Simple methodology for syntheses of porphyrins possessing multiple peripheral substituents with an element of symmetry

Article abstract of DOI:10.1021/jo951870f

New methodology was developed for synthesis of regiochemically pure porphyrins with D_2h symmetry (e.g. 9) via tetramerization reactions involving two different pyrroles. The two pyrrole components were a 2,5-diunsubstituted pyrrole (e.g. 11) and a 2,5-bis[(N,N-dimethylamino)methyl]pyrrole (e.g. 10), the latter being formed from a 2,5-di-unsubstituted pyrrole by treatment with excess Eschenmoser's reagent (N,N-dimethylmethyleneammonium iodide). A bis-butanoporphyrin 16 was transformed into the corresponding opp-bis-benzoporphyrin 17 by treatment with DDQ. The synthetic method was further extended to allow the synthesis of more unsymmetrical porphyrins, with C_2v, symmetry (e.g. 32), by reacting a tripyrrane (e.g. 27) with a 2,5-bis[(N,N-dimethylamino)-methyl]pyrrole (e.g. 18). The structures and substituent arrays in both type of porphyrins were confirmed by single-crystal X-ray crystallography.

Full text of DOI:10.1021/jo951870f

998
J . Org. Chem. 1996, 61, 998-1003
Sim p le Meth od ology for Syn th eses of P or p h yr in s P ossessin g
Mu ltip le P er ip h er a l Su bstitu en ts w ith a n Elem en t of Sym m etr y
Liem T. Nguyen, Mathias O. Senge,† and Kevin M. Smith*,‡
Department of Chemistry, University of California, Davis, California 95616
Received October 17, 1995X
New methodology was developed for synthesis of regiochemically pure porphyrins with D2h symmetry
(e.g. 9) via tetramerization reactions involving two different pyrroles. The two pyrrole components
were a 2,5-diunsubstituted pyrrole (e.g. 11) and a 2,5-bis[(N,N-dimethylamino)methyl]pyrrole (e.g.
10), the latter being formed from a 2,5-di-unsubstituted pyrrole by treatment with excess
Eschenmoser’s reagent (N,N-dimethylmethyleneammonium iodide). A bis-butanoporphyrin 16 was
transformed into the corresponding opp-bis-benzoporphyrin 17 by treatment with DDQ. The
synthetic method was further extended to allow the synthesis of more unsymmetrical porphyrins,
with C2v symmetry (e.g. 32), by reacting a tripyrrane (e.g. 27) with a 2,5-bis[(N,N-dimethylamino)-
methyl]pyrrole (e.g. 18). The structures and substituent arrays in both type of porphyrins were
confirmed by single-crystal X-ray crystallography.
In tr od u ction
Over the past 50 years, numerous advances in por-
phyrin synthetic methodology have been realized. These
developments have advanced systematically through
monopyrrole tetramerization,1-3 dipyrromethene self-
condensation in organic acid melts,4 “2 + 2” MacDonald
dipyrromethane syntheses,5,6 “3 + 1” synthesis using a
tripyrrane and a diformylpyrrole,7 and then on to the
truly general approaches through b-bilenes and a,c-
biladienes.8-10 However, it still remains a fact that if the
target porphyrin is totally symmetrical [e.g. octaethylpor-
phyrin (1) or tetraphenylporphyrin (2)], a one-pot monopyr-
role “tetramerization” approach is the only efficient
method, but if asymmetry is required in the product
porphyrin substituent array, and if extensive chromato-
graphic purification is to be avoided, a more elaborate
route via dipyrroles, tripyrroles, or open-chain tetrapyr-
roles must be employed.9
Most porphyrin cyclization procedures proceed by way
of acid catalysis and if porphyrinogens are intermediates
at any point, acid-catalyzed redistribution of the pyrrole
subunits to give a complex mixture of porphyrin products
is likely (unless the product porphyrin is substituted
throughout with only one kind of substituent, e.g. 1 or
2, which renders the redistribution invisible). Not all
porphyrin syntheses proceed through porphyrinogen
intermediates, but those which do, and which have more
than one type of 3,4-substituent on the monopyrrole (e.g.
3), are usually subject to mixture problems. For example
(Scheme 1), it might be thought possible to obtain a “type-
I”11 porphyrin 4 by acid-catalyzed self-condensation of
pyrrole 3, bearing a 2-substituent with a good leaving
group at the benzylic carbon. Though such an expecta-
tion12,13 is occasionally close to reality,14 it has to be
recognized that contamination with other porphyrin so-
called type-isomers is often the case.15,16 As shown in
Scheme 1, under acidic conditions, the intermediate is
actually a mixture of porphyrinogens 5-8 due to acid-
catalyzed “scrambling” of the pyrrole subunits either at
the macrocyclic porphyrinogen stage or at some earlier
open-chain methylene-linked oligopyrrole stage.17 The
product from such a reaction (Scheme 1) is usually a
mixture of various proportions of all four porphyrin type
isomers.15,16
† Permanent address: Institut fu¨r Organische Chemie (WE02), Freie
Universita¨t Berlin, Takustrasse 3, D-14195 Berlin, Germany
‡ Dedicated to Professor Dr. Horst Senger on the occasion of his 65th
birthday.
X Abstract published in Advance ACS Abstracts, J anuary 15, 1996.
(1) Adler, A. D.; Longo, F. R.; Finarelli, J . D.; Goldmacher, J .; Assour,
J .; Korsakoff, L. J . Org. Chem. 1967, 32, 476.
(2) Lindsey, J . S.; Schreiman, I. C.; Hsu, H. C.; Kearney, P. C.;
Marguerettaz, A. M. J . Org. Chem. 1987, 52, 827. Lindsey, J . S.;
MacCrum, K. A.; Tyhonas, J . S.; Chuang, Y.-Y. J . Org. Chem. 1994,
59, 579, and references cited therein.
(3) Ono, N.; Kawamura, H.; Maruyama, K. Bull. Chem. Soc. J pn.
1989, 62, 3386. Ono, N.; Kawamura, H.; Bougauchi, M.; Maruyama,
K. Tetrahedron 1990, 46, 7483. Ono, N.; Sugi, K.; Ogawa, T. Chem.
Express 1991, 869.
(4) Fischer, H.; Friedrich, H.; Lamatsch, W.; Morgenroth, K. Liebigs
Ann. Chem. 1928, 466, 147.
(5) Arsenault, G. P.; Bullock, E.; MacDonald, S. F. J . Am. Chem.
Soc. 1960, 82, 4384
(6) Wallace, D. M.; Leung, S. H.; Senge, M. O.; Smith, K. M. J . Org.
Chem. 1993, 58, 7245.
(7) Boudif, A.; Momenteau, M. J . Chem. Soc., Chem. Commun. 1994,
2069.
(8) J ohnson, A. W.; Kay, I. T. J . Chem. Soc. 1961, 2418. Baptista
de Almeida, J . A. P. B.; Kenner, G. W.; Rimmer, J .; Smith, K. M.
Tetrahedron 1976, 32, 1793. Smith, K. M.; Craig, G. W. J . Org. Chem.
1983, 48, 4302.
(9) Review: Smith, K. M. In Porphyrins and Metalloporphyrins;
Smith, K. M., Ed.; Elsevier: Amsterdam, 1975; pp 29-58.
(10) Review: Clezy, P. S. Aust. J . Chem. 1991, 44, 1163.
(11) Smith, K. M. In Porphyrins and Metalloporphyrins; Smith, K.
M., Ed.; Elsevier: Amsterdam, 1975, p 5.
(12) Bullock, E.; J ohnson, A. W.; Markham, E.; Shaw, K. B. J . Chem.
Soc. 1958, 1430.
(13) Momenteau, M.; Mispelter, J .; Loock, B.; Lhoste, J . M. Can. J .
Chem. 1978, 56, 2598.
(14) J eandon, C.; Callot, H. J . Bull. Soc. Chim. Fr. 1993, 130, 625.
(15) Kay, I. T. Proc. Natl. Acad. Sci. U.S.A. 1962, 48, 901.
(16) Smith, K. M.; Eivazi, F. J . Org. Chem. 1979, 44, 2591.
(17) Mauzerall, D. J . Am. Chem. Soc. 1960, 82, 2601.
0022-3263/96/1961-0998$12.00/0 © 1996 American Chemical Society

Syntheses of Porphyrins
Sch em e 1
J . Org. Chem., Vol. 61, No. 3, 1996 999
in order to protonate the acetoxy leaving group to
facilitate its displacement by the nucleophilic 2-position
of another pyrrole. In order avoid acid catalysis, the
leaving group on the benzylic carbon at the 2-position of
the pyrrole needs to be very reactive so that it can be
displaced without acid catalysis. An ideal 2-substituent,
capable of fulfilling the above requirement, is the (di-
methylamino)methyl group, which through quaterniza-
tion for example with an alkyl halide, can be readily
displaced from the benzylic carbon under neutral condi-
tions as a trialkylamine. It also occurred to us that it
should be possible, in principle, to obtain a regiochemi-
cally pure porphyrin product (with like pyrrole rings
opposite each other)19 (e.g. 9) if one were to react two
pyrroles together under neutral conditions, provided that
one of these pyrroles (e.g. 10) possessed all of the future
meso-carbons of the porphyrin product, and the other
pyrrole (e.g. 11) contained none of them. The positioning
of the benzylic carbons would, in effect, determine which
of the two constituent pyrroles in the mixture could react
with it next.
Pyrrole Mannich bases [2-[(N,N-dimethylamino)meth-
yl]pyrroles] have previously been used in porphyrin
syntheses.20 In our strategy, 2,5-bis[(N,N-dimethylami-
no)methyl]pyrroles e.g. 10 and 12, were the key inter-
mediates in the approach, and these were readily formed
in 83-86% yields by treatment of the corresponding 2,5-
diunsubstituted pyrroles 13 or 14 in nitromethane with
an excess of Eschenmoser’s reagent.21 It was first neces-
sary to ascertain whether or not the use of a 2,5-bis[(N,N-
dimethylamino)methyl]pyrrole under standard acidic
polymerization conditions would indeed give a mixture
of porphyrins! Thus, pyrrole 10 with 3,4-dimethylpyr-
role22 (11) was treated in acetic acid at reflux in the
presence of oxygen. A mixture of porphyrin products was
obtained [1H NMR (300 MHz, in CDCl3), meso proton
signals at 10.03, 10.07, and 10.10 ppm]; this is presum-
ably the anticipated outcome of acid-catalyzed scrambling
of the initially formed porphyrinogen or partially oxidized
porphomethene species prior to aerobic oxidation to
porphyrin. Similar results were obtained when 10 and
11 were heated together in acetic acid containing potas-
sium ferricyanide as oxidant.23 We did not immediately
proceed to the use of methyl iodide for quaternization of
10 since we wanted to investigate the stability of this
pyrrole in neutral solvents in the presence of nucleophilic
pyrroles. Reaction of pyrroles 10 and 11 in methanol in
the presence of K3Fe(CN)6 gave, after workup, chroma-
tography, and recrystallization, a 19% yield of isomeri-
cally pure porphyrin 9.24 This was evident from the fact
that the proton NMR spectrum showed only one meso
It occurred to us that it might be possible to avoid the
troublesome redistribution of the pyrrole subunits which
leads to the formation of mixtures in such reaction if, (i)
the reaction is carried out under nonacidic conditions and
(ii) the intermediate porphyrinogen is rapidly oxidized
in situ to porphyrin. In this paper,18 we report a new
method for synthesis of porphyrins with like pyrrole rings
opposite to each other, and an extension of this method-
ology to a “3 + 1” synthesis of porphyrins, utilizing a
tripyrrane and a 2,5-bis[(N,N-dimethylamino)methyl]-
pyrrole.
(19) A more lengthy route to opp-dibenzoporphyrins (from benzo-
dipyrromethenes) was recently reported: Bonnett, R; McManus, K.
A. J . Chem. Soc., Chem. Commun. 1994, 1129.
(20) Whitlock, H. W.; Hanauer, R. J . Org. Chem. 1968, 33, 2169.
Eisner, U.; Lichtarowicz, A.; Linstead, R. P. J . Chem. Soc. 1957, 733.
(21) Ono, M.; Lattmann, R.; Imomata, K.; Lehmann, C.; Fruh, T.;
Eschenmoser, A. Croat. Chem. Acta 1985, 58, 627; Schreiber, J .; Maag,
H.; Hashimoto, N.; Eschenmoser, A. Angew. Chem., Int. Ed. Engl. 1971,
10, 330.
(22) Barton, D. H. R.; Zard, S. Z. J . Chem. Soc., Chem. Commun.
1985, 1098.
(23) Inhoffen, H. H.; Fuhrhop, J .- H.; Voigt, H.; Brockmann, H., J r.
Liebigs Ann. Chem. 1966, 695, 133. Siedel, W.; Winkler, F. Ibid. 1943,
554, 162.
Resu lts a n d Discu ssion
P or p h yr in s w ith D2h Sym m etr y fr om On e-P ot
Rea ction s of Tw o Differ en t P yr r oles. One of our
proposed criteria for avoiding the pyrrole unit “scram-
bling” of an intermediate porphyrinogen is to carry out
the reaction under nonacidic conditions. But, tetramer-
ization reactions using pyrroles such as 3 require acid
(24) A single crystal X-ray structure of the bis-perchlorate salt of
porphyrin 9, which fully confirms the substituent regiochemistry, has
been published elsewhere: Senge, M. O.; Forsyth, T. P.; Nguyen, L.
T.; Smith, K. M. Angew. Chem., Int. Ed. Engl. 1994, 33, 2485.
(18) Part of this work has appeared as a preliminary communica-
tion: Nguyen, L. T.; Senge, M. O.; Smith, K. M. Tetrahedron Lett. 1994,
35, 7581.

1000 J . Org. Chem., Vol. 61, No. 3, 1996
Nguyen et al.
proton signal at 10.07 ppm which accounted for four
protons. Thus, even in the absence of a quaternization
agent, the [(dimethylamino)methyl]pyrrole 10 was suf-
ficiently reactive to suffer benzylic displacement by a
reasonably electron-rich monopyrrole. Similar results
were obtained using 10 and 3,4-butanopyrrole22 (15) to
afford porphyrin 16. Porphyrin 16 when treated with
DDQ in refluxing toluene afforded the dibenzoporphyrin
17 in which both of the cyclohexane rings in the precursor
were aromatized.19 This was evident, from 1H NMR
spectroscopy, by the disappearance of peaks at 2.54 and
4.16 ppm and the appearance of aromatic signals at 8.54
and 9.64 ppm. The structural composition of 17 was
further confirmed by HRMS.
F igu r e 1. View of the molecular structure of porphyrin 19.
Hydrogens have been omitted for clarity.
was obtained by X-ray crystallography; Figure 1 shows
the structure.
However, when 2,5-bis[(N,N-dimethylamino)methyl]-
pyrrole (10) was treated with 3,4-diphenylpyrrole25 (14)
under the same conditions, only decomposition products
and a trace amount of porphyrin mixture were observed.
Presumably pyrrole 14 is not as electron-rich as dialkyl-
pyrroles 11, 13, or 15, or possibly, steric effects due to
the bulky phenyl substituents on 14 inhibited its reaction
with pyrrole 10. We therefore proceeded to switch the
functional groups on the starting pyrroles so that the
bridging carbon units were built into the less reactive
3,4-diphenylpyrrrole (14); treatment with excess Echen-
moser’s reagent gave 12. Although the subsequent
macrocyclization reaction with 13 took place, it required
a longer time to complete and a mixture of porphyrins
was obtained [1H NMR (300 MHz, in CDCl3), meso proton
signals at 10.13, 10.17, and 10.21 ppm].
P or p h yr in s w it h C2v Sym m et r y fr om a “3 + 1”
Ap p r oa ch . After the above methodology was success-
fully developed and tested, we further expanded it to
synthesize porphyrins with less symmetry. This ap-
proach is much more versatile than that described above
since it provides access to porphyrin with three different
pyrrole subunits in a predestined array. Boudif and
Momenteau have recently published7 a similar “3 + 1”
approach to porphyrin synthesis involving a tripyrrane
and a 2,5-diformylpyrrole. Our tripyrranes 20-24 were
synthesized (Scheme 2) in 59-84% yields by condensa-
tion of 2,5-diunsubstituted pyrroles (11, 13-15) and
(acetoxymethyl)pyrroles 25 and 2626 in methanol with a
catalytic amount of TsOH.
It seemed clear that the reactivity of the leaving groups
in 12 needed to be enhanced, and so we fell back upon
our original synthetic design involving quaternization of
the (dialkylamino)methyl function. Pyrrole 12 was readily
bis-quaternized by use of excess iodomethane in benzene.
The quaternized pyrrole 18 (not characterized) reacted
smoothly with pyrrole 13 to afford pure porphyrin 19 in
18% yield. Spectrophotometry showed the onset of
porphyrin formation after about 5 min, and the proton
NMR spectrum of the product showed it was the desired
porphyrin as indicated by the observation of only one
meso proton signal at 10.21 ppm (4 H). Unambiguous
proof of the substituent regiochemistry of porphyrin 19
Catalytic debenzylation of the tripyrrane esters 20-
24 afforded the tripyrrane dicarboxylic acids 27-31 in
quantitative yields. These were then dissolved in metha-
nol and heated at reflux for 15 min before 2,5-bis[(N,N-
dimethylamino)methyl]pyrrole (10) or the quaternized
(26) Smith, K. M. In Porphyrins and Metalloporphyrins; Smith, K.
M., Ed.; Elsevier: Amsterdam, 1975; p 763.
(25) Friedman, M. J . Org. Chem. 1965, 30, 859.

Syntheses of Porphyrins
Sch em e 2
J . Org. Chem., Vol. 61, No. 3, 1996 1001
F igu r e 2. View of the molecular structure of porphyrin 35.
Hydrogens have been omitted for clarity.
be obtained; under such circumstances, quaternization
of the bis[(dimethylamino)methyl]pyrrole with methyl
iodide, to give e.g. 18, increases the reaction rate and can
provide isomerically pure porphyrin product. The method
was elevated to the next level of complexity by employing
a “3 + 1” approach, in which a tripyrrane is reacted with
a 2,5-bis[(N,N-dimethylamino)methyl]pyrrole in metha-
nol containing K3Fe(CN)6. Porphyrins 32-36, each
containing three different pyrrole subunits, were syn-
thesized in this manner. This methodology enables the
synthesis a number of porphyrins which might otherwise
require laborious routes such as dipyrromethane con-
densation or b-bilene/a,c-biladiene cyclization. Finally,
the bis-butanoporphyrin 16 was transformed into the
corresponding opp-bis-benzoporphyrin 17 by treatment
with DDQ.
Exp er im en ta l Section
pyrrole 18 and K3Fe(CN)6 were added. The desired
porphyrins 32-36 were isolated in 16-31% yields (un-
optimized) after simple chromatographic separation to
remove trace amounts of other isomers and recrystalli-
zation. Because of symmetry, the proton NMR spectra
of all these porphyrins showed two meso proton signals
of approximately equal intensity. X-ray crystallography
(Figure 2) was used to definitively identify the substitu-
ent array in porphyrin 35, concomitantly validating the
new methodology.
General experimental techniques and analytical measure-
ments were applied as previously described.6 Eschenmoser’s
reagent (N,N-dimethylmethyleneammonium iodide) was pur-
chased from Aldrich and used as received.
2,5-Bis[(N,N-d im et h yla m in o)m et h yl]-3,4-d iet h ylp yr -
r ole (10). 3,4-Diethylpyrrole22 (13) (2.22 g, 18.02 mmol) and
Eschenmoser’s reagent21 (4.48 g, 46.90 mmol) were dissolved
in 200 mL of dry MeNO2 and stirred at rt under N2 for 12 h
before the solvent was removed. The residue was redissolved
in CH2Cl2 and washed with saturated Na2CO3 (3×) and dried
over anhydrous Na2SO4, and the solvent was evaporated to
afford a crude dark brown solid (3.67 g, 86%), pure enough
(NMR) for subsequent reactions without further purification:
1H-NMR (CDCl3) δ 1.08 (t, J ) 7.5 Hz, 6 H), 2.19 (s, 12 H),
2.39 (q, J ) 7.5 Hz, 4 H), 3.32 (s, 4 H), 8.13 (br s, 1 H).
2,5-Bis[(N,N-d im eth yla m in o)m eth yl]-3,4-d ip h en ylp yr -
r ole (12). 3,4-Diphenylpyrrole25 (14) (2.60 g, 11.90 mmol) and
Eschenmoser’s reagent (6.61 g, 35.62 mmol) were dissolved
in 250 mL of dry MeNO2 and stirred at rt under N2 for 12 h.
Another 1.52 g of the Eschenmoser’s reagent was added and
the reaction was heated at reflux for 15 min before the solvent
was evaporated. Workup as described above to give the crude
title compound (3.97 g, 83%): 1H-NMR (CDCl3) δ 2.22 (s, 12
H), 3.46 (s, 4 H), 7.19 (m, 10 H), 8.92 (br s, 1 H).
Con clu sion
A new synthetic method has been developed which
allows the synthesis of regiochemically pure porphyrins
(such as 9, 16, and 19), in reasonable overall yield, by a
simple one-pot monopyrrole tetramerization involving
two different pyrroles; the methodology employs 2,5-bis-
[(N,N-dimethylamino)methyl]pyrroles (e.g. 10), which are
usually sufficiently electrophilic under neutral conditions
to undergo rapid reaction with 2,5-unsubstituted pyrroles
to provide a single pure porphyrinic product by way of a
porphyrinogen intermediate; addition of K3Fe(CN)6 aids
by rapidly oxidizing the porphyrinogen in methanolic
solution. When such macrocyclization reactions are
demonstrated to be slow, mixtures of porphyrins tend to
2,3,12,13-Tetr aeth yl-7,8,17,18-tetr am eth ylpor ph yr in (9).
Pyrrole 10 (0.84 g, 3.55 mmol) and 3,4-dimethylpyrrole22 (11)
(0.34 g, 3.56 mmol) were added to a solution of K3Fe(CN)6 (3.80
g, 11.54 mmol) in MeOH (75 mL). The mixture was heated

1002 J . Org. Chem., Vol. 61, No. 3, 1996
Nguyen et al.
under reflux for 4 h before the solvent was removed. The
residue was dissolved in CH2Cl2 and washed with H2O, 5%
ammonium hydroxide (2×), H2O, and brine, and then dried
over anhydrous Na2SO4. The solvent was evaporated, and the
crude product was chromatographed on silica gel eluting with
10% petroleum ether/CH2Cl2. Recrystallization from CH2Cl2/
cyclohexane afforded the title compound in 19.5% yield (162
mg): mp > 300 °C; vis λmax (CH2Cl2) 397 nm (ꢀ 150000), 498
Hz, 4 H), 2.20 (s, 6 H), 3.52 (s, 6 H), 3.82 (s, 4 H), 4.55 (br s,
4 H), 7.08-7.29 (m, 20 H), 9.51 (br s, 1 H), 11.15 (br s, 2 H).
Anal. Calcd for C52H51N3O8: C, 73.83; H, 6.08; N, 4.97.
Found: C, 73.90; H, 6.09; N, 5.05%.
2,5-Bis[[5-(ben zyloxyca r bon yl)-3-[2-(m eth oxyca r bon -
yl)et h yl]-4-m et h ylp yr r ol-2-yl]m et h yl]-3,4-d im et h ylp yr -
r ole (22). Obtained as a light yellow solid in 59% yield: mp
145-146 °C; 1H-NMR (CDCl3) δ 2.02, 2.24 (each s, 6 H), 2.32,
2.66 (each t, J ) 7.8 Hz, 4 H), 3.58 (s, 4 H), 3.62 (s, 6 H), 4.39
(br s, 4 H), 7.02 (m, 4 H), 7.26 (m, 6 H), 8.83 (br s, 1 H), 10.97
(br s, 2 H). Anal. Calcd for C42H47N3O8: C, 69.88; H, 6.56; N,
5.82. Found: C, 69.75; H, 6.56; N, 5.85%.
1
(13100), 530 (9700), 566 (6400), 618 (4900); H-NMR (CDCl3)
δ -3.79 (br s, 2 H), 1.91 (t, J ) 7.5 Hz, 12 H), 3.61 (s, 12 H),
4.10 (q, J ) 7.5 Hz, 8 H), 10.07 (s, 4 H). Anal. Calcd for
C32H38N4: C, 80.29; H, 8.00; N, 11.70. Found: C, 80.19; H,
7.98; N, 11.65%.
2,5-Bis[[5-(ben zyloxyca r bon yl)-3-[2-(m eth oxyca r bon -
yl)e t h yl]-4-m e t h ylp yr r ol-2-yl]m e t h yl]-3,4-b u t a n op yr -
r ole (23). Obtained as a white powder in 66% yield: mp 149-
7,8:17,18-Dibu ta n o-2,3,12,13-tetr a eth ylp or p h yr in (16).
The title compound was prepared from the corresponding
pyrrole 10 (0.50 g, 2.10 mmol) and 3:4-butanopyrrole22 (15)
(0.25 g, 2.06 mmol) as described above, in a yield of 12% (62
mg): mp > 300 °C; vis λmax (CH2Cl2) 398 nm (ꢀ 147000), 498
(12000), 532 (10000), 566 (6100), 618 (4800); 1H-NMR (CDCl3)
δ -3.78 (br s, 2 H), 1.91 (t, J ) 7.5 Hz, 12 H), 2.54 (s, 8 H),
4.08 (q, J ) 7.5 Hz, 8 H), 4.16 (s, 8 H), 10.00 (s, 4 H). Anal.
Calcd for C36H42N4: C, 81.47; H, 7.98; N, 10.56. Found: C,
81.07; H, 7.80; N, 10.48%.
1
151 °C; H-NMR (CDCl3) δ 1.73 (s, 4 H), 2.23 (s, 6 H), 2.33,
2.67 (each t, J ) 7.8 Hz, 4 H), 2.52 (s, 4 H), 3.53 (s, 4 H), 3.61
(s, 6 H), 4.46 (br s, 4 H), 7.03 (m, 4 H), 7.26 (m, 6 H), 8.78 (br
s, 1 H), 10.80 (br s, 2 H). Anal. Calcd for C44H49N3O8: C,
70.66; H, 6.60; N, 5.62. Found: C, 70.98; H, 6.66; N, 5.65%.
2,5-Bis[[5-(ben zyloxyca r bon yl)-3-eth yl-4-m eth ylp yr r ol-
2-yl]m eth yl]-3,4-bu ta n op yr r ole (24). Obtained as a light
pink powder in 77% yield: mp 204.5-206 °C; 1H-NMR (CDCl3)
δ 0.99 (t, J ) 7.5 Hz, 6 H), 1.73 (s, 4 H), 2.25 (s, 6 H), 2.36 (q,
J ) 7.5 Hz, 6 H), 2.52 (s, 4 H), 3.48 (s, 4 H), 4.39 (br s, 4 H),
7.02 (m, 4 H), 7.24 (m, 6 H), 8.80 (br s, 1 H), 11.04 (br s, 2 H).
Anal. Calcd for C40H45N3O4: C, 76.04; H, 7.18; N, 6.65.
Found: C, 75.76; H, 6.82; N, 6.62%.
7,8:17,18-Dib en zo-2,3,12,13-t et r a et h ylp or p h yr in (17).
Porphyrin 16 (0.10 g. 0.19 mmol) and DDQ (0.22 g, 0.95 mmol)
were dissolved in toluene (50 mL). The mixture was heated
at reflux for 12 h before the solvent was evaporated. The dark
residue was chromatographed on silica gel eluting with CH2-
Cl2. Recrystallization from CH2Cl2/cyclohexane afforded the
title compound as a dull purple crystalline solid (75 mg,
75%): mp > 300 °C; vis λmax (CH2Cl2) 387 nm (ꢀ 74500), 406
(188000), 480 (5000), 514 (10000), 546 (38900), 584 (6800), 642
7,8-Diet h yl-3,12-b is[2-(m et h oxyca r b on yl)et h yl]-2,13-
d im eth yl-17,18-d ip h en ylp or p h yr in (32). Tripyrrane 20
(0.33 g, 0.45 mmol) was dissolved in THF (80 mL), and 10%
Pd-C (0.07 g) and a drop of NEt3 were added. The resulting
mixture was stirred under H2 at rt for 10 h. The catalyst was
removed, and the solvent was evaporated to dryness. Recrys-
tallization from CH2Cl2/n-hexane afforded tripyrrane dicar-
boxylic acid 27 as a white powder in quantitative yield; because
of spontaneous decarboxylation at room temperature, this was
used immediately in the following way. Tripyrrane diacid 27
(0.26 g, 0.45 mmol) was dissolved in MeOH (100 mL) and
heated at reflux for 15 min before pyrrole 18 (0.28 g, 0.45
mmol) and K3Fe(CN)6 (0.96 g, 2.93 mmol) were added. The
resulting mixture was heated at reflux for another 6 h. The
MeOH was removed and the residue was redissolved in CH2-
Cl2. Some insoluble material was filtered off and the filtrate
was washed with H2O, 5% ammonium hydroxide (2×), H2O,
and brine and dried over anhydrous Na2SO4. The solvent was
evaporated, and the crude mixture was chromatographed on
silica gel eluting with CH2Cl2. Recrystallization from CH2-
Cl2/cyclohexane afforded the title compound as a purple
crystalline solid (52 mg, 16%): mp 195-196 °C; vis λmax (CH2-
Cl2) 404 nm (ꢀ 196000), 502 (14400), 538 (14300), 568 (8500),
1
(25300); H-NMR (CDCl3 + TFA) δ -2.65 (br s, 2 H), 1.81 (t,
J ) 7.5 Hz, 12 H), 4.17 (q, J ) 7.5 Hz, 8 H), 8.50 (m, 4 H),
9.60 (m, 4 H), 10.91 (s, 4 H); HRMS calcd for C36H34N4
522.2783, found 522.2780.
2,3,12,13-Tet r a et h yl-7,8,17,18-t et r a p h en ylp or p h yr in
(19). Pyrrole 12 (0.26 g, 0.78 mmol) was dissolved in benzene
(25 mL), and MeI (3 mL) was added dropwise. The mixture
was stirred at rt for 10 min before it was stored at 0 °C for
several h. The product was collected by filtration and washed
with cold benzene to afford pyrrole 18, as a yellow-brown
powder, in quantitative yield. Pyrrole 18 (0.48 g, 0.78 mmol)
and 3,4-diethylpyrrole (13) (0.10 g, 0.80 mmol) were im-
mediately reacted in the same manner as described above for
porphyrin 9 to provide the title compound in 18% yield (45
mg): mp > 300 °C; vis λmax (CH2Cl2) 410 nm (ꢀ 211000), 508
(11000), 548 (23000), 568 (14000), 624 (6500); 1H-NMR (CDCl3)
δ -3.65 (br s, 2 H), 1.86 (t, J ) 7.5 Hz, 12 H), 4.05 (q, J ) 7.5
Hz, 8 H), 7.70 (m, 12 H), 8.04 (m, 8 H), 10.21 (s, 4 H). Anal.
Calcd for C52H46N4: C, 85.92; H, 6.38; N, 7.71. Found: C,
85.61; H, 6.30; N, 7.56%.
1
622 (3100); H-NMR (CDCl3) δ -3.59 (br s, 2 H), 1.96 (t, J )
2,5-Bis[(5-(ben zyloxyca r bon yl)-3-[2-(m eth oxyca r bon -
yl)e t h yl]-4-m e t h ylp yr r ol-2-yl]m e t h yl]-3,4-d ie t h ylp yr -
r ole (20). 3,4-Diethylpyrrole22 (13) (0.37 g, 3.00 mmol) and
benzyl 5-(acetoxymethyl)-4-[2-(methoxycarbonyl)ethyl]-3-meth-
ylpyrrole-2-carboxylate25 (25) (2.02 g, 5.41 mmol) were dis-
solved in MeOH (35 mL) and TsOH (0.10 g) was added. The
mixture was heated at 60 °C under N2 for 12 h before the
volume was reduced to about 20 mL. The resulting suspension
was stored at 0 °C for several hours, and the solid was filtered
and washed with cold MeOH to afford an off-white powder
7.5 Hz, 6 H), 3.30, 4.46 (each t, J ) 7.8 Hz, 4 H), 3.57, 3.68
(each s, 6 H), 4.10 (q, J ) 7.5 Hz, 4 H), 7.69 (m, 6 H), 8.03 (m,
4 H), 10.12 (s, 2 H), 10.17 (s, 2 H). Anal. Calcd for
C46H46N4O4: C, 76.85; H, 6.45; N, 7.79. Found: C, 76.59; H,
6.29; N, 7.86%.
P or p h yr in s 33-36 were prepared from the appropriate
tripyrranes dibenzyl esters and pyrrole 10 using the procedure
described for porphyrin 32:
17,18-Dieth yl-3,12-bis[2-(m eth oxyca r bon yl)eth yl]-2,13-
d im et h yl-7,8-d ip h en ylp or p h yr in (33). Obtained in 31%
yield: mp 238.5-240 °C; vis λmax (CH2Cl2) 404 nm (ꢀ 190000),
502 (13200), 538 (13300), 570 (8400), 624 (2900); 1H-NMR
(CDCl3) δ -3.65 (br s, 2 H), 1.93 (t, J ) 7.5 Hz, 6 H), 3.25,
4.33 (each t, J ) 7.8 Hz, 4 H), 3.64, 3.67 (each s, 6 H), 4.05 (q,
J ) 7.5 Hz, 4 H), 7.66-7.75 (m, 6 H), 8.08 (m, 4 H), 10.07 (s,
2 H), 10.16 (s, 2 H). Anal. Calcd for C46H46N4O4‚H2O: C,
74.98; H, 6.57; N, 7.60. Found: C, 75.12; H, 6.28; N, 7.65%.
17,18-Dieth yl-3,12-bis[2-(m eth oxycar bon yl)eth yl]-2,7,8,-
13-tetr a m eth ylp or p h yr in (34). Obtained in 17% yield: mp
170-172 °C; vis λmax (CH2Cl2) 400 nm (ꢀ 172000), 498 (12900),
532 (10100), 566 (7200), 620 (4200); 1H-NMR (CDCl3) δ -3.90
(br s, 2 H), 1.93 (t, J ) 7.5 Hz, 6 H), 3.27, 4.36 (each t, J ) 7.8
Hz, 4 H), 3.61, 3.71 (each s, total 18 H), 4.12 (q, J ) 7.5 Hz, 4
1
(1.72 g, 84%): mp 163-164 °C; H-NMR (CDCl3) δ 1.16 (t, J
) 7.5 Hz, 6 H), 2.24 (s, 6 H), 2.33, 2.65 (each t, J ) 7.8 Hz, 4
H), 2.50 (q, J ) 7.5 Hz, 4 H), 3.61 (s, 10 H), 4.46 (br s, 4 H),
7.01 (m, 4 H), 7.25 (m, 6 H), 8.72 (br s, 1 H), 10.86 (br s, 2 H).
Anal. Calcd for C44H51N3O8: C, 70.47; H, 6.85; N, 5.60.
Found: C, 70.43; H, 6.81; N, 5.51%.
Tr ip yr r a n es 21-24 were prepared from the appropriate
2,5-diunsubstituted pyrroles (11, 13, 14, 16) and 2-(acetoxy-
methyl)pyrroles (25, 26)26 using the procedure described for
tripyrrane 20:
2,5-Bis[[5-(ben zyloxyca r bon yl)-3-[2-(m eth oxyca r bon -
yl)et h yl]-4-m et h ylp yr r ol-2-yl]m et h yl]-3,4-d ip h en ylp yr -
r ole (21). Obtained as an off-white powder in 79% yield: mp
153-155 °C; 1H-NMR (CDCl3) δ 2.11, 2.34 (each t, J ) 7.8

Syntheses of Porphyrins
J . Org. Chem., Vol. 61, No. 3, 1996 1003
H), 9.96 (s, 2 H), 10.06 (s, 2 H). Anal. Calcd for C36H42N4O4:
C, 72.70; H, 7.12; N, 9.42. Found: C, 72.56; H, 7.19; N, 9.54%.
7,8-Bu t a n o-17,18-d iet h yl-3,12-b is[2-(m et h oxyca r b on -
yl)eth yl]-2,13-d im eth ylp or p h yr in (35). Obtained in 25%
yield: mp 221-222.5 °C; vis λmax (CH2Cl2) 399 nm (ꢀ 172000),
498 (13500), 534 (10900), 566 (6800), 620 (4500); 1H-NMR
(CDCl3) δ -3.84 (br s, 2 H), 1.94 (t, J ) 7.5 Hz, 6 H), 2.57 (s,
4 H), 3.28, 4.36 (each t, J ) 7.8 Hz, 4 H), 3.62, 3.73 (each s, 6
H), 4.16 (m, 8 H), 9.93 (s, 2 H), 10.09 (s, 2 H). Anal. Calcd
for C38H44N4O4: C, 73.52; H, 7.14; N, 9.02. Found: C, 73.17;
H, 7.21; N, 9.14%.
Å, c ) 17.500(5) Å, â ) 108.43(2)°, V ) 4374(2) Å3, Z ) 4, R )
0.0695, wR ) 0.088, S ) 1.68 for 4320 reflections with F >
4.0σ(F) and 541 parameters. 35: Crystals were grown from
CH2Cl2/MeOH. Crystal data for C38H44N4O4‚2CH2Cl2 at 126
K (Cu KR radiation, λ ) 1.54178 Å, 2θmax ) 112°), triclinic,
space group P-1, a ) 7.802(4) Å, b ) 15.463(9) Å, c ) 15.975-
(10) Å, R ) 90.91(2)°, â ) 93.00(2)°, γ ) 96.42(2)°, V ) 1912(2)
Å3, Z ) 2, R ) 0.082, wR ) 0.098, S ) 1.79 for 3240 reflections
with F > 4.0σ(F) and 478 parameters.
Ack n ow led gm en t. This work was supported by
grants from the National Science Foundation (CHE-93-
05577), the National Institutes of Health (HL 22252),
and the Deutsche Forschungsgemeinschaft (M.O.S., Se
543/2-1). Mass spectrometric analyses were performed
by the UCSF Mass Spectrometry Facility (A. L. Burl-
ingame, Director) supported by the Biomedical Research
Technology Program of the National Center for Re-
search Resources, NIH NCRR BRTP 01614.
7,8-Bu ta n o-3,12,17,18-tetr a eth yl-2,13-d im eth ylp or p h y-
r in (36). Obtained in 27% yield: mp > 300 °C; vis λmax (CH2-
Cl2) 398 nm (ꢀ 141000), 498 (14500), 530 (10500), 566 (6500),
1
618 (4900); H-NMR (CDCl3) δ -3.75 (br s, 2 H), 1.90 (m, 12
H), 2.55 (s, 4 H), 3.66 (s, 6 H), 4.12 (m, 12 H), 9.99 (s, 2 H),
10.12 (s, 2 H). Anal. Calcd for C34H40N4: C, 80.91; H, 7.99;
N, 11.10. Found: C, 80.79; H, 7.82; N, 11.11%.
Cr ysta l Str u ctu r e Deter m in a tion s27 (19). Crystals were
grown from CHCl3/MeOH. Crystal data for C52H46N4‚CHCl3
at 130 K (Cu KR radiation, λ ) 1.54178 Å, 2θmax ) 115°),
monoclinic, space group P21/c, a ) 13.793(4) Å, b ) 19.101(7)
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra
(300 MHz, CDCl3) of compounds 10, 12, and 17 (3 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
(27) The authors have deposited atomic coordinates and a full
structure description for 19 and 35 with the Cambridge Crystal-
lographic Data Centre. The structures can be obtained, upon request,
from the Director, Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge, CB2 1EZ, UK.
J O951870F