Investigation of streamlined syntheses of porphyrins bearing distinct meso substituents

Article abstract of DOI:10.1021/op050193g

The use of porphyrins in fundamental studies and diverse applications requires facile access to ample quantities of material in pure form. The existing conditions for the condensation of a dipyrromethane plus a dipyrromethane-dicarbinol employ 2.5 mM reac

Full text of DOI:10.1021/op050193g

Organic Process Research & Development 2006, 10, 118−134
Investigation of Streamlined Syntheses of Porphyrins Bearing Distinct Meso
Substituents
Syeda Huma H. Zaidi, Rosario M. Fico, Jr., and Jonathan S. Lindsey*
Department of Chemistry, North Carolina State UniVersity, Raleigh, North Carolina 27695-8204, U.S.A.
Chart 1
Abstract:
The use of porphyrins in fundamental studies and diverse
applications requires facile access to ample quantities of
material in pure form. The existing conditions for the conden-
sation of a dipyrromethane plus a dipyrromethane-dicarbinol
employ 2.5 mM reactants and afford ∼30% yields with no
detectable scrambling. Large-scale syntheses require condensa-
tion and oxidation conditions that function at higher concentra-
tions. Thirty-one acids (plus additives) have been examined for
reactions at 25 mM reactants using the synthesis of a trans-
A2B2-porphyrin as a model. The porphyrin was formed in
∼20% yield upon condensation in CH2Cl2 at room temperature
using (1) Sc(OTf)3 (3.2 mM) + 2,6-di-tert-butylpyridine (32
mM), or (2) Zn(OTf)2 (10 mM). Nine porphyrins were prepared
in this manner in yields of 15-22% with no detectable
scrambling, whereas three other porphyrins afforded low levels
of scrambling and/or lower yields (8-14%). Conditions for the
oxidation also have been investigated. The reaction of 5-mesi-
tyldipyrromethane and the dicarbinol derived from 1-(4-
methoxybenzoyl)-9-(4-methylbenzoyl)-5-phenyldipyr-
romethane (18 mmol each in 720 mL of CH2Cl2; 25 mM) with
catalysis by Sc(OTf)3/2,6-di-tert-butylpyridine and aerobic oxi-
dation [(t-Bu4FePc)2O and DDQ, 2.5 mol % each with a stream
of O2] afforded 2.88 g (22.8% yield) of the corresponding
ABCD-porphyrin. The present synthesis (25 mM), at 4.5-times
larger scale than the largest prior analogous synthesis (2.5 mM
reactants with stoichiometric use of DDQ), afforded 4.0 times
as much porphyrin on a molar basis while employing about
one-half the amount of solvent and <1/25 the amount of DDQ.
A three-step one-flask process also was developed that employs
(i) condensation at 25 mM reactants, (ii) aerobic oxidation, and
(iii) metal insertion to afford the metalloporphyrin [Mg(II), Ni-
(II), Cu(II), Zn(II), Pd(II)] in a streamlined manner. Taken
together, the various improvements facilitate gram-scale syn-
theses of diverse porphyrins.
1,9-diacyldipyrromethanes are precursors for cis-A2B2-, cis-
A2BC-, and ABCD-porphyrins (4). Simple procedures are
now available for the preparation of dipyrromethanes,1
1-acyldipyrromethanes,2 and 1,9-diacyldipyrromethanes3,4 at
high concentration and in g10-20-g quantities with limited
or no chromatography. On the other hand, the porphyrin-
forming reaction is carried out in dilute solution, employing
2.5 mM each of a dipyrromethane and a dipyrromethane-
dicarbinol.5 Consequently, a 100-mL reaction that proceeds
Introduction
Porphyrins bearing meso substituents are crucial building
blocks in biomimetic and materials chemistry. The quantity
of such porphyrins that can be readily obtained is closely
tied to the availability of the corresponding precursors,
including dipyrromethanes (1), 1-acyldipyrromethanes (2),
and 1,9-diacyldipyrromethanes (3) (Chart 1). Symmetrical
1,9-diacyldipyrromethanes serve as precursors to A3B-, trans-
A2B2-, and trans-AB2C-porphyrins, whereas unsymmetrical
(1) Laha, J. K.; Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.; Lindsey, J. S.
Org. Process Res. DeV. 2003, 7, 799-812.
(2) Muthukumaran, K.; Ptaszek, M.; Noll, B.; Scheidt, W. R.; Lindsey, J. S. J.
Org. Chem. 2004, 69, 5354-5364.
(3) Tamaru, S.-I.; Yu, L.; Youngblood, W. J.; Muthukumaran, K.; Taniguchi,
M.; Lindsey, J. S. J. Org. Chem. 2004, 69, 765-777.
(4) Zaidi, S. H. H.; Muthukumaran, K.; Tamaru, S.-I.; Lindsey, J. S. J. Org.
Chem. 2004, 69, 8356-8365.
* To whom correspondence should be addressed. E-mail: jlindsey@
ncsu.edu.
(5) Rao, P. D.; Dhanalekshmi, S.; Littler, B. J.; Lindsey, J. S. J. Org. Chem.
2000, 65, 7323-7344.
118
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10.1021/op050193g CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/08/2005

Scheme 1
tration revealed that (1) the highest yield of porphyrin is
achieved upon condensation at ∼10 mM reactants,6 (2)
increasing the concentration (>10 mM) of reactants while
keeping the concentration of acid fixed (at the value found
optimal for 10 mM reactants) results in a decline in yield,6
and (3) the decline in yield with increasing concentration of
reactants can be mitigated partially by a commensurate
increase in acid concentration.10,11
The second consideration lies in the challenge of identify-
ing acid-catalysis conditions that afford condensation without
altering the integrity of the pattern of meso substituents in
the reacting components. The substituent patterns of a
dipyrromethane or a dipyrromethane-carbinol are vulner-
able upon exposure to acid.12 Indeed, acidolysis of dipyr-
romethane, dipyrromethane-dicarbinol, or polypyrrane spe-
cies followed by undesired recombination of the fragmen-
tation products (to form undesired polypyrrane or por-
phyrinogen species) leads to a mixture of porphyrin prod-
ucts.13 Such “scrambling” processes must be expressly
avoided in any rational synthesis of porphyrins. Given the
difficulty of separating mixtures of porphyrins, preventing
scrambling is generally a more important objective in
porphyrin chemistry than achieving a high yield of reaction.
After lengthy study, two sets of conditions were identified
that afford no detectable scrambling in the condensation of
a dipyrromethane + a dipyrromethane-dicarbinol (or the
self-condensation of a dipyrromethane-1-carbinol): (1) con-
densation in CH3CN containing TFA at room temperature5,14
and (2) condensation in CH2Cl2 containing a mild Lewis acid
[(Yb(OTf)3, Dy(OTf)3, Sc(OTf)3, or InCl3] at room temper-
ature.15 The latter conditions afford modest yield (15-40%)
and convenient workup. However, both conditions were
identified for condensation with 2.5 mM reactants, a
concentration chosen to give identical concentrations of
pyrrolic species as in the 10 mM pyrrole + aldehyde
condensation. Although the reactions generally proceed with
no detectable scrambling, such a modest reaction concentra-
tion crimps applications where sizable quantities of porphy-
rins are required.
in 30% yield would afford only 60 mg of a porphyrin having
a molecular weight of 800 Da.
There are two considerations that have led to the use of
dilute-solution conditions in the porphyrin-forming reaction,
both of which have a bearing on the acid-catalyzed conden-
sation rather than the oxidation step of the overall process:
The first consideration lies in the competition between
cyclization and polymerization that is inherent in the “2 +
2” condensation of a dipyrromethane plus a dipyrromethane-
dicarbinol. The first step yielding the bilane is an intermo-
lecular process, which increases in rate with increasing
concentration. The second step entails intramolecular cy-
clization of the bilane to give the porphyrinogen, which is
in competition with intermolecular condensation to give
higher oligomers (Scheme 1). Given that one intermolecular
reaction precedes intramolecular cyclization, and the latter
is in competition with continued intermolecular polymeri-
zation, it is expected that the highest yield of the porphy-
rinogen would be observed at modest concentrations.6,7 This
expectation has been observed in the pyrrole + aldehyde
condensation, where analogous cyclization/polymerization
issues also are extant. Studies of the room-temperature
pyrrole + aldehyde condensation8,9 as a function of concen-
In this contribution we describe the investigation of
conditions for the synthesis of meso-substituted porphyrins
at concentrations higher than those employed previously. The
use of high concentrations of reactants (dipyrromethane and
dipyrromethane-dicarbinol) lessens solvent consumption and
the time required for reaction workup. A lengthy study has
been performed of the acid-catalyzed condensation of a
dipyrromethane + dipyrromethane-dicarbinol to achieve the
highest possible yield without detectable scrambling. The
(9) Geier, G. R., III; Lindsey, J. S. J. Chem. Soc., Perkin Trans. 2 2001, 687-
700.
(10) Lindsey, J. S.; MacCrum, K. A.; Tyhonas, J. S.; Chuang, Y.-Y. J. Org.
Chem. 1994, 59, 579-587.
(11) Wagner, R. W.; Li, F.; Du, H.; Lindsey, J. S. Org. Process Res. DeV. 1999,
3, 28-37.
(12) Geier, G. R., III; Littler, B. J.; Lindsey, J. S. J. Chem. Soc., Perkin Trans.
2 2001, 712-718.
(13) Geier, G. R., III; Littler, B. J.; Lindsey, J. S. J. Chem. Soc., Perkin Trans.
2 2001, 701-711.
(6) Lindsey, J. S.; Schreiman, I. C.; Hsu, H. C.; Kearney, P. C.; Marguerettaz,
A. M. J. Org. Chem. 1987, 52, 827-836.
(7) 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.
(14) Littler, B. J.; Ciringh, Y.; Lindsey, J. S. J. Org. Chem. 1999, 64, 2864-
2872.
(8) Geier, G. R., III; Lindsey, J. S. J. Chem. Soc., Perkin Trans. 2 2001, 677-
(15) Geier, G. R., III; Callinan, J. B.; Rao, P. D.; Lindsey, J. S. J. Porphyrins
Phthalocyanines 2001, 5, 810-823.
686.
Vol. 10, No. 1, 2006 / Organic Process Research & Development
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119

Chart 2
distribution of products [porphyrin and N-confused porphyrin
(5, Chart 1)] also has been characterized. In addition to
studies of the acid-catalyzed condensation, conditions for the
oxidation as well as in situ metalation to afford the
metalloporphyrin have been investigated. Taken together, the
procedures described herein enable more rapid and facile
preparation of meso-substituted porphyrins bearing distinct
patterns of substituents.
Scheme 3
Results and Discussion
I. Acid-catalysis Conditions at Higher Concentration.
I.A. Background. Our approach was guided by studies of
the pyrrole + aldehyde condensation, where the yield
declined by less than 2-fold upon a 10-fold increase (from
10 to 100 mM) in reactant concentration and use of
commensurably higher concentrations of acid.10,11 Accord-
ingly, we chose 25 mM as the target concentration for the
dipyrromethane + dipyrromethane-dicarbinol reaction, which
corresponds to a 100 mM pyrrole + aldehyde condensation.
In seeking to identify acid catalysis conditions suitable for
the 25 mM condensation, avoiding scrambling (which is not
an issue in the pyrrole + aldehyde condensation) was of
paramount concern.
The mechanism of acidolytic scrambling is believed to
proceed by protonation of a dipyrromethane species, liberat-
ing the pyrrole and an azafulvene species, which upon
undesired recombination can yield scrambled porphyrin
products.13,16 In principle, such protonation cannot occur upon
strict Lewis acid catalysis. In practice however, the use of a
Lewis acid is often accompanied by Brønsted acid catalysis
owing to the presence of water in the reaction mixture.17
The formation of a Brønsted acid catalyst is shown in Scheme
2.18 The concentration of H2O in reagent-grade CH2Cl2
typically is ∼8-10 mM.19 While the residual water in CH2-
Cl2 can be removed in a variety of ways, the presence of
water in the reaction mixture is not easily avoided in a
condensation; for example, for 25 mM reactants the con-
centration of water formed upon complete condensation is
50 mM.
Scheme 2
effect in porphyrin chemistry.21 In principle, molecular sieves
also should be quite effective, but complications can arise,
given that molecular sieves are typically composed of
aluminosilicates, which can function as acid buffers (i.e., ion-
exchange resins). Both approaches were investigated herein.
I.B. Survey. A survey of acid catalysts was carried out
using the model reaction of 5-phenyldipyrromethane (1a) and
the dicarbinol derived from 5-phenyl-1,9-di-p-toluoyldipyr-
romethane (3a-OH) at 25 mM each in CH2Cl2 at room
temperature (Scheme 3). The reactions were monitored over
time (1, 5, 15, 60, and 90 min) by removing an aliquot,
oxidizing the aliquot with DDQ, and collecting the absorption
spectrum of the oxidized sample to determine the spectro-
Two approaches to suppress acidolysis in a Lewis-acid-
catalyzed dipyrromethane condensation entail the inclusion
of a Brønsted-acid scavenger such as 2,6-di-tert-butylpyri-
dine20 (DTBP, Chart 2), or the inclusion of a desiccant such
as molecular sieves. The former has been employed to good
(16) Chevalier, F.; Geier, G. R., III; Lindsey, J. S. J. Porphyrins Phthalocyanines
2002, 6, 186-197.
(17) Barrett, A. G. M.; Braddock, D. C.; Henschke, J. P.; Walker, E. R. J. Chem.
Soc., Perkin Trans. 1 1999, 873-878.
(18) Kobayashi, S.; Hachiya, I. J. Org. Chem. 1994, 59, 3590-3596.
(19) Li, F.; Yang, K.; Tyhonas, J. S.; MacCrum, K. A.; Lindsey, J. S. Tetrahedron
1997, 53, 12339-12360.
(21) Speckbacher, M.; Yu, L.; Lindsey, J. S. Inorg. Chem. 2003, 42, 4322-
(20) Brown, H. C.; Kanner, B. J. Am. Chem. Soc. 1966, 88, 986-992.
4337.
120
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Vol. 10, No. 1, 2006 / Organic Process Research & Development

Table 1. Survey of diverse acids in the condensation of 1a + 3a-OH (25 mM each in CH2Cl2)
% yield
% yield
(scrambling
level)b
time
(scrambling
time
entry
acid (mM)a
additive (mM) (min)
level)b
entry
acid (mM)a
additive (mM) (min)
1
2
3
4
5
6
7
8
BF3‚OEt2 (10)
BF3‚OEt2 (10)
MgBr2 (10)
Mg(OTf)2 (10)
TMSOTf (10)
TMSOTf (10)
TMSOTf (50)
CaCl2 (10)
Sc(OTf)3 (3.2)
Sc(OTf)3 (10)
FeBr3 (10)
Fe(ClO4)3 (10)
CuCl2 (25)
-
1
1
90
90
1
5
5
60
15
5
15
15
15
15
60
90
90
90
60
60
60
60
15
90
26 (3)
26 (3)
6
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
AgOTf (10)
InCl3 (10)
InBr3 (3.2)
In(OTf)3 (10)
SnCl4 (25)
-
90
5
7
NaCl (625)
-
12 (1)
17 (2)
22 (2)
9
3
20
25 (1)
20 (0)
13 (0)
3
16 (0)
16 (0)
16 (2)
18 (2)
22
22 (0)
24
25 (2)
11
-
-
-
15
15
90
90
15
1
-
7
-
26 (2)
7
13
Et3N (100)
DTBP (25)
SnCl2 (10)
-
DTBP (125)
Sn(OTf)2 (3.2)
Sn(OTf)2 (10)
Sn(OTf)2 (10)
Sn(OTf)2 (25)
La(OTf)3 (10)
Sm(OTf)3 (10)
Eu(OTf)3 (10)
Dy(OTf)3 (10)
Yb(OTf)3 (3.2)
Yb(OTf)3 (10)
Yb(OTf)3 (32)
Hf(OTf)4 (3.2)
Hf(OTf)4 (10)
BiCl3 (10)
-
-
1
-
9
-
20 (0)
22 (0)
17 (2)
20 (2)
22 (2)
13
MS 4Åd
1
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
-
DTBP (250)
-
-
90
15
60
15
60
60
15
60
1
90
5
5
15
15
90
-
-
-
-
CuOTf (10)
Cu(OTf)2 (10)
-
-
-
-
19 (0)
6
-
NH4Cl (250)
-
-
Bu4NCl (10)
Bu4NCl (10)
NDc
2
-
ZnCl2 (10)
-
Zn(OTf)2 (10)
Zn(OTf)2 (10)
Zn(OTf)2 (10)
Ga(OTf)3 (10)
Y(OTf)3 (3.2)
Pd(OCOCF3)2 (10)
-
22 (0)
10
9
20 (3)
20 (0)
4
-
Bu4NCl (10)
-
Ph4NCl (10)
Bi(OTf)3 (1.0)
Bi(OTf)3 (3.2)
Bi(OTf)3 (3.2)
Bi(OTf)3 (10)
ionic liquide
-
24 (1)
29 (1)
20 (0)
28 (2)
7.4 (3)
-
-
-
-
DTBP (32)
-
a
b
In this and subsequent tables, the quantity of acid is denoted by molarity even though the acid may not be completely dissolved
The yield and scrambling
e
level14 are reported for the data point collected at the time indicated. Not detected. The quantity of molecular sieves was 8-fold (w/w) relative to 3a-OH. The
ionic liquid 3-butyl-1-(4-sulfobutyl)imidazolium triflate28 was used in equal volume with CH2Cl2 as described for a pyrrole + aldehyde condensation.25
c
d
scopic yield of the reaction. The reactions also were
monitored for scrambling by examination of reaction aliquots
by laser-desorption mass spectrometry (LD-MS) using a scale
from level 0 (no detectable scrambling) to level 4 (complete
scrambling).14 The combination of phenyl and p-tolyl sub-
stituents allows resolution of scrambled porphyrins upon LD-
MS while minimizing steric and electronic differences. The
yield of N-confused porphyrin was determined by HPLC.22
Thirty-one Lewis acids were screened with and without
additives. The Lewis acids were chosen from three general
categories, including (1) acids previously used in porphyrin
synthesis,15,23-25 (2) acids used in organic reactions such as
condensations of carbonyl-containing compounds, and (3)
acids that are water-stable such as rare-earth triflates and
lanthanide triflates.26 The additives include 2,6-di-tert-
butylpyridine (DTBP), molecular sieves 4 Å or 3 Å, and a
variety of salts. Salts have been found to serve as cocatalysts
with BF3‚O(Et)2 in pyrrole + aldehyde condensations.19,27
Several salts, including an ionic liquid,28 also were investi-
gated as catalysts in the absence of Lewis acids.
The data are summarized in Table 1. The yield data
reported are for the highest yield observed during the course
of reaction. In some cases, the yields plateaued and remained
constant over time, while in other cases the yields peaked
and then declined. The constant yield over time typically
was accompanied by little or no scrambling (level 0 or 1);
on the other hand, any decline in yield over time typically
was accompanied by a higher level of scrambling. The data
from the acid screening enabled categorization of the acids:
(1) Acids with good yield (g20%) but scrambling: BF3‚
O(Et)2, TMSOTf, Fe(ClO4)3, CuCl2, Ga(OTf)3, In(OTf)3, Hf-
(OTf)4, and Bi(OTf)3.
(2) Acids with poor yield (<20%): MgBr2, Mg(OTf)2,
CaCl2, FeBr3, CuOTf, ZnCl2, Pd(OCOCF3)2, AgOTf, InCl3,
InBr3, SnCl2, SnCl4, La(OTf)3, Dy(OTf)3, BiCl3, and an ionic
liquid (3-butyl-1-(4-sulfobutyl)imidazolium triflate).
(3) Acids with reasonable yield (∼15-20%) and no
scrambling: Sc(OTf)3, Cu(OTf)2, Zn(OTf)2, Y(OTf)3, Sn-
(OTf)2, Sm(OTf)3, Eu(OTf)3, and Yb(OTf)3.
Three acids from the latter set [Sc(OTf)3, Zn(OTf)2, and
Sn(OTf)2] were selected for further study. A more in-depth
study of the effects of various reaction parameters was carried
out using Sc(OTf)3, owing in part to its high solubility in
CH2Cl2 versus that of Zn(OTf)2 and Sn(OTf)2. Unless stated
otherwise, each reaction of 1a + 3a-OH (25 mM each) was
carried out in CH2Cl2 containing 10 mM Sc(OTf)3 at room
temperature.
(22) Geier, G. R., III; Lindsey, J. S. J. Org. Chem. 1999, 64, 1596-1603.
(23) Geier, G. R., III; Ciringh, Y.; Li, F.; Haynes, D. M.; Lindsey, J. S. Org.
Lett. 2000, 2, 1745-1748.
(24) Geier, G. R., III; Lindsey, J. S. J. Porphyrins Phthalocyanines 2002, 6,
159-185.
(25) Kitaoka, S.; Nobuoka, K.; Ishikawa, Y. Chem. Commun. 2004, 1902-1903.
(26) Yamamoto, H., Ed. Lewis Acids in Organic Synthesis; Wiley-VCH Verlag
GmbH: Weinheim, Germany, 2000.
(27) Geier, G. R., III; Riggs, J. A.; Lindsey, J. S. J. Porphyrins Phthalocyanines
2001, 5, 681-690.
I.B.1. Amount of Sc(OTf)3. The yield observed at 1 min
increased with an increase in the amount of Sc(OTf)3 from
(28) Cole, A. C.; Jensen, J. L.; Ntai, I.; Tran, K. L. T.; Weaver, K. J.; Forbes,
D. C.; Davis, J. H., Jr. J. Am. Chem. Soc. 2002, 124, 5962-5963.
Vol. 10, No. 1, 2006 / Organic Process Research & Development
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121

Table 2. Time course data for selected acids in the
condensation of 1a + 3a-OH (25 mM each in CH2Cl2)a
% yield (scrambling level)
at given times
entry
acidb
additive 1 min 5 min 15 min 1 h 1.5 h
1
2
3
4
5
Sc(OTf)3 DTBPc 15
22
15 (0)
22
14
19
10
18
23 (0) 23
15 (1) 13
18 (0) 18
11 (1) 11
Sc(OTf)3 MS 4Åd 15
Sn(OTf)2 MS 4Åd 20 (0) 21
e
Sn(OTf)2 DTBPc
Zn(OTf)2
9
11
11 (0)
20 (0)
-
-
22 (0)
Figure 1. Yield of porphyrin 4a as a function of time upon
condensation of 1a + 3a-OH (25 mM each) under various acid
catalysis conditions. One reaction with 10 mM Sc(OTf)3
contained 100 mM DTBP (2,6-di-tert-butylpyridine). The reac-
tions were performed in CH2Cl2 at room temperature. The yield
of porphyrin was determined spectroscopically.
a Each reaction was performed at 25 mM reactants in CH2Cl2 at room
temperature. b 10 mM each. c 100 mM. d The quantity of molecular sieves was
8-fold (w/w) relative to 3a-OH. e Scrambling was detected when the reaction
was carried out at 5-times larger scale.
prior studies of pyrrole + aldehyde condensations, the
N-confused porphyrin was found to be a ubiquitous byprod-
uct present in quantities one-fifth to one-tenth that of the
porphyrin.9,22,24
3.2 to 32 mM (Figure 1). [The acid may not be entirely
dissolved; however, the molarity term is used herein for ease
of comparison with the concentration of reactants.]
We examined the amount of N-confused porphyrin formed
under the new reaction conditions (25 mM reactants), where
the yield of porphyrin was ∼20%. A small amount of
N-confused porphyrin (<0.5%) was detected with each of
the best acid-catalysis conditions (Table 3, entries 1-4). Note
that the formation of the N-confused porphyrin does not stem
from a scrambling process (i.e., the dipyrromethane and
dipyrromethane-dicarbinol remain intact) but instead results
from reaction at the â-position of the dipyrromethane. In
addition, the amount of N-confused porphyrin formed in the
prior, low-concentration (2.5 mM) conditions also was
examined. The five conditions include the following: Yb-
(OTf)3, Dy(OTf)3, Sc(OTf)3, or InCl3 (in CH2Cl2);15 or TFA
in acetonitrile.5 The yield of N-confused porphyrin had
previously been examined upon catalysis with TFA (and
found to be <1% after 1 h)12 but not with the mild Lewis
acids. In each of the five acid-catalysis conditions, the yield
of porphyrin was ∼30%, whereas the yield of N-confused
porphyrin was e1.4% (entries 5-9). Thus, the condensation
performed at higher concentration (25 vs 2.5 mM) affords
no increase in the yield of N-confused porphyrin. Regardless,
N-confused porphyrins are more polar than the corresponding
porphyrin and are readily removed by crystallization or
passage of the crude reaction mixture over a pad of
chromatographic media.
I.D. Semipreparative Synthesis. To confirm key analyti-
cal-scale experiments, semipreparative reactions were per-
formed, and the yield of isolated porphyrin was determined.
In each case, the reaction of 3a-OH + 1a was carried out
with 0.25 mmol of each reactant (25 mM) in CH2Cl2 at room
temperature. The reactions were monitored spectroscopically
to determine when the condensation leveled off, and then
DDQ was added, and the porphyrin product was purified.
I.D.1. The reaction in the presence of Sc(OTf)3 (10 mM)
and DTBP (100 mM) afforded porphyrin in a spectroscopic
yield of 23% by 15 min. Upon filtration through a single
alumina pad with CH2Cl2 elution, porphyrin 4a was obtained
in 21% yield with no detectable scrambling. Essentially
identical results were obtained upon reaction at the 1 mmol
scale using 3.25 mM Sc(OTf)3 and 32.5 mM DTBP.
I.B.2. Effect of a Proton Scavenger. The inclusion of
DTBP had little effect on the rate or yield of reaction (Figure
1), and, again, scrambling was not detected. By contrast, the
more dilute reaction at 2.5 mM reactants with a mild Lewis
acid and DTBP gave a much slower rate than that without
DTBP. The slower rate in the latter case was attributed to
Lewis acid catalysis alone versus concurrent catalysis by the
added Lewis acid and a Brønsted acid formed in situ.21
I.B.3. Temperature. The reaction at -78 °C give 17%
yield after 5 min.
I.B.4. Other Additives. The inclusion of molecular sieves
slowed the reaction and gave a lower yield. Other additives
examined such as salts or the use of lower temperature gave
either lower yields, or higher yields accompanied by
scrambling (see Supporting Information).
I.B.5. Solvents. The acid Sc(OTf)3 has been reported to
function effectively in aqueous solutions.18 The reaction was
attempted in water containing a surfactant, as reported by
Bonar-Law for pyrrole + aldehyde condensations,29 but the
yield was only 2%. Other solvents spanning a range of static
dielectric constants (∼2-37 for toluene to acetonitrile) gave
yields of <15% (see the Supporting Information).
In summary, the best conditions for porphyrin formation
with Sc(OTf)3 employ the acid at 3.25 or 10 mM and DTBP
at 32.5 or 100 mM. The timecourse data for Sc(OTf)3, Sn-
(OTf)2, and Zn(OTf)2 (including use of DTBP or molecular
sieves) are listed in Table 2. Sc(OTf)3 gave no detectable
scrambling with DTBP even after 1 h of condensation, while
with molecular sieves after 1 h there was level 1 scrambling
(entries 1 and 2). On the other hand, Sn(OTf)2 with molecular
sieves gave no detectable scrambling even after 1 h, while
Sn(OTf)2 with DTBP gave level 1 scrambling after 1 h
(entries 3 and 4). With Zn(OTf)2, no additive was required
for moderate yield with no detectable scrambling (entry 5).
I.C. Distribution of Porphyrins and N-confused Por-
phyrins. Condensations leading to porphyrins are known to
give other pyrrolic macrocycles, including the corresponding
N-confused porphyrin (i.e., 5, Chart 1) and sapphyrin. In our
(29) Bonar-Law, R. P. J. Org. Chem. 1996, 61, 3623-3634.
122
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Vol. 10, No. 1, 2006 / Organic Process Research & Development

Table 3. Product distribution under various reaction conditionsa
acid
(mM)
concentration,
mM
time,
min
% yield
of 4a
% yield
of 5a
scrambling
(level)
entry
additive
1
2
3
4
5
6
7
8
9
Sc(OTf)3 (3.2)
Sc(OTf)3 (10)
Sn(OTf)2 (10)
Zn(OTf)2 (10)
Yb(OTf)3 (3.2)
Dy(OTf)3 (1.0)
Sc(OTf)3 (0.32)
InCl3 (0.32)
DTBPb
25
25
25
25
2.5
2.5
2.5
2.5
2.5
15
15
15
15
15
60
15
15
15
21
22
22
18
33
31
33
26
31
0.2
0.3
0.5
0.3
0.9
0.8
1.4
0.9
0.5
0
0
0
0
0
0
0
0
0
DTBPc
MS 4Åd
-
-
-
-
-
-
TFA (30)e
a
All reactions were performed in CH2Cl2 unless noted otherwise. b 32 mM. c 100 mM. d The quantity employed was 8-fold (w/w) relative to 3a-OH. e Performed
in CH3CN.
Scheme 4
I.D.2. The reaction in the presence of Sn(OTf)2 (10 mM)
and molecular sieves (8-fold w/w with respect to 3a-OH)
and similar workup gave porphyrin 4a in 19% yield with
level 1 scrambling.
I.D.3. The reaction in the presence of Zn(OTf)2 (10 mM)
gave a spectroscopic yield of 22% after 15 min. Similar
workup gave porphyrin 4a in 21% yield with no detectable
scrambling.
Thus, both Sc(OTf)3 and Zn(OTf)2 gave porphyrin 4a in
∼20% yield with no detectable scrambling. The isolation of
the porphyrin was straightforward. No N-confused porphyrin
was detected in the isolated porphyrin product upon HPLC
analysis.
II. Scope of Application of Catalysis Conditions. The
conditions using Sc(OTf)3 (3.25 mM) and DTBP (32.5 mM)
were applied to a wider array of dipyrromethane-dicarbinols
and dipyrromethanes. In addition to the previously examined
phenyl and p-tolyl groups, substituents included the more
challenging cases of alkyl groups, electron-releasing groups,
and substrates lacking substituents. Dipyrromethanes bearing
distinct substituents including phenyl (1a),1 4-methoxyphenyl
(1b),1 pentafluorophenyl (1c),1 4-iodophenyl (1d),30 no
substituent (dipyrromethane itself, 1f),1 and mesityl (1g)1
were prepared as described in the literature by reaction of
an aldehyde with excess pyrrole under a refined procedure.
The procedure entails solventless condensation in the pres-
ence of a mild Lewis acid (e.g., InCl3) with workup that
relies on crystallization (avoiding any aqueous-organic
extraction or chromatography).1 5-(4-Methylphenyl)dipyr-
romethane (1e), prepared by earlier small-scale procedures
with more cumbersome workup methods,31,32 was prepared
herein by the refined route at the 0.15 mol scale, affording
27 g of 1e (76%) upon crystallization. Many of the requisite
1,9-diacyldipyrromethanes (3) have been prepared previously
(3a,4 3c,5 and 3e33), while others were previously obtained
as the 9-BBN complexes (3-BBN). The latter (3b-BBN,4 3d-
BBN,4 and 3f-BBN-3h-BBN4) were decomplexed in a
straightforward manner (Scheme 4). The structures of the
various 1,9-diacyldipyrromethanes are conveyed in Table 4.
The results of the condensations are shown in Table 4.
The use of various dipyrromethane species enabled examina-
tion of 12 different substituents. Generally, the yields were
in the 15-22% range with no detectable scrambling. Three
exceptions occurred where lower yields were observed with
dipyrromethane-dicarbinols bearing the following substit-
uents: two anisyl groups (3g), a pentafluorophenyl group at
the carbinol carbon (3h), or no meso substituent (3f).
Reactions with the latter compounds provided the only
instances where a trace of scrambling was observed, and the
resulting porphyrin products were not fully characterized.
III. Oxidation Conditions. III.A. Bulk Oxidations with
Quinones. One set of experiments was performed to examine
whether a less-than-stoichiometric amount of DDQ could be
employed without loss in yield. Given that DDQ is a 2e-/
2H+ acceptor, and the conversion of porphyrinogen f
porphyrin requires removal of 6e-/6H+, stoichiometry re-
quires the use of 3 mol of DDQ per mol of porphyrinogen.7
One porphyrinogen should be formed from each dipyr-
romethane + dipyrromethane-dicarbinol condensation. How-
ever, the porphyrinogen yield is typically e30%, with the
preponderance of material consisting of acyclic products.5,12
The extent to which reaction products other than the
porphyrinogen would consume DDQ was not evident.
The condensation of 3a-OH (0.175 mmol, 25 mM) and
1a (0.175 mmol, 25 mM) was carried out with Sc(OTf)3 (3.2
(30) Thamyongkit, P.; Lindsey, J. S. J. Org. Chem. 2004, 69, 5796-5799.
(31) Lee, C.-H.; Lindsey, J. S. Tetrahedron 1994, 50, 11427-11440.
(32) 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.
(33) Yu, L.; Lindsey, J. S. Tetrahedron 2001, 57, 9285-9298.
Vol. 10, No. 1, 2006 / Organic Process Research & Development
•
123

Table 4. Synthesis of a set of porphyrins at 25 mM reactantsa
a All reactions were carried out at room temperature in CH2Cl2 containing Sc(OTf)3 (3.25 mM) and DTBP (32.5 mM) followed by oxidation with DDQ. The
reaction scale ranged from 0.20 to 1.0 mmol of reactants. b Level 1 or level 0 scrambling. c The reaction was carried out with 18 mmol reactants, and aerobic oxidation
was employed.
mM) and DTBP (32 mM) in CH2Cl2 (7 mL) at room
temperature for 15 min. The reaction mixture was divided
into seven portions. Each one-seventh portion of the crude
reaction mixture was treated with a given quantity of DDQ.
The yield of porphyrin increased linearly with the increasing
amount of DDQ in the substoichiometric range until the
stoichiometric quantity was reached. An increase above the
stoichiometric quantity of DDQ caused no increase in yield
(Figure 2). Accordingly, a stoichiometric amount of DDQ
is required to quench the reactions and give full conversion
of the porphyrinogen to the porphyrin.
susceptible to acidolytic processes leading to scrambling until
oxidation is accomplished. On the other hand, the presence
of acid renders the quinone a more potent oxidant.34 Thus,
it was of interest to characterize the rate of oxidation with
DDQ and p-chloranil, both in the presence of acid and in
neutralized reaction mixtures (achieved by treatment with
TEA, a stronger base than DTBP).
The condensation of 3a-OH (0.10 mmol, 25 mM) and
1a (0.10 mmol, 25 mM) was carried out with Sc(OTf)3 (3.2
mM) and DTBP (32 mM) in CH2Cl2 (4 mL) at room
temperature for 15 min. The reaction mixture was divided
The oxidation of porphyrinogen to porphyrin is most often
performed with either p-chloranil or DDQ.7 If the oxidant is
added in the presence of the acid, the porphyrinogen is
(34) (a) Fukuzumi, S.; Ishikawa, K.; Hironaka, K.; Tanaka, T. J. Chem. Soc.,
Perkin Trans. 2 1987, 751-760. (b) Jeftic, L.; Manning, G. J. Electroanal.
Chem. Interface Electrochem. 1970, 26, 195-200.
124
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Vol. 10, No. 1, 2006 / Organic Process Research & Development

reported data were obtained with DDQ unless noted other-
wise.
III.B. Aerobic Oxidations. Aerobic oxidation processes
are potentially superior to the use of stoichiometric oxidants
from the standpoint of cost, environmental impact, and ease
of workup. In a porphyrin synthesis, the diminished amount
of quinone and hydroquinone byproducts in an aerobic
oxidation process should facilitate workup of the reaction
mixture. An efficient aerobic oxidation process for oxidation
of secondary alcohols was developed by Ba¨ckvall.36-39 We
adapted this process for use in porphyrin-forming reactions.10
The process entails the use of catalytic quantities of DDQ
and an iron phthalocyanine species; a steady stream of
oxygen serves as the stoichiometric oxidant. Upon probing
the iron phthalocyanine species, we found that (1) the µ-oxo
dimer, not the parent iron(II) phthalocyanine, is the active
species40 and (2) little difference is observed with soluble
versus insoluble µ-oxo dimers of iron phthalocyanine spe-
cies.40 The resulting aerobic oxidation process shown in
Scheme 5 was implemented for the pyrrole + aldehyde
reaction. In this application, an anaerobic condensation was
performed at room temperature with pyrrole + benzaldehyde
(0.1 M each) and 0.01 M BF3‚O(Et)2 in CH2Cl2 for 30 min;
oxidation was then initiated by adding catalytic quantities
of the µ-oxo dimer of the iron phthalocyanine and DDQ
(typically 1-5 mol % each) as solid samples and by bubbling
the mixture with air or O2 for 90 min at room temperature.10,40
The only disadvantage to the established aerobic oxidation
process was the slow rate of oxidation. Herein, we explored
a broad set of alternative oxidation processes. A model
system was developed that consisted of the 2e-/2H+ oxida-
tion of a dipyrromethane (e.g., 1a) in the presence of zinc
acetate, which affords the bis(dipyrrinato)zinc(II) complex.
This model system was attractive for several reasons: (1)
the dipyrromethane and dipyrrin represent three-eighths of
a porphyrinogen and a porphyrin, respectively; (2) the dipyr-
romethane is a stable compound that can be prepared in bulk
for oxidation studies; and (3) the absorption spectrum of the
bis(dipyrrinato)zinc(II) complex is very sharp and distinct
(ꢀ483 ) 115,000 M-1 cm-1), unlike the very broad spectrum
of the free base dipyrrin.41 The systems studied included the
following: CuCl‚phenanthroline + diethyl azodicarboxy-
late;42 Pd(OAc)2/pyridine;43 N-hydroxyphthalimide, benzoic
Figure 2. Yield of porphyrin 4a as a function of the amount
of DDQ used for oxidation. The corresponding porphyrinogen
was obtained upon condensation of 1a + 3a-OH with Sc(OTf)3
in the presence of DTBP. The reactions were performed in CH2-
Cl2 at room temperature, and the yield of porphyrin was
determined spectroscopically. The concentrations are as fol-
lows: [1a] ) [3a-OH] ) 25 mM; [Sc(OTf)3] ) 3.2 mM; [DTBP]
) 32 mM. The stoichiometric quantity of DDQ corresponds to
a concentration of 75 mM.
Figure 3. Yield of porphyrin 4a as a function of time upon
oxidation with DDQ or p-chloranil (with or without
triethylamine). The corresponding porphyrinogen was obtained
upon condensation of 1a + 3a-OH with Sc(OTf)3 in the presence
of DTBP in CH2Cl2 at room temperature. The condensation
mixture was split into four portions. Each portion was treated
to the oxidation conditions. Samples were removed periodically
for spectroscopic determination of the yield of porphyrin. The
concentrations are as follows: [1a] ) [3a-OH] ) 25 mM;
[Sc(OTf)3] ) 3.2 mM; [DTBP] ) 32 mM.
into four portions. Two portions (each containing 0.025 mmol
of each reactant) were treated with stoichiometric quantities
of DDQ or p-chloranil (0.075 mmol). The other two portions
were neutralized with 10 mol equiv of TEA (with respect to
acid) followed by addition of DDQ or p-chloranil (0.075
mmol). Absorption spectroscopy for each reaction mixture
was recorded over time. The results are shown in Figure 3.
The addition of DDQ at room temperature gives a nearly
instantaneous conversion of porphyrinogen to porphyrin.
p-Chloranil is a milder oxidant,10,35 requires a slightly longer
exposure time for complete reaction, and affords a yield
slightly higher than that of DDQ. Neutralization of the acid
catalyst (by addition of TEA) prior to the addition of oxidant
(DDQ or p-chloranil) caused no effect on the porphyrin yield,
as observed previously in pyrrole + aldehyde condensations.6
Accordingly, DDQ was employed to provide rapid quenching
during exploratory studies of reaction conditions, and all
(36) Ba¨ckvall, J. E.; Awasthi, A. K.; Renko, Z. D. J. Am. Chem. Soc. 1987,
109, 4750-4752.
(37) Ba¨ckvall, J.-E.; Hopkins, R. B. Tetrahedron Lett. 1988, 29, 2885-2888.
(38) Ba¨ckvall, J.-E.; Hopkins, R. B.; Grennberg, H.; Mader, M. M.; Awasthi,
A. K. J. Am. Chem. Soc. 1990, 112, 5160-5166.
(39) Ba¨ckvall, J.-E.; Chowdhury, R. L.; Karlsson, U. J. Chem. Soc., Chem.
Commun. 1991, 473-475.
(40) Ravikanth, M.; Achim, C.; Tyhonas, J. S.; Mu¨nck, E.; Lindsey, J. S. J.
Porphyrins Phthalocyanines 1997, 1, 385-394.
(41) Yu, L.; Muthukumaran, K.; Savanovich, I. V.; Kirmaier, C.; Hindin, E.;
Diers, J. R.; Boyle, P. D.; Bocian, D. F.; Holten, D.; Lindsey, J. S. Inorg.
Chem. 2003, 42, 6629-6647.
(42) (a) Marko´, I. E.; Giles, P. R.; Tsukazaki, M.; Chelle´-Regnaut, I.; Gautier,
A.; Brown, S. M.; Urch, C. J. J. Org. Chem. 1999, 64, 2433-2439. (b)
Marko´, I. E.; Giles, P. R.; Tsukazaki, M.; Brown, S. M.; Urch, C. J. Science
1996, 274, 2044-2046. (c) Marko´, I. E.; Gautier, A.; Chelle´-Regnaut, I.;
Giles, P. R.; Tsukazaki, M.; Urch, C. J.; Brown, S. M. J. Org. Chem. 1998,
63, 7576-7577.
(43) (a) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. Tetrahedron Lett. 1998,
39, 6011-6014. (b) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org.
Chem. 1999, 64, 6750-6755.
(35) Walker, D.; Hiebert, J. D. Chem. ReV. 1967, 67, 153-195.
Vol. 10, No. 1, 2006 / Organic Process Research & Development
•
125

Scheme 5
results were obtained with PbO2, this approach was decidedly
unattractive from an environmental standpoint. These oxida-
tion studies are described in the Supporting Information.
Accordingly, the established aerobic oxidation process
was employed in conjunction with the reactions described
herein. The condensation of 3a-OH (0.50 mmol, 25 mM)
and 1a (0.50 mmol, 25 mM) was carried out with Sc(OTf)3
(3.2 mM) and DTBP (32 mM) in CH2Cl2 (20 mL) at room
temperature for 15 min. Oxidation was initiated by adding
[(t-Bu)4Fe(III)Pc]2O (the µ-oxo dimer of (t-Bu)4Fe(II)Pc) and
DDQ (5 mol % each) as solid samples, followed by gently
bubbling the mixture with O2 for 90 min at room temperature.
The reaction mixture was chromatographed, affording por-
phyrin 4a (0.055 g, 17% yield). The yield in this preparation
is comparable to that obtained with a stoichiometric amount
of DDQ.
IV. Direct Synthesis of Metalloporphyrins. In many
instances the synthetic target is a metalloporphyrin rather
than a free base porphyrin. We explored treating the crude
reaction mixture (following oxidation) with a metalation
reagent, because (1) one purification process could be
eliminated, and (2) the purification of metalloporphyrins
often is more simple than that of free base porphyrins.
Metalation generally entails treatment of a free base
porphyrin with a metal salt.52 Although the specific condi-
tions (solvent, temperature, presence of a base, duration)
depend on the desired metal, a large number of metallopor-
phyrins can be prepared by reaction of the free base
porphyrin with a metal acetate in a warm solvent. Other
metals can be quite finicky. For example, magnesium
insertion does not work well with magnesium acetate but
can be achieved with a heterogeneous mixture of a reactive
magnesium halide (e.g., MgBr2 or MgI2) and a nonnucleo-
philic amine in a noncoordinating solvent.53
Each condensation of 1a + 3a-OH was performed at 25
mM using Sc(OTf)3 and DTBP in CH2Cl2 at room temper-
ature for 15 min. The mixture was oxidized aerobically upon
addition of catalytic amounts of [(t-Bu)4FePc]2O and DDQ
followed by a steady stream of oxygen for 90 min. Then the
reaction mixture was treated with the respective metalation
reagent. Metalation with zinc or copper was achieved with
methanolic Zn(OAc)2‚2H2O or Cu(OAc)2‚H2O, respectively,
upon stirring overnight at room temperature. For metalation
with palladium, the reaction mixture was concentrated, and
then Pd(O2CCF3)254 in 1,2-dichloroethane and methanol were
added, and the mixture was heated at 45 °C for 1 h. For
metalation with nickel, the reaction mixture was concen-
trated, then toluene and Ni(acac)2 in toluene were added,
and the mixture was refluxed overnight. For metalation with
magnesium, MgI2 and DIEA were employed in CH2Cl2 at
room temperature.53 The course of each reaction was
monitored by TLC and fluorescence spectroscopy. In each
case, after completion of the metalation only one porphyrinic
acid and Co(OAc)2;44 2,2,6,6-tetramethyl-piperidyl-1-oxy,
NaNO2 and 1,3-dibromo-5,5-dimethylhydantoin;45 bis(sali-
cylideniminato-3-propyl)methylaminocobalt(II) and DDQ;46
and Ru(PPh3)3Cl2, DDQ and K2CO3.39,47,48 No improvement
over the established aerobic oxidation system was achieved.
We also explored the use of an inexpensive bulk chemical
reagent [Mn(OAc)3,49 FeCl3,50 or PbO251] for recycling
catalytic amounts of DDQ or p-chloranil. Although good
(44) (a) Iwahama, T.; Sakaguchi, S.; Nishiyama, Y.; Ishii, Y. Tetrahedron Lett.
1995, 36, 6923-6926. (b) Yoshino, Y.; Hayashi, Y.; Iwahama, T.;
Sakaguchi, S.; Ishii, Y. J. Org. Chem. 1997, 62, 6810-6813. (c) Iwahama,
T.; Yoshino, Y.; Keitoku, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2000,
65, 6502-6507. (d) Ishii, Y.; Nakayama, K.; Takeno, M.; Sakaguchi, S.;
Iwahama, T.; Nishiyama, Y. J. Org. Chem. 1995, 60, 3934-3935.
(45) (a) Liu, R.; Liang, X.; Dong, C.; Hu, X. J. Am. Chem. Soc. 2004, 126,
4112-4113. (b) Liu, R.; Dong, C.; Liang, X.; Wang, X.; Hu, X. J. Org.
Chem. 2005, 70, 729-731.
(46) Chen, D.; Martell, A. E. Inorg. Chem. 1987, 26, 1026-1030.
(47) Hanyu, A.; Takezawa, E.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 1998,
39, 5557-5560.
(48) Csjernyik, G.; EÄ ll, A. H.; Fadini, L.; Pugin, B.; Ba¨ckvall, J.-E. J. Org. Chem.
2002, 67, 1657-1662.
(49) Sharma, G. V. M.; Lavanya, B.; Mahalingam, A. K.; Krishna, P. R.
Tetrahedron Lett. 2000, 41, 10323-10326.
(50) Chandrasekhar, S.; Sumithra, G.; Yadav, J. S. Tetrahedron Lett. 1996, 37,
1645-1646.
(51) Kalena, G. P.; Jadhav, S. M.; Banerji, A. Molecules 2000, 5, 240-244.
(52) Adler, A. D.; Longo, F. R.; Kampas, F.; Kim, J. J. Inorg. Nucl. Chem.
1970, 32, 2443-2445.
(53) (a) Lindsey, J. S.; Woodford, J. N. Inorg. Chem. 1995, 34, 1063-1069. (b)
O’Shea, D. F.; Miller, M. A.; Matsueda, H.; Lindsey, J. S. Inorg. Chem.
1996, 35, 7325-7338.
(54) Sharada, D. S.; Muresan, A. Z.; Muthukumaran, K.; Lindsey, J. S. J. Org.
Chem. 2005, 70, 3500-3510.
126
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Vol. 10, No. 1, 2006 / Organic Process Research & Development

Scheme 6
of an ABCD-porphyrin was carried out at the 4.00 mmol
scale in 1600 mL of CH3CN (2.5 mM) and proceeded in
25% yield with the use of a stoichiometric quantity of DDQ,
affording 1.12 g (1.02 mmol, 1094 Da).5 Thus, in comparison
with this particular previous synthesis, the present synthesis
at 4.5-times larger scale afforded 4.0-times as much por-
phyrin on a molar basis while requiring 0.45-times the
amount of solvent and 0.0375-times the amount of DDQ.
Conclusions
The procedures described herein enable porphyrin syn-
thesis by reaction of a dipyrromethane + dipyrromethane-
dicarbinol at 25 mM in ∼20% yield with little or no
scrambling. The acid catalysis conditions entail a mild Lewis
acid catalyst at somewhat higher concentration than that for
the 2.5 mM condensations examined previously. The acid
catalysis conditions were identified by examination of a
challenging substrate (i.e. one that is particularly sensitive
to acidolysis). For less challenging substrates, other acid
conditions may prove effective, including those described
herein that were not examined for scale-up purposes. A very
broad survey of aerobic oxidation catalysts did not identify
a system superior to that employed previously, namely the
use of a µ-oxo dimer of an iron phthalocyanine (either soluble
or insoluble) and DDQ in catalytic quantities, accompanied
by a stream of air or O2. A three-step one-flask procedure
encompassing (1) acid-catalyzed condensation of a dipyr-
romethane + dipyrromethane-dicarbinol, (2) aerobic oxida-
tion of the resulting porphyrinogen, and (3) in situ metalation
of the resulting free base porphyrin provides a streamlined
approach for the rational synthesis of metalloporphyrins
bearing a distinct pattern of substituents. The procedures
outlined herein should provide the foundation for extensions
to larger-scale syntheses of porphyrins, as required for
fundamental studies and diverse applications.
Experimental Section
General. The following procedures were employed unless
1
noted otherwise. H NMR (400 MHz) and 13C NMR (100
MHz) spectra were obtained in CDCl3. Absorption spectra
were collected in CH2Cl2/ethanol (3:1) for spectroscopic yield
determinations or in THF for characterization of purified
samples. The solvents were used as received from com-
mercial sources, including THF (HPLC grade), CH2Cl2
(anhydrous or reagent-grade), and methanol (anhydrous). The
oxygen employed for aerobic oxidation experiments was
99.5% (Medical grade, National Welders, Inc.). Porphyrin-
forming reactions were carried out in anhydrous CH2Cl2.
The progress of the porphyrin-forming reactions was
monitored spectroscopically,6 and the extent of scrambling
in the crude reaction mixture was determined by laser
desorption ionization mass spectrometry (LD-MS) without
a matrix as described previously.14,55 A sonication bath
(Fisher FS 14) was used to sonicate samples during purifica-
product was observed upon TLC analysis. The metallopor-
phyrin was easily isolated by chromatography in 18-20%
overall yield (Scheme 6). This three-step one-flask synthesis
provided the metalloporphyrin without isolation of the
intermediate free base porphyrin.
V. Application. The synthesis of an ABCD-porphyrin
was performed using the three-step procedure. Thus, the
reaction of 3b-OH and 1g was carried out with 18.0 mmol
of each reactant (25 mM, 720 mL of CH2Cl2) with catalysis
by Sc(OTf)3 (2.34 mmol) and DTBP (23.4 mmol). Aerobic
oxidation was subsequently performed for 90 min using [(t-
Bu)4FePc]2O and DDQ (2.5 mol % each) and a stream of
O2. Workup including passage over a short pad of silica
afforded 2.88 g (4.11 mmol, 22.8% yield) of the correspond-
ing porphyrin 4l (molecular mass 701 Da). The porphyrin
contained no detectable scrambled products or N-confused
porphyrin. To our knowledge, the largest previous synthesis
(55) (a) Fenyo, D.; Chait, B. T.; Johnson, T. E.; Lindsey, J. S. J. Porphyrins
Phthalocyanines 1997, 1, 93-99. (b) Srinivasan, N.; Haney, C. A.; Lindsey,
J. S.; Zhang, W.; Chait, B. T. J. Porphyrins Phthalocyanines 1999, 3, 283-
291.
Vol. 10, No. 1, 2006 / Organic Process Research & Development
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127

tion. Melting points are uncorrected. Silica gel (40 µm
average particle size) and alumina (80-200 mesh) were used
for column chromatography.
characterized, it is reasonable to assign the two peaks to
N-confused porphyrin isomers. The peak at 6.7 min is
attributed to 10,20-diphenyl-5,15-di-p-tolyl-2-aza-21-carbap-
orphyrin (5a), which must originate by reaction of dipyr-
romethane 1a at the pyrrolic 3-position with the dipyr-
romethane-dicarbinol 3a-OH. The peak at 6.6 min is
attributed to 10,20-diphenyl-5,15-di-p-tolyl-3-aza-21-carbap-
orphyrin (5a-isomer), which must originate by reaction at
the pyrrolic 5′-position of the N-confused dipyrromethane
with the dipyrromethane-dicarbinol 3a-OH. See the Sup-
porting Information for illustrative schemes concerning these
reactions. Although the relative amount of the putative 5a-
isomer was surprising, N-confused dipyrromethanes and
related species are known to undergo porphyrin-forming
reactions.57
Acid-Screening Experiments. Immediately prior to the
condensation reactions, a sample of 3a (0.092 g, 0.20 mmol)
was reduced to the corresponding dicarbinol with NaBH4
(0.38 g, 10 mmol, 50 mol equiv) in 16 mL of THF/methanol
(3:1).5 After drying under vacuum for 15-30 min, the flask
containing the dipyrromethane-dicarbinol (0.20 mmol as-
suming quantitative reduction) was treated with anhydrous
CH2Cl2 (8 mL) and dipyrromethane 1a (0.044 g, 0.20 mmol).
The mixture was stirred for 5 min to ensure mixing. This
mixture was equally divided into four tightly capped 20-mL
vials (via Hamilton syringe) that were stirred with a microstir
bar. The condensation was performed with the dipyr-
romethane-dicarbinol and the dipyrromethane (25 mM each)
in CH2Cl2. The acid was weighed and transferred im-
mediately into the reaction vials. The reaction was monitored
by absorption spectroscopy, whereby a 10-µL reaction aliquot
was injected into a solution of DDQ (1 mL, 0.01 M in
toluene) (at 1, 5, 15, 60, and 90 min timepoints). This
solution was diluted with 2.5 mL of CH2Cl2. A 25-µL aliquot
of the resulting oxidized solution was dissolved in CH2Cl2/
ethanol (3 mL, 3:1), and the absorption spectrum was
recorded. Prior to LD-MS analysis, the aliquot of the crude,
oxidized reaction mixture (3.5 mL) was passed through a
pipet column packed with alumina, and the eluant was
concentrated.
Noncommercial
Compounds.
Dipyrromethanes
1a,b,c,f,g1 and 1d30 were prepared as described in the
literature and analyzed for purity by gas chromatography.1
Compounds 3a, 3b-BBN, 3d-BBN, and 3f-BBN-3h-BBN;4
3c,5 3e,33 Bi(OTf)3,56 3-butyl-1-(4-sulfobutyl)imidazolium
triflate,28 and [(t-Bu)4FePc]2O40 were prepared as described
in the literature.
Quantitation of N-Confused Porphyrin. The quantita-
tion was carried out using HPLC analysis as described
previously.22 Shortly after DDQ oxidation, the samples were
basified by addition of TEA (10-fold molar excess relative
to acid). Addition of TEA was crucial for accurate detection
of the N-confused porphyrin, otherwise the N-confused
porphyrin was removed during the pre-HPLC sample cleanup.
Strongly adsorbing black materials were removed prior to
HPLC sample analysis by passing a carefully measured
volume of the crude reaction mixture (1.5 mL for 2.5 mM
reactions or 0.25 mL for reactions at 25 mM concentration)
through a Pasteur pipet column packed with 1.4 g of activity
II basic alumina (obtained by adding 3 mL of H2O to 100 g
of alumina with intermittent shaking). The sample was eluted
with three 1-mL portions of CH2Cl2. Solvent was driven off
the column by application of mild pressure using a handheld
pipet bulb. The eluant was transferred immediately to an
autosampler vial and capped.
HPLC analysis was performed using a silica gel analytical
column (Econosphere, CN, 4.6 mm × 250 mm) with an
isocratic solvent mixture of 92.5% hexanes (containing 0.1%
TEA) and 7.5% acetone. The solvent flow rate was controlled
as follows: 0-5 min, 1.0 mL/min; 5-7 min, linear increase
to 2.5 mL/min; 7-10.5 min, 2.5 mL/min; 10.5-11.5 min,
linear decrease to 1 mL/min; and 11.5-13 min, 1 mL/min.
The solvent front occurred at 3.5 min, porphyrin 4a eluted
at 4.2 min, and N-confused porphyrin 5a eluted at 6.6 min.
Detection was performed at 417 nm for 4a, and 438 nm for
5a. The detection limits for 4a and 5a were 1 and 3 pmol,
respectively. For 2.5 mM reactions, the detection limits
correspond to the following yields: 4a ) 0.1%, 5a ) 0.3%.
For 25 mM reactions, these detection limits correspond to
the following yields: 4a ) 0.04%, 5a ) 0.1%.
5-(4-Methylphenyl)dipyrromethane (1e). Following a
standard procedure,1 a solution of p-tolualdehyde (18.0 g,
150 mmol) in pyrrole (1.04 L, 15.0 mol) at room temperature
under argon was treated with InCl3 (3.32 g, 15.0 mmol) for
1.5 h. Powdered NaOH (18.0 g, 0.450 mol) was added. After
stirring for 1 h, the mixture was suction filtered, and excess
pyrrole was removed under high vacuum. The residue was
treated with hexanes (3 × 100 mL) to facilitate removal of
traces of pyrrole. The resulting solid was recrystallized
[MeOH/H2O (4:1)], affording a brown solid (27.0 g, 76%):
Two peaks (tR ) 6.6, 6.7 min; HPLC analysis) were
initially observed in the region expected for the N-confused
porphyrin, both of which exhibited an absorption spectrum
consistent with an N-confused porphyrin. The dipyr-
romethane employed in the condensation step had been
purified by recrystallization, and contained 2-5% of N-
confused dipyrromethane. When the dipyrromethane free
from N-confused dipyrromethane (obtained by chromatog-
raphy) was used, only one peak in the region corresponding
to the N-confused porphyrin was observed (6.7 min). [Note
that the data shown in Table 3 were obtained from dipyr-
romethane samples free from N-confused dipyrromethane.]
Although no N-confused porphyrins were isolated and fully
1
mp 113-114 °C; H NMR δ 2.36 (s, 3H), 5.45 (s, 1H),
5.92-5.94 (m, 2H), 6.15-6.17 (m, 2H), 6.68-6.70 (m, 2H),
7.10-7.12 (m, 4H), 7.91-7.95 (br, 2H); 13C NMR δ 21.3,
43.8, 107.3, 108.6, 117.3, 128.5, 129.5, 132.9, 136.8, 139.2;
FAB-MS obsd 236.1313, calcd 236.1313 (C16H16N2). The
(57) (a) Lee, C.-H.; Kim, H.-J.; Yoon, D.-W. Bull. Korean Chem. Soc. 1999,
20, 276-280. (b) Furuta, H.; Maeda, H.; Osuka, A. J. Am. Chem. Soc.
2000, 122, 803-807. (c) Srinivasan, A.; Ishizuka, T.; Maeda, H.; Furuta,
H. Angew. Chem., Int. Ed. 2004, 43, 2951-2955.
(56) Labrouille`re, M.; Le Roux, C.; Gaspard, H.; Laporterie, A.; Dubac, J.;
Desmurs, J. R. Tetrahedron Lett. 1999, 40, 285-286.
128
•
Vol. 10, No. 1, 2006 / Organic Process Research & Development

data are consistent with those obtained from samples
prepared via earlier routes.31,32
residue was treated with 30 mL of hexanes to afford a solid
residue. The resulting mixture was filtered through a Bu¨chner
funnel. The precipitate was collected and dried in vacuo to
afford a pale-yellow powder (0.940 g, 82%): mp 260 °C
(dec); 1H NMR δ 2.41 (s, 6H), 4.14 (s, 2H), 6.14-6.16 (m,
2H), 6.72-6.74 (m, 2H), 7.25 (d, J ) 8.0 Hz, 4H), 7.76 (d,
J ) 8.0 Hz, 4H), 10.22-10.28 (br, 2H); FAB-MS obsd
383.1752, calcd 383.1760 [(M + H)+, M ) C25H22N2O2].
Due to poor solubility in CDCl3, a 13C NMR spectrum was
not recorded.
1-(4-Bromobenzoyl)-9-(4-methoxybenzoyl)-5-(4-meth-
oxyphenyl)dipyrromethane (3 g). Following a general
procedure,4 a solution of 3g-BBN (1.03 g, 1.50 mmol) in
THF (2.4 mL) was treated with 1-pentanol (0.6 mL). The
reaction mixture was heated at reflux. After 2 h, TLC [silica,
hexanes/ethyl acetate (4:1)] examination showed complete
consumption of boron complex 3g-BBN. The mixture was
concentrated to dryness. The resulting oily residue was
treated with 15 mL of hexanes to afford a solid residue. The
resulting mixture was filtered through a Bu¨chner funnel. The
precipitate was collected and dried in vacuo to afford a light-
pink powder (0.743 g, 87%): mp 113-115 °C; 1H NMR δ
3.83 (s, 3H), 3.84 (s, 3H), 5.60 (s, 1H), 5.91-5.92 (m, 1H),
5.94-5.95 (m, 1H), 6.48-6.49 (m, 2H), 6.88 (d, J ) 8.0
Hz, 2H), 6.92 (d, J ) 8.0 Hz, 2H), 7.46 (d, J ) 8.0 Hz,
2H), 7.52 (d, J ) 8.0 Hz, 2H), 7.62 (d, J ) 8.0 Hz, 2H),
7.77 (d, J ) 8.0 Hz, 2H), 11.57-11.65 (br, 2H); 13C NMR
δ 44.5, 55.5, 55.6, 111.2, 111.5, 113.4, 114.3, 120.2, 121.2,
126.6, 130.1, 130.8, 131.0, 131.2, 131.42, 131.48, 132.02,
132.7, 137.2, 140.9, 142.5, 159.0, 162.7, 183.2, 183.5; FAB-
MS obsd 569.1071, calcd 569.1076 [(M + H)+, M ) C31H25-
BrN2O4]. Anal. Calcd for C31H25BrN2O4: C, 65.38; H, 4.43;
N, 4.92. Found C, 65.79; H, 4.77; N, 4.82.
Decomplexation of a 1,9-Diacyldipyrromethane-BBN
Complex: 1-(4-Methoxybenzoyl)-9-(4-methylbenzoyl)-5-
phenyldipyrromethane (3b). Following a general proce-
dure,4 a solution of 3b-BBN (5.94 g, 10.0 mmol) in THF
(16.0 mL) was treated with 1-pentanol (4.0 mL). The reaction
mixture was heated at reflux. After 2 h, TLC [silica, hexanes/
ethyl acetate (4:1)] examination showed complete consump-
tion of boron complex 3b-BBN. The mixture was concen-
trated to dryness. The resulting oily residue was treated with
50 mL of hexanes to afford a solid residue. The resulting
mixture was filtered through a Bu¨chner funnel. The precipi-
tate was collected and dried in vacuo to afford a light-pink
powder (3.98 g, 84%). The filtrate was concentrated by
4-fold. The resulting precipitate was filtered, dissolved in a
minimal volume of CH2Cl2, and precipitated upon addition
of hexanes, affording an additional 0.284 g of the title
compound. The combined yield (4.26 g) is 90%: mp 106-
108 °C; 1H NMR δ 2.39 (s, 3H), 3.84 (s, 3H), 5.66 (s, 1H),
5.92-5.93 (m, 2H), 6.50-6.53 (m, 2H), 6.88 (d, J ) 8.0
Hz, 2H), 7.18-7.20 (d, J ) 8.0 Hz, 2H), 7.33-7.34 (m,
1H), 7.38-7.42 (m, 2H), 7.54 (d, J ) 8.0 Hz, 2H) 7.68 (d,
J ) 8.0 Hz, 2H), 7.77-7.79 (m, 2H), 11.47-11.51 (br, 2H);
13C NMR δ 21.8, 45.3, 55.6, 111.30, 111.32, 113.4, 120.2
120.7, 127.5, 128.9, 129.0, 130.0, 131.1, 131.2, 131.3, 132.0,
135.8, 140.7, 141.1, 142.3, 162.6, 183.5, 184.5; FAB-MS
obsd 475.2040, calcd 475.2022 [(M + H)+, M ) C31H26N2O3].
1-(Hexanoyl)-9-(4-methylbenzoyl)-5-pentyldipyr-
romethane (3d). Following a general procedure,4 a solution
of 3d-BBN (1.10 g, 2.00 mmol) in THF (3.2 mL) was treated
with 1-pentanol (0.8 mL). The reaction mixture was heated
at reflux. After 2 h, TLC [silica, hexanes/ethyl acetate (4:
1)] examination showed complete consumption of boron
complex 3d-BBN. The reaction mixture was concentrated
(∼1 mL) and filtered through a pad of alumina [CH2Cl2/
ethyl acetate (4:1 f 1:1)], affording a yellow oil. Methanol
was added, affording a pink precipitate on standing for 10
min. The solvent was decanted. The residue was dried under
vacuum to afford a pink amorphous powder (0.671 g,
1-(4-Methylbenzoyl)-9-(pentafluorobenzoyl)-5-phenyl-
dipyrromethane (3h). Following a general procedure,4 a
solution of 3h-BBN (1.96 g, 3.00 mmol) in THF (4.8 mL)
was treated with 1-pentanol (1.2 mL). The reaction mixture
was heated at reflux. After 2 h, TLC [silica, hexanes/ethyl
acetate (4:1)] examination showed complete consumption of
boron complex 3h-BBN. The mixture was concentrated to
dryness. The resulting oily residue was treated with 30 mL
of hexanes to afford a solid residue. The resulting mixture
was filtered through a Bu¨chner funnel. The precipitate was
collected and dried in vacuo to afford a light-pink powder
1
75%): mp 130 °C; H NMR δ 0.82-0.90 (m, 6H), 1.26-
1.35 (m, 10H), 1.67-1.73 (m, 2H), 2.03-2.07 (m, 2H), 2.39
(s, 3H), 2.75 (t, J ) 7.6 Hz, 2H), 4.03-4.17 (t, J ) 7.6 Hz,
1H), 6.10-6.14 (m, 2H), 6.73-6.74 (m, 1H), 6.83-6.84 (m,
1H), 7.23 (d, J ) 8.0 Hz, 2H), 7.75 (d, J ) 8.0 Hz, 2H),
10.42-10.50 (br, 2H); 13C NMR δ 14.1, 14.2, 21.7, 22.7,
25.5, 27.6, 31.7, 31.9, 33.7, 38.0, 38.4, 108.5, 108.8, 118.1,
120.9, 129.0, 129.4, 131.0, 131.7, 141.7, 142.1, 142.2, 184.6,
191.7; FAB-MS obsd 433.2860, calcd 433.2855 [(M + H)+,
M ) C28H36N2O2]. Anal. Calcd for C28H36N2O2: C, 77.74;
H, 8.39; N, 6.48. Found C, 77.66; H, 8.46; N, 6.52.
1,9-Bis(4-methylbenzoyl)dipyrromethane (3f). Follow-
ing a general procedure,4 a solution of 3f-BBN (1.50 g, 3.00
mmol) in THF (4.8 mL) was treated with 1-pentanol (1.2
mL). The reaction mixture was heated at reflux. After 2 h,
TLC [silica, hexanes/ethyl acetate (4:1)] examination showed
complete consumption of boron complex 3f-BBN. The
mixture was concentrated to dryness. The resulting oily
1
(1.31 g, 82%): mp 165 °C; H NMR δ 2.42 (s, 3H), 5.65
(s, 1H), 6.08-6.10 (m, 1H), 6.11-6.13 (m, 1H), 6.63-6.65
(br, 1H), 6.79-6.81 (m, 1H), 7.23-7.27 (m, 4H), 7.31-
7.37 (m, 3H), 7.74 (m, 2H), 9.79-9.83 (br, 1H), 9.99-10.03
(br, 1H); 13C NMR δ 21.8, 44.5, 111.13, 112.2, 120.6, 122.5,
128.1, 128.6, 129.2, 129.3, 129.4, 131.44, 131.48, 135.6,
139.1, 139.3, 142.8, 143.5, 172.1, 184.9; FAB-MS obsd
535.1420, calcd 535.1445 [(M + H)+, M ) C30H19F5N2O2].
Anal. Calcd for C30H19F5N2O2: C, 67.42; H, 3.58; N, 5.24.
Found C, 67.62; H, 3.89; N, 5.15.
Synthesis of 5,15-Bis(4-methylphenyl)-10,20-diphe-
nylporphyrin at 25 mM Reactants Using Zn(OTf)2. A
sample of 3a (0.11 g, 0.25 mmol) was dissolved in dry THF/
methanol (20 mL, 3:1) at room temperature in a round-
Vol. 10, No. 1, 2006 / Organic Process Research & Development
•
129

bottom flask, fitted with a vented rubber septum, and flooded
with argon. The septum was removed as needed to add
NaBH4 (0.47 g, 12.5 mmol, 50 mol equiv) in small portions
with rapid stirring. The progress of the reduction was
monitored by TLC analysis [alumina, CH2Cl2/methanol (97:
3)] of reaction aliquots. After the reaction was complete
(about 40 min), the reaction mixture was poured into a stirred
mixture of saturated aqueous NH4Cl and CH2Cl2. The organic
phase was separated, washed with water, dried (K2CO3), and
concentrated under reduced pressure to yield the dicarbinol
(0.25 mmol, assuming quantitative reduction) as a foamlike
solid. The flask containing the dipyrromethane-dicarbinol
was treated with anhydrous CH2Cl2 (10 mL) and 1a (0.055
g, 0.25 mmol). The mixture was stirred for 5 min to achieve
dissolution, whereupon Zn(OTf)2 (0.036 g, 0.10 mmol, 10
mM) was added. The reaction was monitored by absorption
spectroscopy, whereby a 10 µL reaction aliquot was injected
into a solution of DDQ (1.0 mL, 0.01 M in toluene); this
solution then was diluted with 2.5 mL of CH2Cl2. Then 25
µL of the resulting oxidized mixture was dissolved in CH2-
Cl2/EtOH (3 mL, 3:1), and the absorption spectrum was
recorded. After 15 min (following the addition of Zn(OTf)2),
DDQ (0.17 g, 0.75 mmol) was added to the bulk reaction
mixture, and the mixture was stirred at room temperature
for 15 min. TEA (0.14 mL, 1.0 mmol) was added. The
reaction mixture was filtered (to remove quinone species)
through a pad of alumina (6 cm dia × 7.5 cm) and eluted
with CH2Cl2 until the eluant was no longer purple. The
resulting porphyrin-containing solution was concentrated to
give a purple solid. Methanol was added. The resulting
suspension was placed in a sonication bath for a few minutes,
followed by centrifugation. The methanol was decanted,
was stirred for 5 min to achieve dissolution, whereupon 2,6-
di-tert-butylpyridine (0.293 mL, 1.30 mmol, 32.5 mM) and
Sc(OTf)3 (0.0640 g, 0.130 mmol, 3.25 mM) were added. The
reaction was monitored by absorption spectroscopy, whereby
a 10 µL reaction aliquot was injected into a solution of DDQ
(1.0 mL, 0.01 M in toluene); this solution then was diluted
with 2.5 mL of CH2Cl2. Then 25 µL of the resulting oxidized
mixture was dissolved in CH2Cl2/EtOH (3 mL, 3:1), and the
absorption spectrum was recorded. After 15 min (following
the addition of Sc(OTf)3), DDQ (0.681 g, 3.00 mmol) was
added to the bulk reaction mixture, and the mixture was
stirred at room temperature for 5 min. The reaction mixture
was filtered (to remove quinone species) through a pad of
alumina (6 cm dia × 7.5 cm) and eluted with CH2Cl2
containing 0.1% TEA until the eluant was no longer purple.
The resulting porphyrin-containing solution was concentrated
to give a purple solid. Methanol was added. The resulting
slurry was sonicated for a few minutes and then filtered
through a Bu¨chner funnel. The filtered material was dried
in vacuo, affording a crystalline purple solid (0.125 g,
1
19%): H NMR δ -2.76 (s, 2H), 2.71 (s, 6H), 7.56 (d, J )
8.0 Hz, 4H), 7.68-7.81 (m, 6H), 8.10 (d, J ) 8.0 Hz, 4H),
8.21-8.23 (m, 4H), 8.83 (d, J ) 4.4 Hz, 4H), 8.87 (d, J )
4.4 Hz, 4H); 13C NMR δ 21.7, 120.1, 120.4, 126.8, 127.6,
127.8, 130.2-132.1 (br), 134.73, 134.77, 137.6, 139.4, 142.5;
LD-MS obsd 643.7; FAB-MS obsd 643.2900, calcd 643.2862
[(M + H)+, M ) C46H34N4]; λabs 417, 514, 548, 593, 647
nm.
5-(4-Methoxyphenyl)-10,20-bis(4-methylphenyl)-15-
phenylporphyrin (4b). The condensation of dicarbinol 3a-
OH [derived from reduction of 3a (0.458 g, 1.00 mmol) with
NaBH4 (1.89 g, 50.0 mmol, 50.0 mol equiv) in THF/
methanol (80 mL, 3:1)] and dipyrromethane 1b (0.252 g,
1.00 mmol) was carried out in the presence of 2,6-di-tert-
butylpyridine (0.293 mL, 1.30 mmol) and Sc(OTf)3 (0.0640
g, 0.130 mmol) in CH2Cl2 (40 mL) at room temperature for
10 min followed by the addition of DDQ (0.681 g, 3.0
mmol). After 5 min, the reaction mixture was filtered through
a pad of alumina (CH2Cl2 containing 0.1% TEA). The
resulting porphyrin-containing solution was concentrated to
give a purple solid. Methanol was added. The resulting
suspension was sonicated for 5 min and then filtered through
a filter paper secured in a fritted glass filter holder. The
filtered material was washed with methanol and dried in
vacuo, affording a crystalline purple solid (0.142 g, 21%):
1H NMR δ -2.76 (s, 2H), 2.70 (s, 6H), 4.09 (s, 3H), 7.29
(d, J ) 8.0 Hz, 2H), 7.55 (d, J ) 8.0 Hz, 4H), 7.67-7.79
(m, 3H), 8.10 (d, J ) 8.0 Hz, 4H), 8.12 (d, J ) 8.0 Hz, 2H),
8.20-8.22 (m, 2H), 8.82 (d, J ) 4.8 Hz, 2H), 8.86 (s, 6H);
13C NMR δ 21.7, 55.7, 94.5, 112.4, 120.0, 120.4, 126.9,
127.6, 127.8, 130.0-132.3 (br), 134.7, 134.80, 134.87, 135.8,
137.5, 139.5, 142.5, 159.6; LD-MS obsd 673.9; FAB-MS
obsd 672.2889, calcd 672.2889 (C47H36N4O); λabs 418, 515,
550, 593, 649 nm.
1
affording a crystalline purple solid (0.032 g, 21%): H NMR
δ -2.77 (s, 2H), 2.70 (s, 6H), 7.56 (d, J ) 8.0 Hz, 4H),
7.68-7.80 (m, 6H), 8.10 (d, J ) 8.0 Hz, 4H), 8.20-8.23
(m, 4H), 8.83 (d, J ) 4.4 Hz, 4H), 8.87 (d, J ) 4.4 Hz, 4H);
13C NMR δ 21.7, 120.1, 120.4, 126.9, 127.8, 127.9, 130.4-
132.0 (br), 134.74, 134.77, 137.5, 139.4, 142.5; LD-MS obsd
642.7; FAB-MS obsd 643.2881, calcd 643.2862 [(M + H)+,
M ) C46H34N4]; λabs 417, 513, 548, 592, 647 nm.
Exemplary Procedure Using 25 mM Reactants With
Sc(OTf)3 and DTBP, Given for 5,15-Bis(4-methylphenyl)-
10,20-diphenylporphyrin (4a). A sample of 3a (0.458 g,
1.00 mmol) was dissolved in THF/methanol (80 mL, 3:1) at
room temperature in a round-bottom flask, fitted with a
vented rubber septum, and flooded with argon. The septum
was removed as needed to add NaBH4 (1.89 g, 50.0 mmol,
50.0 mol equiv) in small portions with rapid stirring. The
progress of the reduction was monitored by TLC analysis
[alumina, CH2Cl2/methanol (97:3)] of reaction aliquots. After
the reaction was complete (about 40 min), the reaction
mixture was poured into a stirred mixture of saturated
aqueous NH4Cl and CH2Cl2. The organic phase was sepa-
rated, dried (K2CO3), and concentrated under reduced pres-
sure to yield the dicarbinol as a foamlike solid. The flask
containing the dipyrromethane-dicarbinol (1.00 mmol, as-
suming quantitative reduction) was treated with anhydrous
CH2Cl2 (40 mL) and 1a (0.222 g, 1.00 mmol). The mixture
5,15-Bis(4-methylphenyl)-10-(pentafluorophenyl)-20-
phenylporphyrin (4c). The condensation of dicarbinol 3a-
OH [derived from reduction of 3a (0.229 g, 0.500 mmol)
with NaBH4 (0.947, 25.0 mmol, 50.0 mol equiv) in THF/
130
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Vol. 10, No. 1, 2006 / Organic Process Research & Development

methanol (40 mL, 3:1)] and dipyrromethane 1c (0.156 g,
0.500 mmol) was carried out in the presence of 2,6-di-tert-
butylpyridine (0.147 mL, 0.650 mmol) and Sc(OTf)3 (0.0320
g, 0.0650 mmol) in CH2Cl2 (20 mL) at room temperature
for 10 min followed by the addition of DDQ (0.340 g, 1.50
mmol). After 5 min, the reaction mixture was filtered through
a pad of alumina (CH2Cl2 containing 0.1% TEA). The
resulting porphyrin-containing solution was concentrated to
give a purple solid. Methanol was added. The resulting
suspension was sonicated for 5 min and then filtered through
a filter paper secured in a fritted glass filter holder. The
filtered material was washed with methanol and dried in
vacuo, affording a crystalline purple solid (0.0440 g, 11%).
The filtrate was concentrated. The concentrated product was
passed though a silica column, which was eluted with CH2-
Cl2 until the eluant was no longer purple. The resulting
porphyrin-containing solution was concentrated to give a
purple solid. Methanol was added. The resulting suspension
was sonicated for 5 min and then filtered through a filter
paper secured in a fritted glass filter holder to afford an
additional 0.0110 g of porphyrin. The precipitates were
5,15-Bis(4-tert-butylphenyl)-10-(4-iodophenyl)-20-(4-
methylphenyl)porphyrin (4e). The condensation of di-
carbinol 3c-OH [derived from reduction of 3c (0.334 g, 0.500
mmol) with NaBH4 (0.947 g, 25.0 mmol, 50.0 mol equiv)
in THF/methanol (40 mL, 3:1)] and dipyrromethane 1e
(0.118 g, 0.500 mmol) was carried out in the presence of
2,6-di-tert-butylpyridine (0.147 mL, 0.650 mmol) and Sc-
(OTf)3 (0.0320 g, 0.0650 mmol) in CH2Cl2 (20 mL) at room
temperature for 10 min followed by the addition of DDQ
(0.340 g, 1.50 mmol). After 5 min, the reaction mixture was
filtered through a pad of alumina (CH2Cl2 containing 0.1%
TEA). The resulting porphyrin-containing solution was
concentrated and dried in vacuo, affording a crystalline purple
solid (0.0821 g, 19%): 1H NMR δ -2.79 (s, 2H), 1.61 (s,
18H), 2.71 (s, 3H), 7.55 (d, J ) 8.0 Hz, 2H), 7.76 (d, J )
8.0 Hz, 4H), 7.95 (d, J ) 8.0 Hz, 2H), 8.08-8.14 (m, 8H),
8.80 (d, J ) 4.4 Hz, 2H), 8.86-8.90 (m, 6H); LD-MS obsd
868.0; FAB-MS obsd 867.2853, calcd 867.2924 [(M + H)+,
M ) C53H47IN4]; λabs 418, 515, 550, 592, 648 nm. Due to
poor solubility in various solvents (including CDCl3), a 13
NMR spectrum was not recorded.
C
1
combined to afford a purple solid (0.0550 g, 15%): H NMR
5,10-Bis(4-methylphenyl)-15,20-dipentylporphyrin (4f).
The condensation of dicarbinol 3d-OH [derived from reduc-
tion of 3d (0.216 g, 0.500 mmol) with NaBH4 (0.947 g, 25.0
mmol, 50.0 mol equiv) in THF/methanol (40 mL, 3:1)] and
dipyrromethane 1e (0.118 g, 0.500 mmol) was carried out
in the presence of 2,6-di-tert-butylpyridine (0.147 mL, 0.650
mmol) and Sc(OTf)3 (0.0320 g, 0.0650 mmol) in CH2Cl2
(20 mL) at room temperature for 10 min followed by the
addition of DDQ (0.340 g, 1.50 mmol). After 5 min, the
reaction mixture was filtered through a pad of alumina (CH2-
Cl2 containing 0.1% TEA). The resulting porphyrin-contain-
ing solution was concentrated. The product was recrystallized
(CH2Cl2/methanol) and dried in vacuo, affording a crystalline
purple solid (0.0603 g, 19%): 1H NMR δ -2.70 (s, 2H),
0.96-1.00 (m, 6H), 1.54-1.58 (m, 4H), 1.78-1.82 (m, 4H),
2.53-2.57 (m, 4H), 2.70 (s, 6H), 4.98-5.02 (m, 4H), 7.53
(d, J ) 8.0 Hz, 4H), 8.05 (d, J ) 8.0 Hz, 4H), 8.74 (s, 2H),
8.87 (d, J ) 4.4 Hz, 2H), 9.43 (d, J ) 4.4 Hz, 2H), 9.56 (s,
2H); 13C NMR δ 14.3, 21.7, 22.9, 32.9, 35.7, 38.7, 119.0,
120.0, 127.6, 127.9-129.6 (br), 130.1-131.0 (br), 134.6,
137.3, 139.6; LD-MS obsd 631.4; FAB-MS obsd 631.3781,
calcd 631.3801 [(M + H)+, M ) C44H46N4]; λabs 417, 516,
550, 597, 655 nm.
5,15-Bis(3,5-di-tert-butylphenyl)-10-(4-methylphenyl)-
20-[4-[2-(trimethylsilyl)ethynyl]phenyl]porphyrin (4g). The
condensation of dicarbinol 3e-OH [derived from reduction
of 3e (0.150 g, 0.200 mmol) with NaBH4 (0.379 g, 10.0
mmol, 50.0 mol equiv) in THF/methanol (16 mL, 3:1)] and
dipyrromethane 1e (0.0470 g, 0.200 mmol) was carried out
in the presence of 2,6-di-tert-butylpyridine (0.0590 mL, 0.260
mmol) and Sc(OTf)3 (0.0130 g, 0.0260 mmol) in CH2Cl2 (8
mL) at room temperature for 10 min followed by the addition
of DDQ (0.136 g, 0.600 mmol). After 5 min, the reaction
mixture was filtered through a pad of alumina (CH2Cl2
containing 0.1% TEA). The resulting porphyrin-containing
solution was concentrated to give a purple solid. Methanol
was added. The resulting suspension was sonicated for 5 min
δ -2.76 (s, 2H), 2.71 (s, 6H), 7.56 (d, J ) 8.0 Hz, 4H),
7.72-7.81 (m, 3H), 8.09 (d, J ) 8.0 Hz, 4H), 8.19-8.21
(m, 2H), 8.75 (d, J ) 4.4 Hz, 2H), 8.84 (d, J ) 4.4 Hz, 2H),
8.86 (d, J ) 4.4 Hz, 2H), 8.96 (d, J ) 4.4 Hz, 2H); 13C
NMR δ 21.7, 100.1, 121.2, 122.2, 126.9, 127.7, 128.0, 129.1,
130.5, 130.8-132.9 (br), 132.8-133.8 (br), 134.7, 137.8,
138.9, 142.2, 145.2-145.8 (m), 147.8-148.2 (m); LD-MS
obsd 734.0; FAB-MS obsd 733.2365, calcd 733.2391 [(M
+ H)+, M ) C46H29F5N4]; λabs 416, 512, 546, 589, 646 nm.
5-(4-Iodophenyl)-10-(4-methoxyphenyl)-20-(4-meth-
ylphenyl)-15-phenylporphyrin (4d). The condensation of
dicarbinol 3b-OH [derived from reduction of 3b (0.474 g,
1.00 mmol) with NaBH4 (1.89 g, 50.0 mmol, 50.0 mol equiv)
in THF/methanol (80 mL, 3:1)] and dipyrromethane 1d
(0.348 g, 1.00 mmol) was carried out in the presence of 2,6-
di-tert-butylpyridine (0.293 mL, 1.30 mmol) and Sc(OTf)3
(0.0640 g, 0.130 mmol) in CH2Cl2 (40 mL) at room
temperature for 10 min followed by the addition of DDQ
(0.681 g, 3.00 mmol). After 5 min, the reaction mixture was
filtered through a pad of alumina (CH2Cl2 containing 0.1%
TEA). The resulting porphyrin-containing solution was
concentrated to give a purple solid. Methanol was added.
The resulting suspension was sonicated for 5 min and then
filtered through a filter paper secured in a fritted glass filter
holder. The filtered material was washed with methanol
followed by hexanes and dried in vacuo, affording a
crystalline purple solid (0.135 g, 17%): 1H NMR δ -2.79
(s, 2H), 2.71 (s, 3H), 4.10 (s, 3H), 7.29 (d, J ) 8.0 Hz, 2H),
7.56 (d, J ) 8.0 Hz, 2H), 7.72-7.77 (m, 3H), 7.95 (d, J )
8.0 Hz, 2H), 8.10 (d, J ) 8.0 Hz, 4H), 8.12(d, J ) 8.0 Hz,
2H), 8.20-8.22 (m, 2H), 8.80-8.84 (m, 4H), 8.86-8.89 (m,
4H); 13C NMR δ 21.7, 55.8, 94.2, 112.4, 118.5, 120.3, 120.5,
120.6, 126.8, 127.6, 127.9, 130.0-131.9 (br), 134.6, 134.72,
134.76, 135.8, 136.0, 136.3, 137.6, 139.2, 142.0, 142.3,
159.6; LD-MS obsd 785.8; FAB-MS obsd 785.1745, calcd
785.1777 [(M + H)+, M ) C46H33IN4O]; λabs 418, 514, 550,
593, 648 nm.
Vol. 10, No. 1, 2006 / Organic Process Research & Development
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131

and then filtered through a filter paper secured in a fritted
glass filter holder. The filtered material was washed with
methanol and dried in vacuo, affording a crystalline purple
solid (0.0420 g, 22%): 1H NMR δ -2.74 (s, 2H), 0.37 (s,
9H), 1.52 (s, 36H), 2.69 (s, 3H), 7.54 (d, J ) 8.0 Hz, 2H),
7.79 (s, 2H), 7.86 (d, J ) 8.0 Hz, 2H), 8.07 (s, 4H), 8.10 (d,
J ) 8.0 Hz, 2H), 8.17 (d, J ) 8.0 Hz, 2H), 8.79 (d, J ) 4.4
Hz, 2H), 8.86-8.89 (m, 6H); 13C NMR δ 0.3, 21.7, 31.9,
35.2, 95.6, 105.3, 118.9, 120.5, 121.2, 121.8, 122.6, 127.5,
130.1, 130.5, 130.7-132.1 (br), 134.58, 134.62, 137.5, 139.5,
141.3, 143.0, 148.9; LD-MS obsd 950.2; FAB-MS obsd
949.5577, calcd 949.5605 [(M + H)+, M ) C66H72N4Si];
λabs 419, 515, 550, 592, 650 nm.
7.74-7.79 (m, 3H), 7.89 (d, J ) 8.0 Hz, 2H), 8.08 (d, J )
8.0 Hz, 2H), 8.11-8.13 (m, 4H), 8.20-8.22 (m, 2H), 8.79-
8.85 (m, 4H), 8.80 (s, 4H); 13C NMR δ 55.7, 112.4, 118.3,
120.2, 120.3, 120.5, 122.5, 126.9, 127.9, 130.1, 130.3-132.4
(br), 134.6, 134.7, 135.8, 136.0, 141.4, 142.3, 159.6; LD-
MS obsd 753.3; FAB-MS obsd 753.1877, calcd 753.1865
[(M + H)+, M ) C46H33BrN4O2]; λabs 419, 515, 550, 593,
648 nm.
Exemplary Procedure for Aerobic Oxidation: Syn-
thesis of 5,15-Bis(4-methylphenyl)-10,20-diphenylporphy-
rin (4a). The condensation of dicarbinol 3a-OH [derived
from reduction of 3a (0.229 g, 0.500 mmol) with NaBH4
(0.947 g, 25.0 mmol, 50.0 mol equiv) in THF/methanol (40
mL, 3:1)] and dipyrromethane 1a (0.111 g, 0.500 mmol) was
carried out in the presence of 2,6-di-tert-butylpyridine (0.147
mL, 0.650 mmol) and Sc(OTf)3 (0.0320 g, 0.0650 mmol) in
CH2Cl2 (20 mL) at room temperature. After 15 min (fol-
lowing the addition of Sc(OTf)3), samples of DDQ (0.0056
g, 5 mol %) and [(t-Bu)4FePc]2O (0.0400 g, 5 mol %) were
added, and the reaction mixture was gently bubbled with
oxygen for 90 min. The gas purge caused a slight but
continual decrease in the reaction volume. The loss of solvent
was offset by occasional addition of 1-2 mL of CH2Cl2 via
syringe as required prior to acquisition of samples (total
volume 20 mL over 105 min). The reaction mixture was
filtered through a pad of alumina (6 cm dia × 7.5 cm) with
CH2Cl2 as eluent. The resulting porphyrin-containing solution
was concentrated to give a purple solid. Hexanes was added.
The resulting suspension was sonicated for 5 min and then
filtered through a Bu¨chner funnel. The filtered material was
washed with hexanes and dried in vacuo, affording a
crystalline purple solid (0.055 g, 17%). The characterization
data (1H NMR, 13C NMR, LD-MS, and UV-vis spectra)
were consistent with the above-reported values.
Exemplary Gram-Scale Synthesis: 5-Mesityl-10-(4-
methoxyphenyl)-20-(4-methylphenyl)-10-phenylporphy-
rin (4l). A sample of 3b (8.54 g, 18.0 mmol) was placed in
a 1-L round-bottom flask equipped with a pressure-equalizing
addition funnel. Reagent grade THF (72 mL) and NaBH4
(6.82 g, 180 mmol, 10.0 mol equiv) were added under an
inert atmosphere followed by slow addition of reagent grade
MeOH (30 mL; a water cooling bath was used to maintain
the temperature). When no more starting material was
detected by TLC analysis (∼1 h) [alumina, CH2Cl2/methanol
(97:3)], the reaction mixture was diluted with CH2Cl2 (350
mL). Saturated aqueous NH4Cl (500 mL) was poured slowly
into the reaction mixture. The biphasic mixture was stirred
for 15 min. The organic layer was separated, washed with
water (500 mL), dried (K2CO3), and filtered. The filtrate was
concentrated, affording a yellow foam. The condensation of
dicarbinol 3b-OH and dipyrromethane 1g (4.76 g, 18.0
mmol) was carried out in a 1-L one-neck flask in the presence
of 2,6-di-tert-butylpyridine (5.28 mL, 23.4 mmol) and Sc-
(OTf)3 (1.15 g, 2.34 mmol) in reagent grade CH2Cl2 (720
mL) at room temperature. Then [15 min after the addition
of Sc(OTf)3] samples of DDQ (0.102 g, 2.5 mol %) and [(t-
Bu)4FePc]2O (0.721 g, 2.5 mol %) (see Note 1 below) were
added, a Claisen adapter equipped with a rubber septum and
5-(4-Methoxyphenyl)-15-(4-methylphenyl)-10-phenylpor-
phyrin (4h). The condensation of dicarbinol 3b-OH [derived
from reduction of 3b (0.474 g, 1.00 mmol) with NaBH4 (1.89
g, 50.0 mmol, 50.0 mol equiv) in THF/methanol (80 mL,
3:1)] and dipyrromethane 1f (0.146 g, 1.00 mmol) was
carried out in the presence of 2,6-di-tert-butylpyridine (0.293
mL, 1.30 mmol) and Sc(OTf)3 (0.0640 g, 0.130 mmol) in
CH2Cl2 (40 mL) at room temperature for 10 min followed
by the addition of DDQ (0.681 g, 3.00 mmol). After 5 min,
the reaction mixture was filtered through a pad of alumina
(CH2Cl2 containing 0.1% TEA). The resulting porphyrin-
containing solution was concentrated to give a purple solid.
Methanol was added. The resulting suspension was sonicated
for 5 min and then filtered through a filter paper secured in
a fritted glass filter holder. The filtered material was washed
with methanol and dried in vacuo, affording a crystalline
1
purple solid (0.123 g, 21%): H NMR δ -2.98 (s, 2H), 2.72
(s, 3H), 4.10 (s, 3H), 7.32 (d, J ) 8.0 Hz, 2H), 7.58 (d, J )
8.0 Hz, 2H), 7.71-7.80 (m, 3H), 8.13 (d, J ) 8.0 Hz, 2H),
8.15 (d, J ) 8.0 Hz, 2H), 8.21 (d, J ) 8.0 Hz, 2H), 8.86 (d,
J ) 4.4 Hz, 2H), 8.93 (d, J ) 4.4 Hz, 2H), 9.04 (d, J ) 4.4
Hz, 2H), 9.33 (d, J ) 4.4 Hz, 2H), 10.19 (s, 1H); 13C NMR
δ 21.8, 55.7, 104.9, 112.5, 119.6, 119.8, 120.6, 126.7, 127.7,
127.8, 130.9, 131.3, 131.5, 134.3, 134.7, 134.8, 135.9, 137.5,
139.0, 142.8, 144.0-146.0 (br), 159.6; LD-MS obsd 583.1;
FAB-MS obsd 583.2503, calcd 583.2498 [(M + H)+, M )
C40H30N4O]; λabs 412, 508, 543, 585, 642 nm.
5-(4-Bromophenyl)-10,15-bis(4-methoxyphenyl)-20-
phenylporphyrin (4j). The condensation of dicarbinol 3g-
OH [derived from reduction of 3g (0.285 g, 0.500 mmol
with NaBH4 (0.947, 25.0 mmol, 50.0 mol equiv) in THF/
methanol (40 mL, 3:1)] and dipyrromethane 1a (0.111 g,
0.500 mmol) was carried out in the presence of 2,6-di-tert-
butylpyridine (0.147 mL, 0.650 mmol) and Sc(OTf)3 (0.0320
g, 0.0650 mmol) in CH2Cl2 (20 mL) at room temperature
for 10 min followed by the addition of DDQ (0.340 g, 1.50
mmol). After 5 min, the reaction mixture was filtered through
a pad of alumina (CH2Cl2 containing 0.1% TEA). The
resulting porphyrin-containing solution was concentrated to
give a purple solid. Methanol was added. The resulting
suspension was sonicated for 5 min and then filtered through
a filter paper secured in a fritted glass filter holder. The
filtered material was washed with methanol and dried in
vacuo, affording a crystalline purple solid (0.034 g, 9%):
1H NMR δ -2.78 (s, 2H), 4.10 (s, 6H), 7.28-7.30 (m, 4H),
132
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a condenser was fitted over one neck of the round-bottom
flask, and the reaction mixture was gently bubbled with
oxygen (see Note 2 below) for 90 min. 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 filtered through a pad
of silica (175 g; 8.0 cm dia × 8.0 cm) with CH2Cl2 as eluent.
The resulting porphyrin-containing solution was concentrated
to give a purple solid. Hexanes was added to the solid. The
resulting suspension was sonicated for 1 min and then filtered
through a filter paper secured in a fritted glass filter holder.
The filtered material was washed (first with hexanes and
second with methanol) and then dried in vacuo at room
temperature, affording a crystalline purple solid (2.88 g,
22.8%): (see Note 3 below) 1H NMR δ -2.68 (s, 2H), 1.85
(s, 6H), 2.64 (s, 3H), 2.71 (s, 3H), 4.10 (s, 3H), 7.28-7.30
(m, 4H), 7.56 (d, J ) 8.0 Hz, 2H), 7.73-7.79 (m, 3H), 8.11
(d, J ) 8.0 Hz, 2H), 8.14 (d, J ) 8.0 Hz, 2H), 8.20-8.22
(m, 2H), 8.68-8.70 (m, 2H), 8.80-8.87 (m, 6H); 13C NMR
δ 21.6, 21.7, 21.8, 55.7, 112.4, 118.4, 119.6, 119.9, 120.1,
126.8, 127.6, 127.8, 127.9, 129.5-132.4 (br), 134.7, 135.7,
137.5, 137.9, 138.6, 139.3, 139.6, 142.6, 159.5; LD-MS obsd
700.5; FAB-MS obsd 700.3188, calcd 700.3202 (C49H40N4O);
λabs 418, 514, 549, 591, 649 nm.
Note 1: The 2.5 mol % level is referenced against the
number of moles of the dipyrromethane. The theoretical
amount of DDQ is 300 mol % (assuming a 100% yield of
porphyrinogen and three moles of DDQ per mole of
porphyrinogen). Accordingly, the quantity of DDQ employed
herein is 0.83% of the amount required for a stoichiometric
synthesis.
Note 2: The aerobic oxidation was carried out using
oxygen of 99.999% purity (Research grade, National Weld-
ers, Inc.).
Magnesium Insertion: Mg(II)-5,15-bis(4-methylphe-
nyl)-10,20-diphenylporphyrin (Mg-4a). A one-third portion
of the crude reaction mixture from the aerobic oxidation
(corresponding to 0.200 mmol of each reactant) was treated
with CH2Cl2 (12 mL, giving a reaction volume of 20 mL)
followed by MgI2 (0.556 g, 2.00 mmol) and DIEA (0.697
mL, 4.00 mmol). The reaction mixture was stirred at room
temperature for 30 min. The reaction mixture was poured
over a chromatography column [alumina, 3 cm dia × 15
cm, CH2Cl2 f CH2Cl2/acetone (1:1)], affording purple
fractions (accompanied by some black residue) that were
combined, concentrated, and dried in vacuo. Hexanes was
added. The resulting purple suspension was filtered. The
filtrate was concentrated and dried in vacuo to afford a purple
solid (0.0274 g, 20%): 1H NMR δ 2.70 (s, 6H), 7.53 (d, J
) 8.0 Hz, 4H), 7.69-7.76 (m, 6H), 8.10 (d, J ) 8.0 Hz,
4H), 8.20-8.22 (m, 4H), 8.83 (d, J ) 4.4 Hz, 4H), 8.87 (d,
J ) 4.4 Hz, 4H); 13C NMR δ 21.7, 121.6, 121.8, 126.4,
127.2, 131.9, 132.0, 134.7, 134.8, 136.8, 141.0, 143.9, 149.9,
150.1; LD-MS obsd 664.5; FAB-MS obsd 664.2486, calcd
664.2477 (C46H32N4Mg); λabs 429, 571, 613 nm; λem (λex
)
570 nm) 619, 650 nm.
Nickel Insertion: Ni(II)-5,15-bis(4-methylphenyl)-10,-
20-diphenylporphyrin (Ni-4a). A one-third portion of the
crude reaction mixture from the aerobic oxidation (corre-
sponding to 0.200 mmol of each reactant) was concentrated
(to ∼1 mL), whereupon toluene (10 mL) was added. The
reaction mixture was treated with Ni(acac)2 (0.514 g, 2.00
mmol). The mixture was refluxed overnight. The reaction
mixture was poured over a chromatography column [silica,
3 cm dia × 15 cm, CH2Cl2/hexanes (3:1)]. The purple
fraction was collected and washed with methanol and
1
hexanes to afford a purple solid (0.0247 g, 18%): H NMR
δ 2.64 (s, 6H), 7.47 (d, J ) 8.0 Hz, 4H), 7.67-7.70 (m,
6H), 7.89 (d, J ) 8.0 Hz, 4H), 8.00-8.02 (m, 4H), 8.73 (d,
J ) 4.8 Hz, 4H), 8.77 (d, J ) 4.8 Hz, 4H); 13C NMR δ
21.6, 127.0, 127.8, 127.9, 132.2, 132.4, 133.8, 133.9, 137.6,
138.1, 141.1, 142.7, 142.9; LD-MS obsd 698.3; FAB-MS
obsd 698.1968, calcd 698.1980 (C46H32N4Ni); λabs 414, 527
nm.
Note 3: No N-confused porphyrin (or any other porphyrin
byproduct) was detected in the isolated porphyrin sample
upon HPLC analysis.
Exemplary Three-Step One-Flask Synthesis of Met-
alloporphyrins. The condensation of dicarbinol 3a-OH
[derived from reduction of 3a (0.275 g, 0.600 mmol) with
NaBH4 (1.13 g, 30.0 mmol, 50.0 mol equiv) in THF/
methanol (48 mL, 3:1)] and dipyrromethane 1a (0.133 g,
0.600 mmol) was carried out in the presence of 2,6-di-tert-
butylpyridine (0.176 mL, 0.780 mmol) and Sc(OTf)3 (0.0380
g, 0.0780 mmol) in CH2Cl2 (24 mL) at room temperature.
After 15 min (following the addition of Sc(OTf)3), samples
of DDQ (0.0068 g, 5 mol %) and [(t-Bu)4FePc]2O (0.0480
g, 5 mol %) were added, and the reaction mixture was gently
bubbled with oxygen for 90 min. The gas purge caused a
slight but continual decrease in the reaction volume. The
solvent loss was offset by occasional addition of 1-2 mL
of CH2Cl2 via syringe as required prior to acquisition of
samples (total volume 24 mL after 105 min). The reaction
mixture was divided into portions and employed for meta-
lation as described below. The condensation/oxidation was
performed twice to generate all of the fractional portions
listed below.
Copper Insertion: Cu(II)-5,15-bis(4-methylphenyl)-
10,20-diphenylporphyrin (Cu-4a). A one-third portion of
the crude reaction mixture from the aerobic oxidation
(corresponding to 0.200 mmol of each reactant) was treated
with CH2Cl2 (7 mL, giving a reaction volume of 15 mL)
followed by methanolic Cu(OAc)2‚H2O (0.199 g, 1.00 mmol,
5 mL). The reaction mixture was stirred overnight at room
temperature. The reaction mixture was poured over a
chromatography column [silica, 3 cm dia × 15 cm, CH2-
Cl2/hexanes (3:1)]. The purple fraction was collected and
concentrated. The product was washed with methanol to
1
afford a dark-purple solid (0.027 g, 19%): H NMR δ 2.54
(s, 6H), 7.64-7.29 (m, 18H); LD-MS obsd 704.1; FAB-MS
obsd 703.1951, calcd 703.1923 (C46H32N4Cu); λabs 415, 540
nm.
Zinc Insertion: Zn(II)-5,15-bis(4-methylphenyl)-10,-
20-diphenylporphyrin (Zn-4a). A one-third portion of the
crude reaction mixture from the aerobic oxidation (corre-
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133

sponding to 0.200 mmol of each reactant) was treated with
CH2Cl2 (7 mL, giving a reaction volume of 15 mL) followed
by methanolic Zn(OAc)2‚2H2O (0.219 g, 1.00 mmol, 5 mL).
The reaction mixture was stirred overnight at room temper-
ature. The reaction mixture was poured over a chromatog-
raphy column [silica, 3 cm dia × 15 cm, CH2Cl2/hexanes
(3:1)]. The purple fraction was collected and washed with
and washed with methanol to afford an orange-purple solid
(0.0284 g, 19%): H NMR δ 2.69 (s, 6H), 7.536 (d, J ) 8.0
1
Hz, 4H), 7.76-7.71 (m, 6H), 8.04 (d, J ) 8.0 Hz, 4H), 8.15-
8.17 (m, 4H), 8.79 (d, J ) 4.4 Hz, 4H), 8.83 (d, J ) 4.4 Hz,
4H); 13C NMR δ 21.7, 122.0, 123.0, 126.9, 127.6, 127.9,
131.0, 131.2, 134.2, 134.3, 137.6, 139.0, 141.7, 141.9, 142.0;
LD-MS obsd 747.2; FAB-MS obsd 746.1729, calcd 746.1662
(C46H32N4Pd); λabs 416, 523 nm.
1
methanol to afford a purple solid (0.0254 g, 18%): H NMR
δ 2.71 (s, 6H), 7.56 (d, J ) 8.0 Hz, 4H), 7.77-7.74 (m,
6H), 8.10 (d, J ) 8.0 Hz, 4H), 8.21-8.23 (m, 4H), 8.94 (d,
J ) 4.4 Hz, 4H), 8.98 (d, J ) 4.4 Hz, 4H); 13C NMR δ
21.7, 121.2, 121.4, 126.7, 127.5, 127.6, 132.0, 132.2, 134.5,
134.6, 137.3, 140.0, 143.0, 150.3, 150.5; LD-MS obsd 705.1;
FAB-MS obsd 704.1928, calcd 704.1918 (C46H32N4Zn); λabs
423, 556, 595 nm; λem (λex ) 550 nm) 605, 655 nm.
Palladium Insertion: Pd(II)-5,15-bis(4-methylphenyl)-
10,20-diphenylporphyrin (Pd-4a). A one-third portion of
the crude reaction mixture from the aerobic oxidation
(corresponding to 0.200 mmol of each reactant) was con-
centrated (to ∼1 mL), whereupon a solution of 1,2-
dichloroethane/methanol (4:1, 4 mL) was added. The reaction
mixture was treated with Pd(O2CCF3)2 (0.133 g, 0.400
mmol). The resulting heterogeneous mixture was stirred and
heated at 45 °C for 1 h. The reaction mixture was poured
over a chromatography column [silica, 3 cm dia × 15 cm,
CH2Cl2/hexanes (3:1)]. The orange fraction was collected
Acknowledgment
This work was funded by 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. We thank Mr. Sam Price
for the studies of ionic liquids.
Supporting Information Available
Additional data concerning acid catalysis, interpretation
of data concerning N-confused porphyrins, and description
of aerobic oxidation studies and results. This material is
available free of charge via the Internet at http://pubs.acs.org.
Received for review October 9, 2005.
OP050193G
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