meso-tetra(tert-butyl)porphyrin as a precursor of porphine

Article abstract of DOI:10.1016/S0040-4039(01)02324-3

Treatment of meso-tetra(tert-butyl)porphyrin with sulfuric acid/1-butanol at 90°C over 15 min afforded porphine in an isolated yield of 74%. De-tert-butylation of the substituted porphyrin provides a rational access to porphine.

Full text of DOI:10.1016/S0040-4039(01)02324-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1057–1058
meso-Tetra(tert-butyl)porphyrin as a precursor of porphine
Saburo Neya* and Noriaki Funasaki
Department of Physical Chemisrty, Kyoto Pharmaceutical University, Yamashina, Kyoto 607-8414, Japan
Received 19 November 2001; revised 5 December 2001; accepted 7 December 2001
Abstract—Treatment of meso-tetra(tert-butyl)porphyrin with sulfuric acid/1-butanol at 90°C over 15 min afforded porphine in an
isolated yield of 74%. De-tert-butylation of the substituted porphyrin provides a rational access to porphine. © 2002 Elsevier
Science Ltd. All rights reserved.
Many kinds of oligomeric porphyrins1 and porphyrin
pyrrolic precursors tend to be available only by profi-
isomers2 have appeared as a result of recent advances in
cient preparative hands.
porphyrin synthesis. However, porphine (1), the parent
nucleus of every natural and synthetic porphyrin, is still
difficult to prepare in any amount. It is consequently
quite expensive.3 Continuing effort has been exerted to
improve the porphine synthesis.4,5 Adding 2 ml of
2-hydroxymethyl-pyrrole over 2 weeks to 3 l of ethyl-
benzene at 100°C, Longo et al.6 obtained 1 in an 8–10%
yield. Neya et al.7 prepared porphine from formalin
and pyrrole. Although their yield is as low as 0.9%, the
synthesis is readily carried out on a large scale to afford
more than 100 mg of 1 at one time. In 1999, Taniguchi
et al.8 reported an elegant porphine synthesis through
coupling of tripyrrane and 2,5-bis(hydroxymethyl)-
pyrrole. The yield of 31% is indeed the highest, but the
Porphine 1, owing to the fundamental importance in
porphyrin chemistry, has been the subject of continuing
theoretical9 and experimental10 investigations. Sato et
al.11 employed iron porphine as the prosthetic group of
myoglobin to perturb the heme-globin interaction in the
protein pocket. Neya et al.12 resolved the crystallo-
graphic structure of the myoglobin reconstituted with
iron porphine. Sugiura13 examined the X-ray structure
of various metallo porphines and explained the peculiar
packing modes in crystalline lattice in terms of the
CH-p interactions. In view of the extreme preparative
difficulty as well as increasing chemical and biological
applications for 1, the simple porphine synthesis is to be
developed.
According to the textbook of organic chemistry,14 tert-
butyl group can be cleaved from the aromatic ring
while the primary and secondary alkyl substituents do
not. Removal of tert-butyl group or de-tert-butylation
is effected with proton and Lewis acid. Acid-labile
tert-butyl group has been frequently employed as a
protecting or blocking group in organic synthesis.15 It is
hence expected that a porphyrin bearing tert-butyl sub-
stituents will be used as an intermediary compound for
the synthesis of porphine. The expected porphyrin with
tert-butyl substituents is fortunately present. Smith et
al. first reported in 1994 the synthesis of meso-tetra-
(tert-butyl)porphyrin (2).16,17 This porphyrin was origi-
nally prepared to analyze characteristic spectroscopic
profiles in terms of nonplanar macrocyclic conforma-
tion induced by the flanking bulky substituents.
Scheme 1. Conversion of meso-tetra(tert-butyl)porphyrin (2)
into porphine (1).
Keywords: de-tert-butylation; meso-tetra(tert-butyl)porphyrin; por-
phine.
We attempted the de-tert-butylation of 2 with several
acids such as sulfuric acid, p-toluenesulfonic acid and
* Corresponding author. Tel.: +81-75-595-4664; fax: +81-75-595-4762;
e-mail: sneya@mb.kyoto-phu.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02324-3

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S. Neya, N. Funasaki / Tetrahedron Letters 43 (2002) 1057–1058
References
1. Burrell, A. K.; Officier, D. L.; Plieger, P. G.; Reid, D. C.
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2. Sessler, J. L.; Gebauer, A.; Vogel, E. In The Porphyrin
Handbook; Kadish, K. M.; Smith, K. M.; Guilard, R.,
Eds.; Academic Press: New York, 2000; Vol. 2, pp. 1–54.
3. According to the Sigma catalog in 2000–2001, the price for
1 mg of porphine is 76.8 US dollars.
4. Eisner, U.; Linstead, R. P. J. Chem. Soc. 1955, 3742–3749.
5. Krol, S. J. Org. Chem. 1959, 24, 2065–2067.
6. Longo, F. R.; Thorne, E. J.; Adler, A. D.; Dym, S. J.
Heterocyclic Chem. 1975, 12, 1305–1309.
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1993, 30, 549–550.
8. Taniguchi, S.; Hasegawa, H; Nishimura, M.; Takahashi,
M. Synlett 1999, 73–74.
Figure 1. Visible absorption of porphine in dichloromethane.
9. Edwards, W. D.; Weiner, B.; Zerner, M. C. J. Am. Chem.
Soc. 1986, 108, 2196–2204.
10. Chen, B. L. M.; Tulinski, A. J. Am. Chem. Soc. 1972, 94,
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11. Sato, T.; Tanaka, N.; Neya, S.; Funasaki, N.; Iizuka, T.;
Shiro, Y. Biochim. Biophys. Acta 1992, 1121, 1–7.
12. Neya, S.; Funasaki, N.; Sato, T.; Igarashi, N.; Tanaka, N.
J. Biol. Chem. 1993, 268, 8935–8942.
13. Sugiura, K. 80th National Meeting of the Chemical Society
of Japan; Chiba, September 2001; Abstract paper 3B4–11.
14. March, J. Advanced Organic Chemistry, 4th edn; Wiley
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aluminum chloride. Sulfuric acid diluted with 1-butanol
was found to be the most effective catalyst; an equal
volume mixture of sulfuric acid and 1-butanol smoothly
dealkylated 2 to afford 1 (Scheme 1) in an isolated yield
of 74%.18 The reaction, without protection against air,
was completed within 15 min at 90°C. The Soret peak
sizably blue-shifted from 447 to 394 nm, and the visible
absorption changed from etio- to phyllo-types (Fig. 1).
Since a direct correlation between Soret red-shift and
non-planarity of porphyrin ring is known,16 the
remarkable Soret blue-shift on the acid treatment sug-
gests release of porphyrin distortion and hence removal
of the bulky substituents. Analytical results18 of the
product were consistent with the expected structure.
16. Ema, T.; Senge, M. O.; Nelson, N. Y.; Ogoshi, H.; Smith,
K. M. Angew. Chem., Int. Ed. Engl. 1994, 33, 1879–1881.
17. Senge, M. O.; Bischoff, I.; Nelson, N. Y.; Smith, K. M.
J. Porphyrins Phthalocyanines 1999, 3, 99–116.
Pivalaldehyde and pyrrole for
2 are inexpensive
reagents. Senge et al.17 optimized the synthesis of 2 to
afford multi grams of the product in 15% yield. In
addition, the de-tert-butylation of 2 and subsequent
workup are easy to perform. These observations taken
together allow us to prepare 1 in large amounts. It is
now turned out that compound 2 is a useful precursor
for the synthesis of porphine. More importantly, the
de-tert-butylation referred to porphine preparation will
be generally applicable to the synthesis of asymmetri-
cally substituted porphyrin derivatives.
18. meso-Tetra(tert-butyl)porphyrin 2 (200 mg), dissolved in
sulfuric acid (8 ml)/1-butanol (8ml) mixture, was heated
with stirring in oil bath at 90°C for 15 min. The dark green
solution turned into reddish purple during the incubation.
Methanol (40 ml) and chloroform (200 ml) were added to
the cooled solution before being washed with dilute
aqueous sodium hydroxide and water until neutrality. The
chloroform layer was evaporated to dryness. The residue,
washed on a centrifuge with small portions of methanol
until colorless, was purified by silica-gel column chro-
matography with chloroform. The fast-running red band
containing 1 was collected and evaporated to dryness.
Recrystallization from chloroform/methanol afforded 86
mg of copper-colored leaflets, 1 (74% yield). Anal calcd for
C20H14N4: C, 77.40; H, 4.55; N, 18.05. Found: C, 77.38;
H, 4.82; N, 17.80. MS: m/z, 310 (M+). 1H NMR (300 MHz,
CDCl3, l): 10.38 (s, 4H, meso-H), 9.54 (s, 8H, pyrrole-H),
−3.95 (br s, 2H, NH). Visible (dichloromethane) umax, nm
(m): 394 (272000), 489 (16400), 519 (3200), 560 (5400), 568
(sh, 4800), 613 (1100).
Acknowledgements
This work was supported by a grant-in-aid (Frontier
Research Program) from the Ministry of Education,
Science, Sports, and Culture, Japan. We thank Dr. Seiji
Ishikawa, Kyoto Pharmaceutical University, for edito-
rial help.