Controlled scrambling in porphyrin synthesis - Selective synthesis of 5,10-disubstituted porphyrins

Article abstract of DOI:10.1016/S0040-4039(00)01965-1

Condensation of phenyldipyrromethane with bisnaphthaldehyde 3 leads to unexpected formation of the scrambled 5,10-bridged porphyrin 5; this unprecedented selectivity suggests that an alternative scrambling mechanism to dipyrromethane acidolysis is operating.

Full text of DOI:10.1016/S0040-4039(00)01965-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 355–358
Controlled scrambling in porphyrin synthesis—selective synthesis
of 5,10-disubstituted porphyrins
8
Andrew N. Cammidge* and Orhan Oztu¨rk
School of Chemical Sciences, University of East Anglia, Norwich NR4 7TJ, UK
Received 30 October 2000; accepted 7 November 2000
Abstract—Condensation of phenyldipyrromethane with bisnaphthaldehyde 3 leads to unexpected formation of the scrambled
5,10-bridged porphyrin 5; this unprecedented selectivity suggests that an alternative scrambling mechanism to dipyrromethane
acidolysis is operating. © 2000 Elsevier Science Ltd. All rights reserved.
In nature, elaborate porphyrin derivatives are built up
via stepwise biosynthesis to give tetrapyrrolic interme-
diates (bilanes) which are then cyclised to the por-
phyrinogen (which is subsequently oxidised to
porphyrin). Much work has gone into elaborating
the biosynthetic pathway for their synthesis. In nature
there is often quite remarkable control and this is
exemplified by the biosynthesis of vitamin B12
during which a bilane is cyclised with concomitant
inversion of one of the pyrrole units. Such ‘scram-
bling’ of pyrroles in chemical synthesis is well docu-
mented but is usually an unwanted and uncontrolled
side reaction.2,5 Here, we report the first example of
controlled scrambling in porphyrin synthesis leading
to selective synthesis of a 5,10-disubstituted por-
phyrin.
The synthesis of porphyrins has been widely studied
since the first synthesis of haemin by Fisher and Zeile
in 1929.1 The interest, for the main part, stems from
the wide occurrence of porphyrin derivatives in nature
and the ability of natural and synthetic derivatives to
act as models for biological processes (light harvest-
ing, oxygen transport, catalysis, molecular recogni-
tion).2 Synthesis of porphyrin derivatives typically
involves condensation of pyrroles with aldehydes or
their equivalent.2,3 Such one-pot procedures are only
generally applicable to symmetrical, tetrasubstituted
derivatives. More elaborate approaches are required
in the synthesis of unsymmetrically substituted por-
phyrins. A widely used approach uses preformed
dipyrromethanes. Their condensation with aldehyde
gives access to derivatives with reduced symmetry.2,4
OH
Ph
HO
Ph
N
NH
HN
N
RO
OR
NH
HN
1
Ph
OHC
CHO
OH
Ph
NH HN
Ph
N
HN
N
NH
HO
Ph
2
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01965-1

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A. N. Cammidge, O. Oztu¨rk / Tetrahedron Letters 42 (2001) 355–358
356
As part of a study aimed at the synthesis of efficient
molecular recognition hosts based on the metallopor-
phyrin platform, we targeted derivatives such as 1
which incorporate 8-hydroxyl-substituted naphth-1-yl
substituents at the 5- and 15-porphyrin meso positions
to produce a tight cleft directly above the porphyrin
plane.6 Naphth-1-yl porphyrins are stable to isomerism
(atropisomerism) because of sterically restricted rota-
tion.6 A statistical synthesis (using a dipyrromethanes
and 8-substituted naphth-1-aldehyde) would therefore
be expected to yield two isomers (Scheme 1).
tive mechanism is operating (Scheme 3). Normal elec-
trophilic aromatic substitution at the 5-position of the
dipyrromethane by naphthaldehyde gives intermediate
6. Electrophilic substitution at the 5%-position of the
second pyrrole of the dipyrromethane with the second
naphthaldehyde of the dimer (path A) would lead to
the (expected) 5,15-bridged porphyrin. However, it
would appear that attack at the 2-position of the substi-
tuted pyrrole is preferred (path B) to give intermediate
7. Fragmentation of 7 can occur to give cyclic 2,5-dis-
ubstituted pyrrole 8 and pyrrolic carbocation 9. Com-
pound 8 can react further with another equivalent of
dipyrromethane and 9 (directly or sequentially) with
cyclisation to give the porphyrinogen which, on oxida-
tion, gives the observed 5,10-bridged isomer. Produc-
tion of a small quantity of TPP is easily explained by
this mechanism (tetramerisation of 9).
In order to overcome this problem we adopted a strat-
egy which involved presynthesis of a bis-naphthalde-
hyde to force production of a single atropisomer.
p-Xylyl was chosen as the linking7 group because a
simple molecular model indicated that it could be ac-
commodated across the porphyrin with minimal strain
and it was envisaged that it could be easily removed to
reveal the single atropisomer dihydroxide. Compound 3
was therefore synthesised (by reaction of 2 equivalents
of 8-hydroxynaphth-1-aldehyde8 with a,a%-dibromo-p-
xylene) and condensed with phenyldipyrromethane9 us-
ing BF3·OEt2 as catalyst under standard conditions for
porphyrin synthesis. Quite remarkably, however, con-
densation of the dialdehyde with phenyldipyrromethane
did not yield the expected 5,15-bridged porphyrin 4 but
gave the 5,10 bridged isomer 510 (Scheme 2). The
structure of 5 was elucidated initially by analysis of its
1H NMR spectrum, which was significantly more com-
plex than that expected for 4. Two doublets and a
broad resonance (which does not sharpen significantly
at 80°C) are observed for the a-protons and phenyl
protons, respectively, of the xylyl bridge. The structure
was confirmed by X-ray crystallography.11 Subsequent
careful examination of the reaction mixture allowed
isolation of a trace (<1%) of the expected 5,15-bridged
porphyrin 4.
It is plausible that this mechanism may operate quite
generally in porphyrin syntheses. Noting that it impli-
cates carbocation 9, we undertook a further study to
seek conditions designed to suppress this pathway and
thereby demonstrate control over the fate of species 6.
We reasoned that destabilisation of the carbocation
would disfavour this fragmentation and promote for-
mation of the ‘normal’ 5,15-disubstituted product. This
was indeed found to be the case. Repetition of the
reaction using (pentafluorophenyl)-dipyrromethane
leads to total elimination of the fragmentation/scram-
bling pathway and exclusive isolation of the 5,15-
bridged porphyrin 10 in 12% yield (Scheme 3).
The original target, 4, was eventually synthesised ac-
cording to Scheme 4. Bisnaphthaldehyde 3 was con-
densed with an excess of pyrrole to yield
bis(dipyrromethane) 11. Compound 11 was further con-
densed with benzaldehyde in the presence of zinc ace-
tate using propionic acid in dichloromethane12 to give 4
as its zinc complex (4Zn).10 It is particularly notewor-
thy that 5 is not formed when 11 is treated with
benzaldehyde under identical conditions to those used
for its formation from 3 and phenyldipyrromethane.
This important observation lends further support for
the alternative mechanism because any acidolysis of the
(bis)dipyrromethane would lead to rapid formation of
the 5,10-bridged product.
Scrambling in related dipyrromethane/aldehyde synthe-
ses is usually interpreted as arising from breakdown of
the dipyrromethane under the acidic reaction condi-
tions, eventually giving a complex mixture of all possi-
ble porphyrins.5d From the observation that 5 and
tetraphenylporphyrin (TPP) are the main porphyrin
products from this reaction it is likely that an alterna-
O
Ph
O
N
NH
HN
N
Ph
O
OHC
O
CHO
Ph
O
X
4
HN
NH
NH HN
Ph
26%
3
O
N
NH
Ph
HN
N
Ph
5
Scheme 2.

8
A. N. Cammidge, O. Oztu¨rk / Tetrahedron Letters 42 (2001) 355–358
357
O
O
O
O
path A
O
O
C6F5
O
O
A
A
OH
OHC
N
NH
HN
N
R =C6F5
path A
NH HN
NH HN
R
C6F5
10
6
path B
R =C6H5
R
path B
O
O
O
OH
HO
O
O
O
H
N
N
NH
Ph
OH
AO
HN
N
H
N
8
Ph
Ph
NH
Ph
5
H
N
7
HN
HN
Ph
HN
9
Ph
Scheme 3. Alternative mechanism for scrambling leading to 5.
O
O
O
O
O
Ph
N
PhCHO
N
H
O
N
H
N
H
OHC
CHO
N
N
Zn(OAc)2
37%
excess
56%
Zn
NH
N
HN
Ph
11
4Zn
Scheme 4.
Further work is in progress to determine the generality
of this process and to deprotect and elaborate the novel
porphyrins for investigation as molecular recognition
hosts.
Kearney, P. C.; Marguerettaz, A. M. J. Org. Chem. 1987,
52, 827.
4. Ogoshi, H.; Sugimoto, H.; Nishiguchi, T.; Watanabe, T.;
Matsuda, Y.; Yoshida, Z. I. Chem. Lett. 1978, 29.
5. (a) Shanmugathasan, S.; Edwards, C.; Boyle, R. W.
Tetrahedron 2000, 56, 1025. (b) Littler, B. J.; Ciringh, Y.;
Lindsey, J. S. J. Org. Chem. 1999, 64, 2864. (c) Davoust,
E.; Granet, R.; Krausz, P.; Carre´, V.; Guilloton, M.
Tetrahedron Lett. 1999, 40, 2513. (d) Wallace, D. M.;
Leung, S.; Senge, M. O.; Smith, K. M. J. Org. Chem.
1993, 58, 7245.
Acknowledgements
We thank the EPSRC mass spectrometry service
(Swansea, UK) for FAB and accurate mass
measurements.
6. Meso-naphth-1-yl porphyrins bearing hydroxyl sub-
stituents at the 2- and/or 7-positions have been reported.
(a) Mizutani, T.; Kurahashi, T.; Murakami, T.; Matsumi,
N.; Ogoshi, H. J. Am. Chem. Soc. 1997, 119, 8991. (b)
Hayashi, T.; Miyahara, T.; Koide, N.; Kato, Y.; Masuda,
H.; Ogoshi, H. J. Am. Chem. Soc. 1997, 119, 7281. (c)
Mizutani, T.; Murakami, T.; Ogoshi, H. Tetrahedron
Lett. 1996, 37, 5369. (d) Hayashi, T.; Miyahara, T.;
Aoyama, Y.; Nonoguchi, M.; Ogoshi, H. Chem. Lett.
1994, 1749. (e) Hayashi, T.; Miyahara, T.; Hashizumi, N.
Ogoshi, H. J. Am. Chem. Soc. 1993, 115, 2049. (f)
Hayashi, T.; Asai, T.; Hokazono, H.; Ogoshi, H. J. Am.
Chem. Soc. 1993, 115, 12210. (g) Hayashi, T.; Miyahara,
T.; Aoyama, Y.; Ogoshi, H. Pure Appl. Chem. 1994, 66,
797.
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A. Die Chemie des pyrrols; Akademische Verlag: Leipzig,
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2. The Porphyrin Handbook; Kadish, K. M.; Smith, K. M.;
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3. (a) Adler, A. D.; Longo, R. F.; Finarelli, J. D.; Gold-
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8
A. N. Cammidge, O. Oztu¨rk / Tetrahedron Letters 42 (2001) 355–358
358
8. (a) Packer, R. J.; Smith, D. C. C. J. Chem. Soc. (C) 1967,
7.68 (6H, m, Ph), 7.79 (2H, d, J=8.6), 7.87 (2H, t,
J=7.8), 8.15 (4H, m, Ph), 8.25 (2H, d, J=8.3), 8.51 (2H,
d, J=6.9), 8.62 (4H, d, J=4.6), 8.74 (4H, d, J=4.6); lC
(75.4 MHz, CDCl3): 69.34 (-CH2PhCH2-), 77.19 (-
CH2PhCH2-), 109.57, 120.18, 122.30, 123.07, 123.32,
124.09, 126.28, 126.48, 127.20, 128.50, 128.89, 130.99,
131.44, 132.95, 134.28, 134.93, 138.38, 143.16, 149.21,
149.86, 155.81; m/z (FAB) 912 (M+). Compound 10: mp
>320°C, umax (DCM)/nm: 422.0, 516.0, 551.0, 595.0,
652.0; lH (270 MHz, CDCl3): −3.33 (2H, s, -NH), 3.06
(4H, s, -CH2PhCH2-), 3.67 (4H, s, -CH2PhCH2-), 6.48
(2H, d, J=7.6), 7.37 (2H, t, J=7.9), 7.75 (2H, d, J=
7.9), 7.85 (2H, t, J=7.6), 8.23 (2H, d, J=7.8), 8.43 (2H,
d, J=6.9), 8.50 (8H, dd, J=4.6, 4.3); lC (67.4 MHz,
CDCl3): 69.27, 108.78, 122.03, 123.55, 123.73, 124.09,
126.66, 128.42, 129.03, 131.71, 131.93, 134.93, 136.92,
155.50; m/z (FAB) 1029 (M++1).
2194. (b) Elliger, C. A. Org. Prep. Proc. Int. 1985, 17,
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9. Lee, C. H.; Lindsey, J. S. Tetrahedron 1994, 50, 11427.
10. Selected data. Compound 5: mp >300°C, umax (DCM)/
nm 425.5, 520.0, 557.0, 597.5, 653.5; lH (270 MHz,
CDCl3) (at 24°C): −2.49 (2H, br s, -NH), 3.52 (2H, d,
J=10.2, -CH2-Ph-CH2-), 3.91–3.94 (4H, br s, -CH2-Ph-
CH2-), 4.13 (2H, d, J=10.2, -CH2-Ph-CH2-), 6.79 (2H, d,
J=7.6), 7.53 (2H, t, J=7.6), 7.62–7.79 (10H, m,
napth.+Ph), 7.93 (2H, d, J=6.9), 8.07 (2H, m, Ph), 8.17
(4H, m, pyrrole+naphth), 8.33 (2H, m, Ph), 8.55 (2H, s,
pyrrole), 8.59 (2H, d, J=4.6, pyrrole), 8.85 (2H, s,
pyrrole); lC (67.4 MHz, CDCl3): 69.63, 77.22, 106.27,
119.19, 120.70, 123.16, 124.18, 126.36, 126.55, 127.45,
127.96, 128.28, 129.56, 133.76, 134.41, 134.62, 134.96,
137.80, 142.55, 156.04; m/z acc mass (calcd) 848.315127
(M+), (found) 848.3171 (M+). Compound 4.Zn: mp >
300°C, umax (DCM)/nm: 426.0, 553.0, 596.0; lH (270
MHz, CDCl3): 3.07 (4H, s, -CH2PhCH2-), 3.68 (4H, s,
-CH2PhCH2-), 6.51 (2H, d, J=7.6), 7.38 (2H, t, J=8.1),
11. The crystal structures of 4Zn and 5 will be reported
elsewhere.
12. Setsune, J.; Hashimoto, M.; Shiozawa, K.; Hayakawa, J.;
Ochi, T.; Masuda, R. Tetrahedron 1998, 54, 1407.
.