Optimizing the synthesis of 5,10-disubstituted tripyrromethanes

Article abstract of DOI:10.1016/S0040-4039(00)00672-9

Condensation of aldehydes with pyrrole in the presence of acid catalyst gave the mixture of dipyrromethanes and tripyrromethanes. The major product was switched from dipyrromethanes to tripyrromethanes according to the sequence of adding the reactants and

Full text of DOI:10.1016/S0040-4039(00)00672-9

Tetrahedron Letters 41 (2000) 4609±4613
Optimizing the synthesis of 5,10-disubstituted
tripyrromethanes
Jae-Won Ka and Chang-Hee Lee*
Department of Chemistry, Kangwon National University, Chuncheon 200-701, South Korea
Received 9 March 2000; revised 5 April 2000; accepted 21 April 2000
Abstract
Condensation of aldehydes with pyrrole in the presence of acid catalyst gave the mixture of dipyrro-
methanes and tripyrromethanes. The major product was switched from dipyrromethanes to tripyrro-
methanes according to the sequence of adding the reactants and catalyst. Higher oligomers such as
tetrapyrromethane and pentapyrromethane were isolated and characterized from the reaction of 4-methoxy-
carbonylbenzaldehyde with pyrrole. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: dipyrromethane; tripyrromethane; tetrapyrromethane; pentapyrromethane.
meso-Substituted dipyrromethanes and 5,10-disubstituted tripyrromethanes are important
precursors for the synthesis of various meso-substituted porphyrins,1,2 porphyrinoid macrocycles
and expanded porphyrins.3,4 Since the initial one-¯ask synthesis of dipyrromethanes reported in
1994,5 several re®nements have been made in the puri®cation and isolation of these com-
pounds.6,7 The synthetic method involves the acid catalyzed condensation of an aldehyde with
pyrrole, wherein the suppression of polymerization is achieved by using large excess of pyrrole
without any other solvents. The method has a€orded high yields of 5-substituted dipyrro-
methanes having a variety of functional groups,8 11 in addition to the improved puri®cation with
the elimination of the use of column chromatography. Now it is possible to synthesize multigram
quantities of dipyrromethanes. The tripyrromethanes have also been important in the synthesis of
cis-substituted porphyrins and expanded porphyrin analogues.3,12 14 The typical one-¯ask synthesis
of dipyrromethanes mentioned above usually resulted in the formation of tripyrromethanes 2 as
minor products (Scheme 1).
As part of our e€orts on the selective synthesis of tripyrromethanes (2), we report herein some of
the results obtained from the one-¯ask condensation of an aldehyde with pyrrole in the presence
of catalytic amount of acid. Upon examining the sequence of addition of the reagents, we
found signi®cant di€erence in the product composition. We also have succeeded to synthesize
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00672-9

4610
Scheme 1.
dipyrromethanes and tripyrromethanes bearing carboxylic acid or phenolic hydroxy group on the
meso-positions.
As shown in Scheme 1, we ®rst examined the product distribution formed under the conditions
involving di€erent order of addition of starting material and catalyst: Pre-stirring of pyrrole and
aldehyde (molar ratio, 5/1) for 5 min followed by addition of TFA (0.1 equiv.) at room temperature
(method A) and pre-mixing of aldehydes and catalyst followed by addition of pyrrole at once
(method B). The reaction was quenched with aqueous base after 5 min of the reaction. As
reported by Lindsey et al.,6 dipyrromethanes can be easily puri®ed by vacuum distillation using
Kugelrohr, we adopted the same procedure of Lindsey's and found that dipyrromethanes distilled
out completely under this condition. The residual black solid remained after vacuum distillation
exclusively contained tripyrromethanes and other oligomeric compounds from which the tripyrro-
methanes were cleanly separated by column chromatography on silica. The isolated yields of each
components are listed in Table 1 and the data clearly indicated that method A gives dipyrro-
methanes (1) as the major product as usual. But method B gives tripyrromethanes (2) as the major
Table 1
Isolated yields of the dipyrromethanes (1) and tripyrromethanes (2). (a) Method A: aldehyde and pyrrole were mixed
®rst and stirred for 5 min then added TFA (0.1 equiv.) at room temperature. Method B: aldehyde was mixed with acid
®rst and stirred for 5 min then added pyrrole at once. The reaction time was 5 min in all occasions. (b) Since aldehydes
were solid, method B was not tried. (c) Reaction temperature was 50ꢀC. (d) Higher oligomeric compounds (5) and (6)
were cleanly isolated as minor products (Scheme 2)

4611
product in all the attempted cases. The reaction carried out with varying ratio of pyrrole:aldehyde
from 5:1 to 20:1 gave almost identical product distribution.15 Pre-equilibrium protonation of
aldehyde before the addition of pyrrole somehow resulted in higher yields of tripyrromethane.
The results of method A indicate that the protonated aldehyde may react with one molecule of
pyrrole to give 2-a-hydroxypyrrole which upon dehydrative condensation with another pyrrole lead
to dipyrromethane. This step must be comparably fast and thus the amount of dipyrromethane is
not negligible at the early stage of the reaction. Further reaction of the dipyrromethane with
aldehyde and pyrrole successively would give rise to tripyrromethane. On the other hand, if the
catalyst was introduced after the aldehyde and pyrrole were combined, the predominant protonation
would occur at pyrrole due to its higher basicity. Once pyrrole is protonated, it is not nucleophilic
anymore. Therefore, e€ective concentration of acid is reduced at the early stage of the reaction.
The formation of N-confused dipyrromethanes and tripyrromethanes were negligible in the
above reaction conditions. The reaction of p-carboxybenzaldehyde with pyrrole gave the highest
yield of tripyrromethane. The water soluble meso-(4-carboxyphenyl)dipyrromethane and 5,10-
di(4-carboxyphenyl)tripyrromethane were also synthesized and easily separated by adjustment of
pH of the reaction mixture: The excess pyrrole was removed in vacuo then the remaining solid
were combined with aqueous NaOH solution (pH 8). Then the mixture was extracted with ethyl
acetate until the extract did not contain any organic material. The organic phase exclusively
contained dipyrromethane and no tripyrromethane was extracted at this pH. Evaporation of the
solvent a€orded pure meso-(4-carboxyphenyl)dipyrromethane. Then, the pH of the mother liquor
was adjusted to ꢁ6 by adding dilute HCl and extracted with ethyl acetate resulting in exclusive
extraction of tripyrromethane. Aqueous formaldehyde solution is not miscible well with pyrrole
Scheme 2.

4612
at room temperature causing slower reaction. The reaction was carried out at slightly elevated
temperature (50ꢀC). Dipyrromethane was the major product in both methods and the yield was
higher than the one obtained from the reaction of paraformaldehyde and pyrrole.6 In the case of
solid state aldehydes such as p-methoxycarbonylbenzaldehyde and 4-carboxybenzaldehyde, only
method A was applicable and it was found that meso-substituted dipyrromethanes were formed
as the major products in all cases. In some cases, the higher oligomers (5) and (6) were cleanly
isolated from the residual dark brown solid left over after vacuum distillation (Scheme 2). A large
di€erence in molecular weight and relatively stable nature enabled the isolation of higher oligomers.
1
The H NMR spectra of (4), (5) and (6) showed almost identical resonance of all the pyrrolic
protons16 whereas the presence of increased number of pyrrole rings caused broadening of the
resonance lines.
We examined the utility of the direct condensation of aldehydes with pyrrole in the presence of
acid catalyst. Examination of the sequence of adding reactants and catalyst showed dramatic
in¯uence in the product distribution. We therefore were able to establish the conditions a€ording
tripyrromethanes as the major products. To the best of our knowledge, dipyrromethanes and
tripyrromethanes bearing meso-pyridyl or meso-carboxyphenyl or meso-(methoxycarbonyl)-
phenyl groups have been synthesized for the ®rst time by acid-catalyzed, one-¯ask condensation.
The improvement in the synthetic methodology for the preparation of tripyrromethanes will
enable the rapid development of the porphyrin building blocks which have polar groups in trans-
or cis-fashion at the porphyrin periphery. The predominant formation of tripyrromethanes from
the one-¯ask synthesis will also be bene®cial for the development of various porphyrin-based
model systems.
Acknowledgements
Support from the Korea Research Foundation (KRF-99-005-D00042) is gratefully acknowledged.
The NMR and mass spectral data were obtained from central instrument facilities in Kangwon
National University.
References
1. Lindsey, J. S. In Metalloporphyrin Catalyzed Oxidations; Academic: Netherlands, 1994; pp. 49.
2. Wagner, R. W.; Johnson, T. E.; Lindsey, J. S. J. Am. Chem. Soc. 1996, 118, 11166.
3. Jasat, A.; Dolphin, D. Chem. Rev. 1997, 2267.
4. Park, J. Y.; Kim, H. J.; Lee, C. H. Bull. Korean Chem. Soc. 2000, 21, 97.
5. Lee, C. H.; Lindsey, J. S. Tetrahedron 1994, 50, 11427.
6. Littler, B. J.; Miller, M. A.; Hung, C. H.; Wagner, R. W.; O'Shea, D. F.; Boyle, P. D.; Lindsey, J. S. J. Org. Chem.
1999, 64, 1391.
7. Bruckner, C.; Karunaratne, V.; Rettig, S. J.; Dolphin, D. Can. J. Chem. 1996, 74, 2182.
8. Cornia, M.; Binacchi, S.; Del Soldato, T.; Verboom, W.; Reinhoudt, D. N. J. Org. Chem. 1995, 60, 6585.
9. Halterman, R. L.; Mei, X. Tetrahedron Lett. 1996, 37, 6291.
10. Milgrom, L. R.; Yahioglu, G. Tetrahedron Lett. 1996, 37, 4069.
11. Bruckner, C.; Sternberg, E. D.; Boyle, R. W.; Dolphin, D. J. Chem. Soc., Chem. Commun. 1997, 1689.
12. Shin, K.; Lim, C. S.; Choi, C. L.; Kim, Y. M.; Lee, C. H. Chem. Lett. 1999, 1331.
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14. Lee, C. H.; Oh, K. T. Tetrahedron Lett. 1999, 40, 1921.

4613
15. Typical procedure of method A: the solution of aldehyde (1 equiv.) and pyrrole (5 equiv.) was stirred for 5 min at
room temperature under nitrogen atmosphere then added TFA (0.1 equiv.). The whole mixture was stirred for 5
min and then combined with aqueous NaOH (0.1N, 10 mL) in order to quench the reaction. The mixture was
extracted with CH2Cl2 and the organic layer was dried (NaHCO3). The solvent was removed in vacuo and
resulting dark brown oil was distilled under vacuum. Dipyrromethanes were distilled o€ at 180±200ꢀC (0.05
mmHg) and recrystallized from EtOH/water. The remained black solid contains the most of tripyrranes and other
higher oligomers. Tripyrranes were cleanly separated by column chromatography on silica (CH2Cl2). Method B:
the procedure was the same as method A except the mixing sequence of the reactants. Aldehydes and catalyst were
mixed ®rst and stirred for 5 min at room temperature, then pyrrole was introduced at once.
16. Pyrrole (4.1 g, 60.9 mmole) and 4-methoxycarbonyl benzaldehyde (2 g, 12.2 mmole) were reacted by the typical
procedure (distilled at 200ꢀC, 0.1 mmHg; recrystallized from ethanol/water) giving (3) as a pale green solid.
Compound (4) and higher oligomers (5), (6) were separated by column chromatography on silica (CH2Cl2/
EtOAc=9/1). For (3) mp 160ꢀC; 1H NMR (CDCl3) ꢀ 3.90 (s, 3H, CH3), 5.25 (s, 1H, meso-H), 5.89 (s, 2H, pyrrole-
H), 6.16 (q, 2H, pyrrole-H), 6.71 (q, 2H, pyrrole-H), 7.28 (d, 2H, Ar-H), 7.96 (m, 4H, Ar-H and NH). For (4) mp
67ꢀC; 1H NMR (CDCl3) ꢀ 3.83 (s, 6H, CH3), 5.37 (s, 2H, meso-H), 5.71 (d, 2H, pyrrole-H), 5.81 (s, 2H, pyrrole-H),
6.09 (q, 2H, pyrrole-H), 6.64 (q,ꢀ2H, pyrrole-H), 7.18 and 7.85 (two doublet, 8H, Ar-H), 8.10 (br s, 1H, NH), 8.15
1
(br s, 2H, NH). For (5) mp 108 C; H NMR (CDCl3) ꢀ 3.84 (s, 9H, CH3), 5.31 to 5.37 (t, 3H, meso-H), 5.67 (m,
4H, pyrrole-H), 5.81 (s, 2H, pyrrole-H), 6.11 (q, 2H, pyrrole-H), 6.67 (m, 2H, pyrrole-H), 7.16 and 7.84 (m, 12H,
Ar-H), 8.01 (m, 2H, NH), 8.10 (br s, 2H, NH). 13C NMR (CDCl3) ꢀ 166.92, 147.28, 147.18, 131.86, 131.82, 131.70,
131.48, 129.86, 129.66, 128.71, 128.50, 128.35, 128.29, 117.61, 108.47, 107.76, 107.44, 52.14, 44.11, 44.03. FAB-MS
calcd for C43H38N4O6 706.28, found 706.09 (M+). For (6) mp 152ꢀC; 1H NMR (CDCl3) ꢀ 3.85 (s, 12H, CH3), 5.27
to 5.37 (m, 4H, meso-H), 5.66 (m, 6H, pyrrole-H), 5.81 (s, 2H, pyrrole-H), 6.11 (m, 2H, pyrrole-H), 6.67 (m, 2H,
pyrrole-H), 7.17 (m, 8H, Ar-H), 7.84 to 8.06 (m, 13H, Ar-H and NH). 13C NMR (CDCl3) ꢀ 166.94, 147.37, 147.29,
147.24, 131.91, 131.79, 131.75, 131.70, 131.67, 131.49, 129.84, 128.63, 128.32, 128.27, 117.61, 108.43, 107.72,
107.43, 52.13, 44.08, 44.02. FAB-MS calcd for C56H49N5O8 919.36, found 919.24 (M+).