Concerning the Synthesis of 3,7,13,17-Tetramethyl-5,15-diphenylporphyrin, a Sterically Hindered Porphyrin

Article abstract of DOI:10.1021/jo971807l

The synthesis of the sterically hindered porphyrin 1 (3,7,13,17-tetramethyl-5,15-diphenylporphyrin) could only be achieved by first preparing a 5,15-meso substituted octaalkylporphyrin. Thus, the synthesis of a 2,8,12,18-tetrakis(2-hydroxyethyl)-3,7,13,17-tetramethyl-5,15-diphenylporphyrin (12) had to precede the synthesis of 1. The 2-hydroxyethyl side chains were then converted into vinyl residues via the corresponding 2-chloroethyl intermediates. The four vinyl residues (at C2, C8, C12, C18) were cleaved using a resorcinol melt, and the tetra β-unsubstituted porphyrin 1 was then obtained. Porphyrin 1 could not be prepared by direct condensation of benzaldehyde with 3-methylpyrrole nor with a meso-phenyl β-unsubstituted dipyrrylmethane.

Full text of DOI:10.1021/jo971807l

J . Org. Chem. 1998, 63, 1239-1243
1239
Con cer n in g th e Syn th esis of
3,7,13,17-Tetr a m eth yl-5,15-d ip h en ylp or p h yr in , a Ster ica lly
Hin d er ed P or p h yr in
Aldonia Valasinas,† J orge Hurst,‡ and Benjamin Frydman*,†
S’LIL Pharmaceuticals, LLC, 535 Science Drive, Suite C, Madison, Wisconsin 53711-1066, and
Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, Buenos Aires, Argentina
Received September 30, 1997
The synthesis of the sterically hindered porphyrin 1 (3,7,13,17-tetramethyl-5,15-diphenylporphyrin)
could only be achieved by first preparing a 5,15-meso substituted octaalkylporphyrin. Thus, the
synthesis of a 2,8,12,18-tetrakis(2-hydroxyethyl)-3,7,13,17-tetramethyl-5,15-diphenylporphyrin (12)
had to precede the synthesis of 1. The 2-hydroxyethyl side chains were then converted into vinyl
residues via the corresponding 2-chloroethyl intermediates. The four vinyl residues (at C2, C8,
C12, C18) were cleaved using a resorcinol melt, and the tetra â-unsubstituted porphyrin 1 was
then obtained. Porphyrin 1 could not be prepared by direct condensation of benzaldehyde with
3-methylpyrrole nor with a meso-phenyl â-unsubstituted dipyrrylmethane.
Sch em e 1
Free-base porphyrins have two inner hydrogens that
can migrate between four central nitrogens, giving rise
to two possible tautomers and therefore to a hydrogen-
migration process that has been extensively studied by
means of solution1-3 and solid state4-8 NMR. Since this
reaction can also be activated by photochemical means,9
N-H tautomerism has been proposed as a possible
mechanism for performing data storage in the frequency
domain by means of photochemical hole burning.10,11
1
Solution H NMR studies revealed that the free energies
involved in the N-H tautomerism of porphyrins are
affected by the presence of substituents in the â-positions
of the pyrrole rings.12,13 Similar effects on the hydrogen
migration process were observed when electron-donor or
electron-acceptor groups were employed. The observed
changes were assumed to reflect the effects that are
introduced by bulky substituents in the geometry of the
macrocycle; a fact that if further confirmed could help to
explain (and therefore to control) the N-H tautomeriza-
tion process. It was known that meso-substituents
introduce steric hindrances in the porphyrin ring by
interaction with the â-substituents,14,15 which are relieved
by forcing a distortion of the planar macrocycle.16-21 It
can therefore be expected that steric crowding will affect
the central cavity of the porphyrin ring. The cavity is
usually a square with side lengths of 2.89 Å. Steric
crowding will result in the formation of a rectangle where
the shorter N21-N22 and N23-N24 axes (Scheme 1) will
favor the dynamics of hydrogen migration along these
axes. To probe into the latter, the sterically crowded
porphyrin should also carry free â-pyrrole hydrogens to
help in the analysis of the N-H tautomerism process.1-8
Porphyrin 1 (Scheme 1) seems to fulfill the above-
mentioned requisites. The interaction between the meso-
phenyl residues and the methyl groups at the 3, 7, 13,
and 17 positions will shorten the distance between N21
* Corresponding author. Phone: 608-231-3854. Fax: 608-231-3892.
E-mail: bjf@mail.slil.wisc.edu.
† S’LIL Pharmaceuticals.
‡ Universidad de Buenos Aires.
(1) Storm, C. B.; Teklu, Y. J . Am. Chem. Soc. 1972, 94, 1745.
(2) Eaton, S. S.; Eaton, G. R. J . Am. Chem. Soc. 1977, 99, 3637.
(3) Hennig, J .; Limbach, H. H. J . Am. Chem. Soc. 1984, 106, 292.
(4) Limbach, H. H.; Hennig, J .; Kendrick, R.; Yannoni, C. S. J . Am.
Chem. Soc. 1984, 106, 4059.
(5) Frydman, L.; Olivieri, A. C.; Diaz, L. E.; Frydman, B.; Morin, F.
G.; Mayne, C. L.; Graut, D. M.; Adler, A. D. J . Am. Chem. Soc. 1988,
110, 336.
(6) Frydman, L.; Olivieri, A. C.; Diaz, L. E.; Valasinas, A. L.;
Frydman, B. J . Am. Chem. Soc. 1988, 110, 5856.
(7) Frydman, L.; Olivieri, A. C.; Diaz, L. E.; Frydman, B.; Kustanov-
ich, I.; Vega, S. J . Am. Chem. Soc. 1989, 111, 7001.
(8) Frydman, L.; Rossomando, P. C.; Sambrotta, L.; Frydman, B. J .
Phys. Chem. 1992, 96, 4753.
(14) Woodward, R. B. Angew. Chem. 1960, 72, 651.
(15) Buchler, J . W.; Puppe, L. Liebigs Ann. Chem. 1970, 740, 142.
(16) Lay, K. L.; Buchler, J . W.; Kenny, J . E.; Scheit, W. R. Inorg.
Chim. Acta 1986, 123, 91.
(9) Volker, S.; van der Waals, J . H. Mol. Phys. 1976, 32, 1703.
(10) Rebane, L.; Gorokhouskii, A. A.; Kikas, J . V. Appl. Phys. B.
1982, 29, 235.
(11) Romagnoli, M.; Moerner, W. E.; Schellenberg, F. M.; Levenson,
M. D.; Bjorklund, G. C. J . Opt. Soc. Am. B. 1984, 341, 1.
(12) Crossley, M. J .; Field, L. D.; Harding, M. M.; Sternhell, S. J . J .
Am. Chem. Soc. 1987, 109, 2335.
(17) Smith, K. M.; Bobe, F. W.; Minnetian, O. M. Tetrahedron 1984,
40, 3263.
(18) Abraham, R. J .; J ackson, A. H.; Kenner, G. W.; Warburton, D.
J . Chem. Soc. 1963, 853.
(19) Dolphin, D. J . Heterocycl. Chem. 1970, 7, 275.
(20) Maruyama, K.; Nagata, T.; Osuka, A. J . Phys. Org. Chem. 1988,
1, 61.
(13) Crossley, M. J .; Harding, M. M.; Sternhell, S. J . Org. Chem.
1988, 53, 1132.
(21) Senge, M. O.; Forsyth, T. P.; Nguyen, L. T.; Smith, K. M. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2485.
S0022-3263(97)01807-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/22/1998

1240 J . Org. Chem., Vol. 63, No. 4, 1998
Valasinas et al.
Sch em e 2
and N22 and between N23 and N24 (as is the case of
porphycene and its alkyl derivatives22,23) while H2, H8,
H12, and H18 will be available to study the tautomerism
rates among the central protons. Surprisingly, the
synthesis of 1 posed major challenges which were solved
as reported below. Bringing 3-methyl pyrrole 3 into
reaction with benzaldehyde by means of known proce-
dures24-27 led to mixtures of porphyrins that showed (by
1H NMR analysis) different patterns of meso-substitu-
tion.
Although the synthesis of porphyrin 2 has been re-
ported28 as arising from the reaction of 3 with benzalde-
hyde (Scheme 1), we could not duplicate the procedure.29
To carry out the synthesis of 1 under more restricted
conditions we prepared the hitherto unknown meso-
phenyl dipyrrylmethane 8. Reaction of 4 with benzal-
dehyde gave dipyrrylmethane 5. It was saponified to 6,
the latter was decarboxylated by treatment with iodine
in basic medium, and the resulting tetraiodide 7 was
dehalogenated to 8 by hydrogenolysis in the presence of
sodium acetate. Reaction of 8 with benzaldehyde follow-
ing established procedures24-27 gave a mixture of por-
phyrins with random meso-substitutions. It was there-
fore concluded that 1 can only be obtained if the free
â-pyrrole positions in the reacting dipyrrylmethanes are
“protected” by substituents that could be removed after
the porphyrin ring was formed. The most simple choice
appeared to be the use of â-vinyl residues which can be
removed from a porphyrin by established procedures.30,31
Scheme 2 outlines the synthetic approach used. By
condensation of the meso-substituted dipyrrylmethanes
9 and 10 using procedures established for meso-unsub-
stituted porphyrins,32 followed by a reacetylation step of
the partially deacetylated reaction product, it was pos-
sible to obtain porphyrin 11 in fair yields. Removal of
the acetate ester groups by transesterification with 5%
sulfuric acid in methanol gave 12. Treatment of the tetra
â-hydroxyethyl porphyrin 12 with mesyl chloride in
dimethylformamide gave the tetra â-chloroethyl porphy-
rin 13, which was transformed into the tetravinyl por-
phyrin 14 by dehalogenation with potassium hydroxide
in pyridine. Cleavage of the vinyl residues using the
resorcinol melt of iron-porphyrin 14, followed by de-
metalation33 gave 1 as a pure and simple porphyrin.
nol and sodium acetate. The latter was converted into
the acid 17 by hydrogenolysis of the benzyl ester, the acid
17 was decarboxylated by treatment with iodine-iodide
in a sodium bicarbonate solution, and the resulting iodide
18 was reduced with hydrogen to the â-free pyrrole 19.
Condensation of 19 with benzaldehyde in acid medium
gave the meso-substituted dipyrrylmethane 20 as the sole
reaction product. Reduction of the acetate side chains
with diborane yielded 21, as was the case with analogous
pyrrylmethanes that were not substituted at the meso-
bridge.34,35 Saponification of the nuclear esters of 21 gave
the diacid 22, which could be decarboxylated with
simultaneous formylation to 23 when reacted with tri-
methyl orthoformate in trifluoroacetic acid. Both 22 and
23 were esterified to 9 and 10 (Scheme 2) using acetic
anhydride in pyridine.
The synthetic approach to 9 and 10 is outlined in
Scheme 3. The known trichloromethyl pyrrole 15 was
converted into the triester 16 by treatment with metha-
(22) Vogel, E.; Kocher, M.; Lex, J .; Ermer, O. Isr. J . Chem. 1989,
29, 257.
(23) Vogel, E.; Koch, P.; Hou, X.-L.; Lex, J .; Lausman, M.; Kisters,
M.; Aukauloo, M. A.; Richard, P.; Guillard, R. Angew. Chem., Int. Ed.
Engl. 1993, 32, 1600 and references therein.
(24) Adler, A.; Longo, F. R.; Shergallis, W. J . Am. Chem. Soc. 1964,
86, 3145.
(25) Adler, A.; Longo, F. R.; Finarelli, J . D.; Goldmacher, J .; Assour,
J .; Korsakoff, L. J . Org. Chem. 1967, 32, 476.
(26) Lindsey, J . S.; Schreiman, I. C.; Hsu, H. C.; Kearney, P. C.,
Marguerettaz, A. M. J . Org. Chem. 1987, 52, 827.
(27) Lindsey, J . S.; Wagner, R. W. J . Org. Chem. 1989, 54, 828.
(28) Treibs, A.; Ha¨berle, N. Liebigs Ann. Chem. 1968, 718, 183.
(29) A mixture of porphyrins with random substitution at the meso-
positions was obtained. It should be noted that the original report (ref
28) identified the reaction product only by elemental analysis, where
a mixture of isomers will be overlooked.
(30) Schumm, O. Hoppe-Seiler’s Z. Physiol. Chem. 1928, 178, 1.
(31) DiNello, R. K.; Dolphin, D. H. J . Org. Chem. 1981, 46, 3498.
(32) Valasinas, A.; Frydman, B. J . Org. Chem. 1976, 41, 2991.
(33) Fuhrhop, J . H.; Smith, K. M. In Porphyrins and Metallopor-
phyrins; Smith, K. M., Ed.; Elsevier Sci. Pub. Comp. 1975; pp 803,
822.
In conclusion, the synthesis of a 5,15-meso-substituted
porphyrin â-substituted only at C3, C7, C13, and C17
(34) Buldain, G.; Hurst, J .; Frydman, R. B.; Frydman, B. J . Org.
Chem. 1977, 42, 2953.
(35) Buldain, G.; Diaz, L. E.; Frydman, B. J . Org. Chem. 1977, 42,
2957.

Synthesis of a Sterically Hindered Porphyrin
J . Org. Chem., Vol. 63, No. 4, 1998 1241
Meth yl 3-Meth oxycar bon ylm eth yl-4-m eth yl-5-car boxy-
2-p yr r oleca r boxyla te (17). A solution of 13 g of pyrrole 16
in 300 mL of ethanol was reduced with hydrogen at 50 psi
over 2 g of 10% Pd on charcoal during 2 h. The catalyst was
filtered, the solvent was evaporated to dryness in vacuo, and
the resulting acid crystallized from ethanol-water: 8.7 g
(68%); mp >200 °C (dec). Anal. Calcd for C11H11NO6: C,
52.17; H, 4.35; N, 5.53. Found: C, 52.07; H, 4.39; N, 5.71.
Meth yl 3-Meth oxyca r bon ylm eth yl-4-m eth yl-5-iod o-2-
p yr r oleca r boxyla te (18). Carboxypyrrole 17 (10 g, 40 mmol)
was dissolved in a solution of 20 g (200 mmol) of NaHCO3 in
200 mL of water, the mixture was heated to 65 °C, and a
solution of 10 g (80 mmol) of iodine and 20 g of potassium
iodide in ethanol-water was slowly added with stirring. After
a further heating for 1 h, the suspension was filtered and
crystallized from ethanol-water; 11.6 g (97%) of 18 were
obtained: mp 127-128 °C; 1H NMR (CDCl3) δ 9.40 (s, 1H),
3.85 (s, 3H), 3.80 (s, 3H), 3.73 (s, 2H), 2.00 (s, 3H). Anal. Calcd
for C10H12NO4I: C, 35.60; H, 3.56; N, 4.15. Found: C, 35.49;
H, 3.60; N, 4.20.
Sch em e 3
Met h yl 3-(Met h oxyca r b on ylm et h yl)-4-m et h yl-2-p yr -
r oleca r boxyla te (19). Iodopyrrole 18 (10 g) dissolved in 200
mL of methanol was reduced with hydrogen over 1 g of 10%
Pd-C in the presence of 2.5 g of sodium acetate. After 2 h at
50 psi, the catalyst was filtered-off, the solution was evapo-
rated to dryness in vacuo, the residue was partitioned between
chloroform-water, and the chloroform layer was separated and
evaporated to dryness. The residue was crystallized from
benzene-hexane; 5.5 g (74%) of 19 was obtained; mp 81 °C;
1H NMR (CDCl3) δ 9.20 (s, 1H), 6.65 (d, 1H), 3.85 (s, 2H), 3.80
(s, 3H), 3.70 (s, 3H), 2.00 (s, 3H). Anal. Calcd for C10H13NO4:
C, 56.87; H, 6.16; N, 6.63. Found: C, 57.00; H, 6.27; N, 6.71.
Dim eth yl 2,8-Bis(m eth oxycar bon ylm eth yl)-3,7-dim eth -
yl-5-p h en yl-1,9-d ip yr r ylm eth a n ed ica r boxyla te (20). Ben-
zaldehyde (5.3 g, 50 mmol) was added to a solution of 4.2 g
(20 mmol) of 19 in 100 mL of chloroform, 0.7 g of p-
toluensulfonic acid was added, and the mixture was heated
under reflux for 2 h. The solution was then cooled, washed
with a NaCO3H solution and then with water, dried (Na2SO4),
and evaporated to dryness. The residue was purified by flash
chromatography on a silica gel column using chloroform as
an eluant followed by 3% methanol in chloroform to elute the
dipyrrylmethane. The latter was recovered from the eluates
by evaporation in vacuo and was crystallized from methanol-
could only be achieved by first preparing a â-octasubsti-
tuted porphyrin. The more direct approach, using meso-
substituted dipyrrylmethanes with â-free positions led
to a mixture of porphyrins. Porphyrin 1 was very
1
insoluble in the usual solvents, therefore the H NMR
spectrum of its dication was recorded. The spectrum
showed an upfield shift of the methyl groups flanking
the phenyl meso-substituents, as expected from the steric
repulsions among the substituents. Steric repulsions
between meso- and â-substituents cause distortions in
the planarity of the macrocycle, which result in a general
decrease in the ring current and a nonuniform perturba-
tion of the chemical shifts throughout the molecule.36,37
The dynamics of the tautomerism of the nitrogen bound
protons of 1 will be discussed elsewhere.
1
water: 8.1 g (80%); mp 137-138 °C; H NMR (CDCl3) δ 8.52
(b, 2H), 7.36 (m, 3H), 7.14 (m, 2H), 5.55 (s, 1H), 3.85 (s, 4H),
3.78 (s, 6H), 3.70 (s, 6H), 1.80 (s, 6H). Anal. Calcd for
Exp er im en ta l Section
C
27H30N2O8: C, 63.53; H, 5.88; N, 5.49. Found: C, 63.50; H,
5.92; N, 5.53.
Gen er a l. NMR spectra were obtained using a Bruker MSL
300 spectrometer. Reactions were monitored using TLC on
silica gel plates (0.25 mm thick, with the fluorescent dye F-254,
Merck Darmstadt). Flash chromatography was performed on
silica gel columns packed with TLC-Kieselgel (Merck or
Riedel de Hann). Pyrroles and dipyrrylmethanes were spotted
on TLC using a 2% p-dimethylaminobenzaldehyde solution in
6 N hydrochloric acid. Melting points were determined on a
Ko¨fler block.
Dim eth yl 2,8-Bis(2-h ydr oxyeth yl)-3,7-dim eth yl-5-ph en -
yl-1,9-d ip yr r ylm et h a n ed ica r b oxyla t e (21). Dipyrryl-
methane 20 (5 g) was dissolved in 250 mL of dry tetrahydro-
furan and a stream of diborane was slowly bubbled through
the solution using nitrogen gas as a carrier during 2 h. The
solution was kept in the closed vessel for a further 24 h at 25
°C, it was then cooled to 5 °C, excess methanol was added to
decompose the borates, and the mixture was evaporated to
dryness. The solid residue was partitioned between chloroform
and water, the organic layer was repeatedly washed with
water, dried (Na2SO4), and evaporated to dryness, and the
residue was purified by flash chromatography on silica gel
using chloroform as an eluant. The product recovered after
evaporation of the eluates was crystallized from methanol-
water; 3.0 g (66%) of 21 was obtained: mp 161-162 °C; 1H
NMR (CDCl3) δ 8.87 (b, 2H), 7.30 (m, 3H), 7.10 (m, 2H), 5.55
(d, 1H), 3.51 (s, 2H), 3.48 (s, 6H), 3.03 (t, 4H), 2.40 (b, 2H),
1.90 (s, 6H). Anal. Calcd for C25H30N2O6: C, 66.08; H, 6.61;
N, 6.17. Found: C, 66.19; H, 6.72; N, 6.25.
Ben zyl 3-Met h yl-4-m et h oxyca r b on ylm et h yl-5-m et h -
oxyca r bon yl-2-p yr r oleca r boxyla te (16). A mixture of the
trichloromethylpyrrole 1538 (20 g) and 10 g of anhydrous
sodium acetate was dissolved in 350 mL of dry methyl alcohol
and the solution was stirred at 50 °C for 72 h. It was then
poured over ice water, the precipitate was collected and
crystallized from methanol; 15 g (70%) of 16 was obtained; mp
1
90-91 °C; H NMR (CDCl3) δ 9.60 (b, 1H), 7.35 (s, 5H), 5.35
(s, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.70 (s, 2H), 2.30 (s, 3H).
Anal. Calcd for C18H19NO6: C, 62.60; H, 5.50; N, 4.05.
Found: C, 62.63; H, 5.59; N, 14.15
2,8-Bis(m eth oxyca r bon ylm eth yl)-3,7-d im eth yl-5-p h en -
yl-1,9-d ica r boxyd ip yr r ylm eth a n e (22). Dipyrrylmethane
21 (3 g) was dissolved in 20 mL of ethanol, 20 mL of a 10%
KOH solution in water was added, and the mixture was heated
to dryness with stirring at 110 °C in an open vessel. The
residue was dissolved in water, the solution adjusted to pH 5
with concentrated HCl, and the precipitate was filtered,
(36) Abraham, R. J .; J ackson, A. H.; Kenner, G. W.; Warburton, D.
J . Chem. Soc. 1963, 853.
(37) Burbidge, P. A.; Collier, G. L.; J ackson, A. H.; Kenner, G. W.
J . Chem. Soc. B. 1967, 930.
(38) Cox, M. T.; J ackson, A. H.; Kenner, G. W.; McCrombie, S. W.;
Smith, K. M. J . Chem. Soc., Perkin Trans. 1 1974, 517.

1242 J . Org. Chem., Vol. 63, No. 4, 1998
Valasinas et al.
1
washed with water and dried: 2.1 g (74%); H NMR (Py-d6-
D2O) δ 7.10 (s, 2H), 6.30 (m, 5H), 5.10 (d, 1H), 3.60 (s, 4H),
3.10 (t, 4H), 1.90 (s, 6H); EI-MS, m/z 426 (M+).
was then cooled and diluted with 50 mL of water, a drop of
triethylamine was added, and the solution was extracted with
methylene chloride (3 × 30 mL). The pooled extracts were
dried (Na2SO4) and evaporated to dryness, and the residue was
dissolved in chloroform and purified by flash chromatography
on silica gel using the same solvent as eluant; 48 mg (52%) of
porphyrin 13 was obtained: mp dec above 300 °C (chloroform-
heptane); 1H NMR (CDCl3-TFA) R 10.17 (s, 2H), 8.04 (d, 4H),
7.75 (m, 6H), 4.46 (t, 8H), 4.22 (t, 8H), 2.52 (s, 12H), -2.34 (b,
4H); FAB-MS (4-nitrobenzyl alcohol used as matrix) 769 (M+
+ 1). Anal. Calcd for C44H42Cl4N4: C, 68.75; H, 5.47, N, 7.29.
Found: C, 68.66; H, 5.52; N, 7.31.
2,8,12,18-Te t r a vin yl-3,7,13,17-t e t r a m e t h yl-5,15-d i-
p h en ylp or p h yr in (14). Tetrachloroethylporphyrin 13 (48
mg) was dissolved in 10 mL of dry pyridine heated under
reflux, 3 mL of a 3% aqueous KOH was added, and the mixture
was heated under reflux for 3 h. It was then evaporated to
dryness in vacuo, the residue was dissolved in chloroform, the
latter was washed with water, dried (Na2SO4), and evaporated
to dryness, and the residue was purified by flash chromatog-
raphy on silica gel using chloroform as eluant; 28 mg (72%) of
14 was obtained: mp dec above 300 °C (chloroform-heptane);
1H NMR (CDCl3-CF3CO2H) δ 10.11 (s, 2H) 8.34 (m, 4H), 7.87
(m, 6H), 7.70 (dd, J trans ) 17.6 Hz, J cis ) 12.9 Hz, 4H), 6.25 (d,
J cis ) 12.9 Hz, 4H), 5.82 (d, J trans ) 17.6 Hz), 2.28 (s, 12H),
-1.42 (b, 4H); EI-MS, m/z 623 (M+ + 1), 311 (M2+). Anal.
Calcd for C44H38N4: C, 84.89; H, 6.11; N, 9.00. Found: C,
84.86; N, 6.09; N, 8.96.
2,8-Bis(2-h yd r oxyeth yl)-3,7-d im eth yl-5-p h en yl-1,9-d i-
for m yld ip yr r ylm eth a n e (23). Dipyrrylmethane 22 (1.7 g,
4 mmol) was dissolved in 25 mL of trifluoroacetic acid, the
solution was cooled to 0-5 °C under a stream of nitrogen, and
trimethylorthoformate (4.2 g, 40 mmol) was added after 10
min. The mixture was kept for additional 15 min, ice water
was then added followed by concentrated ammonium hydrox-
ide to adjust to pH 7, the oily layer that separated was
dissolved in chloroform, and the latter was separated, washed
with NaHCO3 and then with water, dried (Na2SO4), and
evaporated to dryness in vacuo. The residue was purified by
flash chromatography on a silica gel column using 6% metha-
nol in chloroform as an eluant. Evaporation of the eluates left
behind an oily residue: 800 mg (51%); 1H NMR (CDCl3) δ 9.84
(b, 2H), 9.18 (s, 2H), 6.88 (b, 5H), 5.42 (d, 1H), 3.78 (s, 4H),
2.85 (t, 4H), 1.80 (s, 6H); EI-MS, m/z 396 (M+), 367 (M+
CHO), 338 (M+ - 58, 2CHO).
-
2,8-Bis(2-a cetoxyeth yl)-3,7-d im eth yl-5-p h en yl-1,19-d i-
for m yld ip yr r ylm eth a n e (10). Diformyldipyrrylmethane 23
(800 mg) was dissolved in 60 mL of dry pyridine, and acetic
anhydride (12 mL) was added at 25 °C. After 2 h the solvent
was evaporated to dryness in vacuo, and the residue was
purified by flash chromatography on silica gel using 3%
methanol in chloroform. The diacetate 10 was recovered from
the eluate as an oil that crystallized from chloroform-
1
heptane: 640 mg (66%); mp 140-141 °C; H NMR (CDCl3) δ
3,7,13,17-Tetr am eth yl-5,15-diph en ylpor ph yr in (1). Tet-
ravinylporphyrin 14 (62.2 mg, 0.1 mmol) was dissolved in 10
mL of boiling glacial acetic acid, and a saturated ferrous
acetate solution in acetic acid was then added (4 × 0.25 mL).
The mixture was heated under reflux under nitrogen for 5 min
and then cooled and diluted with 40 mL of chloroform. The
solution was washed with 25% HCl (2 × 10 mL) and then with
brine, dried (Na2SO4), and evaporated to dryness, and the
residue was purified by flash chromatography on silica gel
using 1% methanol-chloroform to elute nonreacted 14 followed
by 2% methanol-chloroform to elute the iron-porphyrin. The
latter was mixed with 190 mg of resorcinol, and the mixture
was heated at 180 °C for 30 min under oxygen-free nitrogen.
The fused mass was dissolved in 5 mL of boiling glacial acetic
acid, 0.5 mL of a saturated ferrous acetate solution of glacial
acetic acid was added, the reflux continued for further 5 min,
0.1 mL of concentrated HCl was then added, and the solution
was allowed to cool to 25 °C. Chloroform (20 mL) was added,
the mixture was washed with a 7% NaHCO3 solution and then
with water, dried (Na2SO4), and evaporated to dryness, and
the residue was purified by flash chromatography on silica gel
using 5% hexane in chloroform as eluant; 6.2 mg (27%) of 1
was obtained after crystallization from methylene chloride-
methanol: mp dec above 300 °C; 1H NMR (CDCl3-TFA) δ 10.37
(s, 2H), 8.90 (s, 4H), 8.26 (d, 4H), 7.95 (m, 6H), 2.45 (s, 12H),
-2.05 (b, 4H). EI-MS m/z 519 (M+ + 1), 518 (M+). Anal.
Calcd for C36H30N4: C, 83.40; H, 5.79; N, 9.00. Found: C,
83.37; H, 5.74; N, 8.97.
Dieth yl 3,7-Dim eth yl-5-p h en yl-1,9-d ip yr r ylm eth a n ed i-
ca r boxyla te (5). Ethyl 3-methyl-2-pyrrole carboxylate 4 (7.65
g, 50 mmol)39 was dissolved in 150 mL of dry ethanol,
benzaldehyde (4 g, 38 mmol) and p-toluensulfonic acid (160
mg, 0.9 mmol) were added, and the mixture was heated under
reflux during 2 h. The mixture was then poured over ice
water, the dipyrrylmethane was extracted into chloroform, the
latter was washed with water, dried (Na2SO4), evaporated to
dryness, and the residue crystallized from ethanol: 7.0 g (76%);
mp 104-106 °C; 1H NMR (CDCl3) δ 8.95 (b, 2H), 7.30 (m, 3H),
7.10 (m, 2H), 6.70 (b, 2H), 5.55 (b, 1H), 4.15 (q, 6H), 1.90 (s,
6H), 1.20 (t, 6H). Anal. Calcd for C23H26N2O4: C, 70.05; H,
6.60; N, 7.11. Found: C, 70.09; H, 6.58; N, 7.15.
9.75 (b, 2H), 9.55 (s, 2H), 7.35 (m, 3H), 7.05 (m, 2H), 5.55 (d,
1H), 4.10 (t, 4H), 2.90 (t, 4H), 1.95 (s, 6H), 1.83 (s, 6H). Anal.
Calcd for C27H30N2O6: C, 67.78; H, 6.27; N, 5.86. Found: C,
67.81; H, 6.30; N, 5.82.
2,8-Bis(2-a cetoxyeth yl)-3,7-d im eth yl-5-p h en yl-1,19-d i-
ca r boxyd ip yr r ylm eth a n e 9 was obtained from 22 (600 mg)
following the procedure described for the preparation of 10;
450 mg (62%) of 9 was obtained as an oil: 1H NMR (CDCl3) δ
10.85 (b, 2H), 9.85 (b, 2H) 7.25 (m, 3H), 7.00 (m, 2H), 5.50 (d,
1H), 4.10 (t, 4H), 2.95 (t, 4H), 1.95 (b, 6H), 1.85 (s, 6H); EI-
MS m/z 510 (M+), 420 (M+ - 2CO2H).
2,8,12,18-Tetr akis(2-acetoxyeth yl)-3,7,13,17-tetr am eth yl-
5,15-d ip h en ylp or p h yr in (11). A mixture of 300 mg (0.3
mmol) of 10 and 300 mg (0.31 mmol) of 9 was dissolved in 250
mL of dry methylene chloride and 25 mL of dry methanol, 700
mg (5 mmol) of p-toluensulfonic acid was added, and the
solution was kept in the dark for 72 h at 25 °C. The solution
was first washed with water (100 mL), with a 5% solution of
NaHCO3 (100 mL), and then with water again (100 mL), dried
(Na2SO4), and evaporated to dryness. The porphyrin residue
was redissolved in 12 mL of dry pyridine and 3 mL of acetic
anhydride, the mixture was kept for 2 h in the dark and then
evaporated to dryness, and the residue was purified by flash
chromatography on silica gel using 1% methanol in chloroform
as eluant. Pure porphyrin tetracetate (160 mg, 26%) was thus
1
obtained: mp 245-247 °C (methylene chloride-hexane); H
NMR (CDCl3) δ 10.38 (s, 2H) 8.06 (d, 4H), 7.77 (q, 6H), 4.80
(t, 8H), 4.40 (t, 8H), 2.54 (s, 12H), 2.04 (s, 12), -2.32 (b, 2H).
Anal. Calcd for C52H54N4O8: C, 72.39; H, 6.26; N, 6.49.
Found: C, 72.30; H, 6.23; N, 6.46.
2,8,12,18-Te t r a k is(2-h yd r oxye t h yl)-3,7,13,17-t e t r a -
m eth yl-5,15-d ip h en ylp or p h yr in (12). Tetracetoxyporphy-
rin 11 (120 mg) was dissolved in 20 mL of 5% sulfuric acid in
dry methanol, the mixture was kept during 24 h in the dark
at 25 °C and then diluted with water, and the porphyrin was
extracted into chloroform (100 mL plus 1 mL of triethylamine).
The latter was evaporated to dryness and left behind 87 mg
(90%) of porphyrin 12 which could not be purified further due
to its insolubility: 1H NMR (CDCl3-TFA) δ 10.43 (b, 2H), 8.22
7.87 (qd, 10H), 4.70 (t, 8H), 4.05 (t, 8H), 2.14 (s, 12H), -1.81
(b, 4H); EI-MS, m/z 695 (M+ + 1).
2,8,12,18-Tetr akis(2-ch lor oeth yl)-3,7,13,17-tetr am eth yl-
5,15-d ip h en ylp or p h yr in (13). Tetrahydroxyethylporphyrin
12 (87 mg, 0.125 mmol) was dissolved in 9 mL of dry
dimethylformamide, mesyl chloride (1.1 mL, 6.6 mmol) was
added, and the mixture was heated at 75 °C during 18 h. It
3,3′-D im e t h y l-5-p h e n y l-1,2,8,9-t e t r a io d o d ip y r r y l-
m eth a n e (7). Dipyrrylmethane 5 (7 g) was dissolved in 50
(39) Alonso Garrido, D. O.; Buldain, G.; Ojea, M. I.; Frydman, B. J .
Org. Chem. 1988, 53, 403.

Synthesis of a Sterically Hindered Porphyrin
J . Org. Chem., Vol. 63, No. 4, 1998 1243
mL of ethanol and 50 mL of 10% NaOH and heated in an open
vessel at 110 °C until dry. The residue was dissolved in water
and the diacid 6 was precipitated by adjusting the solution to
pH 3 with concentrated HCl. The precipitate was filtered,
dried, and dissolved in a solution of 10 g of NaHCO3 in 200
mL of water. The mixture was cooled to 5 °C and a solution
of 16 g of iodine in 150 mL of ethanol was added dropwise
with constant stirring. After the addition was completed, the
mixture was kept at 25 °C for 30 min, 200 mL of water was
then added, and the precipitate was filtered, dried, and
crystallized from ethanol-water: 11.8 g (76%); mp 98-99 °C;
1H NMR (CDCl3) δ 7.70 (b, 2H), 7.30 (m, 3H), 7.05 (m, 2H),
5.50 (s, 1H), 1.85 (s, 6H). Anal. Calcd for C17H14I4N2: C, 27.05;
H, 1.86; N, 3.71. Found: C, 27.10; H, 1.95; N, 3.76.
charcoal in the presence of 17 g of anhydrous sodium acetate.
After 2 h the catalyst was filtered-off, the solution was
evaporated to dryness in vacuo, the residue was partitioned
between chloroform and water, the chloroform layer was
evaporated to dryness, and the residual oil was purified by
flash chromatography on silica gel using dichloromethane as
eluant; 1.4 g (86%) of 8 was obtained as an oil: 1H NMR
(CDCl3) δ.50 (b, 2H), 7.30 (m, 3H), 7.05 (m, 2H), 6.55 (t, 2H),
6.05 (t, 2H), 5.50 (s, 1H), 1.90 (s, 3H). EI-MS m/z 250 (M+),
169 (M+ - 3-methylpyrrole), 81 (3-methylpyrrole).
Ack n ow led gm en t. The partial support of The Con-
sejo Nacional de Investigaciones Cientificas y Tecnicas
(Argentina) is gratefully acknowledged.
3,3′-Dim eth yl-5-p h en yld ip yr r ylm eth a n e (8). Tetraiodo-
dipyrrylmethane 7 (5.0 g) dissolved in 250 mL of methanol
was reduced with hydrogen at 40 psi over 2 g of 10% Pd-
J O971807L