A survey of acid catalysts for use in two-step, one-flask syntheses of meso-substituted porphyrinic macrocycles

Article abstract of DOI:10.1021/ol005917h

(matrix presented) Diverse Lewis acids and Bronsted acids were examined in the two-step, one-flask synthesis of meso-tetraphenylporphyrin, N-confused tetraphenylporphyrin, and tetraphenylsapphyrin. The scope of acid catalysis was found to be very broad, with 35 of 45 acids providing TPP in yields ranging from 5% to 58%. NC-TPP was also widely observed in yields of 1-40%, and TPS was infrequently observed in yields of <1%. Additionally, conditions were found for direct preparation of magnesium TPP and copper TPP.

Full text of DOI:10.1021/ol005917h

ORGANIC
LETTERS
2
000
Vol. 2, No. 12
745-1748
A Survey of Acid Catalysts for Use in
Two-Step, One-Flask Syntheses of
Meso-Substituted Porphyrinic
Macrocycles
1
G. Richard Geier III, Yangzhen Ciringh, Feirong Li, Denise M. Haynes, and
Jonathan S. Lindsey*
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
jlindsey@ncsu.edu
Received April 9, 2000
ABSTRACT
Diverse Lewis acids and Brønsted acids were examined in the two-step, one-flask synthesis of meso-tetraphenylporphyrin, N-confused
tetraphenylporphyrin, and tetraphenylsapphyrin. The scope of acid catalysis was found to be very broad, with 35 of 45 acids providing TPP
in yields ranging from 5% to 58%. NC-TPP was also widely observed in yields of 1−40%, and TPS was infrequently observed in yields of <1%.
Additionally, conditions were found for direct preparation of magnesium TPP and copper TPP.
The acid-catalyzed condensation of pyrrole + aldehyde
two-step, one-flask reaction conditions. Such conditions
provide only modest yields of N-confused porphyrin (<8%),
sapphyrin (<2%), and corrole (<12%) macrocycles. Thus,
we undertook a survey of acid catalysts to examine the scope
of acid catalysis in porphyrin synthesis and to potentially
identify reaction conditions for efficient synthesis of other
porphyrinic macrocycles.
followed by oxidation provides a convenient synthesis of
1
meso-substituted porphyrins. The dominant acid catalysts
3
for this reaction have been TFA and BF -etherate, with only
2
a few additional acid catalysts having been examined. The
absence of studies examining diverse acid catalysts for use
in porphyrin synthesis contrasts with the active study of acid
catalysis in other key areas of organic and polymer synthesis.
The critical role of the acid in porphyrin synthesis has
prompted us to examine a much broader selection of acid
catalysts. Further encouragement for this examination has
come from the recent observations of additional meso-
substituted porphyrinic macrocycles (N-confused porphyrin,
The condensation of pyrrole + benzaldehyde leading to
tetraphenylporphyrin (TPP) served as our model reaction.
One exciting discovery from this study has already been
reported: the efficient synthesis of N-confused TPP (NC-
5
TPP) in ∼40% yield using methanesulfonic acid. In this
3
4
sapphyrin, and corrole) formed under standard or related
(4) (a) Chmielewski, P. J.; Latos-Grazynski, L.; Rachlewicz, K.; Glowiak,
T. Angew. Chem., Int. Ed. Engl. 1994, 33, 779-781. (b) Furuta, H.; Asano,
T.; Ogawa, T. J. Am. Chem. Soc. 1994, 116, 767-768. (c) Chmielewski,
P. J.; Latos-Grazynski, L.; Rachlewicz, K. Chem. Eur. J. 1995, 1, 68-73.
(d) Gross, Z.; Galili, N.; Saltsman, I. Angew. Chem., Int. Ed. Engl. 1999,
38, 1427-1429. (e) Paolesse, R.; Jaquinod, L.; Nurco, D. J.; Mini, S.;
Sagone, F.; Boschi, T.; Smith, K. M. Chem. Commun. 1999, 1307-1308.
(5) Geier, G. R., III; Haynes, D. M.; Lindsey, J. S. Org. Lett. 1999, 1,
1455-1458.
(
1) Lindsey, J. S.; Schreiman, I. C.; Hsu, H. C.; Kearney, P. C.;
Marguerettaz, A. M. J. Org. Chem. 1987, 52, 827-836.
2) Lindsey, J. S. In The Porphyrin Handbook; Kadish, K. M., Smith,
(
K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol. 1,
pp 45-118.
(3) Geier, G. R., III; Lindsey, J. S. J. Org. Chem. 1999, 64, 1596-1603.
1
0.1021/ol005917h CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/18/2000

Table 1. Rank Ordering of Acids Providing the Highest Yield of TPPa
entry
acid
[acid], mMb
solubilityc
time, h
% TPP
% NC-TPPd
1
2
3
4
5
6
7
8
9
BF3-etherate/NaCl
TFA/BF3-etherate
p-CH3C6H4SO3H‚H2O
CH3SO3H
K10f
MgBr2
SbF5
GeBr4
PBr5
BBr3
TiBr4
CCl3CO2H
TFA
CuCl2
AlCl3
MgBr2-etherate
TiCl4
GaCl3
SnCl4
1.0e
15/0.32
0.32
0.32
20 g/L
32
0.32
10
0.10
0.10
0.70
32
20
32
3.2
32
1.0
1.0
1.0
1.0
32% satd
0.32
1.0
1.0
1.0
1000
32
100
10
100 g/L
3.2
1.0
yes
yes
no
yes
no
1
1
1
1
1
2
2
4
58
53
50
46
43
43
43
43
41
41
40
39
38
37
36
34
34
34
34
34
31
31
30
30
26
26
23
23
21
19
17
10
9.6
9.5
5.0
2.7
5.5
9.2
8.3
1.8
5.8
5.1
5.0
4.5
4.3
2.9
2.3
3.0
0
0.6
0.9
1.0
5.5
4.8
4.4
0.6
1.0
0.7
0.6
7.7
0.9
0.8
0
no
yes
yes
yes
yes
no
yes
yes
no
0.25
1
1 min
1
1
0.5
0.25
0.5
1
2
2
4
1
1
0.5
1
4
4
2
8
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
no
no
yes
yes
yes
no
yes
yes
yes
no
yes
no
yes
yes
no
FeCl3
HCl(g)g
SiCl4
BCl3
TeCl4
BF3-etherate
C6F5CO2H
GeI4
BEt3
HCl(aq)h
Nafioni
TiF4
24
4
8
2
4
5.3
5.0
6.8
8.4
5.2
6.7
2.3
no
no
yes
no
no
CF3SO3H
Yb(OTf)3
Sc(OTf)3
SnF4
100
3.2
32
8
8
no
a
b
Reactions were performed with 10 mM pyrrole and 10 mM benzaldehyde in CH2Cl2 at room temperature. Acid concentration affording the highest
c
yield of TPP. Acid solubility was assessed visually with “yes” meaning that all acid dissolved and “no” meaning that at least some solid acid was observed.
NC-TPP yield at the identical reaction time. 25 equiv of NaCl relative to pyrrole was used. Montmorillonite K10 was activated for 3 h at 120 °C and
1 Torr. HCl gas was bubbled through CH2Cl2 for 15 min followed by dilution with fresh CH2Cl2. Aqueous concentrated HCl. In this case the reaction
solvent was 3:1 toluene/EtOH. See ref 1. Nafion SAC-13 (Aldrich, 47,454-1).
d
e
f
g
h
<
i
letter, we now report a summary of the entire study, including
a further set of conditions providing NC-TPP in ∼25% yield
and conditions that provide direct access to selected metal-
loporphyrins. A comprehensive description of this study will
be reported elsewhere.
application in organic synthesis. In all, 45 acids (or combina-
tions of acids) were examined.
The acids were initially screened to determine whether
TPP was formed and the approximate concentration of acid
required for the maximum yield of TPP (see Supporting
8
For this study, efforts were made to select a diverse set of
Information). Of the 45 acids examined, only 10 provided
6
acids. Lewis acids and Brønsted acids were chosen from
no detectable TPP (<1%). Those acids were AlF
Dy(OTf) , InCl , oxalic acid, phosphotungstic acid hydrate,
SmCl ‚6H O, tungstic acid, ZnCl , and Zn(OAc)
3 3
, CrF ,
four general categories, including (1) acids previously used
in porphyrin synthesis, (2) acids commonly used in other
organic reactions involving condensations of carbonyl con-
taining compounds (e.g., aldol condensation, Friedel-Crafts
acylation), (3) recently reported acids with novel properties
3
3
3
2
2
2
.
The 35 acids found to provide TPP were examined in
greater detail. Reactions were performed using the ap-
proximately optimal acid concentration determined from the
screening experiments. The reactions were monitored from
(
e.g., rare earth triflates and lanthanide triflates that are water-
7
stable), and (4) novel acids with no known previous
1
min to 24 h by DDQ oxidation of aliquots from the reaction
mixture. The crude, oxidized samples were analyzed for the
(
6) Carlson, R.; Lundstedt, T.; Nordahl, A.; Prochazka, M. Acta Chem.
Scand. 1986, B40, 522-533.
7) Kobayashi, S. Eur. J. Org. Chem. 1950, 15, 5-27.
yields of TPP (UV-vis and HPLC), NC-TPP (HPLC), and
9
(
tetraphenylsapphyrin (TPS) (HPLC).
1746
Org. Lett., Vol. 2, No. 12, 2000

The highest yields of TPP for each acid were found to
p-Toluenesulfonic acid provided NC-TPP in a maximum
yield of 25% (20 mM acid, 30 min), and trifluoromethane-
sulfonic acid provided only 9.0% (1.0 mM acid, 1 h; see
Supporting Information). The origin of the anomalously high
levels of NC-TPP with sulfonic acids remains to be
determined, but this observation provides further direction
for studies of catalysts for NC-TPP synthesis.
10
range from 5.0% to 58% (Table 1). The highest yield was
obtained with the previously reported cocatalytic system of
11
BF
3 3
-etherate/NaCl. In second place was a TFA/BF -etherate
cocatalytic system discovered during our recent studies on
12
the reaction course of TPP synthesis. Acids that have been
previously examined for use in porphyrin syntheses (p-
1
3
14
toluenesulfonic acid, methanesulfonic acid, Montmoril-
2 2
Finally, the Lewis acid catalysts MgBr -etherate and CuCl
lonite K10,15 trichloroacetic acid,16 and SnCl
found to be suitable catalysts.
17
) were also
4
were found to metalate the free base porphyrin following
DDQ oxidation and treatment with triethylamine. These
provide the first examples of the direct one-flask preparation
of metalloporphyrins in which the metal complex serves to
both catalyze porphyrinogen formation and insert into the
In general, there was tremendous diversity among the acids
found to provide TPP. Polymeric acids, mineral acids, Lewis
acid complexes involving diverse metals, and Brønsted acids
with a wide range of pK
The effective acid concentrations spanned a 10,000-fold
range from 0.1 mM (PBr and BBr ) to 1 M (C CO H).
a
values were found to be active.
2
free base porphyrin. The case of MgBr -etherate is particu-
larly significant given the importance of porphyrinic mag-
nesium chelates in nature. These present results extend a
5
3
F
6 5
2
Both homogeneous and heterogeneous catalyst systems were
found to provide good yields of TPP, though the soluble
catalysts generally provided better day-to-day consistency.
18
previously reported method for magnesium insertion to the
direct preparation of MgTPP from pyrrole and benzaldehyde.
At the reaction time of highest TPP yield, all acids but BEt
and CuCl were found to provide at least some NC-TPP
3
Note that MgBr
conditions of the oxidation, consistent with previous obser-
2
vations of slow metalation from MgBr compared to MgBr -
etherate. Also, as previously reported triethylamine was
required for magnesium insertion. With 150 mM triethyl-
amine, the insertion was quantitative by approximately 2-4
h according to UV-vis, TLC, and HPLC analysis. Larger
scale preparations were performed allowing isolation of both
metalloporphyrins and conclusive identification by absorption
2
does not result in metalation under the
2
(
<10%). TPS was rarely observed (detection limit of ∼0.3%)
2
1
8
and was never detected at >1% yield. Under the reaction
conditions reported in Table 1, the highest yields of NC-
TPP observed at any time were also generally <10% and
typically occurred after the maximum yield of TPP had been
obtained (Table 2). Although there was no clear correlation
between TPP and NC-TPP formation, the three acids giving
the highest yields of NC-TPP all were sulfonic acids.
The three sulfonic acids were examined further for NC-
TPP production. The results for methanesulfonic acid have
(8) The preliminary acid screening experiments also allowed identification
of acids providing high yields of other porphyrinic products. At appropriate
concentration, methanesulfonic acid and p-toluenesulfonic acid gave rise
to a strong peak at 438 nm (characteristic of the NC-TPP Soret band) in
the UV-vis spectrum of the crude, oxidized reaction mixture (see
Supporting Information). Thus, prior to more detailed experiments, it was
clear that those acids were good catalysts for NC-TPP formation. No other
acids provided clear evidence for NC-TPP, and no acids showed peaks
associated with tetraphenylsapphyrin (TPS) in these screening experiments.
(9) Triphenlycorrole (TPC) could not be reliably detected in these
experiments. Control experiments with authentic TPC showed that TPC
was retained by the pre-HPLC sample cleanup column for removal of polar
impurities. The retention was exacerbated by the presence of triethylamine
5
already been reported (∼40% yield using 7 mM acid).
Table 2. Rank Ordering of Acids Providing the Highest Yield
of NC-TPP at Any Time from Optimal Conditions for TPP
Synthesisa
[
acid], time,
%
%
entryb
NC-TPP TPPc
acid
mM
h
(
required for accurate detection of NC-TPP), which deprotonates the acidic
4e
3
4
p-CH3C6H4SO3H‚H2O 0.32
4
8
4
4
24
8
8
24
24
10.3
10.0
8.5
7.7
7.1
6.8
6.7
6.2
6.2
6.1
6.0
5.8
5.5
5.5
5.4
5.3
5.2
46
43
10
26
30
17
9.5
26
7.5
17
20
41
34
53
34
21
39
corrole leading to a polar ionic species. Furthermore, the Soret band of
TPC is almost identical to that of TPP, making UV-vis detection of small
quantities impossible. LD-MS analysis of crude reaction mixtures provided
our only means to qualitatively address TPC formation. No peak or a minor
peak at m/z ) 526 (mass of TPC) was observed, indicating that TPC is
probably a minor product or absent under the conditions found to be optimal
for TPP formation for each acid.
CH3SO3H
CF3SO3H
BF3-etherate
MgBr2
0.32
1.0
1.0
32
3
2
2
5
6
1
4
8
3
0
1
9
8
2
9
9
7
3
3
TiF4
Sc(OTf)3
GeBr4
3.2
3.2
10
(10) The analytically determined yields of TPP, NC-TPP, and TPS
reported here compare well with isolated yields in all cases where preparative
scale synthesis has been performed.
3
3
1
Yb(OTf)3
Nafion
100
100 g/L 24
(11) Li, F.; Yang, K.; Tyhonas, J. S.; MacCrum, K. A.; Lindsey, J. S.
Tetrahedron 1997, 53, 12339-12360.
(12) Geier, G. R., III; Lindsey, J. S. Manuscripts in preparation.
(13) Gunter, M. J.; Mander, L. N. J. Org. Chem. 1981, 46, 4792-4795.
(14) Lindsey, J. S.; MacCrum, K. A.; Tyhonas, J. S.; Chuang, Y. Y J.
TiBr4
0.7
0.5
8
2
1
4
PBr5
GaCl3
0.10
1.0
1
Org. Chem. 1994, 59, 579-587.
15) (a) Onaka, M.; Shinoda, T.; Izumi, Y.; Nolen, E. Chem. Lett. 1993,
17-120. (b) Onaka, M.; Shinoda, T.; Izumi, Y.; Nolen, E. Tetrahedron
Lett. 1993, 34, 2626-2628. (c) Wijesekera, T. P. Can. J. Chem. 1996, 74,
868-1871. (d) Freeman, B. A.; Smith, K. M. Synth. Commun. 1999, 29,
(
TFA/BF3-etherate
SnCl4
15/0.32
1.0
1
1
2
HCl(aq)
SbF5
10
0.32
24
0.5
1
1843-1855.
(16) (a) Osuka, A.; Nagata, T.; Kobayashi, F.; Maruyama, K. J.
a
Only acids providing >5% NC-TPP are listed. Reactions were
Heterocycl. Chem. 1990, 27, 1657-1659. (b) Baldwin, J. E.; Crossley, M.
J.; Klose, T.; O’Rear, E. A., III; Peters, M. K. Tetrahedron, 1982, 38, 27.
(17) Srinivasan, A.; Mahajan, S.; Pushpan, S. K.; Ravikumar, M.;
Chandrashekar, T. K. Tetrahedron Lett. 1998, 39, 1961-1964.
performed with 10 mM pyrrole and 10 mM benzaldehyde in CH2Cl2 at
room temperature. The entry number for each acid is the same as that in
Table 1. TPP yield at the identical reaction time.
b
c
(18) Lindsey, J. S.; Woodford, J. N. Inorg. Chem. 1995, 34, 1063-1069.
Org. Lett., Vol. 2, No. 12, 2000
1747

spectroscopy, fluorescence spectroscopy, and mass spec-
trometry.
of potential catalysts, especially newly developed acid
catalysts, for use in this versatile reaction. Also, the discovery
of a wide array of catalysts provides much more latitude in
identifying effective catalysts for recalcitrant aldehydes and
pyrroles, for use with even milder reaction conditions or
different solvents, and for reactions with dipyrromethane
species in which irreversibility (no acid-promoted scram-
bling) is imperative.
In conclusion, we have examined 45 diverse acid catalysts
in the two-step, one-flask reaction of pyrrole + benzaldehyde
leading to TPP. The scope of acid catalysis is very broad,
and the effective acid concentration varies widely from acid
to acid (0.1 mM to 1 M). Under the best conditions identified
for each acid for producing TPP, NC-TPP was found to be
a widespread but minor byproduct (<10% yield). However,
conditions optimized for NC-TPP formation were found to
provide NC-TPP in yields of up to 40%. An apparent trend
of anomalously high yields of NC-TPP from catalysis by
sulfonic acids was uncovered. Conditions for efficient
synthesis of TPS were not found from this survey. Finally,
the direct synthesis of metalloporphyrins from the two-step,
one-flask reaction of pyrrole + benzaldehyde was demon-
strated for the first time.
Acknowledgment. This work was supported by the NIH
(GM36238).
Supporting Information Available: A description of
experimental methods, illustrative UV-vis spectra showing
detection of NC-TPP in acid screening experiments, and
plots showing yields of TPP and NC-TPP under p-toluene-
sulfonic acid and trifluoromethanesulfonic acid catalysis.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The success of the two-step, one-flask porphyrin synthesis
has relied in part on finding effective catalysts for the
pyrrole-aldehyde condensation. The large scope of effective
acids identified here should encourage further examination
OL005917H
1748
Org. Lett., Vol. 2, No. 12, 2000