An efficient one-flask synthesis of N-confused tetraphenylporphyrin.

Article abstract of DOI:10.1021/ol9910114

[formula: see text] N-Confused meso-substituted porphyrin is a porphyrin isomer previously available from one-flask porphyrin syntheses as a low-yield byproduct (< 7.5%). We have found that methanesulfonic acid catalyzed condensation of pyrrole and benzaldehyde followed by DDQ oxidation provides N-confused tetraphenylporphyrin (NC-TPP) in up to 39% yield in analytical scale experiments. Preparative synthesis provided an isolated yield of 35% (800 mg). This represents a > 5-fold yield improvement and makes significant quantities of NC-TPP readily available.

Full text of DOI:10.1021/ol9910114

ORGANIC
LETTERS
1999
Vol. 1, No. 9
1455-1458
An Efficient One-Flask Synthesis of
N-Confused Tetraphenylporphyrin
G. Richard Geier III, Denise M. Haynes, and Jonathan S. Lindsey*
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
jlindsey@ncsu.edu
Received September 6, 1999
ABSTRACT
N-Confused meso-substituted porphyrin is a porphyrin isomer previously available from one-flask porphyrin syntheses as a low-yield byproduct
(<7.5%). We have found that methanesulfonic acid catalyzed condensation of pyrrole and benzaldehyde followed by DDQ oxidation provides
N-confused tetraphenylporphyrin (NC-TPP) in up to 39% yield in analytical scale experiments. Preparative synthesis provided an isolated yield
of 35% (800 mg). This represents a >5-fold yield improvement and makes significant quantities of NC-TPP readily available.
In 1994, the groups of Latos-Grazynski1 and Furuta2
independently reported the isolation of a meso-substituted
porphyrin isomer in ∼5% yield from the acid-catalyzed
condensation of pyrrole and an aryl aldehyde followed by
oxidation. This intriguing isomer, 2-aza-21-carba-5,10,15,
20-tetraarylporphyrin (also called carbaporphyrin, N-con-
fused or N-inverted porphyrin), has distinctive coordination
properties and reactivity.3 The condensation conditions
reported to lead to N-confused porphyrin were somewhat
unusual. Latos-Grazynski used 70 mM pyrrole and 40 mM
p-tolualdehyde in CH2Cl2 at room temperature with 8 mM
BF3-etherate catalysis, whereas Furuta used equimolar
pyrrole and benzaldehyde in tert-butyl alcohol/CH2Cl2 (1:
1) at room temperature with HBr catalysis. Although these
conditions led to the discovery of N-confused porphyrin, this
isomer was only available in marginal yield (∼5%) as a
byproduct accompanying the porphyrin (∼20%).
To explore the generality of N-confused porphyrin forma-
tion, we examined a much broader range of condensation
conditions for pyrrole + benzaldehyde using BF3-etherate
and TFA,4 the most commonly employed acids in two-step,
one-flask syntheses of meso-substituted porphyrins (Scheme
1).5 We found N-confused tetraphenylporphyrin (NC-TPP)
to be a ubiquitous reaction byproduct under virtually any
condition providing at least ∼10% yield of tetraphenylpor-
phyrin (TPP). NC-TPP yields were generally less than 5%,
with 7.5% being the highest yield observed. In addition,
changes in the yield of NC-TPP as a function of reaction
parameters were found to mirror those of TPP.
Recently, we examined the effects of a broad range of
acids on the products formed in one-flask porphyrin syn-
theses. Analytical scale reactions (10 mL reaction volume)
have been performed with pyrrole and benzaldehyde (reac-
tants) at 10 mM or 100 mM in CH2Cl2 at room temperature
followed by oxidation with DDQ. Acid concentrations
ranging from 0.1 to 1000 mM were examined. The yield of
TPP was determined spectrophotometrically and by HPLC,
and the yield of NC-TPP was determined by HPLC using
established methodology.4,5 The full details of this study will
(1) Chmielewski, P. J.; Latos-Grazynski, L.; Rachlewicz, K.; Glowiac,
T. Angew. Chem., Int. Ed. Engl. 1994, 33, 779-781.
(2) Furuta, H.; Asano, T.; Ogawa, T. J. Am. Chem. Soc. 1994, 116, 767-
768.
(3) (a) Latos-Grazynski, L.; Chmielewski, P. J. New. J. Chem. 1997,
27, 691-700. (b) Chmielewski, P. J.; Latos-Grazynski, L. Inorg. Chem.
1997, 36, 840-845. (c) Chmielewski, P. J.; Latos-Grazynski, L.; Glowiak,
T. J. Am. Chem. Soc. 1996, 118, 5690-5701. (d) Chmielewski, P. J.; Latos-
Grazynski, L. J. Chem. Soc., Perkin Trans. 2 1995, 503-509. (e) Ishikawa,
Y.; Yoshida, I.; Akaiwa, K.; Koguchi, E.; Sasaki, T.; Furuta, H. Chem.
Lett. 1997, 453-454. (f) Ariga, K.; Kunitake, T.; Furuta, H. J. Chem. Soc.,
Perkin Trans. 2 1996, 667-672. (g) Ghosh, A. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1028-1030.
10.1021/ol9910114 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/29/1999

(10 mM each) were monitored at 8 min, 30 min, and 1 h
after addition of acid. The optimal range of MSA was found
to be 5-15 mM, providing NC-TPP in yields of close to
40%.
Scheme 1
The effects of MSA concentration on yields of TPP and
NC-TPP were examined and found to be very different
(Figure 2). By changing the MSA concentration, the yields
Figure 2. NC-TPP and TPP yields as a function of MSA
concentration. Reactions were performed using 10 mM reactants
in CH2Cl2 at room temperature. Yields from DDQ-oxidized reaction
samples were determined by HPLC. The highest yield obtained at
8 min, 30 min, or 1 h is plotted.
be reported elsewhere, but of immediate interest is the finding
of reaction conditions providing unusually high yields of NC-
TPP.
During the course of examining diverse acid catalysts, we
found that methanesulfonic acid (MSA) efficiently produces
NC-TPP. This finding was surprising, as lower concentrations
of MSA had previously been used to prepare TPP.6 The effect
of MSA concentration on the yield of NC-TPP was inves-
tigated (Figure 1). Reactions of pyrrole and benzaldehyde
of TPP and NC-TPP were inverted. Optimal conditions for
TPP (∼40%) provided a yield of <10% for NC-TPP, while
optimal conditions for NC-TPP (∼40%) provided TPP in
<10% yield. The maximum yield of TPP was obtained at
30-fold lower MSA concentration than the maximum yield
of NC-TPP. These findings are in sharp contrast to the results
obtained with BF3-etherate and TFA catalysis, where the
yields of TPP and NC-TPP responded similarly to changes
in acid concentration.4
Because the maximal NC-TPP yield was obtained with
MSA concentrations higher than required for maximal TPP
yield, we examined whether exposure of pyrrole to MSA
prior to benzaldehyde addition might further increase the
yield of NC-TPP. Pyrrole (10 mM) was treated with MSA
(7 mM) for 0, 5, 15, or 30 min prior to benzaldehyde
addition. Reactions carried out in this way showed a
significant decrease in NC-TPP (to <5%) with increasing
time prior to benzaldehyde addition (see Supporting Infor-
mation). Interestingly, very little decrease in TPP yield was
observed. The decreased yield of NC-TPP but not TPP was
unexpected and indicates the presence of processes involving
pyrrole and MSA that selectively affect the pathway leading
Figure 1. NC-TPP yield as a function of MSA concentration.
Reactions were performed using 10 mM reactants in CH2Cl2 at
room temperature, and yields were determined by HPLC analysis
of DDQ-oxidized reaction samples taken at the times indicated.
(4) Geier, G. R., III; Lindsey, J. S. J. Org. Chem. 1999, 64, 1596-1603.
(5) Lindsey, J. S.; Schreiman, I. C.; Hsu, H. C.; Kearney, P. C.;
Marguerettaz, A. M. J. Org. Chem. 1987, 52, 827-836.
(6) Lindsey, J. S.; MacCrum, K. A.; Tyhonas, J. S.; Chuang, Y. Y. J.
Org. Chem. 1994, 59, 579-587.
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Org. Lett., Vol. 1, No. 9, 1999

to NC-TPP. The reverse experiment with benzaldehyde and
MSA revealed no change in yield of NC-TPP or TPP.
One set of conditions leading to the discovery of N-
confused porphyrin employed excess pyrrole;1 thus, we
examined the effect of various ratios of pyrrole and benz-
aldehyde on NC-TPP yield. The ratios examined ranged from
a 3-fold excess of benzaldehyde to a 4.5-fold excess of
pyrrole (the limiting reactant was 10 mM) with a MSA
concentration of 9 mM. The maximum yield of NC-TPP was
found to occur at equimolar concentrations pyrrole and
benzaldehyde, indicating that excess pyrrole is not required
for optimal NC-TPP production.
of NC-TPP and low yield of TPP rendered the overall
synthesis and isolation straightforward, readily affording
substantial quantities of NC-TPP.
To further refine the preparative scale synthesis to require
less solvent, we examined the formation of NC-TPP at higher
reaction concentrations (20, 50, and 100 mM). At each
concentration, a range of MSA concentrations was examined
(2.5-320 mM). For each concentration of reactants, the MSA
concentration and time affording the highest yield of NC-
TPP have been determined (Table 1). In general, maximum
The yields of TPP and NC-TPP from a reaction of 10 mM
reactants and 7 mM MSA were followed as a function of
time (Figure 3). The maximum TPP yield (32%) occurred
Table 1. Optimal Conditions for Synthesis of NC-TPP at
Different Reactant Concentrationsa
[reactants], mM [MSA], mM time, min % NC-TPP %TPP
10
20
50
7
20
40
50
30
8
8
39
29
20
12
5
2
6
100
8
12
a See Supporting Information for complete data.
yields of NC-TPP were found to decline with increasing
reactant concentration consistent with previous findings of
high concentration porphyrin syntheses.6 Nevertheless, the
29% yield of NC-TPP obtained with 20 mM reactants offers
a reasonable compromise between yield and solvent require-
ment for the preparative scale synthesis of NC-TPP.
The efficient synthesis of NC-TPP under MSA catalysis
is not only of clear practical value for the preparation of
this intriguing porphyrin isomer but this finding also reveals
additional mechanistic complexity and richness of chemistry
possible in two-step, one-flask porphyrin syntheses. With
BF3-etherate or TFA catalysis, the formation of NC-TPP
in low levels under conditions producing significant quanti-
ties of TPP could be explained by the expected low level of
â-pyrrolic substitution. The ubiquitous presence of NC-TPP
and the similar changes in yield of NC-TPP and TPP as a
function of reaction parameters suggested that both share a
common reaction pathway. The anomalously high production
of NC-TPP under MSA catalysis and the divergence of TPP
and NC-TPP yields as a function of MSA concentration or
time raise a number of questions. (1) Why do appropriate
concentrations of TFA, BF3-etherate, and MSA provide
good yields of TPP, while only MSA provides good yields
of NC-TPP? (2) Why does a change in MSA concentration
alone invert the quantities of TPP and NC-TPP produced?
(3) How is the course of reactionsrates, equilibrium,
porphyrinogen and N-confused porphyrinogen stabilities,
reactivity of intermediates, oligomer distribution, etc.saltered
with TFA, BF3-etherate, or MSA catalysis? (4) Can condi-
tions be found that provide efficient one-flask syntheses of
other porphyrinic macrocycles (corrole, sapphyrin, penta-
phyrin, etc.)? The resolution of such questions awaits further
experimentation.
Figure 3. NC-TPP and TPP yields as a function of time (note the
log scale). The reaction was performed using 10 mM reactants, 7
mM MSA in CH2Cl2 at room temperature. Yields from DDQ-
oxidized reaction samples were determined by HPLC.
at 30 s after addition of acid, but the yield was only 10%
after 10 min. The maximum NC-TPP yield (39%) occurred
15 min after addition of acid. Again, this difference in rate
of reaction leading to TPP and NC-TPP sharply contrasts
with observations under BF3-etherate and TFA catalysis
where the reaction rates are comparable. The difference in
yields of TPP and NC-TPP as a function of time under MSA
catalysis is of practical utility, as <5% TPP was present at
reaction times affording >35% NC-TPP (30 min), simplify-
ing preparative isolation of NC-TPP.
The results of the analytical scale experiments were
extended to a 1.5-L preparative scale reaction employing 10
mM reactants and 7 mM MSA. After condensation for 30
min, DDQ was added. HPLC analysis of an aliquot obtained
after DDQ oxidation revealed NC-TPP and TPP yields of
37% and 5%, respectively. Filtration of the crude reaction
mixture through a pad of basic alumina (CH2Cl2) followed
by column chromatography on basic alumina (hexanes/
CH2Cl2) afforded NC-TPP and TPP in yields of 35% (800
mg) and 6% (140 mg), respectively. The relatively high yield
In summary, we have reported an efficient, one-flask
synthesis of NC-TPP utilizing MSA catalysis. The isolated
yield of 35% (800 mg) represents a >5-fold improvement
Org. Lett., Vol. 1, No. 9, 1999
1457

over previously reported conditions. The inversion of TPP
and NC-TPP yields obtained with these reaction conditions
(making TPP a low-yield byproduct and NC-TPP the
dominant product) provides ready access to significant
quantities of NC-TPP. This methodology should open the
door to the preparation of a wide variety of NC-TPP
derivatives, facilitate further studies of metal coordination,
organometallic reactivity, and fundamental physical proper-
ties, and stimulate continued investigation of methods for
one-flask porphyrin syntheses.
Acknowledgment. This work was supported by the
National Institutes of Health (GM36238).
Supporting Information Available: Experimental pro-
cedures and additional data of NC-TPP and TPP yields. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL9910114
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Org. Lett., Vol. 1, No. 9, 1999