Nearly chromatography-free synthesis of the A3B-porphyrin 5-(4-hydroxymethylphenyl)-10,15,20-tri-p-tolylporphinatozinc(II)

Article abstract of DOI:10.1021/op0502553

Rational routes to synthetic porphyrins bearing distinct meso-substituents have typically been implemented at modest scale (<1 g quantities). The A ₃B-porphyrin 5-(4-hydroxymethylphenyl)-10,15,20-tri-p- tolylporphinatozinc(II) (Zn-1) is required in multigram quantities for possible commercial use in information storage applications. The synthesis of Zn-1 has been carried out by reaction of 5-(4-hydroxymethylphenyl)dipyrromethane and the dicarbinol derived from 1,9-di-p-toluoyl-5-p-tolyldipyrromethane. Four improvements have been made to the steps leading to the dipyrromethane and dipyrromethane-dicarbinol: (i) use of 50 equiv of pyrrole in the condensation of an aldehyde to give the dipyrromethane (versus 100 equiv previously), (ii) 1,9-diacylation of a dipyrromethane using the hindered Grignard reagent 2,6-dimethylphenylmagnesium bromide and p-toluoyl chloride to give the 1,9-diacyl versus 1-acyl products in > 10:1 ratio (versus 4:1 using EtMgBr), (iii) isolation of the dibutyltin complex of the 1,9-diacyldipyrromethane from the crude reaction mixture by direct crystallization using methanol/methyl tert-butyl ether (MTBE) (versus silica chromatography), and (iv) reduction of the dibutyltin complex of the 1,9-diacyldipyrromethane (250 mM) with ～10-15 mol equiv of NaBH₄ (versus 25 mM and 40 mol equiv). The procedures have been carried out with no chromatography at large scale, affording the dipyrromethane (31, 59, or 79 g), the dibutyltin complex of a 1,9-diacyldipyrromethane (361 g), and reduction of the latter (45 g). The porphyrin-forming reaction has been performed (25 mM reactants at 50-mmol scale, or 10 mM at 64-mmol scale) in a two-step process of condensation and oxidation to give the free base porphyrin 1 in 3.7- or 5.8-g quantities. Metalation with zinc acetate afforded Zn-1, which was isolated by direct crystallization. Taken together, the various improvements facilitate synthesis of the target porphyrin Zn-1 and may have broad applicability.

Full text of DOI:10.1021/op0502553

Organic Process Research & Development 2006, 10, 304−314
Nearly Chromatography-Free Synthesis of the A3B-Porphyrin
5-(4-Hydroxymethylphenyl)-10,15,20-tri-p-tolylporphinatozinc(II)
Syeda Huma H. Zaidi,‡ Robert S. Loewe,*,† Brad A. Clark,† Marc J. Jacob,† and Jonathan S. Lindsey*,‡
ZettaCore, Inc., Englewood, Colorado 80112, U.S.A., and Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204, U.S.A.
Abstract:
The current methods of synthesis for such A4-porphyrins,
which entail one-flask reaction of an aldehyde and pyrrole,
should support large-scale synthesis where the substituents
are rather simple.1,2 For many applications, a distinct pattern
of up to four different meso-substituents is desired, which
generally requires a rational, stepwise synthesis.
Rational routes to synthetic porphyrins bearing distinct meso-
substituents have typically been implemented at modest scale
(<1 g quantities). The A3B-porphyrin 5-(4-hydroxymethylphe-
nyl)-10,15,20-tri-p-tolylporphinatozinc(II) (Zn-1) is required in
multigram quantities for possible commercial use in information
storage applications. The synthesis of Zn-1 has been carried
out by reaction of 5-(4-hydroxymethylphenyl)dipyrromethane
and the dicarbinol derived from 1,9-di-p-toluoyl-5-p-tolyldipyr-
romethane. Four improvements have been made to the steps
leading to the dipyrromethane and dipyrromethane-di-
carbinol: (i) use of 50 equiv of pyrrole in the condensation of
an aldehyde to give the dipyrromethane (versus 100 equiv
previously), (ii) 1,9-diacylation of a dipyrromethane using the
hindered Grignard reagent 2,6-dimethylphenylmagnesium bro-
mide and p-toluoyl chloride to give the 1,9-diacyl versus 1-acyl
products in >10:1 ratio (versus 4:1 using EtMgBr), (iii) isolation
of the dibutyltin complex of the 1,9-diacyldipyrromethane from
the crude reaction mixture by direct crystallization using
methanol/methyl tert-butyl ether (MTBE) (versus silica chro-
matography), and (iv) reduction of the dibutyltin complex of
the 1,9-diacyldipyrromethane (250 mM) with ∼10-15 mol equiv
of NaBH4 (versus 25 mM and 40 mol equiv). The procedures
have been carried out with no chromatography at large scale,
affording the dipyrromethane (31, 59, or 79 g), the dibutyltin
complex of a 1,9-diacyldipyrromethane (361 g), and reduction
of the latter (45 g). The porphyrin-forming reaction has been
performed (25 mM reactants at 50-mmol scale, or 10 mM at
64-mmol scale) in a two-step process of condensation and
oxidation to give the free base porphyrin 1 in 3.7- or 5.8-g
quantities. Metalation with zinc acetate afforded Zn-1, which
was isolated by direct crystallization. Taken together, the
various improvements facilitate synthesis of the target porphy-
rin Zn-1 and may have broad applicability.
A new commercial application of porphyrins may reside
in next-generation memory devices, such as dynamic random
access memory (DRAM) chips.3-5 In this information storage
application, the porphyrin serves as a charge-storage element
in a hybrid molecular semiconductor chip. The porphyrin is
attached to an electroactive surface, and hence must bear
one surface attachment group. Other groups may be incor-
porated to alter the electrochemical potentials, provide steric
bulk, or provide a site for derivatization with other compo-
nents to complete the memory cell. Meso-substituted por-
phyrins that satisfy these architectural requirements are of
the A3B-, AB2C-, or ABCD-type. For a monolayer of
porphyrin in a memory device, a 1-cm2 chip would incor-
porate ∼0.3 µg of porphyrin (assuming a 50 Å2 molecular
footprint and a molecular weight of 1000 Da). Although the
amount of porphyrin per chip is tiny, the market for DRAM
chips is vast. Moreover, the attachment procedures for
incorporating porphyrins into chips are quite inefficient at
present.6,7 Accordingly, the development of streamlined
procedures for the preparation of large quantities of porphy-
rins bearing multiple distinct meso substituents is of con-
siderable importance.
A current candidate for incorporation in DRAM cells is
a zinc porphyrin that bears three p-tolyl groups and one
p-hydroxymethylphenyl moiety (Chart 1). This A3B-porphy-
rin has been used in several applications as the zinc chelate
(Zn-1) or as the free base form (1), including the preparation
(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) Crossley, M. J.; Thordarson, P.; Bannerman, J. P.; Maynard, P. J. J.
Porphyrins Phthalocyanines 1998, 2, 511-516.
(3) Roth, K. M.; Dontha, N.; Dabke, R. B.; Gryko, D. T.; Clausen, C.; Lindsey,
J. S.; Bocian, D. F.; Kuhr, W. G. J. Vac. Sci. Technol. B 2000, 18, 2359-
2364.
(4) Liu, Z.; Yasseri, A. A.; Lindsey, J. S.; Bocian, D. F. Science 2003, 302,
1543-1545.
Introduction
The growing importance of porphyrins in fundamental
studies as well as possible commercial applications places a
premium on synthetic methods that afford substantial quanti-
ties of pure compounds in a straightforward manner. Por-
phyrins bearing four identical meso-substituents have been
available commercially in gram quantities for some time.
(5) Kuhr, W. G.; Gallo, A. R.; Manning, R. W.; Rhodine, C. W. Mater. Res.
Soc. Bull. 2004, 838-842.
(6) Roth, K. M.; Yasseri, A. A.; Liu, Z.; Dabke, R. B.; Malinovskii, V.;
Schweikart, K.-H.; Yu, L.; Tiznado, H.; Zaera, F.; Lindsey, J. S.; Kuhr, W.
G.; Bocian, D. F. J. Am. Chem. Soc. 2003, 125, 505-517.
(7) Liu, Z.; Yasseri, A. A.; Loewe, R. S.; Lysenko, A. B.; Malinovskii, V. L.;
Zhao, Q.; Surthi, S.; Li, Q.; Misra, V.; Lindsey, J. S.; Bocian, D. F. J. Org.
Chem. 2004, 69, 5568-5577.
* To whom correspondence should be addressed. E-mail: Rob.Loewe@
zettacore.com, jlindsey@ncsu.edu.
† ZettaCore, Inc.
‡ North Carolina State University.
304
•
Vol. 10, No. 2, 2006 / Organic Process Research & Development
10.1021/op0502553 CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/23/2006

Chart 1
(i) Dipyrromethane formation: the prior solventless
synthesis18 was modified to include use of a larger excess
of pyrrole (100 equiv) relative to the amount of aldehyde,
use of a mild Lewis acid (e.g., InCl3) for catalysis, and
workup by removal of the catalyst and pyrrole followed by
direct crystallization of the dipyrromethane. In this manner,
the dipyrromethane could be obtained in 100-g quantities
without aqueous-organic extraction, distillation, or chro-
matography.19
(ii) Synthesis and isolation of a 1,9-diacyldipyr-
romethane: the prior method for diacylation of a dipyrro-
methane20 was modified to use a ratio of dipyrromethane/
EtMgBr/acid chloride of 1:5:2.217 or 1:5:2.5.21 Regardless,
the attempted diacylation of a dipyrromethane typically
affords a mixture of the dipyrromethane, 1-acyldipyr-
romethane, 1,9-diacyldipyrromethane, and diacyldipyr-
romethane isomers.17,20 Acyldipyrromethanes typically afford
amorphous foams upon crystallization (or exist as oils),
requiring resort to chromatography, where extensive streak-
ing results in excessive consumption of solvents, chromato-
graphic media, and the experimentalist’s time. An incisive
method of isolation entails treatment of the crude reaction
mixture with Bu2SnCl2 and TEA, which selectively affords
the dibutyltin complex of the 1,9-diacyldipyrromethane. The
complex is nonpolar, easily purified, and has been obtained
at the 20-g scale in procedures with only limited reliance on
chromatography.21 (Note that dibutyltin compounds are
generally nontoxic, unlike their trialkyl or tetraalkyl cousins;
for a more thorough discussion and entry into the literature
on this topic, see ref 21.)
(iii) Acid catalysis for porphyrin formation: the use of
TFA in CH3CN with 2.5 mM reactants17 has been supplanted
by two advances. One advance entailed the use of a mild
Lewis acid in CH2Cl2 at room temperature, which afforded
condensation without detectable scrambling and also facili-
tated chromatographic isolation of the porphyrin.22 A second
advance identified conditions that supported condensation
at 10-fold higher concentration (25 versus 2.5 mM). The
refined acid catalysis conditions were employed in the
condensation of a dipyrromethane and a dipyrromethane-
dicarbinol (18-mmol scale with catalysis by Sc(OTf)3),
affording 2.88 g (22.8% yield) of an ABCD-porphyrin.23
We sought to apply these improvements to the synthesis
of Zn-1. Two approaches to Zn-1 are outlined in Scheme 2.
Both routes employ the dibutyltin complex of 1,9-diacyl-
of porphyrin dyads,8,9 attachment to silicon surfaces for
studies of electron-transfer reactions,10 and as one ligand in
a lanthanide triple-decker sandwich coordination com-
pound.11 The applications have motivated several syntheses.
An early synthesis employed statistical condensation of
4-carbomethoxybenzaldehyde (or the acetal thereof) and
p-tolualdehyde under Adler conditions9,12 or at room tem-
perature13 to give 5-(4-methoxycarbonylphenyl)-10,15,20-
tri-p-tolylporphyrin (2). Reduction of porphyrin-ester 2 gave
the free base porphyrin-alcohol 1.8,9 In general, the simplic-
ity of statistical syntheses is offset by diminished yield and
the complexity of the chromatography required to separate
the desired product. Few exceptions to this rule are observed
in porphyrin chemistry.
The most recent synthesis of Zn-1, via a rational ap-
proach, is shown in Scheme 1.14 Condensation of p-
tolualdehyde with excess pyrrole in the presence of TFA
followed by bulb-to-bulb distillation afforded 5-p-tolyldipyr-
romethane (3). Acylation of the dipyrromethane was achieved
upon treatment with 5 mol equiv each of EtMgBr and
p-toluoyl chloride, affording the 1,9-diacyldipyrromethane
4. Reduction of the latter with NaBH4 in THF/methanol gave
the corresponding dipyrromethane-dicarbinol 4-diol. The
critical porphyrin-forming step was carried out by the
condensation of ester-dipyrromethane 5 (prepared in a
manner similar to that of 3) and 4-diol in acetonitrile
containing TFA at room temperature. The resulting porphy-
rinogen was oxidized to give the free base porphyrin 2. These
conditions support reaction without detectable acidolysis,
thereby affording the porphyrin with the desired pattern of
meso substituents. Subsequent metalation with zinc acetate
gave the zinc porphyrin-ester Zn-2, which upon reduction
with LiAlH4 gave the target zinc porphyrin-alcohol Zn-1.
Although this approach afforded the desired porphyrin Zn-
1, each step in the synthesis typically required chromato-
graphic separation procedures.
Over the past few years we have devoted a great deal of
effort to refine the rational synthesis of meso-substituted
porphyrins.15-17 The pertinent improvements include the
following:
(15) Littler, B. J.; Ciringh, Y.; Lindsey, J. S. J. Org. Chem. 1999, 64, 2864-
2872.
(16) Rao, P. D.; Littler, B. J.; Geier, G. R., III; Lindsey, J. S. J. Org. Chem.
2000, 65, 1084-1092.
(17) Rao, P. D.; Dhanalekshmi, S.; Littler, B. J.; Lindsey, J. S. J. Org. Chem.
2000, 65, 7323-7344.
(18) (a) Lee, C.-H.; Lindsey, J. S. Tetrahedron 1994, 50, 11427-11440. (b)
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.
(19) Laha, J. K.; Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.; Lindsey, J. S.
Org. Process Res. DeV. 2003, 7, 799-812.
(8) Tamiaki, H.; Suzuki, S.; Maruyama, K. Bull. Chem. Soc. Jpn. 1993, 66,
2633-2637.
(9) Hombrecher, H. K.; Ohm, S. Tetrahedron 1993, 49, 2447-2456.
(10) (a) Yasseri, A. A.; Syomin, D.; Loewe, R. S.; Lindsey, J. S.; Zaera, F.;
Bocian, D. F. J. Am. Chem. Soc. 2004, 126, 15603-15612. (b) Erratum J.
Am. Chem. Soc. 2005, 127, 9308.
(11) Balakumar, A.; Lysenko, A. B.; Carcel, C.; Malinovskii, V. L.; Gryko, D.
T.; Schweikart, K.-H.; Loewe, R. S.; Yasseri, A. A.; Liu, Z.; Bocian, D. F.;
Lindsey, J. S. J. Org. Chem. 2004, 69, 1435-1443.
(12) Anton, J. A.; Loach, P. A. J. Heterocycl. Chem. 1975, 573-576.
(13) Williamson, D. A.; Bowler, B. E. Tetrahedron 1996, 52, 12357-12372.
(14) Carcel, C. M.; Laha, J. K.; Loewe, R. S.; Thamyongkit, P.; Schweikart,
K.-H.; Misra, V.; Bocian, D. F.; Lindsey, J. S. J. Org. Chem. 2004, 69,
6739-6750.
(20) Lee, C.-H.; Li, F.; Iwamoto, K.; Dadok, J.; Bothner-By, A. A.; Lindsey, J.
S. Tetrahedron 1995, 51, 11645-11672.
(21) Tamaru, S.-I.; Yu, L.; Youngblood, W. J.; Muthukumaran, K.; Taniguchi,
M.; Lindsey, J. S. J. Org. Chem. 2004, 69, 765-777.
(22) Geier, G. R., III; Callinan, J. B.; Rao, P. D.; Lindsey, J. S. J. Porphyrins
Phthalocyanines 2001, 5, 810-823.
(23) Zaidi, S. H. H.; Fico, R. M., Jr.; Lindsey, J. S. Org. Process Res. DeV.
2006, 10, 118-134.
Vol. 10, No. 2, 2006 / Organic Process Research & Development
•
305

Scheme 1
Scheme 2
dipyrromethane 4 (4-SnBu2) as a starting material, owing
to its ready isolation. The corresponding dipyrromethane-
dicarbinol is condensed with either dipyrromethane 6 or 5
to give the free base porphyrin 1 or 2, respectively. Complex-
ation affords the zinc chelate Zn-1 or Zn-2. Porphyrin Zn-2
can be reduced with LiAlH4 to give Zn-1.
the 1,9-diacyldipyrromethane-dibutyltin complex, and dipyr-
romethane-1,9-dicarbinol formation. The two approaches
shown in Scheme 2 are employed to prepare the A3B-
porphyrin Zn-1 in multigram quantities with limited reliance
on chromatography.
In attempting to carry out syntheses of Zn-1 in multigram
quantities, we developed additional refinements to the
methods for preparing the porphyrin precursors. The refine-
ments, which are reported herein, include dipyrromethane
formation, 1,9-diacyldipyrromethane formation, isolation of
Results and Discussion
I. Preparation of Porphyrin Precursors. I. A. 4-Hy-
droxymethylbenzaldehyde (7). 4-Hydroxymethylbenzalde-
hyde (7) is not commercially available in large quantities.
Compound 7 has been prepared in the literature via statistical
306
•
Vol. 10, No. 2, 2006 / Organic Process Research & Development

reduction of terephthalaldehyde using either NaBH4 or
LiAlH4, followed by chromatographic workup,24,25 or via
catalytic hydrogenation using Pd/C catalysis.26 Slight modi-
fications to the latter procedure (use of i-PrOH instead of
EtOH, 25 versus 45 psi of hydrogen pressure) afforded 7 in
87% yield after crystallization from a mixture of methyl tert-
butyl ether (MTBE)/hexanes (1:1, v/v) (eq 1). Only minor
amounts of 1,4-bis(hydroxymethyl)benzene (<5%) were
formed after complete consumption of terephthalaldehyde.
The use of MeOH or EtOH as solvent was found to produce
sizable amounts of the corresponding monoacetal and diacetal
byproducts. The use of i-PrOH as solvent diminished the
acetal byproducts to <1% levels (as detected by GC-MS).
subsequent dipyrromethane reactions were employed with a
50:1 pyrrole/aldehyde ratio. The reactions were readily
monitored by GC or TLC. After 90 min, no aldehyde starting
material was detected in each of the three cases examined.
The reaction was quenched by the addition of solid NaOH.
A second modification to the standard procedure was
introduced in the workup procedure. Upon removal of pyrrole
under reduced pressure, the crude dipyrromethane (obtained
as an oil, gum, or solid) typically contains residual pyrrole
that is difficult to remove. The addition of a small amount
of toluene followed by an evaporative co-strip of pyrrole
and toluene afforded a cleaner dipyrromethane product.
Application of the two modifications (50:1 pyrrole/
aldehyde ratio, toluene co-strip during workup) to the
standard procedure19 afforded dipyrromethane 323 or 519 in
60% (0.42 mol scale) or 66% (0.17 mol scale) yield upon
recrystallization, respectively. No chromatography was re-
quired. For dipyrromethane-benzyl alcohol 6, the crude
product could not be obtained as a solid despite the use of
the toluene co-strip. Hence, the resulting oil was passed
through a silica column (7.6 × 20 cm) using an eluent of
CHCl3/MeOH (98:2 v/v). This step removed the tripyrrane
and higher-molecular weight oligomers but did not separate
the dipyrromethane and N-confused dipyrromethane. The
product-containing fractions were concentrated to give a
solid, which was recrystallized from toluene/EtOH (10:1 v/v)
to afford 6 in 71% yield. The purity as determined by GC
analysis was found to be >96%, with 3% of N-confused
dipyrromethane as the sole identified byproduct after puri-
fication.
I. B. Preparation of Dipyrromethanes. The dipyr-
romethanes were prepared using a solventless reaction of
an aldehyde with excess pyrrole in the presence of a mild
Lewis acid (e.g., InCl3) at room temperature.19 An excess of
pyrrole is essential to suppress the continued reaction that
leads to linear or cyclic oligomers. The reaction is quenched
by addition of powdered NaOH. Filtration removes insoluble
organic material including inactivated catalyst and yields the
crude dipyrromethane and excess pyrrole in the filtrate.
Removal and recovery of excess pyrrole from the filtrate
affords the crude dipyrromethane, which typically can be
obtained by crystallization. The procedure generates little
waste and does not require aqueous/organic extraction,
distillation, or often, chromatography.
I. B.1. Pyrrole Purity. During the course of this work,
we examined the purity of the pyrrole employed in the
dipyrromethane synthesis. Significant variation was observed
in the quality of commercial samples of pyrrole. Some
commercial samples contained ∼1% of methylated pyrrole
impurities, which severely hamper the purification step in
the dipyrromethane synthesis. GC traces of two commercial
samples of pyrrole are shown in Figure 1. The pyrrole
obtained from Detrex, Inc. was found to have the highest
quality among the suppliers examined and was used in all
studies reported herein.
The dipyrromethanes employed in this work are shown
in eq 2.
I. C. Diacyldipyrromethane 4 and Tin Complex 4-SnBu2.
Diacylation of dipyrromethane 3 with p-toluoyl chloride leads
to formation of the corresponding 1,9-diacyldipyrromethane
intermediate (4), which is subsequently converted to the
highly crystalline tin complex 4-SnBu2 (Scheme 3). Fol-
lowing the published method21 using EtMgBr as Grignard
reagent, the yield was not reproducible during preliminary
development experiments. In addition, the exotherm of the
reaction was difficult to control.
A chief challenge in this reaction is the requirement for
2 mol equiv of Grignard reagent to give the dipyrromethane
bis(Grignard reagent) analogous to the pyrrole Grignard
reagent. Upon each R-acylation process, 1 equiv of HCl is
liberated. Accordingly, 2 equiv of base is required to
neutralize the HCl liberated upon diacylation. The general
approach has been to include 2 additional mol equiv of
Grignard reagent (giving 4 mol equiv total) to provide the
One modification to the prior procedure19 was that 50 mol
equiv of pyrrole was used instead of 100 mol equiv. The
resulting reduction in the amount of pyrrole is advantageous
on a large scale as it diminishes the raw material cost and
shortens the time needed to remove the excess pyrrole via
rotary evaporation. For the preparation of dipyrromethane
3, no significant differences were observed in the reaction
using 50 vs 100 equiv of pyrrole (as determined by GC-
MS of the crude reaction mixtures). Accordingly, all
(24) Mak, C. C.; Bampos, N.; Darling, S. L.; Montalti, M.; Prodi, L.; Sanders,
J. K. M. J. Org. Chem. 2001, 66, 4476-4486.
(25) Gennari, C.; Ceccarelli, S.; Piarulli, U.; Aboutayab, K.; Donghi, M.; Paterson,
I. Tetrahedron 1998, 54, 14999-15016.
(26) Dunlop, A. P.; Sherman, E.; Wuskell, J. P. U.S. Patent 3,845,138, 1974.
Vol. 10, No. 2, 2006 / Organic Process Research & Development
•
307

Scheme 3
Figure 1. GC traces of commercial samples of pyrrole. (A)
Pyrrole obtained from a large commercial supplier (purity
98.2%). (B) Pyrrole obtained from Detrex, Inc. (purity >99.9%).
necessary base. Not surprisingly, the use of EtMgBr results
in reaction with p-toluoyl chloride to produce the corre-
sponding ketone and alcohol (as determined by HPLC). In
other studies we found that 9-acylation of a 1-acyldipyr-
romethane could be improved by use of hindered Grignard
reagents or with bases other than EtMgBr to neutralize the
liberated HCl.27 On the other hand, a preliminary study (1-
mmol scale) did not show improved 1,9-diacylation with use
of hindered Grignard reagents (see Supporting Information
of ref 27).27
The 1,9-diacylation of dipyrromethane 3 was examined
using several commercially available Grignard reagents. The
key issues are the ratio of the diacyldipyrromethane to the
monoacyldipyrromethane, and the isolated yield of 1,9-
diacyldipyrromethane. The diacyl/monoacyl ratio was as-
sessed by HPLC analysis. The progress of the acylation also
was examined by TLC. Using the solvent system hexanes/
CH2Cl2/ethyl acetate (3:6:1) on silica, the dipyrromethane,
1-acyldipyrromethane, and 1,9-diacyldipyrromethane were
readily separated with no streaking on TLC. The yield of
1,9-diacyldipyrromethane was assessed upon isolation as the
dibutyltin complex (vide infra). With these analytical pro-
cedures in hand, the data in Table 1 were obtained for the
1,9-diacylation of 3 (8.46-mmol scale). The benchmark
reaction with EtMgBr affords a diacyl/monoacyl ratio of
∼4:1 and a yield of ∼50% (entry 1). The use of hindered
Grignard reagents afforded better ratios and higher yields
(entries 2-4), reaching >10:1 and 70% in the case of 2,4,6-
trimethylphenylmagnesium bromide (entry 2). The use of
p-tolylmagnesium bromide (entry 5) gave results comparable
to that of EtMgBr, indicating the essential role of steric
Table 1. Effect of various Grignard reagents on the
1,9-diacylation reaction of 3a
entry
Grignard
diacyl/monob
yield (%)c
1
2
3
4
5
EtMgBrd
mesitylMgBr
2,6-Me2PhMgBr
o-tolylMgCl
4:1
>10:1
>10:1
>10:1
3:1
45-50
70
69
64
p-tolylMgBr
not isolated
a All reactions were carried out with 8.46 mmol of 3 in toluene, 4.2 mol
equiv of Grignard reagent (in THF) and 2.1 mol equiv of p-toluoyl chloride
unless noted otherwise. b Ratio of 1,9-diacyldipyrromethane/1-acyldipyr-
romethane was assessed by HPLC analysis with absorption spectral detection at
220 nm (raw data without any correction for molar absorption coefficients).
c Isolated yield of 4-SnBu2 upon crystallization. d 5.0 mol equiv of Grignard
reagent and 2.5 mol equiv of p-toluoyl chloride were employed.
hindrance in the improved results rather than an effect of
aryl versus alkyl Grignard reagents. The amount of reagent
also was optimized, wherein only 2.1 mol equiv of p-toluoyl
chloride and 4.2 mol equiv of Grignard reagent (versus 2.5
and 5 mol equiv, respectively21) were utilized. Owing to price
considerations, we chose 2,6-dimethylphenylmagnesium
bromide versus mesitylmagnesium bromide as the Grignard
reagent of choice for the diacylation process.
(27) Zaidi, S. H. H.; Muthukumaran, K.; Tamaru, S.-I.; Lindsey, J. S. J. Org.
Chem. 2004, 69, 8356-8365.
308
•
Vol. 10, No. 2, 2006 / Organic Process Research & Development

Table 2. Conditions for the diacyldipyrromethane reduction
(4-SnBu2 to 4-diol)
It is assumed that the hindered Grignard reagents are
sufficiently reactive to form the pyrrole Grignard species but
participate slowly in the side reaction with p-toluoyl chloride
to produce the corresponding ketone and/or tertiary alcohol.
By comparison with the prior diacylation study with mesi-
tylmagnesium bromide (reported in the Supporting Informa-
tion of ref 27),27 the present conditions are characterized by
a dipyrromethane concentration of 0.5 M and a final solvent
composition of toluene/THF of ∼1:2. The prior conditions
(1-mmol scale) entailed 1 M dipyrromethane with THF as
the sole solvent.27 The specific origin of the improved
diacylation results must await a more comprehensive study.
Regardless, the present conditions with sterically hindered
Grignard reagents afford better reproducibility, improved
purity of the crude product, and higher yields versus that
achieved previously.
The 1,9-diacylation of 3 was carried out at large scale
(0.19 mol, 45 g of 3) using 2,6-dimethylphenylmagnesium
bromide and p-toluoyl chloride. The crude reaction mixture
(containing 1,9-diacyldipyrromethane 4) was treated with
Bu2SnCl2 and triethylamine (TEA) in ethyl acetate to yield
the corresponding tin complex, 4-SnBu2, a known com-
pound7 (Scheme 3). The tin-complexation method affords a
nonpolar complex and is selective for the 1,9-diacyldipyr-
romethane.21 Ethyl acetate was chosen versus CH2Cl27,21 as
the solvent for tin complexation owing to environmental
considerations. The reaction mixture was washed with water.
This set of changes eliminated the need for filtration on silica
gel.7,21 The product was obtained by direct crystallization
from a mixture of MeOH/MTBE (3:1 v/v). MTBE was
chosen for recrystallization as a safer alternative to diethyl
ether,7,21 although MTBE is not without limitations given
its environmental persistence. This new method was repro-
ducible and has been implemented successfully at the 1-mol
scale (50% yield, 361 g).
reaction
parameters
literature
refined
conditions
conditionsa
reaction
20-30
40
250
10
concentration (mM)
amount of NaBH4
(mol equiv)
reaction time
isolation of
crude product
2-4 h
<1 h
rotary evaporate dilute with CH2Cl2
to dry product
for porphyrin
formation
a Reference 21.
preparation of dipyrromethane-dicarbinols on a large scale
required modification. The specific changes made for the
preparation of 4-diol are as follows: (1) The reduction of
4-SnBu2 to 4-diol was carried out at 10-fold higher
concentration (250 mM vs 20-30 mM) to diminish the
amount of solvent required. (2) The order of addition was
changed wherein methanol was added to a suspension of
NaBH4 in the THF/4-SnBu2 mixture, thereby limiting
handling of NaBH4 powder on a large scale. (3) By changing
the order of addition, a lesser amount of NaBH4 (10 mol
equiv) was required to achieve full reduction of 4-SnBu2 to
4-diol. The lesser amount of unspent borohydride after the
reduction also provided for safer workup. (4) The solvent
system hexanes/ethyl acetate/methanol (4:1:1) was found to
be an excellent TLC solvent (on silica) for monitoring the
reduction to the dipyrromethane-dicarbinol. The diacyl-
dipyrromethane, partially reduced intermediate (the mono-
carbinol), and dipyrromethane-dicarbinol were readily
separated without streaking. (5) Workup of the dipyr-
romethane-dicarbinol species was achieved with a single
wash with saturated aqueous NH4Cl, rather than multiple
water/brine washings. The pH of the organic layer was
checked using pH paper and was found to be ∼7. (6) Given
that dipyrromethane-dicarbinols such as 4-diol are typically
rather reactive, the dried organic extract was simply diluted
with CH2Cl2 to achieve the requisite 10 mM (or 25 mM,
vide infra) concentration for subsequent porphyrin formation
rather than concentrating the solution containing 4-diol to
the dry product. For large-scale reactions, the rotary evapora-
tion step could require >1 h, thereby potentially compromis-
ing the integrity of the dicarbinol species. A summary of
the modifications made to the diacyldipyrromethane reduc-
tion is given in Table 2.
I. D. Reduction of 4-SnBu2 to 4-Diol. Equation 3 shows
the reduction of 4-SnBu2 to 4-diol using NaBH4 in THF/
MeOH.
Other reducing agents were explored to convert 4-SnBu2
to 4-diol. Sodium bis(2-methoxyethoxy)aluminum hydride
(Red-Al) gave poor conversion to the dicarbinol, and removal
of the spent aluminum salts proved tedious. Sodium tri-
methoxyborohydride showed no reactivity with 4-SnBu2
even at 40 °C. The use of sodium borohydride at 0.3 M in
a caustic solution (an alternate safe way to handle NaBH4)
was examined, but no reduction product(s) were detected,
which we attribute to the nonreactive biphasic mixture
formed under these conditions.
In prior reports,17,21 this reduction was carried out via
portionwise addition of NaBH4 to a ∼25 mM solution of
the diacyldipyrromethane in THF/MeOH (10:1 or 3:1). In
addition, 20-40 mol equiv of NaBH4 was employed to
achieve complete reduction to the dipyrromethane-di-
carbinol. While suitable for small to modest scales, the
II. Synthesis of the porphyrins. The prior rational
synthesis of Zn-1 (Scheme 1) provided small quantities of
Vol. 10, No. 2, 2006 / Organic Process Research & Development
•
309

Table 3. Summary of the porphyrin-forming reactions to prepare 1 and Zn-2a
porphyrin
reaction parameters
reactants
2b
1
Zn-2
5 + 4-diol
6 + 4-diol
5 + 4-diol
[reactant],c mM
acid
2.5
TFA
30
10
Yb(OTf)3
3.0
25
Sc(OTf)3
3.2
10
Yb(OTf)3
3.2
25
Sc(OTf)3
3.2
d
[acid], mMe
DTBP
solvent
in situ Zn(II) complexation
reaction scale (mmol)
isolated yield
isolated amount
-
-
32 mM
CH2Cl2
No
50
11%
-
32 mM
CH2Cl2
Yes
15
22%
CH3CN
No
CH2Cl2
No
CH2Cl2
Yes
7.0
16%
0.798 g
64
13%
5.87 g
7.1
23%
1.27 g
3.78 g
2.64 g
a All reactions were performed at room temperature. b Literature data from ref 14. c The dipyrromethane and dipyrromethane-dicarbinol were used in equal
concentrations. d Used as the hydrate (degree of hydration ) 1-2). e The Lewis acids may not be entirely soluble but the amount employed is indicated in molar
quantities for clarity.
porphyrin but was not well suited for larger-scale imple-
mentation.14 The limitations were as follows: (i) the
condensation was carried out at 2.5 mM in acetonitrile to
give the porphyrin-ester 2, (ii) at least one (usually two)
chromatographic procedures were required to obtain the free
base porphyrin 2, and (iii) reduction and metalation were
required to obtain the desired Zn-1.
Two subsequent studies of the porphyrin-forming reaction
identified improved acid catalysis conditions that also afford
condensation with little or no detectable scrambling. The
avoidance of scrambling, which results in formation of
unwanted mixtures of porphyrins, is of utmost importance
given the difficulty of separating mixtures of porphyrins. The
improvements entail use of a mild Lewis acid (e.g., Yb-
(OTf)3, Sc(OTf)3, Dy(OTf)3, InCl3) for catalysis in CH2Cl2
at 2.5 mM reactants22 or at higher concentrations (10 or 25
mM versus 2.5 mM).23 In some cases, the hindered base 2,6-
di-tert-butylpyridine is included,23,28 which serves as a
Brønsted acid scavenger without significant interference with
the Lewis acid. The new catalysis conditions were applied
herein as described below.
The synthesis of Zn-1 was attempted via the three-step
one-flask reaction of hydroxymethyl-dipyrromethane 6 and
the dipyrromethane-dicarbinol 4-diol. However, the zinc
porphyrin proved difficult to purify from residual black
materials. The purification may be hindered by self-associa-
tion owing to coordination of the hydroxy group on one
porphyrin with the apical site on the central zinc atom of
another porphyrin. Regardless, the synthesis was carried out
by a two-step one-flask reaction of 6 and 4-diol to give free
base porphyrin 1. The synthesis with 10 or 25 mM reactants
proceeded well without detectable scrambling, and porphyrin
1 was isolated by a single chromatographic procedure in 13
or 11% yield. The free base porphyrin 1 was metalated with
zinc acetate, affording Zn-1 in pure form without chroma-
tography in 95% yield. In the synthesis of both Zn-2 and 1,
an aerobic oxidation process29 was examined wherein
catalytic quantities (2.5 mol %) of an iron-phthalocyanine
species and DDQ are combined with a stream of air (or O2),
but in both cases the yield of porphyrin was only ∼2-3%.
The origins of the low yields in the aerobic process are not
known.
The routes shown in Scheme 2 were followed for the
preparation of the desired porphyrin-alcohol Zn-1 and the
porphyrin-ester Zn-2. Four porphyrin-forming reactions
were carried out, two for each porphyrin under different
condensation conditions. One set of conditions employed 10
mM reactants with catalysis by Yb(OTf)3 (3.2 mM) in CH2-
Cl2. A second set of conditions employed 25 mM reactants
with Sc(OTf)3 (3.2 mM) and 2,6-di-tert-butylpyridine (32
mM) in CH2Cl2 at room temperature.
The results are summarized in Table 3. The synthesis of
Zn-2 was carried out in a three-step one-flask reaction of
ester-dipyrromethane 5 and the dipyrromethane-dicarbinol
4-diol. The three steps include condensation, oxidation, and
in situ zinc insertion. The synthesis with 10 or 25 mM
reactants afforded porphyrin-ester Zn-2 in 23 or 22% yield,
respectively. In each case the crude reaction mixture
exhibited no detectable scrambling, and the porphyrin was
isolated by a single chromatography procedure.
Summary
The following improvements have been made in the
synthesis of Zn-1:
(i) Three dipyrromethanes were prepared using a literature
procedure19 with slight modification (50 equiv of pyrrole
instead of 100 equiv; use of a toluene co-strip upon workup).
Use of pyrrole of high purity was essential. A diminished
amount of pyrrole becomes a significant advantage in large-
scale reactions.
(ii) The diacylation of the dipyrromethane was carried
out using a hindered Grignard reagent (e.g., 2,6-dimeth-
ylphenylmagnesium bromide) instead of EtMgBr,17 affording
a diacyl/monoacyl ratio of >10:1 versus 4:1.
(iii) Complexation of the 1,9-diacyldipyrromethane with
dibutyltin dichloride was carried out with the crude acylation
mixture in the standard manner. On account of the relative
(29) (a) Ravikanth, M.; Achim, C.; Tyhonas, J. S.; Mu¨nck, E.; Lindsey, J. S. J.
Porphyrins Phthalocyanines 1997, 1, 385-394. (b) Lindsey, J. S.; MacCrum,
K. A.; Tyhonas, J. S.; Chuang, Y.-Y. J. Org. Chem. 1994, 59, 579-587.
(28) Speckbacher, M.; Yu, L.; Lindsey, J. S. Inorg. Chem. 2003, 42, 4322-
4337.
310
•
Vol. 10, No. 2, 2006 / Organic Process Research & Development

cleanliness of the diacylation process, a water wash, and use
of more appropriate solvents for crystallization (MTBE/
MeOH), the dibutyltin complex of the diacyldipyrromethane
was isolated from the crude reaction mixture by crystalliza-
tion rather than silica pad filtration as used previously.21 The
new route was carried out to give 79 or 361 g of 4-SnBu2
(versus 8.54 g previously7).
(iv) The reduction of the dibutyltin complex of the
diacyldipyrromethane (4-SnBu2) to give the dipyrromethane-
dicarbinol 4-diol was carried out at 250 mM reactant
concentration with ∼10-15 mol equiv of NaBH4 over the
course of 1-2 h, to be compared with 20-30 mM reaction
concentration and 40 mol equiv of NaBH4 over 2-4 h.17,21
The new route was carried out with 45 g (64 mmol) of
4-SnBu2.
(v) The prior synthesis of porphyrin-alcohol 1 entailed
reduction of porphyrin-ester 2, which in turn was prepared
by condensation of ester-dipyrromethane 5 and 4-diol (2.5
mM reactant concentration, 0.17-7.00 mmol scale) followed
by oxidation.14 The new synthesis of 1 was carried out by
the condensation of hydroxymethyl-dipyrromethane 6 and
4-diol at 4-10-fold higher concentration (10 or 25 mM)
followed by oxidation, affording 5.87 g (10 mmol, 64-mmol
scale) or 3.78 g (25 mM, 50-mmol scale) of 1.
desorption ionization mass spectrometry (LD-MS) without
a matrix as described previously.30
HPLC Analysis. HPLC analysis was carried out with a
HP 1050 instrument using a Hypersil column (125 mm × 4
mm) with detection wavelengths of 220 and 325 nm. The
solvent was acetonitrile/water (flow rate ) 1 mL/min). The
gradient program proceeded from 45% acetonitrile to 90%
acetonitrile over 25 min with a hold at 90% acetonitrile for
3 min.
GC Analysis. All GC traces were recorded with a HP
6890 instrument equipped with a HP-5MS column (length
) 30 m; diameter ) 0.25 mm; film thickness ) 0.25 µ) and
a HP-5973 mass selective detector. The method was as
follows: initial temperature 45 °C (hold 5 min); ramp at 15
°C per min until 270 °C is reached. The inlet temperature
was 250 °C.
Representative procedure for diacylation studies:
Compound 3 (2.00 g, 8.46 mmol) was dissolved in toluene
(17 mL) and the solution was cooled to 0 °C. The Grignard
reagent (4.2 mol equiv) was added dropwise. After 30 min,
p-toluoyl chloride (2.1 mol equiv) was added dropwise at 0
°C. After stirring for 1 h, the mixture was poured over a
mixture (1:1) of half-saturated aqueous NH4Cl and ethyl
acetate. The organic layer was washed with brine. The
organic layer was dried (MgSO4) and filtered. The filtrate
was concentrated to an oil. An aliquot was taken for HPLC
analysis. The oil was dissolved in ethyl acetate (40 mL),
whereupon TEA (2.1 mL) was added. A sample of Bu2SnCl2
was added, keeping the temperature below 25 °C. After 1 h,
the reaction was quenched by addition of water. The layers
were separated. The organic layer was washed with brine,
dried (MgSO4), and filtered. The filtrate was concentrated
to an oil. Crystallization from a mixture of MTBE/MeOH
(1:3, v/v) afforded 4-SnBu2.
5-[4-(Hydroxymethyl)phenyl]-10,15,20-tri-p-tolylpor-
phyrin (1) (10 mM reactants). A sample of 4-SnBu2 (45.0
g, 64.0 mmol) was placed in a 1-L, three-necked round-
bottomed flask equipped with a condenser, a pressure-equal-
izing addition funnel, a thermometer, and a mechanical over-
head stirrer. Samples of NaBH4 (24.3 g, 0.64 mol) and THF
(270 mL) were added under an inert atmosphere, followed
by the slow addition of MeOH (117 mL). The reaction
temperature rose and was kept between 35 and 45 °C during
the addition of methanol. After the addition was complete,
the reaction was allowed to cool to room temperature with
stirring. When starting material was no longer detected by
TLC analysis (∼2 h), the reaction mixture was diluted with
CH2Cl2 (250 mL). The resulting mixture was poured slowly
into a mixture of CH2Cl2/saturated aqueous NH4Cl (1:2 v/v,
3 L). The biphasic mixture was stirred for 30 min. The layers
were separated. The organic layer was washed with water,
dried (Na2SO4), and filtered. The filtrate was diluted with
CH2Cl2 (total volume ) 6.4 L). The resulting 4-diol solution
was added to a 12-L round-bottomed flask equipped with
an overhead stirrer. Dipyrromethane 6 (16.2 g, 64.0 mmol)
was added, and the mixture was stirred for 10 min. A sample
(vi) The metalation of 1 with zinc acetate was carried
out without chromatography or aqueous-organic extraction,
affording 10.0 g of Zn-1.
In summary, the advances described herein provide ready
access to gram quantities of the A3B-porphyrin Zn-1. The
refined procedures for dipyrromethane formation, dipyr-
romethane diacylation, isolation of the dibutyltin complex
of the diacyldipyrromethane, and reduction of the latter may
prove useful for a broad set of substrates. The sole impedi-
ment to an entirely chromatography-free synthesis resides
in the porphyrin-forming reaction. Fundamentally new ap-
proaches are required to overcome this obstacle. In the
interim, this work provides the foundation for the synthesis
of porphyrins at a scale suitable for consideration of
commercial applications.
Experimental Section
General. 1H NMR (400 MHz) and 13C NMR (100 MHz)
spectra were obtained in CDCl3 unless noted otherwise.
Absorption spectra were collected in toluene at room
temperature. Silica gel (40 µm average particle size) was
used for column chromatography. Pyrrole (Detrex, Inc.),
Pd/C (Johnson and Matthey, lot #C-6757), 2,6-di-tert-
butylpyridine (DTBP, Aldrich, 97%), Sc(OTf)3 (Aldrich,
99%), Yb(OTf)3‚xH2O (Aldrich, degree of hydration 1-2),
Yb(OTf)3 (Aldrich, 99.99%), InCl3 (Aldrich, 98%), NaOH
beads (20-40 mesh, Aldrich, 97%), NaBH4 (Aldrich, 98%),
p-toluoyl chloride (Aldrich, 98%), Bu2SnCl2 (Alfa Aesar,
95+%), and Zn(OAc)2‚2H2O (Alfa Aesar, 98-101%), THF
(HPLC grade or reagent-grade), CH2Cl2 (anhydrous or
reagent-grade) and methanol (anhydrous or reagent-grade)
were used as received from commercial sources.
The progress of the porphyrin-forming reactions was
monitored by absorption spectroscopy. The extent of scram-
bling in the crude reaction mixture was determined by laser
(30) Srinivasan, N.; Haney, C. A.; Lindsey, J. S.; Zhang, W.; Chait, B. T. J.
Porphyrins Phthalocyanines 1999, 3, 283-291.
Vol. 10, No. 2, 2006 / Organic Process Research & Development
•
311

of Yb(OTf)3‚xH2O (11.9 g, 19.0 mmol) was added. After
15 min, a sample of DDQ (43.6 g, 192 mmol) was added in
one portion. The resulting black mixture was stirred for 1 h.
TEA (36 mL) was then added. The reaction mixture was
poured over silica gel (1 kg) and purified by flash column
chromatography using CH2Cl2/ethyl acetate (97:3) as eluent.
The product-containing fractions were combined and con-
centrated. A sample of i-PrOH (500 mL) was added, and
the mixture was stirred at 25 °C for 30 min. The solid was
collected by filtration and washed with MeOH until the
washings were colorless, affording 5.87 g (13.4%) of a purple
(m, 6H), 8.22 (d, J ) 8.0 Hz, 2H), 8.82-8.87 (m, 8H); LD-
MS obsd 686.8; FAB-MS obsd 686.3066, calcd 686.3046
(C48H38N4O); λabs 420, 516, 551, 592, 648 nm.
Zn(II)-5-[4-(Hydroxymethyl)phenyl]-10,15,20-tri-p-
tolylporphyrin (Zn-1). A sample of 1 (9.68 g, 14.0 mmol)
was added to a 2-L, three-necked round-bottomed flask
equipped with a heating mantle, a condenser, a thermometer,
and a mechanical overhead stirrer. A sample of Zn(OAc)2‚
2H2O (3.71 g, 17.0 mmol) was added followed by THF (500
mL). The mixture was heated to reflux and stirred for 2 h.
The mixture was checked by LD-MS and found to contain
small amounts of free base porphyrin (1). Therefore, more
Zn(OAc)2‚2H2O (3.71 g) was added. After 2 h, the reaction
mixture was filtered at 40 °C. The filtrate was concentrated
to a purple solid. MeOH (300 mL) was added to the solid,
and the resulting suspension was stirred at 25 °C for 2 h.
The solid was collected and washed with MeOH until the
washings were colorless. The solid was dried in vacuo,
yielding 10.0 g (95%) of the title compound as a purple solid.
The characterization data (1H NMR, LDMS, FAB-MS, UV-
vis spectra) were consistent with the reported values.14
Zn(II)-5-(4-Methoxycarbonylphenyl)-10,15,20-tri-p-
tolylporphyrin (Zn-2) (10 mM reactants). A solution of
4-SnBu2 (5.00 g, 7.11 mmol) in THF (28 mL, 250 mM)
was treated with a sample of NaBH4 (1.34 g, 35.5 mmol).
A sample of methanol (12 mL) was then added dropwise by
syringe over 5 min. Gas evolution began during the addition
and was quite intense after the addition. After 30 min, TLC
[alumina, CH2Cl2/ethyl acetate (95:5)] showed the reduction
to the dipyrromethane-dicarbinol to be complete. After 1
h, the reaction mixture was poured into a stirred mixture of
CH2Cl2/saturated aqueous NH4Cl (150:200 mL), and stirred
for 15 min. The organic layer was collected using a
separatory funnel. The organic layer was dried (Na2SO4) and
filtered. The filtrate was concentrated to give the dipyr-
romethane-diol 4-diol as a yellow foam. A sample of
dipyrromethane 5 (1.99 g, 7.11 mmol) was added to the flask
containing 4-diol followed by CH2Cl2 (711 mL). After a clear
solution was obtained, a sample of Yb(OTf)3 (1.41 g, 2.30
mmol, 3.2 mM) was added. After 15 min, a sample of DDQ
(4.84 g, 21.3 mmol) was added. After 30 min, a solution of
Zn(OAc)2‚2H2O (1.56 g, 7.11 mmol) in methanol (30 mL)
was added. The reaction mixture was then stirred at room
temperature under air for 2 h. Analysis by TLC and
fluorescence excitation spectroscopy indicated complete
metalation. The reaction mixture was concentrated. The crude
solid was treated with methanol (250 mL). The suspension
was sonicated for 30 s. The mixture was filtered. The
resulting dull purple precipitate was washed with methanol
(50 mL). The solid was found to contain significant amounts
of dark impurities. Several attempts to precipitate the title
porphyrin resulted in improvements in purity, but complete
removal of the dark impurities was not successful. Therefore,
column chromatography [silica, CHCl3/THF (10:1)] was used
to afford the pure title compound in 23% yield (1.27 g). The
characterization data (1H NMR, LD-MS, FAB-MS, UV-
Vis) were found to be in agreement with those from the
product of a previous synthesis.14
1
solid: H NMR δ -2.76 (s, 2H), 2.69 (s, 9H), 5.05 (d, J )
5.2 Hz, 2H). 7.53-7.55 (m, 6H), 7.74 (d, J ) 8.0 Hz, 2H),
8.07-8.09 (m, 6H), 8.19 (d, J ) 8.0 Hz, 2H), 8.82-8.87
(m, 8H); LD-MS obsd 686.4; FAB-MS obsd 686.3042, calcd
686.3046 (C48H38N4O); λabs 421, 516, 551, 594, 650 nm.
5-[4-(Hydroxymethyl)phenyl]-10,15,20-tri-p-tolylpor-
phyrin (1) (25 mM reactants). A sample of 4-SnBu2 (35.2
g, 50.0 mmol) was added to a 1-L, three-necked round-
bottomed flask equipped with a condenser, a pressure-
equalizing addition funnel, and a thermometer. Reagent grade
THF (200 mL) and NaBH4 (18.9 g, 0.500 mol) were added
under an inert atmosphere, followed by slow addition of
reagent grade MeOH (100 mL). The reaction temperature
rose and was kept between 35 and 45 °C during the addition
of methanol; a water-cooled bath was used to maintain the
temperature. After the addition was complete, the reaction
mixture was stirred and allowed to cool to room temperature.
The mixture was checked by TLC analysis (∼1.5 h) and
found to contain small amounts of starting material and the
partially reduced, 1-acyldipyrromethane-9-monocarbinol.
Therefore, more NaBH4 (9.47 g, 0.250 mol) was added
followed by slow addition of MeOH (50 mL). After 0.5 h,
at which point no starting material was detected by TLC
analysis, the reaction mixture was diluted with CH2Cl2 (250
mL). The resulting mixture was poured slowly into a mixture
of CH2Cl2/saturated aqueous NH4Cl (1:1.5 v/v, 2.5 L). The
biphasic mixture was stirred for 15 min. The layers were
separated. The organic layer was washed with water, dried
(Na2SO4), and filtered. The filtrate was diluted with reagent
grade CH2Cl2 (total volume ) 2.0 L). The resulting 4-diol
solution was added to a 3-L round-bottomed flask. Dipyr-
romethane 6 (12.6 g, 50.0 mmol) was added, and the mixture
was stirred for 5 min. A sample of 2,6-di-tert-butylpyridine
(DTBP; 14.7 mL, 65.0 mmol) was added followed by
addition of Sc(OTf)3 (3.20 g, 6.50 mmol). After 15 min, a
sample of p-chloranil (36.9 g, 150 mmol) was added in one
portion. The resulting black mixture was stirred for 30 min.
The reaction mixture was poured over a short column of
silica (500 g, 8 cm dia × 20 cm) with CH2Cl2/ethyl acetate
(97:3) as eluent containing 0.1% TEA. The product-contain-
ing fractions were combined and concentrated. A sample of
i-PrOH (500 mL) was added, and the suspension was stirred
at room temperature for 30 min. The solid was collected by
filtration and washed with MeOH until the washings were
1
colorless, affording a purple solid (3.78 g, 11%): H NMR
δ -2.76 (s, 2H), 2.71 (s, 9H), 5.08 (d, J ) 5.2 Hz, 2H).
7.55-7.57 (m, 6H), 7.76 (d, J ) 8.0 Hz, 2H), 8.09-8.11
312
•
Vol. 10, No. 2, 2006 / Organic Process Research & Development

Zn(II)-5-(4-Methoxycarbonylphenyl)-10,15,20-tri-p-
tolylporphyrin (Zn-2) (25 mM reactants). A sample of
4-SnBu2 (10.5 g, 15.0 mmol) was added to a three-necked,
1-L round-bottomed flask equipped with a condenser, a
pressure-equalizing addition funnel, and a thermometer.
Reagent grade THF (60 mL) and NaBH4 (5.68 g, 150 mmol)
were added under an inert atmosphere, followed by the slow
addition of reagent grade MeOH (30 mL) over a period of
10 min. The reaction temperature rose during the addition
of methanol and was kept between 35 and 45 °C through
the use of a water-cooling bath. After the addition was
complete, the reaction mixture was stirred and allowed to
cool to room temperature. The mixture was checked by TLC
analysis [alumina, CH2Cl2/methanol (97:3)] after ∼1 h and
found to contain small amounts of starting material and the
intermediate reduction product, the 1-acyldipyrromethane-
9-carbinol. Therefore, an additional quantity of NaBH4 (2.84
g, 75.0 mmol) was added, followed by the slow addition of
MeOH (15 mL). After 0.5 h, at which point no starting
material was detected by TLC analysis, the reaction mixture
was diluted with CH2Cl2 (100 mL). The resulting mixture
was poured slowly into a mixture of CH2Cl2/saturated
aqueous NH4Cl (1:1.5 v/v, 1.25 L). The biphasic mixture
was stirred for 15 min. The layers were separated. The
organic layer was washed with water, dried (Na2SO4), and
filtered. The filtrate was concentrated to give the dipyr-
romethane-dicarbinol 4-diol as a yellow foam. The flask
containing 4-diol was treated with reagent grade CH2Cl2 (600
mL) and dipyrromethane 5 (4.20 g, 15.0 mmol). The mixture
was stirred for ∼5 min to give a clear solution. A sample of
2,6-di-tert-butylpyridine (DTBP; 4.40 mL, 19.5 mmol) was
added followed by addition of Sc(OTf)3 (0.960 g, 1.95
mmol). After 10 min, a sample of p-chloranil (11.1 g, 45.0
mmol) was added in one portion. After 30 min, a solution
of Zn(OAc)2‚2H2O (9.87 g, 45.0 mmol) in methanol (180
mL) was added. The reaction mixture was then stirred at
room temperature under air for 1 h. Analysis by TLC and
fluorescence excitation spectroscopy indicated complete
metalation. The reaction mixture was washed with water (1
L). The organic layer was separated, dried (Na2SO4), and
concentrated to a volume of ∼20 mL. The resulting mixture
was passed over a silica column [250 g; 7.0 cm i.d. × 14
cm, CH2Cl2 f CH2Cl2/THF (10:1)]. The porphyrin-contain-
ing eluant was concentrated to give a purple solid. Methanol
was added to the solid. The resulting suspension was
sonicated (benchtop sonication bath) for 5 min. The suspen-
sion was filtered through a filter paper secured in a fritted
glass filter holder. The filtered material was washed (first
with methanol and second with hexanes) and then dried in
vacuo at room temperature, affording a purple solid (2.64 g,
22%): The characterization data (1H NMR, LD-MS, FAB-
MS, UV-vis) were in agreement with those from the product
of a previous synthesis.14
synthesis.23 The elemental analysis data are as follows: Anal.
Calcd for C16H16N2: C, 81.32; H, 6.82; N, 11.85. Found:
C, 81.07; H, 6.80; N, 11.78.
Dibutyl(5,10-dihydro-1,9-di-p-toluoyl-5-p-tolyldipyrri-
nato)tin(IV) (4-SnBu2). Samples of 3 (45.0 g, 190 mmol)
and toluene (385 mL) were placed in a 2-L three-necked
round-bottomed flask equipped with a pressure-equalizing
addition funnel and a mechanical overhead stirrer. The
mixture was cooled to 0 °C, whereupon 2,6-dimethylphe-
nylmagnesium bromide (800 mL, 0.8 mol, 1 M solution in
THF) was added dropwise, keeping the temperature of the
mixture below 15 °C. At the end of the addition, the mixture
was stirred for 30 min and cooled to 0 °C. A sample of
p-toluoyl chloride (53 mL, 400 mmol) was added dropwise,
keeping the temperature below 25 °C. The mixture was
stirred for 1 h after the addition. The solvent system hexanes/
CH2Cl2/ethyl acetate (3:6:1) was found to be an excellent
TLC solvent (on silica) for monitoring the progress of
diacylation reaction. The reaction was quenched by addition
of a mixture of saturated aqueous NH4Cl/ethyl acetate (1:1
v/v, 1 L). After 15 min, the layers were separated. The
organic layer was washed with saturated aqueous NH4Cl and
brine. The organic layer was dried (MgSO4), filtered, and
concentrated to a red oil. The oil was dissolved in ethyl
acetate (1.4 L) and added to a 2-L three-necked round-
bottomed flask equipped with an overhead stirrer. The
mixture was cooled to 15 °C, whereupon TEA (66 mL) was
added followed by Bu2SnCl2 (69.3 g, 230 mmol). After TLC
analysis showed the disappearance of 7 (about 1 h), the
reaction was quenched by addition of water. The layers were
separated. The organic layer was washed with brine, dried
(MgSO4), and filtered through a short pad of Celite. The
filtrate was concentrated to a dark oil and co-stripped with
MTBE. Crystallization of the residue from a mixture of
MTBE/MeOH (1:3, v/v) yielded the tin complex as a brown
powder (93 g, 70% yield, >97% pure). Recrystallization
from a mixture of MTBE/MeOH (1:2 v/v) yielded the title
compound as a tan powder (79 g, 60%). Characterization
data (1H NMR, 13C NMR, mp, elemental analysis) were
consistent with the literature.7 This reaction also was
successfully implemented on a 1 mol scale to yield 361 g
(50%) of the title compound.
5-(4-Methoxycarbonylphenyl)dipyrromethane (5). Com-
pound 5 was prepared in 66% yield (0.17 mol scale)
following the literature procedure19 but at a 50:1 pyrrole/
aldehyde ratio and with a toluene co-strip during workup
(as described for 6). The characterization data were in
agreement with those from the product of previous synthe-
ses.19,31 Characterization data are as follows: mp 160-162
1
°C; H NMR δ 3.90 (s, 3H), 5.51 (s, 1H), 5.89-5.90 (m,
2H), 6.15-6.18 (m, 2H), 6.71-6.72 (m, 2H), 7.27-7.29 (m,
2H), 7.94-7.99 (m, 4H); 13C NMR δ 44.1, 52.3, 107.7,
108.8, 117.7, 128.6, 129.0, 130.1, 131.7, 147.5, 167.1;
FABMS obsd 280.1209, calcd 280.1212 (C17H16N2O2). Anal.
Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found:
C, 72.58; H, 5.78; N, 9.97.
5-p-Tolyldipyrromethane (3). Compound 3 was prepared
in 60% yield (0.42 mol scale) following the literature
procedure19 but at a 50:1 pyrrole:aldehyde ratio and with a
toluene co-strip during workup (as described for 6). The
characterization data (1H NMR, 13C NMR, mp, FAB-MS)
were in agreement with those from the product of a previous
(31) Bru¨ckner, C.; Zhang, Y.; Rettig, S. J.; Dolphin, D. Inorg. Chim. Acta 1997,
263, 279-286.
Vol. 10, No. 2, 2006 / Organic Process Research & Development
•
313

5-[4-(Hydroxymethyl)phenyl]dipyrromethane (6). Fol-
lowing a standard procedure but using 50 mol equiv of
pyrrole,19 aldehyde 7 (60.0 g, 0.44 mol) and pyrrole (1.5 L,
22 mol) were added to a 3-L, three-neck round-bottomed
flask equipped with a mechanical overhead stirrer. The
mixture was stirred under Ar. When a clear solution was
obtained, InCl3 (8.9 g, 40 mmol) was added, and the mixture
was stirred for 1.5 h. The reaction was quenched by addition
of NaOH beads (53 g, 1.3 mol). The mixture was stirred for
1.5 h. The reaction mixture was allowed to settle over 20
min. The reaction mixture was filtered through Celite. The
filtrate was concentrated under vacuum to give an oil,
recovering the majority of excess pyrrole. The remaining
traces of pyrrole were removed via three toluene costrips (3
× 100 mL). A viscous oil remained. Attempts to obtain a
solid from the crude mixture were not successful; therefore,
the mixture was diluted with MeOH and passed through a
silica gel column [CHCl3/MeOH (98:2); (7.6 cm × 20 cm)].
The product-containing fractions were concentrated to afford
a bright yellow solid. Recrystallization of the latter from a
mixture of toluene/EtOH (10:1 v/v) yielded a light-brown
Anal. Calcd for C16H16N2O: C, 76.16; H, 6.39; N, 11.10.
Found: C, 76.18; H, 6.37; N, 11.07.
4-(Hydroxymethyl)benzaldehyde (7). Terephthalalde-
hyde (20.0 g, 150 mmol), i-PrOH (100 mL) and 5% Pd/C
(0.15 g) were added to a 500-mL Parr hydrogenation bottle.
The mixture was purged with hydrogen, and the slurry was
shaken under hydrogen at 25 psi for 6 h at room temperature.
The reaction was monitored by TLC analysis [silica, hexanes/
ethyl acetate/acetic acid (20:10:1)]. When less than 2% of
terephthalaldehyde was detected by TLC/GC analysis, the
catalyst was removed by filtration through Celite. The filtrate
was concentrated to an oil. The crude oil was crystallized
with MTBE/hexanes (1:1 v/v), yielding a white solid (17.7
g, 87%). Characterization data for this sample were consistent
with the literature data (1H NMR,24,25 13C NMR,24 mp,32
elemental analysis25) as well as the expected FAB-MS
analysis.
Acknowledgment
We thank Dr. Ignacio Sanchez for technical advice. This
work was funded by ZettaCore, Inc., and by a grant to J.S.L.
from the NIH (GM36238). Mass spectra were obtained at
the Mass Spectrometry Laboratory for Biotechnology. Partial
funding for the Facility was obtained from the North Carolina
Biotechnology Center and the National Science Foundation.
1
solid (79 g, 71%): mp 103-104 °C; H NMR δ 4.67 (s,
2H), 5.47 (s, 1H), 5.89 (s, 2H), 6.14 (q, J ) 2.9 Hz, 2H),
6.69 (m, 2H), 7.19-7.32 (m, 4H), 7.91 (br, 2H);13C NMR
δ 43.8, 65.2, 107.3, 108.5, 117.4, 127.5, 128.7, 132.6, 139.6,
141.8; FABMS obsd 252.1249, calcd 252.1263 (C16H16N2O).
Received for review December 21, 2005.
OP0502553
(32) Endtner, R.; Rentschler, E.; Bla¨ser, D.; Boese, R.; Sustmann, R. Eur. J.
Org. Chem. 2000, 3347-3352.
314
•
Vol. 10, No. 2, 2006 / Organic Process Research & Development