Rational Synthesis of Meso-Substituted Porphyrins Bearing One Nitrogen Heterocyclic Group

Full text of DOI:10.1021/jo9918100

J . Org. Chem. 2000, 65, 2249-2252
2249
fords a mixture of up to six porphyrins, from which the
desired porphyrin is typically separated by laborious
chromatography. For many nonheterocyclic aldehydes the
milder conditions of the two-step one-flask synthesis (at
room temperature in CH2Cl2 with TFA or BF3-etherate
followed by oxidation with DDQ) are attractive, generally
affording higher yields and more tractable non-porphyrin
byproducts.1 However, small heterocyclic aldehydes gen-
erally fail in this method, which has been attributed to
the poor solubility of the heterocyclic aldehyde (or its
intermediate reaction products with pyrrole) in acidified
CH2Cl2 or CHCl3. Indeed, the room-temperature pyrrole-
aldehyde condensation has succeeded with more soluble
heterocyclic aldehydes, such as pyrimidinecarboxalde-
hydes bearing bulky groups adjacent to both nitrogens,12
pyrazolecarboxaldehydes bearing protecting groups (ben-
zyl, SEM) on one of the nitrogens,13 or benzaldehydes to
which heterocycles are attached.1 A complementary ap-
proach has been developed for the Pd-mediated attach-
ment of heterocyclic groups to a dihalogenated porphyrin,
thereby avoiding the acid-catalyzed condensations with
heterocyclic aldehydes.14 Still, a direct and nonstatistical
method is required to avoid performing additional syn-
thetic steps and extensive chromatographic separation
of multiple porphyrin products.
Ra tion a l Syn th esis of Meso-Su bstitu ted
P or p h yr in s Bea r in g On e Nitr ogen
Heter ocyclic Gr ou p
Dorota Gryko and J onathan S. Lindsey*
Department of Chemistry, North Carolina State University,
Raleigh, North Carolina 27695-8204
Received November 23, 1999
Tailoring the perimeter of the porphyrin macrocycle
with diverse substituents in defined patterns is essential
for studies in biomimetic and materials chemistry.1,2
Small nitrogen heterocycles are substituents of particular
interest,3 providing sites for metal coordination, hydrogen-
bonding, alkylation (water solubilization), and modula-
tion of the electronic properties of the porphyrin. Indeed,
pyridine substituents have yielded a broad array of
metal-coordinated multiporphyrin architectures,4 imida-
zole groups have yielded stacked multiporphyrin as-
semblies,5 and quinoline,6 pyrimidine/purine,7,8 or pyra-
zole9 units have enabled molecular recognition and self-
assembly studies of porphyrins with complementary
molecules. In these diverse architectures, a recurring
pattern entails the incorporation of one heterocyclic group
and three nonheterocyclic groups at the four meso
positions of a porphyrin.
We now report such a method for the preparation of
porphyrins bearing one nitrogen heterocycle. Our ap-
proach builds on our recent success in developing two
reactions: (1) a one-flask synthesis of dipyrromethanes
and (2) the condensation of the dipyrromethane and a
dipyrromethane-dicarbinol. For both reactions we have
identified conditions (solvent, catalyst, temperature) that
are suitable for the heterocyclic substrates.
Despite the widespread attraction of porphyrins bear-
ing a single nitrogen heterocyclic group,10 the synthesis
of such porphyrins has presented vexing challenges. The
prevalent method of synthesis involves a mixed aldehyde
condensation with pyrrole via the Adler method in
refluxing propionic acid.11 This statistical approach af-
Dipyrromethanes are available via the one-flask room-
temperature condensation of an aldehyde with excess
pyrrole (in the absence of any solvent) in the presence of
TFA or BF3-etherate.15,16 This reaction has been used to
prepare dipyrromethanes bearing a wide variety of
substituents.1 The dipyrromethane-forming reaction also
can be performed at elevated temperature in the absence
of added acid, albeit in lower yield than with acid at room
temperature.16 Upon application of the standard proce-
dure at room temperature with acid to a set of hetero-
cyclic aldehydes (2-, 3-, or 4-pyridinecarboxaldehyde,
quinoline-3-carboxaldehyde, imidazole-2-carboxaldeyde,
uracil-5-carboxaldehyde) with pyrrole, no dipyrromethane
was obtained.17 While the “high-temperature no-acid”
conditions have had no utility with aryl or aliphatic
aldehydes, we felt the ability to forego any acid warranted
examination in this case, given that identifying a suitable
acidic medium for heterocyclic aldehydes has proved so
problematic. Upon performing the pyrrole-aldehyde
(1) 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.
(2) Lindsey, J . S. In Metalloporphyrin-Catalyzed Oxidations; Mon-
tanari, F.; Casella, L., Eds.; Kluwer Academic Publishers: The
Netherlands, 1994; pp 49-86.
(3) Chambron, J .-C.; Heitz, V.; Sauvage, J .-P. In The Porphyrin
Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic
Press: San Diego, CA, 2000; Vol. 6, pp 1-42.
(4) (a) Ding, L.; Casas, C.; Etemad-Moghadam, G.; Meunier, B.; Cros,
S. New J . Chem. 1990, 14, 421-431. (b) Sari, M. A.; Battioni, J . P.;
Dupre, D.; Mansuy, D.; Le Pecq, J . B. Biochemistry 1990, 29, 4205-
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1693-1699. (d) Fleischer, E. B.; Shachter, A. M. Inorg. Chem. 1991,
30, 3763-3769. (e) Drain, C. M.; Lehn, J .-M. J . Chem. Soc., Chem.
Commun. 1994, 2313-2315. (f) Milgrom, L.; Hill, J . P.; Dempsey, P.
J . F. Tetrahedron 1994, 50, 13477-13484. (g) Yuan, H.; Thomas, L.;
Woo, L. K. Inorg. Chem. 1996, 35, 2808-2817. (h) Takeuchi, M.; Imada,
T.; Ikeda, M.; Shinkai, S. Tetrahedron Lett. 1998, 39, 7897-7900. (i)
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37, 5641-5650. (j) Funatsu, K.; Imamura, T.; Ichimura, A.; Sasaki, Y.
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1996, 52, 9877-9890. (b) Kobuke, Y.; Miyaji, H. Bull. Chem. Soc. J pn.
1996, 69, 3563-3569.
(11) (a) Little, R. G.; Anton, J . A.; Loach, P. A.; Ibers, J . A. J .
Heterocycl. Chem. 1975, 12, 343-349. (b) Little, R. G. J . Heterocycl.
Chem. 1981, 18, 129-133.
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Ogoshi, H. J . Am. Chem. Soc. 1997, 119, 8991-9001. (b) McCurry, J .;
Roberts, J . E. Polyhedron 1990, 9, 2527-2531.
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dron Lett. 1999, 40, 7545-7548.
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117, 704-714.
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Soc., Chem. Commun. 1993, 243-245.
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58, 5983-5993.
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(16) 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, 1391-1396.
(9) Ikeda, C.; Nagahara, N.; Motegi, E.; Yoshioka, N.; Inoue, H.
Chem. Commun. 1999, 1759-1760.
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10.1021/jo9918100 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/15/2000

2250 J . Org. Chem., Vol. 65, No. 7, 2000
Notes
Ta ble 1. Con d ition s for th e On e-F la sk Syn th esis of
Dip yr r om eth a n esa
Sch em e 1
a
All reactions were performed with 14 mol of pyrrole per mol
b
of aldehyde in the absence of any solvent. With addition of TFA
(See Supporting Information).
reaction without added acid at 85 °C overnight, the
desired dipyrromethanes 1a -c were obtained in reason-
able yields as shown in Table 1. Dipyrromethanes 1d ,e
required higher temperatures and also were obtained
after heating overnight. Uracil-5-carboxaldehyde afforded
only a small amount of dipyrromethane upon application
of the acidic conditions at room temperature or using
elevated temperature without acid. In this case the
desired dipyrromethane 1f was obtained upon condensa-
tion with pyrrole in the presence of TFA (0.3 equiv) at
60 °C for 1 h. The dipyrromethanes generally were
purified by removal of excess pyrrole by high-vacuum
distillation, filtration of the crude mixture over an
alumina pad, bulb-to-bulb distillation to remove the
dipyrromethane from oligomeric materials, and final
crystallization to remove any N-confused dipyrromethane.
Dipyrromethanes 1d and 1f were not distilled but were
chromatographed and then crystallized.
romethane 2 in good yield. Similar reaction of 5-(p-tolyl)-
dipyrromethane with p-toluoyl chloride gave the diacyl-
dipyrromethane 3. Reduction of the diacyldipyrromethanes
with NaBH4 in THF-methanol afforded the correspond-
ing dipyrromethane-dicarbinols, which were not charac-
terized but were used immediately in the subsequent
reaction.
The reaction of a dipyrromethane and a dipyrro-
methane-dicarbinol provides a means of preparing a
porphyrin bearing a regiospecific pattern of meso sub-
stituents (Scheme 2).18-20 The success of this approach
hinges on the absence of acid-promoted scrambling of the
dipyrromethane and dipyrromethane-dicarbinol. We re-
cently developed conditions (30 mM TFA in CH3CN at
room temperature for 5 min followed by oxidation with
DDQ) for this reaction that give 20-30% yields without
detectable scrambling.20,21 (The condensation of a dipyr-
romethane and an aldehyde under similar conditions
proceeds without detectable scrambling.22) Given the
expectation that heterocyclic substrates behave differ-
The desired dipyrromethane-dicarbinols were prepared
in a two-step process (Scheme 1).18-20 Treatment of
5-phenyldipyrromethane with ethylmagnesium bromide
followed by benzoyl chloride afforded the 1,9-diacyldipyr-
(17) Two examples of one-flask syntheses of dipyrromethanes bear-
ing heterocyclic substituents have been reported but without delinea-
tion of scope. Reaction of 4-pyridinecarboxaldehyde and pyrrole in the
presence of gaseous HCl afforded 5-(4-pyridyl)dipyrromethane (Na-
garkatti, J . P.; Ashley, K. R. Synthesis 1974, 186-187). Reaction of a
uridinecarboxaldehyde with pyrrole in CHCl3 containing SnCl4 afforded
the corresponding dipyrromethane (Cornia, M.; Binacchi, S.; Del
Soldato, T.; Zanardi, F.; Casiraghi, G. J . Org. Chem. 1995, 60, 4964-
4965).
(18) Cho, W.-S.; Kim, H.-J .; Littler, B. J .; Miller, M. A.; Lee, C.-H.;
Lindsey, J . S. J . Org. Chem. 1999, 64, 7890-7901.
(19) Lee, C.-H.; Li, F.; Iwamoto, K.; Dadok, J .; Bothner-By, A. A.;
Lindsey, J . S. Tetrahedron 1995, 51, 11645-11672.
(20) Rao, P. D.; Dhanalekshmi, S.; Littler, B. J .; Lindsey, J . S.
Manuscript in preparation.

Notes
J . Org. Chem., Vol. 65, No. 7, 2000 2251
Sch em e 2
Ta ble 2. Con d ition s for th e Syn th esis of th e
P or p h yr in sa
ently in acidified solvents than most aromatic com-
pounds, we surveyed the effects of various amounts of
TFA on the reaction course with dipyrromethanes 1a -e
and dipyrromethane-dicarbinol 2-d ica r bin ol in aceto-
nitrile. The reactions were monitored by treating small
reaction aliquots with excess DDQ followed by absorption
spectroscopy in order to determine the overall porphyrin
yield. For each dipyrromethane examined, the reactions
with 75 mM acid were complete in 5 min and the yield
remained constant over 1 h. At 0.6 mM TFA, the
reactions were slower but the yields were higher. The
only exception occurred with the imidazole-dipyrromethane
1e, which gave only trace amounts of porphyrin with low
TFA, and about 2% yield with 75 mM TFA. A synopsis
of the results is provided in Table 2 (see Supporting
Information for comprehensive data). The superior re-
sults obtained with trace acid catalysis are counter to
the expectation that excess acid is required to overcome
the basicity of the pyridine-like nitrogen atom.
yield (%)b
porphyrin
TFA (mM)
5 min
1 h
20
11
4.2
other time
4a
0.6
75
0.6
75
0.6
75
0.6
75
0.6
75
0.6
75
5.7
11
trace
7.1
0
3.9
2.1
6.1
0
1.5
21
4b
4c
4d
4e
4f
9.2 (4 h)
6.5 (6 h)
11 (2 h)
7.3
1.9
3.9
9.7
5.9
0
1.5c
21d
-
-
a
All reactions were performed using 2.5 mM dipyrromethane
and 2.5 mM dipyrromethane-dicarbinol (2-d ica r bin ol) in aceto-
nitrile containing TFA at room temperature for the time indicated,
b
followed by oxidation with DDQ at room temperature. Yields
determined spectroscopically. c Scrambling was observed; thus,
d
this yield represents the total yield of all porphyrins formed. 30
These conditions were applied to prepare the porphy-
rins 4a -g. In the synthesis of porphyrins 4a -d , 4f, and
4g (condensation at 0.6 mM), only a single porphyrin
product was observed on chromatography, making puri-
fication quite straightforward. The isolated yields were
essentially identical to those determined by spectroscopic
monitoring of the reactions. The absence of scrambling
in these reactions was confirmed by examining the crude
reaction mixtures.23 (The reaction with the imidazole-
dipyrromethane 1e at 75 mM TFA gave tetraphenylpor-
phyrin in an amount comparable to that of the desired
porphyrin 4e.) Porphyrins 4b, 4f, and 4g also were
prepared at the semipreparative scale (∼1-4 mmol
min.
dipyrromethane). In each case the pure porphyrin was
isolated by filtration over alumina, chromatography on
one silica column, and crystallization. The yields are
(23) To probe acid-catalyzed scrambling during porphyrin-forming
reactions, we applied an LD-MS assay for examining crude reaction
mixtures, enabling identification of scrambling that might be missed
following chromatographic workup.22 The crude reaction mixtures in
the synthesis of porphyrin 4d or 4f (0.6 mM TFA) each gave a dominant
peak in the mass spectrum corresponding to the expected porphyrin
with no peaks corresponding to scrambled porphyrin products. At-
tempts to scrutinize putative scrambling processes in the reactions
affording the pyridyl-substituted porphyrins 4a -c were stymied by
insufficient mass differences among potential scrambled products (C6H5
) 77 Da; C5H4N ) 78 Da). The crude reaction mixture obtained with
the pyridyl-substituted porphyrin 4g was examined. A dominant
molecule ion peak was observed, and no other peaks were observed
which could be assigned as scrambled porphyrins, indicating the
integrity of the dipyrromethanes under the mild reaction conditions.
(21) Rao, P. D.; Littler, B. J .; Geier, G. R., III; Lindsey, J . S. J .
Org. Chem. 2000, 65, 1084-1092.
(22) Littler, B. J .; Ciringh, Y.; Lindsey, J . S. J . Org. Chem. 1999,
64, 2864-2872.

2252 J . Org. Chem., Vol. 65, No. 7, 2000
Notes
size 25 × 4 cm) with CH2Cl2 and then CH2Cl2:ethyl acetate
(4:1). Appropriate fractions were collected, affording a dark
brown mixture. Bulb-to-bulb distillation afforded the desired
dipyrromethane which then was crystallized.
modest (4-20%) but generally exceed those of mixed
aldehyde condensations.
In summary, we have identified conditions for two
reactions that enable the rational synthesis of porphyrins
bearing one small heterocyclic group. In the synthesis of
dipyrromethanes, reaction of a heterocyclic aldehyde and
excess pyrrole occurs at elevated temperatures without
added acid. In the synthesis of the porphyrin, reaction
of a dipyrromethane and a dipyrromethane-dicarbinol
occurs with trace acid catalysis (0.6 mM TFA) in the polar
solvent acetonitrile. The use of little or no acid in these
reactions appears to be novel, as excess acid has typically
been employed with heterocyclic substrates. The desired
porphyrin was obtained without statistical reactions and
was purified in a straightforward manner. This approach
should prove useful for the preparation of a broad variety
of porphyrins bearing a single heterocyclic substituent.
Syn th esis of P or p h yr in s (gen er a l p r oced u r e). Samples
of the dipyrromethane (0.072 mmol) and the dipyrromethane-
dicarbinol (0.072 mmol) were dissolved in acetonitrile (29.0 mL)
at room temperature and protected from light, and then TFA
(0.018 mmol, 0.60 mM) was added. The reactions were monitored
by treating small reaction aliquots with excess 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) followed by absorption spec-
troscopy (418 nm, assuming ꢀ ) 5 × 105 M-1 cm-1) in order to
determine the overall porphyrin yield.26 The reaction mixture
was stirred for the period described in Table 2 at room temper-
ature before adding DDQ (0.216 mmol). (As little as 0.055 mmol
DDQ has been employed in these reactions with no apparent
decrease in porphyrin yield.) After 1 h the solvent was evapo-
rated and the residue was filtered over a pad of alumina
(CH2Cl2, CH2Cl2:ethyl acetate). The porphyrin fraction was
chromatographed on a silica column (CHCl3) to remove small
amounts of non-porphyrin pigments, affording a highly pure
product. Crystallization was then performed to remove non-
porphyrinic materials that gave peaks in the aliphatic region of
the 1H NMR spectrum.
Exp er im en ta l Section
Gen er a l. Bulb-to-bulb distillation was performed using a
standard-size Kugelrohr short-path distillation apparatus (Al-
drich). All reagents were obtained commercially except for uracil-
5-carboxaldehyde, which was prepared as described in the
literature.24 Porphyrins (from crude reaction mixtures, or fol-
lowing purification) were analyzed by laser desorption ionization
mass spectrometry (LD-MS) without a matrix.25
Syn th esis of Dip yr r om eth a n es (gen er a l p r oced u r e). An
aldehyde (20 mmol) was added to pyrrole (280 mmol, 20 mL),
and the resulting mixture was stirred for 15 or 24 h at the
temperature specified in Table 1. Then the reaction mixture was
evaporated to dryness and chromatographed on alumina (column
Ack n ow led gm en t. This work was funded by the
NIH (GM36238). Mass spectra were obtained at the
Mass Spectrometry Laboratory for Biotechnology. Par-
tial funding for the Facility was obtained from the North
Carolina Biotechnology Center and the National Science
Foundation. We thank Mr. Mark A. Miller for the
preparation of compound 2.
Su p p or tin g In for m a tion Ava ila ble: Detailed synthetic
1
procedures for the preparation of 1a -f, 2, 3, 4a -g; H NMR
spectra of dipyrromethanes 1a -f; 1H NMR and LD-MS spectra
of porphyrins 4a -g; a table of data concerning the effects of
acid concentration on the yields of porphyrins 4a -e. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(24) Wiley, R. H.; Yamamoto, Y. J . Org. Chem. 1960, 25, 1906-
1909.
(25) Srinivasan, N.; Haney, C. A.; Lindsey, J . S.; Zhang, W.; Chait,
B. T. J . Porphyrins Phthalocyanines 1999, 3, 283-291.
(26) Lindsey, J . S.; Schreiman, I. C.; Hsu, H. C.; Kearney, P. C.;
Marguerettaz, A. M. J . Org. Chem. 1987, 52, 827-836.
J O9918100