b
a
I. Azócar , F. Isaacs , J. Guerrero , W. Dehaen & M. J. Aguirre
a
Department of Applied Chemistry, Faculty of Chemistry and Biology ,
University of Santiago of Chile , Santiago, Chile
b
Department of Chemistry , University of Leuven , Leuven, Belgium
Published online: 22 Jun 2007.
To cite this article: I. Azócar , F. Isaacs , J. Guerrero , W. Dehaen & M. J. Aguirre (2007) Controlled Synthesis
of meso‐Veratrylporphyrins under Acid‐Catalyzed Scrambling Conditions, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:12, 2001-2009
To link to this article: http://dx.doi.org/10.1080/00397910701356496
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Synthetic Communications , 37: 2001–2009, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701356496
Controlled Synthesis of meso-
Veratrylporphyrins under Acid-Catalyzed
Scrambling Conditions
I. Az o´ car, F. Isaacs, and J. Guerrero
Department of Applied Chemistry, Faculty of Chemistry and Biology,
University of Santiago of Chile, Santiago, Chile
W. Dehaen
Department of Chemistry, University of Leuven, Leuven, Belgium
M. J. Aguirre
Department of Applied Chemistry, Faculty of Chemistry and Biology,
University of Santiago of Chile, Santiago, Chile
Abstract: 5,15-Bis(veratryl)porphyrin (1), 5,10,15-tris(veratryl)porphyrin (2), and
5
,10,15,20-tetrakis(veratryl)porphyrin (3), C36
were synthesized by an acid-catalyzed, one-pot reaction of meso-dipyrromethane, 3,4-
di-OCH -benzaldehyde (veratraldehyde), and trifluoroacetic acid (TFA). These three
30 4 4 38 4 46 4 8
H N O , C44H N O6, and C52H N O
3
different products were obtained as a result of scrambling reactions. The molecular struc-
tures have been characterized by elemental analysis, ESI mass spectra, 1D and 2D NMR
1 13
techniques ( H and C), and UV-visible spectroscopy.
Keywords: 5,15-bis(veratryl)porphyrin, dipyrromethane, porphyrins
INTRODUCTION
The synthesis of porphyrins has special importance in bioorganic and bioinor-
[1]
ganic chemistry and their application in biomedical sciences, solar energy
Received in the USA October 27, 2006
Address correspondence to I. Az o´ car, Department of Applied Chemistry, Faculty of
Chemistry and Biology, University of Santiago of Chile, Av. Libertador Bernardo
O’Higgins 3363, Santiago, Chile. E-mail: manuel.azocar@correo.usach.cl
2
001

2
002
I. Az o´ car et al.
[
2]
[3]
conversion, and catalysis. 5,15-Diphenylporphyrins have been used in the
synthesis of meso-linked porphyrin arrays as a model of light-harvesting
[
antenna systems, dendritically appended models of cytochromes, and
4]
[5]
[6]
rod-like liquid crystal porphyrins and for their evaluation as potential anti-
[
7]
microbial photosensitizers.
Condensation of (substituted) benzaldehyde and dipyrromethane in acidic
[8]
media is the most common way to get 5,15-diaryl substituted porphyrins. In
this McDonald-type synthesis of these porphyrins, a scrambling process
generally may occur depending on several experimental conditions
including solvent, acid catalyst, reagent concentration, reagent stoichiometry,
temperature, and salts present. The acidolysis of the porphyrinogen or dipyr-
romethane can lead to recombination of the fragments and the isolation of a
[9]
mixture of different symmetric and unsymmetric porphyrins.
In this
article we report a method to synthesize three different porphyrins in good
yields using this polypyrrolic rearrangement. We also describe a method to
avoid scrambling in this synthesis.
EXPERIMENTAL
Apparatus and Procedures
One-dimensional (1D) and two-dimensional (2D) NMR spectra were
acquired on a Bruker Avance 400 spectrometer equipped with a broadband
inverse probe with z-gradient. The chemical shifts are reported in parts per
million (ppm) referenced to TMS and calibrated with respect to residual
1
13
solvent protons ( H) or the carbon signal of deuterated solvents ( C). Mass
spectrometry data were obtained with a Micromass Quattro II apparatus (ESI,
solvent: CH OH). UV-vis spectra were taken on Analytikjena Specord S 100.
3
Materials
Solvents for spectroscopy were distilled from the appropriate drying agents
Other materials were
reagent grade and used without further purification.
[10]
˚
and stored under dry N over 3-A molecular sieves.
2
Porphyrin Syntheses: 5,15-Bis(veratryl)porphyrin (1), 5,10,15-
Tris(veratryl)porphyrin (2), and 5,10,15,20-
Tetrakis(veratryl)porphyrin (3)
[
11]
A solution of meso-dipyrromethane (18 mg, 0.123 mmol) in CH Cl (50 ml)
2
2
was degassed by bubbling with N for 10 min. 3,4-Methoxybenzaldehyde
2
(20.57 mg, 0.123 mmol) was added to this solution. The flask was wrapped in
aluminum foil, and stirred magnetically for 15 min. Trifluoroacetic acid (TFA,

Synthesis of meso-Veratrylporphyrins
2003
65 mL) was added. The flask contents were stirred in the dark for 16 h (to avoid
scrambling, the same reaction was repeated for 3 h) in an N atmosphere at room
2
temperature. Then 2,3,5,6-tetrachloro-1,4-benzoquinone (TCQ) (0.2 mmol,
50 mg) was added to the solution, and the resulting solution was stirred for an
additional 3 h. The reaction mixture was neutralized by triethylamine.
The reaction was monitored by UV/vis spectroscopy and thin-layer
chromatography (TLC). The solvent was removed under high vacuum for
1
2 h. The solid residue was dissolved in 20 ml of dichloromethane, and
silica gel (5 g, 230–400 mesh) was added to the solution. The solvent was
evaporated, and the crude product, absorbed on silica gel, was loaded onto
the top of a chromatography column (25 ꢀ cm) packed with silica gel. The
products were eluted with CH Cl – hexane (60:40, 80:20, and 90:10) to
2
2
obtain different dark pink fractions. These fractions were concentrated
under reduced pressure. The dark purple products were air dried to give 1,
2
, and 3 respectively (Scheme 1).
Data
5
,15-Bis(veratryl) porphyrin (1): (7.7 mg; 21%). Mp . 3008C; visible
spectrum: lmax/nm/(log 1) (CH Cl ): 411 (5.03), 504 (3.20), 540 (2.29),
2
2
Scheme 1. Synthesis of 5, 15-bis(3,4-methoxyphenyl) porphyrin (2).

2
004
I. Az o´ car et al.
1
78 (2.25), 633 (1.08) nm; H NMR (400.13 MHz, CDCl ): 10.31
5
3
(
o-PhH), 7.32 (d, 2H, m-PhH), 4.21 (s, 3H, OCH ), 4.04 (s, 3H, OCH ),
s, 2H, meso), 9.39 (d, 4H, b-H), 9.14 (d, 4H, b-H), 7.83 (m, 4H,
3
3
1
3
2
3.07 (s, 2H, NH). C NMR (100.61 MHz, CDCl ): d 149.2 (Ar-C),
3
1
1
5
47.4 (Ar-C), 134.3 (Ar-C), 127.8 (Ar-C), 118.9 (Ar-C), 110.0 (Ar-C),
31.86 (C-pyrrole), 145.24 (C-pyrrole), 105.38 (meso CH), 56.32 (OCH ),
3
þ
6.28 (OCH ). MS(ESI): m/z 583.6 [M þ H] , calc. 583.6. Anal. calcd.
3
for C H N O : C, 74.21; H, 5.19; N, 9.62. Found: C, 74.34; H, 5.33;
6 30 4 4
3
N, 9.57.
5
3
5
1
,10,15-Tris(3,4-OCH -phenyl) porphyrin (2): (12.2 mg; 34%). Mp .
3
008C; visible spectrum: lmax/nm (CH Cl ): 418 (5.62), 512.7 (4.09),
2
2
1
48.8 (3.75), 586 (3.63), 642 (3.35) nm; H NMR (400.13 MHz, CDCl ):
0.20 (s, 1H, meso), 9.34 (d, 2H, b-H), 9.08 (d, 2H, b-H), 8.96 (d, 2H,
3
b-H), 8.93 (d, 2H, b-H), 7.81 (m, 6H, o-PhH), 7.28 (d, 3H, m-PhH),
.19 (s, 6H, OCH ), 4.18 (s, 3H, OCH ), 4.01 (s, 6H, OCH ), 3.97
4
3
3
3
1
3
(
s, 6H, OCH ), 22.95 (s, 2H, NH). C NMR (100.61 MHz, CDCl ): d
3 3
149.2 (Ar-C), 147.4 (C-pyrrole), 134.6 (Ar-C), 131.6 (C-pyrrole), 130.85
(
(
C-pyrrole), 127.7 (Ar-C), 118.6 (Ar-C), 104.9 (meso CH), 56.42
þ
OCH ), 56.38 (OCH ). MS(ESI): m/z 719.7 [M þ H] , calc. 719.8.
3
3
Anal. calcd. for C H N O : C, 73.52; H, 5.33; N, 7.79. Found: C,
4
4 38 4 6
7
3.47; H, 5.44; N, 7.82.
5,10,15,20-Tetrakis(3,4-OCH -phenyl) porphyrin (3): (10.5 mg; 29%).
Visible spectrum: lmax/nm/(log 1) (CH Cl ): 425 (4.92), 520 (3.71), 557.8
3
2
1
2
(
3.48), 592 (3.25), 651 (3.16) nm; H NMR (400.13 MHz, CDCl3):
.86 (s, 8H, b-H), 7.18 (m, 8H, o-PhH), 7.69 (d, 4H, m-PhH), 3.92 (s, 12H,
8
OCH ), 4.18 (s, 12H, OCH ), 22.80 (s, 2H, NH). C NMR (100.61 MHz,
1
3
3
3
CDCl ): d 149.16 (Ar-C), 135.05 (Ar-C), 127.60 (Ar-C), 118.53 (C-Ar),
3
1
09.73 (C-Ar), 131.24 (C-pyrrole), 147.35 (C-pyrrole), 120.06 (meso-C), 56.32
þ
(OCH ), 56.34 (OCH ). MS (ESI): m/z 855.7 [M þ H] , calc. 855.9. Anal.
3
3
calcd. for C H N O : C, 73.05; H, 5.42; N, 6.55. Found: C, 73.17; H, 5.54;
N, 6.43.
52 46 4 8
RESULTS AND DISCUSSION
The synthesis of the 5,15-disustitued porphyrins occurs by a [2 þ 2] conden-
sation of the respective dipyrromethane with an aldehyde catalyzed by trifluor-
[
12]
oacetic acid.
such as 2,3-dicyano-5,6-dichloro-parabenzoquinone (DDQ) and TCQ or
This reaction gives porphyrinogen, but with oxidizing agents
bubbling with O , the respective porphyrins can be obtained. Scrambling in
2
an acid-catalyzed dipyrromethane–aldehyde condensation is well known, and
it is controlled by the acid catalyst, reagent concentration, reagent stoichiometry,

Synthesis of meso-Veratrylporphyrins
2005
[
13]
solvent, salts, and temperature.
Following the conditions reported by Litter
et al. to avoid scrambling, we repeated this synthesis but varied the reaction
time. First we tested the reaction for 16 h prior to addition of TCQ. The
results showed yields of 21% of 1, 34% of 2, and 29% of 3. In a second
reaction with the same conditions, the reaction was stirred only for 3 h. In this
way, only 1 was obtained (58.6%) after chromatographic purification over
[
14]
silica gel. Fox et al.
scrambled porphyrin products. Litter et al.
described the acidolysis of dipyrromethane to explain
also proposed a mechanism to
[13]
explain the exchange processes of polypyrranes by acid catalysis. In concor-
dance with our results, the scrambling process is also controlled by the
reaction time, increasing the exchange process with the time.
1
The H NMR spectra shows the chemical shifts for pyrrole (Hb) and meso
10.31 and 10.2 ppm) hydrogens (Fig. 1). These data were used to characterize
(
the porphyrins, because these signals are typical for this kind of systems.
Tetrasubstituted arylporphyrins do not show meso protons, but b-proton
signals appear like a singlet. Between 7 and 8 ppm, a multiplet signal
appears corresponding to the phenyl protons. Three singlet signals for
1
Figure 1. H NMR spectra of the porphyrins taken in CDCl
3
:15-Bis(veratryl)
porphyrin (1), 5,10,15-tris(veratryl)porphyrins (2), and 5,10,15,20-tetrakis(veratryl)
porphyrin.

3
Figure 2. HMBC spectra of 5,10,15-tris(veratryl)porphyrin (2) taken in CDCl .

Synthesis of meso-Veratrylporphyrins
2007
methoxy groups appear in 2 in concordance with its structure. Compounds 1
and 3 show two kinds of signals in the same region, but integration allowed us
to differentiate each porphyrin. Three different N-H pyrrole signals were
observed for these compounds. These chemical shifts show differences with
the number of the phenyl groups, shifting to high field with the number of
the free meso carbons.
Correlation spectroscopy (COSY) correlations were useful to check the
proton assignment for these porphyrins. H-meso show a singlet signal in
accord with no interaction expected with other protons. On the other hand,
H-b pyrrole protons show the correlations arise because of the coupling with
each other in 1 and 2. Correlation between phenyl protons could be established,
confirming the assignments to meta and ortho protons (H-Ar
1
! H-Arortho).
13
meta
3
C assignments were realized using the proton information previously
1
3
1
discussed and concerted analyses of 1D C spectrum and 2D H and C corre-
lation spectra. Figure 2 shows the long-range correlations for each H-C coupling
1
13
in H and C heteronuclear multiple bond correlation (HMBC) spectra.
In this spectrum the coupling betwen H-meso and the closer C-b pyrrole
is observed. Two different C-b pyrroles showed very similar chemical shifts in
1
3
C spectrum, but in this experiment we can differentiate according to this
[
15]
spectrum and the literature. The methoxy groups display the corresponding
aromatic carbon correlations of each compound (Fig. 2).
Figure 3 shows the UV-vis absorption spectra of 1, 2, and 3. The Soret
(411-, 418- and 425-nm) bands are slightly shifted to higher wavelengths
when the porphyrins are more substituted (going from 1 to 3). The second
set of weaker bands (the Q bands) can be found between 450 and
[
16]
7
aryl groups increases.
00 nm,
and again slight bathochromic shifts are seen as the amount of
Figure 3. UV-vis absorption spectra of 1, 2, and 3 taken in CH Cl .
2
2

2
008
I. Az o´ car et al.
CONCLUSIONS
In summary, by controlling the reaction time in the synthesis of 5,15-bis(ver-
atryl) porphyrin, scrambling provides an easy entry to get (or to avoid) other
new products in a good yield. ESI-mass spectra and NMR spectroscopy (1D
and 2D) were very useful to determinate the structure.
The chemical shifts in NMR and UV-vis bands show dependence on
number of the phenyl groups in the periphery of the ring. This effect could
be associated with an inductive effect, increasing with the number of the
veratryl substituens. Consequently, the conjugation is increasing, shifting
the bands to higher wavelengths and NH protons to high field.
These kind of porphyrins are important as possible precursors of systems
[
17]
of the supramolecular systems,
[
photosensitisers for photodynamic
and potentially good catalysts because of the versatility for
18]
therapy,
inserting different metals and to get modified electrodes.
[19]
Further studies
are currently under way to explore the electrocatalytic activities with these
kinds of systems.
ACKNOWLEDGMENTS
The authors thank Fondecyt (project 1010695) for financial support. I. A.
acknowledges Conicyt, Mecesup-USA 0007, and Usach-digrega doctoral
fellowship.
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