Synthesis of meso substituted porphyrins in air without solvents or catalysts

Article abstract of DOI:10.1039/a704600f

meso-Tetraarylporphyrins are synthesized from pyrrole and aryl aldehydes cleanly and efficiently in one step without solvents or catalysts by reactions at temperatures 10-15°C above the boiling point of the starting aldehydes using air as oxidant.

Full text of DOI:10.1039/a704600f

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Synthesis of meso substituted porphyrins in air without solvents or catalysts
Charles M. Drain* and Xianchang Gong
Department of Chemistry, Hunter College of the City University of New York, 695 Park Avenue, New York, NY 10021, USA
meso-Tetraarylporphyrins are synthesized from pyrrole and
aryl aldehydes cleanly and efficiently in one step without
solvents or catalysts by reactions at temperatures 10–15 °C
above the boiling point of the starting aldehydes using air as
oxidant.
point of benzaldehyde to result in yields of meso-tetra-
phenylporphyrin (TPP) greater than a few percent, but the yield
levels off by 210 °C. That the rapid removal of water from the
condensing porphyrin (intermediates) is one key to these
reaction conditions is shown by the decreased yield (ca. 12%)
when a 5:1 water:aldehyde mixture is used.10 Consistent with
the known chemistry of aryl aldehydes, benzaldehyde can serve
as an oxidant, since greater than 20% yields are obtained in
experiments where the ratio of benzaldehyde to pyrrole is 3:1
and the amount of dioxygen is limiting. Catalytic amounts ( < 5
mol%) of HCl or NH3 block porphyrin formation almost
entirely, but washing the reaction vessel with 1.0 m HCl or KOH
and thorough drying has no effect. TFA diminishes the
formation of TPP, but increases the yield of tetramesityl-
porphyrin from trace amounts to about 7% for reasons still
under investigation.
This method is general enough to make a wide variety of
meso substituted porphyrins in yields ranging from 7 to 23%
(not optimized) (Table 1). For those reactions using aldehydes
that have boiling points greater than ca. 250 °C at 1 atm, where
the pyrrole begins to decompose too rapidly, a thin film of the
melted or liquid aldehyde is coated into the reaction vessel sides
at ca. 220 °C before the pyrrole is injected. Thus a 15% yield of
tetrakis(4A-tert-butylphenyl)porphyrin are obtained.
The remarkably diverse photo-, electro- and bio-chemical
properties of the porphyrins continue to attract the attention of
researchers even after well over a hundred years. In this century
porphyrin research has gone from Hans Fischer’s pioneering
synthesis of hemin in the 1920s,1 to their use as redox catalysts,2
molecular electronic devices3 and photodynamic therapy
agents. In order to exploit their chemistry and fine tune their
properties, a variety of synthetic methods have been developed
for non-natural porphyrins, especially for the meso tetra-
substituted porphyrins.4–8 We have developed a simple way to
synthesize many meso substituted porphyrins without solvents,
catalysts or man-made oxidants, and the reaction is complete in
minutes. This is the synthesis of porphyrins at high temperatures
and/or in the gas phase.
Previous syntheses using pyrrole and aromatic aldehydes are
typified by the Ruthemund sealed-tube anaerobic reaction in
pyridine at 200 °C (ca. 5% yield),4 the Adler–Longo reaction in
propionic or acetic acid under aerobic conditions (10–30%
yield),5 the MacDonald coupling of dipyrroles (10–20% yield)6
and most recently the Lindsey, anaerobic condensation to form
the porphyrinogen followed by oxidation to the porphyrin
(10–60% yield).7 The rapid appearance of water and what is
now known to be the porphyrinogen8 in a pseudo zero-order
reaction in the Adler–Longo method, the equilibrium conditions
of the Lindsey method, and the stability of the porphyrin to high
temperatures of the Rothemund method, led us to attempt
porphyrin synthesis at high temperatures and in the gas phase.
Although solventless mixtures of the pyrrole and aldehyde
rapidly heated to > 200 °C form the corresponding porphyrins,9
better yields but similar side product distributions are observed
by mixing the two reagents in the gas phase at the same
temperature.† Whether the porphyrin is formed entirely in the
gas phase is unknown at present, but a brown–purple vapour is
observed within ca. 2 s of adding the pyrrole to gaseous
aldehyde, and a blue–black tar begins to condense on the sides
of the reaction vessel soon afterwards. In the rapid heating
experiments, porphyrins condense at the top of the reaction
vessel, which is below the reaction temperature, with the same
purity as that found in the bottom containing the original
solution.
We are currently examining the complex balance between
temperature, pressure and concentrations of all three reactants
in order to maximize the yield and gain a deeper understanding
of the reaction mechanism and thermodynamics. Porphyrin
formation is believed to be driven by enthalpic changes9 and the
macrocycle is preferred over the polymer for entropic reasons
(DH 2212 kcal mol21, DG 2166 kcal mol21, and DS 2153
e.u.).7–9 If this data is correct, then the favourable DG is
dominated by the entropy term, and cooler temperatures should
favour porphyrin formation. However, the porphyrin yield
increases with temperature up to ca. 250 °C, thus under these
conditions the high temperature gas phase formation of
porphyrins represents a kinetically controlled reaction domi-
nated by the reactivity of dioxygen—as the oxidation studies
suggest. The glass walls of the vial do not directly participate in
N
(a)
H
N
N
H
2
(b)
N
High temperature gas phase conditions allow for the rapid
aldehyde–pyrrole condensation, for the removal of water from
the proximity of the intermediate and for an increase in the rate
of oxidation by dioxygen. This latter reaction is proposed to be
the rate limiting step in the Adler–Longo method.5 Examination
of yield and products versus time indicates that oxidation of the
porphyrinogen, or its intermediates, occurs very rapidly, since
we detect no porphyrinogen and no chlorin in the UV–VIS
spectra (Fig. 1) even after reaction times of a few seconds.
Anaerobic reaction conditions result in very low porphyrin
yields and only traces of porphyrinogen, indicating the crucial
role of dioxygen in trapping the porphyrin products. Studies
show that the reaction temperature must be above the boiling
(c)
1
0
(a)
(b)
(c)
400
600
l / nm
Fig. 1 Unpurified CHCl3 rinses from two gas phase reactions: (a) a 3:1 and
(b) a 1:1 ratio of benzaldehyde to pyrrole are compared to (c) the UV–VIS
absorption spectra of known pure H2TTP from a large gas phase reaction,
showing the purity of the soluble materials and the lack of dipyrromethanes
and chlorins in the product mixture. The inset absorbance scale is 310.
Chem. Commun., 1997
2117

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Table 1 Isolated, unoptimized yields of porphyrin derivatives
Centers in Minority Institutions (RR-03037) grants to Hunter
College are acknowledged, as is a Eugene Lang Faculty
development award to C. M. D.
R
R
R
N
N
Footnotes and References
HN
NH
* E-mail: cdrain@shiva.hunter.cuny.edu
† Synthesis of meso-tetraphenylporphyrin is used as an example. A 5 ml vial
is closed by a cap fitted with a rubber septum, placed in a temperature
controlled sand bath and heated to ca. 200 °C, at which time benzaldehyde
(10 ml, 0.1 mm) is injected into the system. After a few minutes, when the
aldehyde is in the gas phase, 1 equiv. of pyrrole is injected slowly into the
vial. (Alternatively both reagents can be placed in the vial, stirred and placed
in the sand bath, but the yields are 25–30% lower.) The vial is kept at ca.
200 °C for another 15 min. Rinsing the reaction vessel sparingly with
CH2Cl2 or CHCl3 removes most of the porphyrin in ca. 80% purity as
measured by UV–VIS spectroscopy,7 while the remaining insoluble
material contains < 1% of the porphyrin yield. Isolated yields are listed in
Table 1. All compounds had satisfactory 1H NMR, UV–VIS and FAB mass
spectra. Caution: the rapid formation of gases and the flash point of all
compounds should be considered. Under these conditions there is some
benzaldehyde decomposition, and little decomposition of the pyrrole.
‡ A plethora of methods result in spectroscopically detectable quantities of
porphyrins, including gamma ray irradiation, supercritical fluids, very high
pressures, DC plasmas and fluidized bed reactors (ref. 9).
R
R
Yield (%)a
Ph
23
20
12
15
10
20
10
7
4-MeC6H4
4-PriC6H4
4-ButC6H4
4-ClC6H4
4-MeOC6H4
4-MeSC6H4
Mesb
C5H11
4-Pyridyl
1–2
10c
a
b
c
± 3%. 5 mol% TFA added to reaction. 25 mol% Zn(Ac)2 added to
1 For a remarkable book on porphyrin history, chemistry, and applica-
tions, see The Chemical and Physical Behavior of Porphyrin Com-
pounds and Related Structures, ed. A. D. Adler, Ann. N.Y. Acad. Sci.,
1973, vol. 206.
2 For a review, T. Mlodnicka, J. Mol. Catal., 1986, 36, 205.
3 For example, C. M. Drain and J.-M. Lehn, J. Chem. Soc., Chem.
Commun., 1994, 2313; C. M. Drain, K. C. Russell and J.-M. Lehn,
Chem. Commun., 1996, 337; C. M. Drain and D. Mauzerall, Biophys. J.,
1992, 63, 1556; C. M. Drain and D. Mauzerall, Bioelectrochem.
Bioenerg., 1990, 24, 263.
reaction.
the reaction since control experiments, whereby glass wool is
inserted into the reaction vial or the vial has been silanated,
show similar yields and reactivities. We are further investigat-
ing the possibilities of surface catalysis.
Our results show that the commercially important meso
arylporphyrins may be synthesized without catalysts or solvent,
and using only dioxygen as an oxidant. The polymeric
byproducts are insoluble, so washing the reaction vessel with
minimal amounts of solvent followed by a short silica gel
column results in pure porphyrin. Dioxygen is a key require-
ment for porphyrin synthesis under these conditions. While the
unoptimized 7–23% isolated yields resulting from our high
temperature gas phase method are typically not as good as the
Lindsey method and on a par with the Adler–Longo and
MacDonald methods, the great advantages of this method are its
simplicity and minimal waste production. Purification is
generally easier since there is virtually no chlorin formation and
the tarry byproducts are less soluble than other byproducts from
other procedures. We have been able to scale up this method for
the synthesis of 0.1–0.3 g of several porphyrins using a glass
tube wrapped with heating tape (or in a zone refining furnace)
whereby the aldehyde is slowly injected at one end, and the
pyrrole is slowly added at the other end, of a 1.5 3 60 cm tube
closed with glass wool to allow sufficient dioxygen for the
reaction. The product is removed with 100–200 ml CHCl3 and
a very short silica gel column yields pure material. Thus, this
method is quite amenable for industrial-type reactors.
4 P. Rothemund, J. Am. Chem. Soc., 1939, 61, 2912; P. Rothemund and
A. R. Menotti, J. Am. Chem. Soc., 1941, 63, 267.
5 A. D. Adler, F. R. Longo and W. Shergalis, J. Am. Chem. Soc., 1964, 86,
3145; A. D. Adler, F. R. Longo, J. D. Finarelli, J. Goldmacher, J. Assour
and L. Korasakoff, J. Org. Chem., 1967, 32, 476; R. A. W. Johnstone,
M. L. P. G. Nunes, M. M. Pereira, A. M. Gonsalves and A. C. Serra,
Heterocycles, 1996, 43, 1423.
6 G. P. Arsenault, E. Bullock and S. F. MacDonald, J. Am. Chem. Soc.,
1960, 82, 4384; L. T. Nguyen, M. O. Senge and K. M. Smith, J. Org.
Chem., 1996, 61, 998.
7 J. S. Lindsey, I. C. Schreiman, H. C. Hsu, P. C. Kearney and
A. M. Marguerattaz, J. Org. Chem., 1987, 52, 827; J. S. Lindsey,
K. A. MacCrum, J. S. Tyhonas and Y.-Y. Chuang, J. Org. Chem., 1994,
59, 579 and references cited therein.
8 D. Mauzerall, in The Porphyrins, ed. D. Dolphin, Academic Press, New
York, 1978, vol. 2.
9 P. George, p. 84 in ref. 1; trace amounts of porphyrin are formed at room
temperature and pressure: G. W. Hodgson, Ann. N.Y. Acad. Sci., 1972,
194, 86.
10 These results suggest that the porphyrin condensation reactions in the
presence of clays may be enhanced by the local removal of water or salt
effects rather than by specific surface interactions. For example,
T. Shinoda, Y. Izumi and M. Onaka, J. Chem. Soc., Chem. Commun.,
1995, 1801.
We thank D. Mauzerall for his consistently insightful ideas.
Financial support from MBRS (GM08176-18) and Research
Received in Columbia, MO, USA, 1st July 1997; 7/04600F
2118
Chem. Commun., 1997