Solvent-free synthesis of meso-tetraarylporphyrins in air: Product diversity and yield optimization

Article abstract of DOI:10.1142/S1088424610002422

The scope and optimization of a solvent-free method for the rapid preparation and facile purification of technologically important meso-substituted aryl porphyrins, such as 5,10,15,20-tetraphenylporphyrin is presented. This one-step method involves heating the aromatic aldehyde to ～200°C in a vial fitted with a septum-lined cap, followed by addition of the pyrrole and maintaining the temperature for about 20 minutes. The dioxygen in air serves as the oxidant. Present results show that the addition of benzoic acid as a catalyst improves the yield of 5,10,15,20-tetraphenylporphyrin from 22% to 32% and of para halogenated phenylporphyrins from 10% to ～25%. Herein is also presented an examination of the many factors that influence the yield, the ease of purification, and the ability to scale up the reaction. Since the tarry by-products from this method are much less soluble than in most other synthetic strategies, much less solvent is required for purification; simple extraction is often sufficient. This method can be scaled in the lab to > 300 mg, and provides an attractive route to many meso-substituted porphyrins because of its minimal waste generation in terms of both solvent and chromatography support.

Full text of DOI:10.1142/S1088424610002422

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2010; 14: 621–629
DOI: 10.1142/S1088424610002422
Published at http://www.worldscinet.com/jpp/
Solvent-free synthesis of meso-tetraarylporphyrins in air:
product diversity and yield optimization
Shabnam Niaa, Xianchang Gonga, Charles Michael Drain*a,b◊, Matthew Jurowa,
Waqar Rizvia and Meroz Qureshya
a Department of Chemistry, Hunter College of the City University of New York, 695 Park Avenue, New York,
NY 10065, USA
b The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
Dedicated to Professor David Mauzerall on the occasion of his 80th birthday
Received 7 May 2010
Accepted 4 June 2010
ABSTRACT: The scope and optimization of a solvent-free method for the rapid preparation and
facile purification of technologically important meso-substituted aryl porphyrins, such as 5,10,15,20-
tetraphenylporphyrin is presented. This one-step method involves heating the aromatic aldehyde to
~200 °C in a vial fitted with a septum-lined cap, followed by addition of the pyrrole and maintaining the
temperature for about 20 minutes. The dioxygen in air serves as the oxidant. Present results show that
the addition of benzoic acid as a catalyst improves the yield of 5,10,15,20-tetraphenylporphyrin from
22% to 32% and of para halogenated phenylporphyrins from 10% to ~25%. Herein is also presented
an examination of the many factors that influence the yield, the ease of purification, and the ability
to scale up the reaction. Since the tarry by-products from this method are much less soluble than in
most other synthetic strategies, much less solvent is required for purification; simple extraction is often
sufficient. This method can be scaled in the lab to >300 mg, and provides an attractive route to many
meso-substituted porphyrins because of its minimal waste generation in terms of both solvent and
chromatography support.
KEYWORDS: solvent-free, synthesis, green chemistry.
self-assembly or self-organization of these chromophores
INTRODUCTION
into functional supramolecular materials [10–12].
Porphyrins are extremely versatile molecules [1–4]. In
Tetraarylporphyrins are most commonly synthesized
addition to their biological functions [5], synthetic deriv-
by one of three strategies [4, 13–15]: by Adler-Longo
atives are used for a tremendous variety of applications
synthesis [16, 17] in propionic or acetic acid in air, by
including photodynamic therapy [6], oxidation catalysis
multi-step coupling of dipyrroles based on the MacDonald
[7, 8], molecular photonic devices, dye-based sensors,
synthesis [18], or by the Lindsey equilibrium synthesis
inks, and others [9]. Tetraarylporphyrins continue to be
[19]. There are intermediate two-step methods [20, 21]
a primary focus of research efforts because of the ease
and many variations for all three. The one-step method is
by which their various derivatives can be synthesized
amenable to large-scale synthesis while the latter methods
from pyrroles and arylaldehydes. Combined with appro-
allow for the directed, rational synthesis of less symmet-
priate functional groups that enable the aforementioned
rically substituted porphyrins [22, 23]. The addition of
applications, the molecular topology is poised to drive the
mild oxidants, such as nitrobenzene, to the Adler-Longo
procedure increases the yield of many tetraarylporphy-
rins [21], and the azeotropic removal of water in a tosy-
SPP full member in good standing
late/benzene system increases the yield of meso-alkyl
porphyrins [24]. Clays and zeolites also have been used
*Correspondence to: Charles Michael Drain, email: cdrain@
hunter.cuny.edu, tel: +1 212-650-3791, fax: +1 212-772-5332
Copyright © 2010 World Scientific Publishing Company

622
S. NIa et al.
R
as catalysts for tetraarylporphyrin synthe-
ses [25]. A resurgence in the investigation
of new methods to synthesize these ver-
satile compounds began with Lindsey’s
method whereby the porphyrinogen is
formed under anaerobic conditions in an
organic solvent with a Lewis acid cata-
lyst, and then oxidized with reagents such
as quinones or phthalocyanines [26, 27].
This strategy takes much of its inspiration
from the pioneering work of Mauzerall on
the biosynthesis of uroporphyrins [28, 29].
The equilibrium method has many advan-
tages such as increased yield and tolerance
of many functional groups. Nejad and
co-workers reported the use of CF3SO2Cl
under aerobic conditions and room tem-
perature to make a variety of tetraarylpor-
phyrins in 25–67% yields [30]. Given the
R
O
R
4
4
N
N
H
NH
HN
solvent-free, in air
NH
R
R
Scheme 1. A gas-tight septum-capped vial containing two equivalents of
benzaldehyde and one equivalent of benzoic acid is heated at 200 °C in
air for five minutes at which time one equivalent of pyrrole is injected and
the system heated for an additional 20 min. The dioxygen in air is the primary
oxidant. Isolated yields of H2TPP are 32 2%. Abbreviations: R = H, H2TPP =
(5,10,15,20-tetraphenylporphyrin); R = CH3, H2TTP = tetrakis(4′-tolyl)porphy-
rin; H2TPyP = tetrakis(4′-pyridyl)porphyrin
widespread use of porphyrins with 1–3 meso-pyridyl
groups for self-assembled and self-organized multichro-
mophore materials, a direct route to several of the possi-
ble isomers and compounds using 1-acyldipyrromethanes
and a non-coordinating base catalyst was reported [31].
Green chemical research into solventless (or solvent-
free) synthetic methods has been explored over the last
decade in an effort to reduce environmental impacts [32].
Our solvent- and catalyst-free method [33] reported in
1997 is akin to the Rothmund [34, 35] and Adler-Longo
[16, 17] methods in that the aldehydes and pyrroles are
mixed and heated. Subsequently, a similar method was
used to prepare corroles using perfluorobenzaldehyde and
a 4:3 pyrrole:aldehyde stoichiometry [36]. Using micro-
wave radiation, Momenteau and co-workers synthesized
meso-tetraphenyl porphyrin in ~9.5% yield by using a
silica-gel catalyst [37], and other groups recently explored
similar solvent-free reactions for metalation of porphyrins
[38–40] and for the preparation of phthalocyanines [39,
41, 42]. It is interesting to note that almost 40 years ago
Hodgson reported the synthesis of porphyrin from pyrrole
and formaldehyde in a fluid-bed reactor, and from ammo-
nia, graphite and formaldehyde in a plasma reactor [43].
Our solvent- and catalyst-free reaction is complete
in minutes, uses temperatures 10–20 °C over the boil-
ing point of the aldehyde used, and uses the dioxygen
in air as the oxidant [33]. This method is used to teach
principles of green chemistry in an undergraduate labo-
ratory experience [39]. The salient finding of the initial
report are summarized: (1) Some of the aryl aldehyde is
also oxidized. (2) A significant fraction of the reactions
between the pyrrole and aldehyde occur rapidly after the
reagents enter the gas phase, as shown by the presence of
the porphyrin at the site of condensation on the reaction
vial. (3) The elevated temperatures allow for the removal
of water from the proximity of the intermediate, as well
as for an increase in the rate of oxidation by dioxygen.
The oxidative reaction is proposed to be the rate-limiting
step in the Adler-Longo method [16]. (4) The reaction is
not highly dependent on surface area thus it is not cata-
lyzed by the glass walls of the vessel. (5) This method is
general enough to make a cadre of meso-substituted por-
phyrins in yields ranging from 5 to 32%. (6) The soluble
portion of the reaction products is mostly the porphyrin.
Herein we report our exploration of the complex inter-
play between temperature, pressure, concentration, acid
catalysts, and oxidants for this solvent-free synthetic
strategy (Scheme 1). The present study shows that use of
benzoic acid as a catalyst substantially improves yields
from 20% to 32% for 4′-alkylphenyl- and many other
porphyrins (Fig. 1). Although the physical properties of
each aldehyde are different, such as the vapor pressure at
200 °C, there are definite trends and significant consid-
erations that will serve as guides to the utilization of this
procedure both in the laboratory and for larger-scale syn-
thesis of aryl porphyrins. Secondly, we show that micro-
wave heating of the pyrrole and aldehyde in solvent-free
reactions efficiently produces porphyrins without solid
catalysts such as silica gel.
Fig. 1. The yield of H2TPP vs. reaction temperature. The reac-
tion utilized a 3:1 mole ratio of benzaldehyde to pyrrole, and
five-minute preheating of the aldehyde. The pressure was kept
at approximately 3.6 atm
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RESULTS AND DISCUSSION
Temperature, pressure, and aldehyde volatility
Porphyrinformationisbelievedtobedrivenbyenthalpy
changes where entropy favors the macrocycle over the
polymer. For volatile aldehydes, much of the present
reaction occurs in the gas phase. The thermodynamic val-
ues for 5,10,15,20-tetraphenylporphyrin (TPP) formation
are estimated in the literature to be: ∆G = -166 kcal.mol-1,
∆H = -212 kcal.mol-1, and ∆S = -153 e.u, while for
solution phase reactions ∆G = -171 kcal.mol-1, ∆H =
-230 kcal.mol-1, and ∆S = -199 e.u. [44]. If this data is
correct, then the favorable value of ∆G is governed by
the entropy contribution, and cooler temperatures should
favor porphyrin formation. However, under our reaction
conditions, the porphyrin yield increased with tempera-
ture up to ~175 °C (Fig. 1), thus under these conditions
the high-temperature gas phase formation of porphyrins
and/or their intermediates appears to represent a kineti-
cally controlled reaction limited by the reaction with
dioxygen, as the oxidation studies suggest. The obser-
vation that the polymeric by-products are much less
soluble, indicating the minimal formation of short pyr-
romethanes, and the temperature data may also suggest
variation in the complex thermodynamics and equilibria
between reactants and the intermediates leading to the
products. A series of reactions at different temperatures
were carried out to test the relationship between tempera-
ture and yield. As shown for benzaldehyde (Fig. 1), the
yield of H2TPP increases with temperature, but levels off
at ~175 °C. The pressure was maintained at ~3.6 atm, and
measured using a pressure gauge attached to the vial.
The rate of porphyrin formation is rapid at these tem-
peratures. About half of the yield is obtained in the first
1.3 minutes, followed by a much slower, ~8 minute time
constant. For the benzoic acid catalyzed reactions the
time constants are 1.4 and 14 minutes. Thus, most of the
porphyrin is formed within the first 20 minutes (Fig. 2).
Surprisingly, similar trends for the temperature and the
kinetics are observed for the other 4-alkyl benzaldehydes,
so the reactivity is not determined solely by the volatility
of the starting materials. Of course, the nature of the alde-
hyde dictates the amount in the vapor phase. However,
in virtually every case, some dark red to brown gas is
observed in the first few minutes of the reaction. It seems
likely that the condensation reactions occur quite rapidly
in aerosol dispersions, which then precipitate. This is
consistent with the observation of a dark liquid forming
on the reaction vessel walls after only about two minutes,
and with fractal-like patterns of almost pure porphyrin
often found on the sides of the vial after cooling.
Fig. 2. The yield of H2TPP vs. reaction time. The lower data
points ● used 2.5:1 benzaldehyde to pyrrole, and five-minute
preheating of the benzaldehyde. The solid line represents a
two exponential rise to a constant value (τ1 = 1.3 ± 0.1 min, τ2 =
8.3 ± 0.9 min) and the dashed line represents a single exponen-
tial rise for comparison. The upper data points ▲ are for reac-
tions used 1:2.5:1 benzoic acid:benzaldehyde:pyrrole. The fit is
for a double exponential rise (τ1 = 1.4 ± 0.2 min, τ2 = 13.9 ±
1.5 min)
from ∼2 atm to ∼10 atm at constant temperature were
examined. The concomitant decrease in the partial pres-
sure of the reactants, as well as the increased amounts of
reactants condensed onto the walls of the reaction vessel
both correlate with the observed decrease in porphyrin
yield with increasing pressure. Reduced yield of porphy-
rin was associated with increased yield of polymers and
not lower reactivity of the reagents. The yield of H2TPP
decreases at lower pressures as well. Under our standard
conditions of ~3.6 atm and 200 °C, the concentration of
benzaldehyde and pyrrole in the gas phase is estimated
to be ~1.2 mM.
Under these conditions, not all of the aldehyde and
perhaps not all of the pyrrole is in the gas phase. Note
that the yield is not simply related to the boiling point
of the aldehyde, at least for the series of 4-alkylphenyl
groups tested (Tables 1 and 2). The yield is essentially the
same when R = H, Me, tBu (boiling point at 1 atm = 178,
204, 245 °C, respectively). It is unclear why the yield
of the iPr derivative is lower. Other experiments indicate
that the reaction does not take place entirely in the vapor
phase. Mixing equimolar amounts of tolyl and tBu alde-
hydes in a 205 °C reaction results in porphyrins with the
expected statistical distribution of tolyl and tBu groups
determined by NMR and TLC. If aldehyde volatility
were the primary consideration, the two populations of
porphyrins would be observed: one that contains mostly
methyl groups from the gas phase, and one that contains
mostly tBu groups from the solution phase.
Aldehyde and carboxylic acid
The role of reaction pressure was examined. In typi-
cal conditions, the reaction pressure is ~3.6 atm. Pres-
sures in a stainless steel reaction vessel with a pressure
gauge were increased by addition of N2 or by an inert
solvent such as toluene. Using both methods, pressures
There is a complex relationship between the total yield
and the amount of aldehyde used in the reaction. Some
of the aldehyde is converted to the corresponding acid
under these conditions. Also, the presence of benzoic
acid not only decreases aldehyde oxidation, but increases
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S. NIa et al.
Table 1. Other reagents for H2TPP synthesisa
Reagent
Mole, %
Yields, %
relative to pyrrole
Salts
NaCl
20
14
100
9
ZnO
800
11
Template
Oxidants
Zn(Ac)2
VOCl3
25
12 (ZnTPP)
20
0
5.0
<1
12
9.0
32
26
27
18
15
16
19
18
18
17
6.2
2.8
11
13
13
16
6
C6H5NO2
Na2S4O6
150
150
Water
15-fold
55-fold
Acid Catalyst
X-C6H4COOH X = H
X = 2-Me
100
100
X = 3-Cl
100
X = 2,6-Me
CCl3COOH
CH3COOH
100
5
8.3
16
100
400
CH3CH2COOH
CF3COOH
100
4.5
9.0
Alcohols
C6H5OH
100
10
C6H5CH2OH
100
10
2-carboxybenzaldehyde
2-carboxybenzaldehyde
BF3
100
200 (no benzaldehyde)
0
4
0
Base
NH4OH
170
85
9
11
a The yields of H2TPP using various additives known to enhance the yield in other synthetic methods,
see text. A 3:1 ratio of aldehyde to pyrrole is used with a five-minute preheating of the aldehyde. Note
that the pK of acetic acid = 4.75, propionic acid = 4.87, benzoic acid = 4.19, 2-toluic acid = 3.91,
mesitic acid = 4.49, 3-chlorobenzoic acid = 3.82, and trichloroacetic acid = 0.7. All data represent the
average of at least three trials by two different researchers.
the yield of porphyrin. The rate of benzaldehyde oxida-
tion is greatly increased when heated in air at 200 °C for
five minutes such that ∼1/3 of the aldehyde is converted
both porphyrin yields and the ease of purification. Under
our standard 3:1 conditions, the yields pass through a
maximum at a preheating time ~5 min. Increasing the
amount of time the aldehyde is preheated increases the
amount of benzoic acid formed, thus there is a trade-off
between the oxidation of this reactant vs. catalysis by
the resulting acid. For costly or synthetically difficult
aldehydes, the addition of benzoic acid to the reaction
ameliorates degradation of the reactant, but the effective-
ness of this modification depends largely on the relative
reactivity of the substituted aldehyde to oxidation and
1
to its acid as indicated by H NMR. This oxidation pro-
cess is greatly inhibited by the presence of benzoic acid,
as shown by the bi-exponential decrease of aldehyde and
concomitant increase in benzoic acid with time constants
of ~2 and ~10 min. In all cases, other decomposition
products account for <5% of the total.
The amount of time that the aldehyde is preheated
prior to pyrrole addition also plays an important role in
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Table 2. Yields of various meso aryl porphyrins
R (4′ unless noted)
Yield with no
BA catalysta
Yield with 1:2:1
BP aldehyde °Cc
BA:aldehyde:pyrroleb
H
23
20
12
15
7
32
30
24
33
5d
178
204
235
~245
237
~248
—
CH3
(CH3)2CH
(CH3)3C
Mesityl
CH3O
20
—
10
10
—
—
—
25
19
11
25
26
15
15
CH3OOC
CH3S
~250
—
Cl
Br
—
3,4,5 trimethoxy
3,5 dibenzyloxy
Other porphyrins
Tetrakis (1′-pyrenyl) porphyrin
Tetrakis (4′-pyridyl) porphyrin
Tetra n-heptyl porphyrin
—
—
—
10
—
5
—
7e
2f
~200
153
b
c
d
aFrom reference 13. Standard reaction conditions. Estimates for 1 atmosphere. NH2OH•ΗCl : aldehyde :
e
f
pyrrole = 1:2:1; propionic acid : aldehyde : pyrrole = 6.8:2:1; 0.35 g silica gel added in place of benzoic
acid.
porphyrin formation. For arylaldehyde derivatives that
oxidize faster than benzaldehyde at these temperatures
in air, this synthetic method may be disadvantageous.
Pyrrole is relatively stable when heated in air at these
temperatures as demonstrated by the 1H NMR. The por-
phyrin yield vs. the ratio of aldehyde to pyrrole is plotted
in Fig. 3, and the optimum ratio is shown to be ~3:1.
The longer the aldehyde is incubated before pyrrole
addition, the easier it is to purify the porphyrin, because
even though the yield of H2TPP decreases, the forma-
tion of insoluble, polymeric by-products increases
at the cost of the smaller, soluble materials. There is
no evidence that the benzoic acid is incorporated into
any of the porphyrins, nor into the side products.
1
Only H2TPP is observed by H NMR as the product
Fig. 3. The complex relation between benzaldehyde and ben-
from experiments using a 4-methylbenzoic acid cata-
lyst with benzaldehyde, and only tetratolylporphyrin
(H2TTP) is observed when benzoic acid is present with
4-methylbenzaldehyde.
zoic acid. All reactions are at 200 °C ~3.6 atm. The ○ shows the
yield of H2TPP vs. the mole ratio of benzaldehyde and pyrrole
with one-minute preheating of the aldehyde so there is minimal
benzoic acid formed. The ● shows the results when the alde-
hyde is preheated five minutes before addition of the pyrrole,
so there is ~33% conversion to the corresponding benzoic acid.
The ■ shows the effects of adding benzoic acid to the aldehyde,
preheating for five minutes, followed by addition of the pyrrole
using a 2:1 ratio of benzaldehyde to pyrrole
Effect of acid catalysis
The excess aldehyde increases the yield either from
oxidation to benzoic acid which then can serve as a cata-
lyst [14, 16], or compensation for the loss of this reagent
due to oxidation. The benzoic acid formed when there is
a three-fold excess of the aldehyde still does not bring the
yield up to the level of the reaction observed with added
benzoic acid. These results suggest that the role of ben-
zoic acid is to retard the aldehyde oxidation, which uses
up the oxygen in the closed vial and lowers the porphyrin
yield. Unlike the conditions used to obtain ~32% yields
(Fig. 3), addition of the aldehyde to the preheated mix-
ture of benzoic acid and pyrrole has only a small effect on
the yield, increasing it from ~18% to ~20%. Again, since
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626
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most of the benzoic acid remains on the vessel walls even
at 200 °C, it is likely that benzoic acid affects the inter-
mediate steps in porphyrin formation rather than the ini-
tial, gas phase reactions.
Lindsey and Adler conditions [14]. These observations
imply that the key water-producing steps, both dehydra-
tion and oxidation, occur rapidly and irreversibly because
water is removed from the vicinity of the reaction. Some
of the reduced yield in the presence of water can be
recovered by prolonging the reaction times. Increasing
the reaction time from 20 to 40 minutes increases the
porphyrin yield from 12% to 16% in the presence of a
15-fold excess of water, using standard reaction condi-
tions. Much longer reaction times, >60 minutes, actually
decrease the porphyrin yield.
As mentioned above, the presence of the added ben-
zoic acid inhibits the destruction of the aldehyde, but it
may also inhibit the destruction of porphyrin intermedi-
ates by the radicals involved in the oxidation pathway.
Small quantities of other possible aromatic aldehyde
decomposition products such as perbenzoic acid, phenol,
and benzyl alcohol are found to inhibit porphyrin forma-
tion (Table 1). The possibility that some hemiacetal is
formed between the aldehyde and the acid is supported
by the fact that the presence of 2,6-dimethylbenzoic acid
has virtually no effect on the yield (Table 1). As can be
seen in Table 1, there is a balance between pKa, the nature
of the acid, and the yield. Aromatic acids are effective
reagents, whereas alkyl acids are not. The reasons for this
are unclear, but may have to do with the stability of the
proposed hemiacetal at these temperatures. It is interest-
ing to note that the initial rates for the reactions with and
without the benzoic acid catalyst are essentially the same
(Fig. 2). Catalytic amounts of ammonium hydroxide,
HCl, and BF3 decrease yields to trace amounts (see Sup-
porting information).
Other observations
There are several reports that the yield of tetraarylpor-
phyrins can be substantially increased by the addition
of various salts and other reagents [4, 7, 14], but these
reagents are ineffective under the present conditions. ZnCl2
may increase the pyridyporphyrin yield by templating and/
or altering the reactivity of the aldehydes. When the prod-
ucts at various places in the vial are carefully removed
and analyzed, it is observed that the porphyrin is found
both at the top and the bottom of the vial. In fact, very thin
1–4 mm branched leaflets of nearly pure porphyrin are
found on the sides of the glass reaction vessel that are just
above the sand bath. Small purple islands of porphyrin in
the mist of dark brownish polymer are also observed. These
arise from a nucleation process during the reaction and
subsequent cooling [45]. The surface of the glass vial does
not directly participate in the reaction since control experi-
ments, whereby glass wool is inserted into the reaction vial
to increase surface area or the vial has been silanated to
reduce surface energy, show similar yields and rates.
Oxidation
Figure 2 indicates that porphyrin formation occurs
very rapidly. Oxidation of the intermediate polypyr-
romethanes and/or the porphyrinogen is the rate limiting
step in the propionic acid synthesis. Oxidation must be
occurring rapidly and efficiently under these conditions,
since we detect no porphyrinogen and no chlorins even
after reaction times of a few seconds. Anaerobic reaction
conditions with no benzoic acid result in trace amounts
of porphyrin, and some dipyrromethane indicating the
crucial role of dioxygen in formation of the porphyrin
products. Excess oxygen and some non-volatile oxidants
results in little or no detectable porphyrin in the black
tarry products (Table 1). At these elevated temperatures,
these oxidants probably react with the pyrrole, the alde-
hyde, and even the porphyrin.
Porphyrin formation
The mechanism of porphyrin formation has been well
reviewed [4, 14, 16], and we have no evidence that the
fundamental condensation reactions or oxidation steps are
different under the conditions of this synthesis. The loca-
tion of the reaction is likely aldehyde-dependent. In this
procedure, there are several pathways to TPP formation
that are not mutually exclusive: (a) the porphyrin forms in
the gas phase and then condenses on the reaction vessel
sides; (b) the porphyrin forms in a film coated onto the
reaction vial surface; (c) the initial condensation step(s)
occur in the gas phase and the final steps on the surface.
The extent of porphyrin formation in the vapor and
condensed phases depends on the aldehyde used. Several
observations imply that at least the initial reactions take
place in the gas phase for TPP formation and when other
volatile aldehydes are used. The atmosphere in the vial
containing only benzaldehyde remains clear after it is
heated for five minutes at 210 °C, but a brown-purple gas
forms immediately upon addition of the pyrrole and this
begins to liquefy within the next two minutes. Reactions
at temperatures much lower than the boiling point of
the aldehyde result in significant reduction in porphyrin
Water
The substantial amount of water needed to reduce
the yield of H2TPP under these reaction conditions is an
indication that the rapid removal of water away from the
condensing porphyrin (intermediates) is one key to the
success of these reactions. When one equivalent of pyr-
role is added to 15:3 water:benzaldehyde mixture that
has been preheated for five minutes at 200 °C, the yield
decreases by about a third, from 18% to 12%. Similarly,
if a 55-fold excess of water is added the yield drops to
about half (9%). Thus, water is a relatively weak inhibi-
tor. We observed that presence of two equivalents of water
significantly quenches porphyrin formation under both
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formation. Experiments where pyrrole and benzaldehyde
closed by a cap fitted with a gas-tight rubber septum.
The bottom 2/3 of the vial was placed in a temperature-
controlled sand or oil bath for visual monitoring of
the progress of the reaction. The procedure for the acid
catalyzed reaction is as follows. Benzoic acid (12.2 mg,
0.1 mmol) was placed in a septum-capped vial, and
when the vial reached 200 5 °C, benzaldehyde (20 µL,
0.2 mmol) was injected through the septum in the cap.
After 5 min, pyrrole (7µL, 0.1 mmol, 1 equiv.) was
injected and the vial kept at 200 °C for another 20 min.
Afterward, the vial was removed from the sand bath and
cooled in ambient air. Once at room temperature, a mini-
mum volume of chloroform (1–2 mL) was used to wash
the vial. Sonication facilitated the extraction of all the
porphyrin. The resulting solution was loaded directly
onto a pipette column packed with (<1 g) flash silica gel,
and eluted with another (5 mL) chloroform. Yields were
determined spectroscopically [19] and routinely com-
pared to the isolated yields; interestingly the latter were
typically greater. Caution should be used in this synthesis
due to the rapid formation of gases. The flash point of all
compounds must be considered. Under these conditions,
there is some benzaldehyde decomposition and little
are mixed as gases at 210 °C by diffusion from opposite
sides of a reaction tube show similar results as when the
liquid pyrrole is injected to a preheated vapor of the alde-
hyde. Quenching the reaction ~10 s after addition of the
pyrrole indicates that the dark vapor consists of reactants,
dipyrromethanes, and H2TPP. Assuming ideal solutions,
the concentration of the reactants approach 3 M in this
solventless film. Small amounts of H2TPP are known to
form at room temperature and pressure [43, 44]. When
the reactants are mixed at room temperature and flash-
heated to 210 °C, a great increase in insoluble polymer
formation is observed.
A third pathway, where the initial reactions take place
in the gas phase and the intermediates condense on the
walls of the reaction vessel where the porphyrin is formed,
is also consistent with our experiments. Several consid-
erations, however, lead us to conclude that the interme-
diates condensed on the glass are closed macrocycles.
Since porphyrinogens rapidly oxidize, it is unlikely that
large amounts of this species are formed in any phase of
the reaction. At these temperatures, the dipyrromethanes
condense so that “2+2” and “3+1” MacDonald-type cou-
pling may occur in both condensed and vapor phases with
subsequent oxidation to form the porphyrin. The obser-
vation that the yields continue to increase with increasing
temperature up to ~175 °C for H2TPP is consistent with
the idea of keeping more of the small pyrrolic multimer
intermediates in the gas phase. The fast time constants
shown in Fig. 2 may suggest that most of the porphyrin
is formed in the initial minutes in the gas phase, and the
slower time scale is a result of reactions on the surface
and in the condensed phase where the benzoic acid exerts
its greatest effects. Note that the initial time-constants are
essentially the same for both sets of reaction conditions.
Increased reaction temperatures may increase the yield of
the higher boiling aldehydes.
1
decomposition of the pyrrole. H NMR in (CDCl3): δ,
ppm (mult, int) 8.85, s, 8H pyrrole βH; 8.24, m, 8H 2,6-
phenyl; 7.77, m, 8H 3,5-phenyl; 7.73, m, 4-phenyl; -2.75,
s, 2H pyrrole NH. UV-vis (CH2Cl2): λmax, nm (log ε) 418
(5.66), 514 (4.20), 549 (3.81), 595 (3.60), 645 (3.49). MS
(ES): m/z 615, 616, 617. The procedures used for H2TPP
were then used to obtain the porphyrins listed below. The
spectroscopic yield is calculated by subtracting the base-
line absorbance at 437 nm from that at λmax at 418 nm;
∆abs, and using ε = 4.27 × 105 M-1.cm-1 for the Soret band
(see Supporting information).
The reaction was scaled up to afford 0.1–0.3 g H2TPP
by use of a 1.5 × 60 cm glass tube with the ends sealed
by glass wool and rubber septa. The tube was heated with
heating tape. After the tube was heated to ~200 °C, benz-
aldehyde (0.75 mL) was injected from one side and pyr-
role (0.175 mL) was injected from the other side wherein
the reagents diffused and reacted. After 20 min the tube
was cooled, washed with ~150 mL CHCl3, loaded directly
onto a 2 × 30 cm silica gel column and eluted with
CHCl3 to yield pure porphyrins. Alternatively, larger-
scale reactions can use jars with lids modified with small
rubber septa and heated in a lab oven. We note here, and
consistent with previous reports, a standard microwave
oven also can be used to heat a solvent-free reaction
between benzaldehyde and pyrrole. Mixing of benzalde-
hyde and pyrrole in a cleaning sonicator also yields some
detectable porphyrin.
EXPERIMENTAL
Materials and instrumentation
Pyrrole and the aldehydes were passed through short
pipette columns of basic alumina before use. All other
1
reagents were used as received from Aldrich. H-NMR
spectra were obtained on 300 MHz Brüker or 400 MHz
JEOL spectrometers. UV-visible spectra were taken on
a Carey Bio-3 spectrophotometer. All compounds were
characterized by NMR, UV-visible spectroscopy, and
electrospray ionization mass spectrometry, and were
consistent with the structures and data reported in the
literature [46].
Preparation of 5,10,15,20-tetrakis(4-pyridyl)por-
phyrin. To a 8.3 mL vial was added zinc acetate (0.0149 g,
0.075 mmol) and 4-pyridinecarboxaldehyde (30 µL,
0.3 mmol). After the mixture was heated to 200 °C for
one minute, pyrrole (7 µL) was injected and the system
heated for 20 min. This porphyrin was extracted and
Synthesis
Preparation of 5,10,15,20-tetraphenylporphyrin
(H2TPP). The reactions were performed in 8.3 mL vials
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628
S. NIa et al.
eluted with 9:1 chloroform:methanol. NMR, UV-visible
and mass spectra were consistent with those reported in
the literature.
6. Sternberg ED, Dolphin D and Brückner C. Tetra-
hedron 1998; 54: 4151–4202.
7. Dolphin D, Traylor TG and Xie LY. Acc. Chem.
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8. Gong X, Milic T, Xu C, Batteas JD and Drain CM.
J. Am. Chem. Soc. 2002; 124: 14290–14291.
9. Kadish K, Smith KM and Guilard R. Handbook of
Porphyrin Science, 2010.
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2009; 109: 1630–1658.
11. Beletskaya I, Tyurin VS, Tsivadze AY, Guilard R
and Stern C. Chem. Rev. 2009; 109: 1659–1713.
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Curr. Chem. 2005; 245: 55–88.
13. Kenner GW and Smith KM. In Annals of the
New York Academy of Sciences: The Chemical
and Physical Behavior of Porphyrin Compounds
and Related Structures, Vol. 206, Adler AD. (Ed.)
New York Academy of Sciences: New York, 1973;
pp 138–150.
14. Lindsey JS. In The Porphyrin Handbook, Vol. 1,
Kadish KM, Smith KM and Guilard R. (Eds.) Aca-
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CONCLUSION
A new synthetic method has been developed to syn-
thesize commercially important porphyrins. The method
tolerates a variety of functional groups, but the specific
reaction conditions vary depending on the nature of the
aldehyde. Mixed, or combinatorial libraries of porphy-
rins [38, 47, 48] can be made using this strategy; however
as in the traditional Adler synthesis of these libraries, the
product distribution is influenced by the relative reac-
tivity of the aldehydes. The 20–30% yields of many of
the meso-tetraarylporphyrins studied is quite acceptable,
the rate of the reactions noteworthy, and the reaction is
modestly scalable. Since the reaction utilizes no solvent,
and the purification is substantially simplified due to the
insolubility of the tarry by-products, there is much less
waste generated in terms of solvent, chromatography
supports, and heating energy used. The utilization of air
in the oxidative steps also substantially reduces the cost
of the procedure and is a greener approach. Thus, this is
a greener synthesis of purple porphyrins.
Acknowledgements
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827–836.
We would like to thank Profs. Klaus Grohmann and
Richard Franck for helpful discussions. This work was
supported by the National Science Foundation (NSF,
CHE-0848602, CHE-0847997 to C.M.D). Hunter Col-
lege science infrastructure is supported by the NSF, the
National Institutes of Health (including RCMI, G12-RR-
03037), and CUNY.
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Supporting information
Detailed experimental data and discussion of results
are given in the supplementary material. This material is
available free of charge via the Internet at http://www.
worldscinet.com/jpp/jpp.shtml.
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