De novo synthesis of stable tetrahydroporphyrinic macrocycles: Bacteriochlorins and a tetradehydrocorrin

Article abstract of DOI:10.1021/jo050467y

Bacteriochlorins (tetrahydroporphyrins) are attractive for diverse photochemical applications owing to their strong absorption in the near-infrared spectral region, as exemplified by the bacterial photosynthetic pigment bacteriochlorophyll α, yet often are labile toward dehydrogenation to give the chlorin. Tetradehydrocorrins (ring-contracted tetrahydroporphyrins) are attractive for studies of catalysis analogous to that of vitamin B₁₂. An eight-step synthesis toward such tetrahydroporphyrinic macrocycles begins with p-tolualdehyde and proceeds to a dihydrodipyrrin-acetal (1) bearing a geminal dimethyl group and a p-tolyl substituent. Self-condensation of 1 in CH₃CN containing BF₃·OEt₂ at room temperature afforded a readily separable mixture of two free base bacteriochlorins and a free base B,D-tetradehydrocorrin. Each bacteriochlorin contains two geminal dimethyl groups to lock-in the bacteriochlorin hydrogenation level, p-tolyl substituents at opposing (2,12) β-positions, and the absence (H-BC) or presence (MeO-BC) of a methoxy group at the 5- (meso) position. The B,D-tetradehydrocorrin (TDC) lies equidistant between the hydrogenation levels of corrin and corrole, is enantiomeric, and contains two geminal dimethyl groups, 2,12-di-p-tolyl substituents, and an acetal group at the pyrroline-pyrrole junction. Examination of the effect of the concentrations of 1 (2.5-50 mM) and BF₃·OEt₂ (10-500 mM) revealed a different response surface for each of H-BC, MeO-BC, and TDC, enabling relatively selective preparation of a given macrocycle. The highest isolated yield of each was 49, 30, and 66%, respectively. The macrocycles are stable to routine handling in light and air. The bacteriochlorins display characteristic spectral features; for example, H-BC exhibits near-IR absorption (λ_Qy = 737 nm, ε_Qy = 130 000 M^-1 cm^-1) and emission (λ_em = 744 nm, Φ_f = 0.14). In summary, this simple entry to stable bacteriochlorins and tetradehydrocorrins should facilitate a wide variety of applications.

Full text of DOI:10.1021/jo050467y

De Novo Synthesis of Stable Tetrahydroporphyrinic Macrocycles:
Bacteriochlorins and a Tetradehydrocorrin
Han-Je Kim and Jonathan S. Lindsey*
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204
jlindsey@ncsu.edu
Received March 9, 2005
Bacteriochlorins (tetrahydroporphyrins) are attractive for diverse photochemical applications owing
to their strong absorption in the near-infrared spectral region, as exemplified by the bacterial
photosynthetic pigment bacteriochlorophyll a, yet often are labile toward dehydrogenation to give
the chlorin. Tetradehydrocorrins (ring-contracted tetrahydroporphyrins) are attractive for studies
of catalysis analogous to that of vitamin B12. An eight-step synthesis toward such tetrahydropor-
phyrinic macrocycles begins with p-tolualdehyde and proceeds to a dihydrodipyrrin-acetal (1) bearing
a geminal dimethyl group and a p-tolyl substituent. Self-condensation of 1 in CH3CN containing
BF3‚OEt2 at room temperature afforded a readily separable mixture of two free base bacteriochlorins
and a free base B,D-tetradehydrocorrin. Each bacteriochlorin contains two geminal dimethyl groups
to lock-in the bacteriochlorin hydrogenation level, p-tolyl substituents at opposing (2,12) â-positions,
and the absence (H-BC) or presence (MeO-BC) of a methoxy group at the 5- (meso) position.
The B,D-tetradehydrocorrin (TDC) lies equidistant between the hydrogenation levels of corrin and
corrole, is enantiomeric, and contains two geminal dimethyl groups, 2,12-di-p-tolyl substituents,
and an acetal group at the pyrroline-pyrrole junction. Examination of the effect of the concentrations
of 1 (2.5-50 mM) and BF3‚OEt2 (10-500 mM) revealed a different response surface for each of
H-BC, MeO-BC, and TDC, enabling relatively selective preparation of a given macrocycle. The
highest isolated yield of each was 49, 30, and 66%, respectively. The macrocycles are stable to
routine handling in light and air. The bacteriochlorins display characteristic spectral features; for
example, H-BC exhibits near-IR absorption (λQ ) 737 nm, ꢀQ ) 130 000 M-1 cm-1) and emission
y
y
(λem ) 744 nm, Φf ) 0.14). In summary, this simple entry to stable bacteriochlorins and
tetradehydrocorrins should facilitate a wide variety of applications.
Introduction
changes in physical properties have been famously
exploited by biological systems; the chlorin macrocycle
provides the basis for chlorophylls a and b in plant
photosynthesis, while the bacteriochlorin macrocycle
provides the basis for bacteriochlorophyll a in bacterial
photosynthesis. The strong absorption in the near-IR
makes bacteriochlorins well suited for a wide variety of
applications in the life sciences, medicine, and materials
chemistry.
The progressive 2e-/2H+ reduction of the porphyrinic
macrocycle along the series porphyrin, chlorin (a dihy-
droporphyrin), and bacteriochlorin (a tetrahydroporphy-
rin) causes profound changes in chemical and physical
properties (Chart 1). The reduction alters the symmetry,
yet each macrocycle maintains an 18-π-electron-conju-
gated system as required for aromaticity. One striking
change upon reduction is the large increase in absorption
in the red or near-IR region of the spectrum.1 The
Surprisingly few methods exist for the preparation of
bacteriochlorins despite the importance of this class of
compounds.2 To our knowledge, no total syntheses of
photosynthetic bacteriochlorophylls have been reported.
(1) Gouterman, M. In The Porphyrins; Dolphin, D., Ed.; Academic
Press: New York, 1978; Vol. III, pp 1-165.
10.1021/jo050467y CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/07/2005
J. Org. Chem. 2005, 70, 5475-5486
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Kim and Lindsey
CHART 1
obtained by modification of naturally occurring chloro-
phylls8-10 or bacteriochlorophylls,9,11 but the inherent
lability of the naturally available starting materials and
the presence of a nearly full complement of peripheral
substituents restrict synthetic flexibility.
The bacteriochlorin chromophore is not inherently
unstable. Tolyporphin A, a nonphotosynthetic bacterio-
chlorin pigment from the Pacific microalga Tolypothrix
nodosa,12 is a stable compound. The total synthesis of the
O,O-diacetate of tolyporphin A was reported by Kishi,
entailing >20 steps and affording <5 mg of product.13
A
key structural difference between tolyporphins and pho-
tosynthetic bacteriochlorophylls is the presence of two
geminal dialkyl units in each reduced, pyrroline ring;
such groups lock-in the reduction level of the bacterio-
chlorin.
A chief obstacle to handling bacteriochlorophyll a is its
pronounced tendency to undergo dehydrogenation to give
the corresponding chlorin.3 Bacteriochlorophyll b4,5 and
bacteriochlorophyll g6 are even more labile given their
susceptibility to tautomerization, also affording the cor-
responding chlorin. For example, both bacteriochloro-
phylls b and g undergo conversion to the chlorin with
half-lives of a few minutes upon exposure to light in
vitro.5,6 Both oxidation and tautomerization processes are
illustrated in Scheme 1.
A simple method developed several decades ago for
preparing synthetic bacteriochlorins entails reduction
with diimide of a porphyrin or chlorin.7 This direct
reduction method is accompanied by several problems,
including (1) the difficulty of separating chlorin and
bacteriochlorin species, (2) the adventitious dehydroge-
nation of the bacteriochlorin yielding the chlorin and
porphyrin, and (3) the possible formation of bacteriochlo-
rin isomers depending on the nature of meso or â-pyrrole
substituents. More resilient bacteriochlorins have been
prepared by derivatization of porphyrins or chlorins,
including vicinal dihydroxylation (with optional subse-
quent pinacol rearrangement), photooxygenation of di-
vinylporphyrins, Diels-Alder reactions, 1,3-dipolar cy-
cloadditions, and successive addition of carbon nucleo-
philes.2 Each method has merit yet also suffers from the
potential formation of regioisomers owing to reaction at
distinct pyrrole rings or at the same or opposite faces of
the macrocycle. Elaborate bacteriochlorins have been
A similar geminal dialkyl motif is present in diverse
naturally occurring hydroporphyrins, including vitamin
B12, isobacteriochlorins (Factor II, Factor III, siroheme),
and nonphotosynthetic chlorins (bonellin, Factor I).14
Indeed, vitamin B12 contains a geminal dialkyl group in
each reduced ring (Chart 2). Syntheses of most of these
stable hydroporphyrins have been achieved. However, the
rich pattern of substituents in natural hydroporphyrins
has resulted in elegant yet elaborate syntheses that
afford minute quantities of products. Consequently, fully
unsaturated synthetic analogues of the naturally occur-
ring hydroporphyrins are typically employed as sur-
rogates given the greater ease of preparation of the
unsaturated analogues. Thus, porphyrins are employed
as models of bacteriochlorins in a wide variety of photo-
chemical studies, and corroles or octadehydrocorrins are
(8) (a) Tamiaki, H.; Kouraba, M.; Takeda, K.; Kondo, S.-I.; Tanikaga,
R. Tetrahedron: Asymmetry 1998, 9, 2101-2111. (b) Kunieda, M.;
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Heterocycles 1997, 44, 165-168. (c) Fukuzumi, S.; Ohkubo, K.; Chen,
Y.; Pandey, R. K.; Zhan, R.; Shao, J.; Kadish, K. M. J. Phys. Chem. A
2002, 106, 5105-5113. (d) Mironov, A. F.; Grin, M. A.; Tsiprovskiy, A.
G.; Kachala, V. V.; Karmakova, T. A.; Plyutinskaya, A. D.; Yakubov-
skaya, R. I. J. Porphyrins Phthalocyanines 2003, 7, 725-730. (e)
Mironov, A. F.; Grin, M. A.; Tsiprovskii, A. G.; Segenevich, A. V.;
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M. R.; Patterson, G. M. L.; Larsen, L. K.; Smith, C. D. Tetrahedron
1995, 51, 10523-10530. (c) Prinsep, M. R.; Patterson, G. M. L.; Larsen,
L. K.; Smith, C. D. J. Nat. Prod. 1998, 61, 1133-1136.
(13) Wang, W.; Kishi, Y. Org. Lett. 1999, 1, 1129-1132.
(14) (a) Montforts, F.-P.; Gerlach, B.; Ho¨per, F. Chem. Rev. 1994,
94, 327-347. (b) Montforts, F.-P.; Glasenapp-Breiling, M. Fortschr.
Chem. Org. Naturst. 2002, 84, 1-51.
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1134.
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4500-4506.
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5476 J. Org. Chem., Vol. 70, No. 14, 2005

De Novo Synthesis of Stable Tetrahydroporphyrinic Macrocycles
SCHEME 1
CHART 2
CHART 3
While our goal was solely to prepare bacteriochlorins, a
tetradehydrocorrin has emerged as a fortuitous byprod-
uct. The route employs the self-condensation of a dihy-
drodipyrrin-acetal. We describe the synthesis of the
dihydrodipyrrin-acetal, a study of conditions for the self-
condensation, and the characterization of the resulting
tetrahydroporphyrinic macrocycles.
Results and Discussion
1. Exploration. The route that we developed draws
on our prior work concerning the rational synthesis of
chlorins.15,16 The chlorins, which contain one geminal
dialkyl unit, were prepared by reaction of a dihy-
drodipyrrin (A) (or a tetrahydrodipyrrin) and a 1-bromo-
dipyrromethane-9-carbinol (B). In the hydrodipyrrins
(e.g., A), both pyrrole and pyrroline entities served as
nucleophiles, while component B reacted as a bis-elec-
trophile. For the synthesis of bacteriochlorins, the con-
densation of two hydrodipyrrins requires complementary
reactivity of pyrrole and pyrroline sites. We prepared a
number of hydrodipyrrins each containing one pyrrole
and one pyrroline unit with complementary reactivity,
and eventually found that a dihydrodipyrrin (C) bearing
a dimethyl acetal moiety attached to the R-pyrroline
position underwent self-condensation to give bacterio-
chlorins (Scheme 2). This result validated the approach
of employing a dihydrodipyrrin bearing pyrrole/pyrroline
moieties with complementary nucleophilic/electrophilic
reactivity, respectively, although the yield was very low
(∼1%). The synthesis of C and other new hydrodipyrrins
developed in the course of the exploratory work will be
described elsewhere.
used as model corrins in organometallic chemistry and
studies of catalysis. A corrole is an aromatic tautomer of
an octadehydrocorrin, as illustrated for R ) H in Chart
2.
The use of hydroporphyrins in applications and fun-
damental studies requires simple synthetic methods that
afford access to ample quantities of stable compounds.
Specific attributes of the desired methodology include the
ability (1) to construct a macrocycle that is locked at the
desired hydroporphyrin reduction level through the use
of geminal dialkyl groups and (2) to place a limited
number of substituents at designated sites around the
perimeter of the macrocycle. The structure of a target
bacteriochlorin core (lacking peripheral substituents
other than the geminal dimethyl groups) is shown in
Chart 3.
Dihydrodipyrrin analogues that bear a â-substituent
in the pyrrole ring (D) are known to be more stable than
the unsubstituted species (A).16 Accordingly, we focused
(15) Strachan, J.-P.; O’Shea, D. F.; Balasubramanian, T.; Lindsey,
J. S. J. Org. Chem. 2000, 65, 3160-3172.
(16) Balasubramanian, T.; Strachan, J. P.; Boyle, P. D.; Lindsey, J.
S. J. Org. Chem. 2000, 65, 7919-7929.
In this paper, we describe a de novo synthesis of
bacteriochlorins where structural features in acyclic
precursors establish the bacteriochlorin reduction level.
J. Org. Chem, Vol. 70, No. 14, 2005 5477

Kim and Lindsey
SCHEME 2
SCHEME 3
on the development of a route to dihydrodipyrrin-acetal
1, a â-pyrrole-substituted analogue of C. The p-tolyl
group was chosen as an inert substituent that is readily
of piperidine gave the known R,â-unsaturated ester 219
in 79% yield. Reaction of 2 with (p-tolylsulfonyl)methyl
isocyanide (TosMIC) afforded â-substituted pyrrole 3 (a
known compound with incomplete data20) in 74% yield.
Removal of the ethoxycarbonyl group of pyrrole 3 by
treatment with NaOH in ethylene glycol at 160 °C gave
the known â-substituted pyrrole 421-23 in 71% yield.
Vilsmeier-Haack formylation of 4 yielded a mixture of
regioisomers owing to substitution at the 2- or 5-position.
1
characterized by H NMR spectroscopy.
(17) (a) Silva, N. M.; Tributino, J. L. M.; Miranda, A. L. P.; Barreiro,
E. J.; Fraga, C. A. M. Eur. J. Med. Chem. 2002, 37, 163-170. (b) D´ıaz,
J. L.; Villacampa, B.; Lo´pez-Calahorra, F.; Velasco, D. Chem. Mater.
2002, 14, 2240-2251. (c) Ren, X.; Chen, X.; Peng, K.; Xie, X.; Xia, Y.;
Pan, X. Tetrahedron: Asymmetry 2002, 13, 1799-1804.
(18) Breslow, D. S.; Baumgarten, E.; Hauser, C. R. J. Am. Chem.
Soc. 1944, 66, 1286-1288.
(19) (a) Tsuge, O.; Sone, K.; Urano, S.; Matsuda, K. J. Org. Chem.
1982, 47, 5171-5177. (b) Colas, C.; Goeldner, M. Eur. J. Org. Chem.
1999, 1357, 7-1366. (c) Chuzel, O.; Piva, O. Synth. Commun. 2003,
33, 393-402.
2. Synthesis of Bacteriochlorin Precursors. The
synthesis of dihydrodipyrrin-acetal 1 was initiated in a
fashion similar to that of dihydrodipyrrin D (Scheme 3).16
Components 2-4 of the synthesis have been prepared
via different routes or have been reported with incom-
plete characterization data. A full description is reported
here.
Application of the previously unused Knoevenagel
condensation17 of p-tolualdehyde with malonic acid mo-
noethyl ester18 in pyridine containing a catalytic amount
(20) Di Santo, R.; Costi, R.; Artico, M.; Massa, S.; Musiu, C.; Milia,
C.; Putzolu, M.; La Colla, P. Med. Chem. Res. 1997, 7, 98-108.
(21) Sakai, K.; Suzuki, M.; Nunami, K.-I.; Yoneda, N.; Onoda, Y.;
Iwasawa, Y. Chem. Pharm. Bull. 1980, 28, 2384-2393.
(22) Campi, E. M.; Fallon, G. D.; Jackson, W. R.; Nilsson, Y. Aust.
J. Chem. 1992, 45, 1167-1178.
(23) Pavri, N, P.; Trudell, M. L. J. Org. Chem. 1997, 62, 2649-2651.
5478 J. Org. Chem., Vol. 70, No. 14, 2005

De Novo Synthesis of Stable Tetrahydroporphyrinic Macrocycles
SCHEME 4
After column chromatography, the two regioisomers were
determined to be present in ∼13:1 ratio by 1H NMR
integration of the methyl unit of the p-tolyl group.
Selective precipitation readily afforded the major regio-
isomer 5 in 64% yield. The same formylation method was
used to prepare 2-formyl-3-(4-iodophenyl)pyrrole, which
1
was characterized by H NMR spectroscopy and X-ray
crystallography.16 The chemical shift of the two peaks (δ
6.42-6.44 and 7.10-7.13 ppm) from the pyrrolic protons
of the major isomer 5 were quite similar to those for
2-formyl-3-(4-iodophenyl)pyrrole (δ 6.42 and 7.14 ppm)16
or 2-formyl-3-phenylpyrrole (δ 6.50 and 7.30 ppm).24 The
minor isomer, 2-formyl-4-(4-methylphenyl)pyrrole (δ 7.20-
7.22 and 7.36-7.38 ppm), also showed similar chemical
shifts for the respective pyrrolic protons of the previously
characterized 2-formyl-4-(4-iodophenyl)pyrrole (δ 7.21
and 7.39 ppm).16
Treatment of 5 to the standard conditions16 for con-
densation of a pyrrole-2-carboxaldehyde with nitromethane
afforded the crude 2-(2-nitrovinyl)pyrrole as a brown
solid. Reduction of the latter with NaBH4 gave the
â-substituted nitroethylpyrrole 6. The R-keto acetal (7)
required for the next step, previously prepared at the 2
mmol scale by reaction of mesityl oxide with a catalytic
amount of diphenyl diselenide and excess ammonium
peroxydisulfate,25 was carried out at the 160 mmol scale,
affording 7 (∼7 g) in 29% yield. The Michael reaction of
6 with excess 7 (10 equiv) in the presence of CsF at 65
°C gave 8 in 40% yield, accompanied by recovery of 7
(∼50%) upon bulb-to-bulb distillation and column chro-
matography. Treatment of 8 with NaOMe followed by a
buffered TiCl3 solution afforded the dihydrodiyrrin-acetal
1 as a yellow solid in 28% yield.
3. Investigation of Reaction Conditions for Bac-
teriochlorin Formation. A series of microscale studies
(∼1-2 mg of 1 per reaction) was performed to investigate
the effects of reaction parameters that are known to
influence the course of condensations leading to porphy-
rinic macrocycles, including concentration of 1, acid
composition, acid concentration, solvent, and time.26 The
standard conditions employed initially included acetal 1
(5 mM) in CH3CN containing acid (50 mM) at room
temperature, which closely resemble those employed in
the self-condensation of the unsubstituted dihydrodipyr-
rin-acetal A. Samples were removed periodically over the
course of ∼24 h, neutralized with TEA, and examined
by absorption spectroscopy. Yields were calculated on the
basis of the assumption (vide infra) that each bacterio-
Sc(OTf)3, or SnCl4 (18-16%); p-TsOH‚H2O (4.9%); Yb-
(OTf)3, SnF4, TiCl4, BBr3, or HCl (1.5-0.4%); and AcOH,
TFA, MgBr2, ZnCl2, or Zn(OAc)2 (∼0%). The acids InCl3
and Yb(OTf)3 afforded a free base bacteriochlorin, a
metalated bacteriochlorin, and a non-bacteriochlorin
macrocycle. This work will be described elsewhere.
B. Solvents. The effect of solvent on the self-conden-
sation of 1 was examined with BF3‚OEt2 catalysis under
the standard conditions. The bacteriochlorin yields were
∼30% (CH3CN), <2% (CHCl3 or ClCH2CH2Cl), and not
detectable (CH2Cl2, toluene, DMF, DMSO, THF, 1,4-
dioxane, methanol, ethanol).
The standard reaction was scaled-up using BF3‚OEt2
in CH3CN at room-temperature exposed to air for 6 h
(Scheme 4). Chromatographic workup on silica followed
by 1H NMR spectroscopy and laser-desorption mass
spectrometry (LD-MS) analysis led to two surprises. The
first surprise was that two bacteriochlorins were iso-
lated: one relatively nonpolar bacteriochlorin (H-BC)
has no meso substituent, while one more polar bacterio-
chlorin (MeO-BC) has a methoxy group at the 5-posi-
tion. The two bacteriochlorins were isolated in 11 and
30% yield, respectively. The second surprise emerged
chlorin has ꢀQ ) 120 000 M-1 cm-1. The intense absorp-
y
tion of the bacteriochlorin enabled quantitative analysis
of crude reaction mixtures.
A. Acids. A screening study was performed to identify
the effects of a variety of acids on the self-condensation
of 1. Brønsted acids (4) and Lewis acids (11) (previously
employed in porphyrin chemistry)27 were examined in
CH3CN exposed to air. The acids can be categorized on
the basis of bacteriochlorin yields: BF3‚OEt2 (31%); InCl3,
(24) Cue, B. W., Jr.; Chamberlain, N. J. Heterocycl. Chem. 1981,
18, 667-670.
(25) Tiecco, M.; Testaferri, L.; Tingoli, M.; Bartoli, D. J. Org. Chem.
1990, 55, 4523-4528.
(27) (a) Geier, G. R., III; Ciringh, Y.; Li, F.; Haynes, D. M.; Lindsey,
J. S. Org. Lett. 2000, 2, 1745-1748. (b) Geier, G. R., III; Callinan, J.
B.; Rao, P. D.; Lindsey, J. S. J. Porphyrins Phthalocyanines 2001, 5,
810-823. (c) Geier, G. R., III; Lindsey, J. S. J. Porphyrins Phthalo-
cyanines 2002, 6, 159-185.
(26) 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.
J. Org. Chem, Vol. 70, No. 14, 2005 5479

Kim and Lindsey
upon carrying out the reaction at lower concentrations
of BF3‚OEt2, whereupon another porphyrinic macrocycle
was identified. The macrocycle proved to be a B,D-
tetradehydrocorrin (TDC), a ring-contracted tetrahydro-
porphyrinic species containing two opposing pyrroline
rings. The tetradehydrocorrin is a 4e-/4H+ oxidized
analogue of a corrin and hence lies equidistant between
the reduction levels of a corrin and a corrole or octade-
hydrocorrin.28 Each macrocycle was characterized by
absorption spectroscopy, 1H NMR spectroscopy, LD-MS,
and high-resolution FAB-MS (vide infra). In summary,
the dramatic increase in yield (versus the <1% yield with
the unsubstituted dihydrodipyrrin-acetal A) validated our
hunch that â-substitution would afford a more stable
dihydrodipyrrin and more efficient reaction.
C. Effect of Reactant and Acid Concentrations.
To broadly characterize the effect of reactant concentra-
tion and acid concentration on the yield of each of the
macrocycles, a grid-search experiment was performed at
the microscale level (0.5-2 mL reactions). The search
space was defined by the concentrations of dihydrodipyr-
rin-acetal 1 (2.5-50 mM) and BF3‚OEt2 (10-500 mM).
Points at the corners, faces, core, and center of the search
space were examined. Each reaction was monitored over
time (23 h), and the total yield of bacteriochlorins (but
not TDC) was determined spectroscopically from the
crude mixture. Each reaction mixture was then separated
chromatographically to determine the isolated yield (by
spectrophotometry of purified fractions) of bacteriochlo-
rins (H-BC, MeO-BC) and the tetradehydrocorrin
TDC.
The time course for bacteriochlorin formation is shown
in Figure 1 for the reactions carried out at the lowest,
midpoint, and highest concentrations of both 1 and BF3‚
OEt2. The data from the crude reaction samples estimate
the summed yield of H-BC + MeO-BC. The bacterio-
chlorins form smoothly, and the yields generally remain
constant over time. Little variation in rate was observed
upon increasing the concentration of BF3‚OEt2 from 10
to 500 mM.
The isolated yields at each point in the search space
are shown in Figure 2. The segmented histogram shows
the yield of each of the three macrocycles and the
summed yields. Note that the ratio of H-BC:MeO-BC:
TDC changes with alteration in the concentration of acid
and reactant. The yield of TDC is highest at the lowest
acid concentration examined, and no TDC is observed
at the highest acid concentrations. On the other hand,
the yield of H-BC generally increased with increasing
acid concentration. The yield of MeO-BC was highest
at modest concentrations of acid and reactant. From a
practical standpoint, this limited study has identified
FIGURE 1. Yield of bacteriochlorins (sum of H-BC + MeO-
BC) as a function of time. The data points were taken for
concentrations of 1 and BF3‚OEt2 located along the diagonal
of the grid described in Figure 2 ([, 2.5 mM 1, 10 mM BF3‚
OEt2; 9, 11 mM 1, 71 mM BF3‚OEt2; 2, 50 mM 1, 500 mM
BF3‚OEt2). The yield values were determined by absorption
spectroscopy of crude reaction samples (assuming ꢀQ
)
y
120 000 M-1 cm-1 for both bacteriochlorins).
conditions that afford a relatively good, albeit not exclu-
sive, yield of each of the macrocycles.
Three semipreparative reactions were performed. In
each reaction, the concentrations of 1 and BF3‚OEt2 were
chosen on the basis of the response-surface data to favor
one of the three macrocycles (H-BC, MeO-BC, TDC).
The results are listed in Table 1. The reaction designed
to favor H-BC gave H-BC in 49% yield (20 mg; entry
1). The reaction designed to favor MeO-BC gave MeO-
BC in 30% yield (24 mg; entry 2). The reaction to favor
TDC gave TDC in 66% yield (30 mg; entry 3). In each
case, the desired macrocycle was readily isolated, as was
a lesser amount of one (but not both) of the other
macrocycles. The product ratios generally mirrored the
trends observed in the microscale work (Figure 2),
although the isolated yields were somewhat higher.
These results augur well for relatively selective prepara-
tion of workable quantities of each tetrahydroporphyrinic
macrocycle.
4. Mechanistic Considerations. At present, we know
very little about the mechanistic course leading from the
dihydrodipyrrin-acetal to the bacteriochlorin or tetrade-
hydrocorrin species. The balanced reaction for formation
of each product is shown in Scheme 5. The conversion of
two molecules of 1 to give MeO-BC proceeds with
elimination of three molecules of methanol. Note that the
acetal unit of 1 serves as an electrophile for the bacte-
riochlorin-forming reaction. Examples are known where
an acetal functions as an electrophile, leaving one alkyl
ether unit intact.29 The formation of TDC entails elimi-
nation of two molecules of methanol. Thus, the self-
condensation of 1 to give MeO-BC and TDC does not
require any change in oxidation state. By contrast, the
formation of H-BC must proceed with elimination of
four molecules of methanol and addition of 2e- and 2H+.
Neither the source of the reductant nor the nature of the
(28) Nomenclature of dehydrogenated corrinoids is not yet fully
systematized. Many workers would refer to TDC as a didehydrocorrin
because two double bonds have been introduced relative to the corrin;
by the same token, a corrole would be a tetradehydrocorrin tautomer.
In IUPAC recommendations, TDC is a tetradehydrocorrin (4e-/4H+
removed from the corrin), and corrole is an octadehydrocorrin tautomer
(8e-/8H+ removed from corrin).28a A clear review concerning octade-
hydrocorrins is provided by Genokhova et al.28b TDC is at the same
reduction level as a tetrahydrocorrole, but given the interrupted path
of conjugation and lack of aromatic character, TDC is named as a
dehydrogenated corrin rather than as a hydrogenated corrole. (a) Pure
Appl. Chem. 1976, 48, 495-502. (b) Genokhova, N. S.; Melent’eva, T.
A.; Berezovskii, V. M. Russ. Chem. Rev. 1980, 49, 1056-1067.
(29) (a) Jiang, B.; Zhang, X.; Shi, G. Tetrahedron Lett. 2002, 43,
6819-6821. (b) Mu¨ller, P.; Nury, P.; Bernardinelli, G. Eur. J. Org.
Chem. 2001, 4137-4147. (c) Mu¨ller, P.; Nury, P. Org. Lett. 2000, 2,
2845-2847.
5480 J. Org. Chem., Vol. 70, No. 14, 2005

De Novo Synthesis of Stable Tetrahydroporphyrinic Macrocycles
SCHEME 5
intermediate that undergoes reduction is known. It is
worthwhile to contrast this overall transformation with
that of porphyrin formation from an aldehyde and
pyrrole, which proceeds via condensation to give a
hexahydroporphyrin (porphyrinogen) intermediate; the
latter is converted via a 6e-/6H+ oxidation to give the
porphyrin.26
From the standpoint of oxidation-state and structural
considerations, the B,D-tetradehydrocorrin is to a bac-
teriochlorin what an octadehydrocorrin is to a porphyrin.
Syntheses of octadehydrocorrins were developed several
decades ago,28b and more recent activity has been devoted
to methodology for preparing substituted corroles,30,31 the
aromatic counterpart of octadehydrocorrins.28 Recent
directed routes to corroles entail cyclization of a 1,19-
unsubstituted bilane,32,33 a,c-biladiene,34 or 22,24-dihy-
dro-a,b,c-bilatriene.34 The conversion of each such acyclic
species to give the A-D ring junction of the corrole
requires oxidation (the mechanisms of which remain
under active investigation). A typical oxidant is DDQ or
FIGURE 2. Yields of H-BC, MeO-BC, and TDC as a
function of the concentrations of 1 and BF3‚OEt2. The reactions
were performed at the microscale level. Each reaction was
worked up after 23 h. The yields are based on spectrophotom-
etry of purified fractions using the known molar absorption
coefficients of each species. The segmented histogram (top)
shows the yield of each species and the summed yield of
macrocycles. The contour diagrams below illustrate the yield
of each species H-BC, MeO-BC, and TDC in the same
search space. The actual numerical data are listed; the
interpolated contours are provided to guide the eye. In each
contour, coloration is provided to illustrate the 60% cutset data
(i.e., those regions that afford a yield that is at least 60% of
the highest value recorded anywhere in the search space).
(30) Paolesse, R. In The Porphyrin Handbook; Kadish, K. M., Smith,
K. M., Guilard, R., Eds.; Academic Press: San Diego, CA, 2000; Vol.
2, pp 201-232.
(31) Gryko, D. T. Eur. J. Org. Chem. 2002, 1735-1743.
(32) Ka, J.-W.; Cho, W.-S.; Lee, C.-H. Tetrahedron Lett. 2000, 41,
8121-8125.
(33) (a) Guilard, R.; Gryko, D. T.; Canard, G.; Barbe, J.-M.; Ko-
szarna, B.; Brande`s, S.; Tasior, M. Org. Lett. 2002, 4, 4491-4494. (b)
Geier, G. R., III; Chick, J. F. B.; Callinan, J. B.; Reid, C. G.;
Auguscinski, W. P. J. Org. Chem. 2004, 69, 4159-4169.
(34) Paolesse, R.; Froiio, A.; Nardis, S.; Mastroianni, M.; Russo, M.;
Nurco, D. J.; Smith, K. M. J. Porphyrins Phthalocyanines 2003, 7, 585-
592.
J. Org. Chem, Vol. 70, No. 14, 2005 5481

Kim and Lindsey
TABLE 1. Isolated Yields of Macrocycles from Semipreparative Reactionsa
entry
[1], mM
[BF3‚OEt2], mM
H-BC yield
MeO-BC yield
TDC yield
1b
2d
3b
18
5.0
11
140
50
10
49% (21%)c
11%
1.9% (1.5%)c
30%
6.3% (8.7%)c
66% (48%)c
a Yields were determined gravimetrically. b Reaction was performed using 0.15 mmol of 1. c Yield obtained in the microscale grid-
search experiment (Figure 2). d Reaction was performed using 0.27 mmol of 1.
p-chloranil. By contrast, the self-condensation of 1 pro-
vides a very facile, nonoxidative entry into B,D-tetrade-
hydrocorrins. It is interesting that both 1 and corroles31-33
are formed in the presence of quite low acid concentra-
tions.
5. Characterization. A. The B,D-Tetradehydro-
corrin. The absorption spectrum of TDC shows λmax at
341 nm, a shoulder at 438 nm, and a broad, weaker band
in the region 500-1000 nm (Figure 3). The absorption
spectral features are similar to a Ni(II) 1-methyloctade-
hydrocorrin.35,36 The 1H NMR spectrum showed relatively
complex features due to the lack of symmetry (C1) of TDC
(see Supporting Information for assignments). Two note-
worthy features are that (1) the NH protons exhibit two
broad peaks in the region of δ 11.34-11.40 ppm and δ
FIGURE 3. Absorption spectrum of TDC in toluene at room
temperature.
11.89-11.96 ppm, to be contrasted with the resonance
at δ ca. -1 to -3 ppm of aromatic porphyrinic com-
pounds, and (2) all peripheral alkenyl protons (5-, 8-, 10-,
A,B,C,D-octadehydrocorrin;28b each defined using IUPAC
15-, and 18-positions) fall in the range δ 5.4-6.6 ppm, to
nomenclature28) by direct synthesis or by reduction of an
be contrasted with δ ca. 8-9.5 ppm for aromatic porphy-
existing macrocycle,42 to our knowledge there are no prior
rinic compounds. LD-MS and FAB-MS analysis of TDC
gave a molecule ion peak (m/z ) 612.7 and 612.3447,
respectively) consistent with the proposed structure
B. Bacteriochlorins. Absorption Spectra. The ab-
(Scheme 4). Further proof of structure for TDC came
sorption spectra of H-BC and MeO-BC in toluene are
from a single-crystal X-ray analysis, which will be
shown in Figure 4. Bacteriochlorin H-BC exhibits strong
published elsewhere.
reports concerning the synthesis of B,D-tetradehydro-
corrins.
bands (By, Bx) at 351 and 374 nm, a weak Qx(0,0) band
at 499 nm, and a strong Qy(0,0) band at 737 nm.
The progressive reduction along the series from corrole
to TDC to corrin alters the path of conjugation in the
Bacteriochlorin MeO-BC exhibits a broadened B band
macrocycle. The reduction state of the pyrrolic rings that
with peaks at 356 and 374 nm, a weak Qx(0,0) band at
form the A-D ring junction as well as the hybridization
511 nm, and a strong Qy(0,0) band at 732 nm. The overall
absorption spectra of H-BC and MeO-BC resemble
those of bacteriopheophytin a (the free base analogue of
of the joined carbon atoms (C1-C19) also change along
the series of corrole (pyrrole-pyrrole; sp2-sp2), TDC
(pyrroline-pyrrole, sp3-sp2), and corrin (pyrroline-pyr-
bacteriochlorophyll a) as well as synthetic, meso-substi-
rolidine, sp3-sp3). On account of the interrupted path of
tuted bacteriochlorins such as 5,15-diphenylbacteriochlo-
conjugation and the presence of only 16-π-electrons due
rin43 and 5,10,15,20-tetraphenylbacteriochlorin (λabs 356,
to reduction in rings A and C, TDC is not aromatic. TDC
378, 520, and 742 nm; ꢀ742
) 130 000 M-1 cm-1).7,44
nm
is a B,D-tetradehydrocorrin where the 1-acetal substitu-
ent defines the A ring, and the B and D rings are
dehydrogenated relative to corrin (Chart 2).28 While a
number of dehydrocorrins have been prepared (e.g.,
D-didehydrocorrin,37 C,D-tetradehydrocorrin,38,39 B,C-
tetradehydrocorrin,40 B,C,D-hexadehydrocorrin,41 and
The bacteriochlorins exhibit a light green appearance in
dilute solution in CH2Cl2 or toluene.
Fluorescence Properties. The fluorescence spectra
and fluorescence quantum yields of H-BC and MeO-
BC were collected in toluene at room temperature. The
fluorescence spectrum of each bacteriochlorin is domi-
nated by a Qy(0,0) band with Stokes shift of ∼7-9 nm
(Figure 4). Measurements of the fluorescence quantum
yield (Φf) using chlorophyll a (Φf ) 0.325)45 as a reference
gave a value of 0.14 or 0.18 for H-BC or MeO-BC,
respectively, upon illumination in the B-band region (see
Supporting Information).
(35) Engel, J.; Gossauer, A.; Johnson, A. W. J. Chem. Soc., Perkin
Trans. 1 1978, 871-875.
(36) Grigg, R.; Johnson, A. W.; Shelton, K. W. J. Chem. Soc. C 1968,
1291-1296.
(37) (a) Rasetti, V.; Kra¨utler, B.; Pfaltz, A.; Eschenmoser, A. Angew.
Chem. Int. Ed. Engl. 1977, 16, 459-461. (b) Kra¨utler, B.; Hilpert, K.
Angew. Chem. Int. Ed. Engl. 1982, 21, 152.
(38) Ofner, S.; Rasetti, V.; Zehnder, B.; Eschenmoser, A. Helv. Chim.
Acta 1981, 64, 1431-1443.
(39) Angst, C.; Kratky, C.; Eschenmoser, A. Angew. Chem. Int. Ed.
Engl. 1981, 20, 263-265.
(42) Melent′eva, T. A. Russ. Chem. Rev. 1983, 52, 1136-1172.
(43) Wang, T. Y.; Chen, J. R.; Ma, J. S. Dyes Pigments 2002, 52,
199-208.
(44) Fajer, J.; Borg, D. C.; Forman, A.; Felton, R. H.; Dolphin, D.;
Vegh, L. Proc. Natl. Acad. Sci. U.S.A. 1974, 71, 994-998.
(45) Weber, G.; Teale, F. W. J. Trans. Faraday Soc. 1957, 53, 646-
655.
(40) Inhoffen, H. H.; Fattinger, F.; Schwarz, N. Liebigs Ann. Chem.
1974, 412-438.
(41) (a) Montforts, F.-P. Angew. Chem. Int. Ed. Engl. 1982, 21, 214-
215. (b) Montforts, F.-P.; Bats, J. W. Helv. Chim. Acta 1987, 70, 402-
411.
5482 J. Org. Chem., Vol. 70, No. 14, 2005

De Novo Synthesis of Stable Tetrahydroporphyrinic Macrocycles
LD-MS analysis without requirement for use of a ma-
trix.51 LD-MS analysis of H-BC or MeO-BC gave a
molecule ion peak (m/z ) 580.1 or 550.0) consistent with
the proposed structures. The mass difference (∼30)
between H-BC and MeO-BC is consistent with the
presence of the methoxy group in the former compound.
1H NMR Spectra. The 1H NMR spectra of H-BC and
MeO-BC were readily assigned by NOESY and COSY
measurements (see Supporting Information). In the case
of H-BC, which nominally has C2h symmetry, a rela-
tively simple 1H NMR spectrum is observed. Noteworthy
features include a broad upfield peak (δ -1.96 ppm), a
singlet at δ 1.93 ppm, and a singlet at δ 4.46 ppm, which
are attributed to the two NH protons, the pair of geminal
dimethyl groups, and the CH2 groups of the pyrroline
rings, respectively. A doublet (J ) 2.0 Hz) at δ 8.73 ppm
and two singlets at δ 8.81 and 8.86 ppm stem from the
six protons (3-, 5-, 10-, 13-, 15-, and 20-positions) about
the perimeter of the bacteriochlorin. Bacteriochlorin
MeO-BC has generally similar features, but the pres-
ence of the 5-methoxy group nominally results in Cs
symmetry and more complex splittings (see Supporting
Information). Taken together, the absorption, fluores-
1
cence, LD-MS, and H NMR spectroscopic data support
the structures proposed for bacteriochlorins H-BC and
MeO-BC. The structure of MeO-BC has been con-
firmed by single-crystal X-ray analysis, the results of
which will be presented elsewhere.
6. Stability. The synthetic tetrahydroporphyrinic mac-
rocycles (H-BC, MeO-BC, and TDC) are quite robust.
For example, each compound was stable upon standing
on the benchtop in solution exposed to air for more than
10 days, chromatography on silica in air in the presence
of ambient lighting, dissolution in a variety of solvents
(CH2Cl2, CHCl3, THF, hexanes, toluene, DMF), or treat-
ment with mild bases. Unlike bacteriochlorins derived
from photosynthetic bacteria,3-6 the synthetic bacterio-
chlorins do not undergo adventitious dehydrogenation
upon routine handling.
FIGURE 4. Electronic spectra of H-BC and MeO-BC in
toluene at room temperature. Absorption (solid line); emission
(dashed line).
The few data available concerning the fluorescence
quantum yields of free base bacteriochlorins are quite
varied. The free base analogue of the naturally occurring
bacteriochlorophyll a (bacteriopheophytin a) has Φf es-
timated to be 0.1246 or 0.094,47 whereas a 131-deoxo-20-
formyl-pyropheophorbide derivative gave Φf ∼0.002.10
Synthetic bacteriochlorins such as meso-tetrakis(3-hy-
droxyphenyl)bacteriochlorin48 or 5,15-diphenylbacterio-
chlorin43 gave Φf values of 0.11 or 0.14, respectively. A
series of halogenated meso-tetraarylbacteriochlorins gave
Φf ) 0.068 (Ar ) 2,6-difluorophenyl), 0.048 (Ar ) 2-chlo-
rophenyl), and 0.012 (Ar ) 2,6-dichlorophenyl).49 On the
other hand, the dioxobacteriochlorin derived from octa-
Conclusion
A straightforward eight-step synthesis from simple
precursors has been developed that affords free base
tetrahydroporphyrinic macrocycles, including two bacte-
riochlorins and a B,D-tetradehydrocorrin. The macro-
cycles are stable toward dehydrogenation due to the
presence of a geminal dimethyl group in each of the
pyrroline rings. The synthesis entails self-condensation
of dihydrodipyrrin-acetal 1 under mild acid catalysis at
room temperature without requirement for an oxidant.
The formation of the tetradehydrocorrin is understood
in part by the recognition that a tetradehydrocorrin is
to a bacteriochlorin what an octadehydrocorrin (a corrole
tautomer) is to a porphyrin. The tetradehydrocorrin and
bacteriochlorins lie at the same oxidation state (4e-/4H+
reduced) relative to the fully unsaturated corrinoid and
porphyrinoid macrocycles. One key difference, however,
is that the tetradehydrocorrin is not aromatic whereas
the bacteriochlorins are aromatic macrocycles. Mere
ethylporphyrin was reported to have Φf of 0.48.50
A
deeper understanding of the effects of substituents on the
fluorescence properties of bacteriochlorins will require the
examination of a larger and more systematic collection
of bacteriochlorins, the preparation of which may be
enabled by the new synthesis described herein.
Laser Desorption Mass Spectrometry (LD-MS).
Porphyrins typically give a strong molecule ion peak upon
(46) Connolly, J. S.; Samuel, E. B.; Janzen, A. F. Photochem.
Photobiol. 1982, 36, 565-574.
(47) Gouterman, M.; Holten, D. Photochem. Photobiol. 1977, 25, 85-
92.
(48) Bonnett, R.; Charlesworth, P.; Djelal, B. D.; Foley, S.; Mc-
Garvey, D. J.; Truscott, T. G. J. Chem. Soc., Perkin Trans. 2 1999,
325-328.
(49) Pineiro, M.; Gonsalves, A. M. d.’A. R.; Pereira, M. M.; Formos-
inho, S. J.; Arnaut, L. G. J. Phys. Chem. A 2002, 106, 3787-3795.
(50) Papkovsky, D. B.; Ponomarev, G. V. Spectrochim. Acta, Part A
2001, 57, 1897-1905.
(51) (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 Phthalo-
cyanines 1999, 3, 283-291.
J. Org. Chem, Vol. 70, No. 14, 2005 5483

Kim and Lindsey
the resulting residue in a known volume of solvent (typically
3 mL). A sample from this solution was then analyzed by
absorption spectroscopy using the measured molar absorption
adjustment of the concentrations of 1 and BF3‚OEt2
enables a given macrocycle (H-BC, MeO-BC, TDC) to
be obtained in reasonable yield. The bacteriochlorins
exhibit characteristic absorption and fluorescence proper-
ties and are stable to a variety of reaction conditions. The
synthesis described herein should provide ready access
to tetrahydroporphyrinic macrocycles bearing a variety
of substituents, which are essential for fundamental
studies and diverse applications.
coefficients for each species: H-BC (ꢀ737
) 130 000 M-1
nm
cm-1); MeO-BC (ꢀ732 nm ) 120 000 M-1 cm-1); TDC (ꢀ431 nm
)
24 000 M-1 cm-1).
Alternatively, absorption spectroscopy of the isolated bac-
teriochlorins was used to determine the relative amount of
product; the actual amount of bacteriochlorin produced was
calculated on the basis of the spectroscopic yield of the mixture
of bacteriochlorins (as described in the preceding paragraph)
and the relative ratios of the two species. No such correction
was possible for TDC; the yields of TDC refer to isolated
material.
Experimental Section
Survey of Conditions for Bacteriochlorin-Forming
Reactions. The condensations were carried out in 4 mL vials
containing magnetic stir bars. A freshly prepared sample of 1
(0.85-1.7 mg) was dissolved in a specific amount (0.50-2.0
mL) of a solvent. The condensation was initiated by adding
the desired acid to the stirred reaction mixture at room
temperature. The progress of the reaction was monitored by
taking aliquots periodically from the reaction mixture via
syringe and neutralizing with TEA, followed by absorption
spectroscopy. In particular, for 5 mM reactions of 1, 10 µL
aliquots were removed from the reaction vessel and diluted
with 3 mL of CH2Cl2. The diluted solution was treated with
one drop of TEA, and the visible absorption spectrum was
recorded. [In cases where the acid yielded a heterogeneous
mixture (e.g., InCl3, Yb(OTf)3), or broadened absorption in the
Qy region, the 10 µL aliquots were passed through a 2 cm long
pipet column (CH2Cl2/ethyl acetate). The first collected sample
(green; eluted with CH2Cl2) and the second collected sample
(pink; eluted with ethyl acetate) were separately concentrated
and then diluted with 3 mL of CH2Cl2. The visible absorption
spectrum was recorded with the diluted solutions.] The yield
of bacteriochlorins was determined by the intensity of the Qy
band (above 700 nm, ꢀ ) 120 000 M-1 cm-1) measured from
the apex to the middle point of the baseline, established across
the blue to red edge of the band. This eliminated the contribu-
tion of any other components that may absorb in the region
>700 nm. In the case of insoluble acids, 1 and the insoluble
acids were preweighed in the vial followed by addition of a
microstir bar and the desired solvent.
Examination of Effects of Concentration (1, BF3‚OEt2).
Stock solutions of 1 (100 mM, ∼2 mL, ∼50 mg of 1) and BF3‚
OEt2 (1.0 M, 2 mL, 253 µL of BF3‚OEt2) in acetonitrile were
prepared immediately before the reactions were carried out.
Solutions of 1 (5.0, 14, 22, 36, and 100 mM) in 0.5 mL of
acetonitrile were prepared by taking a specific volume from
the stock solution of 1. Similarly, the BF3‚OEt2 solutions (20,
74, 140, 280, and 1000 mM) in 0.5 mL of acetonitrile were
prepared by taking specific volumes from the stock solution.
Each condensation was carried out in a 4 mL vial containing
1 and BF3‚OEt2 in acetonitrile with stirring and exposure to
air. The condensation was initiated by adding the acid solution
(0.50 mL) to the stirred acetal solution (0.50 mL) at room
temperature, giving a total reaction volume of 1.0 mL. The
progress of the reaction was monitored for 23 h by taking
aliquots (5 µL) periodically from the reaction mixture. The
aliquot was diluted into CH2Cl2 (3 mL). The diluted solution
was neutralized with TEA (2-3 µL) and examined by absorp-
tion spectroscopy. The total yield of bacteriochlorins (H-BC
+ MeO-BC) was determined by the intensity of the Qy band
(733-737 nm, ꢀ ) 120 000 M-1 cm-1) as described above.
After stirring for 23 h, the reaction vials were treated with
TEA (1-3 drops). The solvent was removed, and the residue
was chromatographed (silica). Elution with CH2Cl2/hexanes
(1:1) gave two bacteriochlorins. The first product, H-BC, was
nonpolar (Rf ) 0.70). The second product, MeO-BC, was
slightly more polar (Rf ) 0.54). Subsequent elution of the
column with CH2Cl2 gave TDC. Each isolated product was
relatively pure. In each case, the isolated yield was determined
by concentrating the product to dryness and then dissolving
1-(1,1-Dimethoxymethyl)-3,3-dimethyl-7-(4-methyl-
phenyl)-2,3-dihydrodipyrrin (1). Following the procedure
for preparing a â-substituted pyrrole,16 a solution of 8 (237
mg, 0.610 mmol) in anhydrous THF (3.00 mL) under argon
was treated with NaOMe (165 mg, 3.05 mmol), and the
mixture was stirred for 1 h at room temperature (first flask).
In a second flask, TiCl3 (8.6 wt % TiCl3 in 28 wt % HCl, 4.56
mL, 3.05 mmol, 5.0 mol equiv) and H2O (24 mL) were
combined; NH4OAc (18.8 g, 244 mmol) was added to buffer
the solution to pH 6.0, and then THF (1.60 mL) was added.
The solution in the first flask containing the nitronate anion
of 8 was transferred via a cannula to the buffered TiCl3
solution in the second flask. The resulting mixture was stirred
at room temperature for 6 h under argon. Then, the mixture
was extracted with ethyl acetate. The organic extract was
washed with 5% aqueous NaHCO3 and water, dried (NaSO4),
and concentrated under reduced pressure at room tempera-
ture. The crude product was passed through a short column
[alumina, hexanes/ethyl acetate (2:1)] to afford a light yellow
1
solid (57 mg, 28%): mp 104-105 °C; H NMR δ 1.19 (s, 6H),
2.38 (s, 3H), 2.62 (s, 2H), 3.45 (s, 6H), 5.03 (s, 1H), 6.11 (s,
1H), 6.28-6.30 (m, 1H), 6.86-6.88 (m, 1H), 7.22 (d, J ) 8.0
Hz, 2H), 7.35 (d, J ) 8.0 Hz, 2H), 10.80-10.90 (br, 1H); 13C
NMR δ 21.3, 29.3, 40.5, 48.3, 54.8, 103.0, 106.2, 109.3, 119.2,
124.7, 126.9, 128.7, 129.4, 134.2, 135.4, 160.1, 174.2; FAB-MS
obsd 338.2020, calcd 338.1994. Anal. Calcd for C21H26N2O2: C,
74.52; H, 7.74; N, 8.28. Found: C, 74.46; H, 7.79; N, 8.08. λabs
(CH2Cl2) 358 nm.
Ethyl-3-(4-methylphenyl)prop-2-enoate (2).19 A solution
of ethyl malonate potassium salt (27.0 g, 158 mmol) in water
(20.0 mL) was treated with concentrated HCl (∼35%, 15.0 mL),
and the resulting mixture was stirred for 10 min at room
temperature. The mixture was extracted with ether. The
extract was washed with water, dried (Na2SO4), and concen-
trated to give a colorless oil (16.7 g, 79%), which was used
without characterization.18 A solution of p-tolualdehyde (11.6
g, 96.9 mmol) and monoethyl malonate (16.7 g, 126 mmol) in
pyridine (39.2 mL, 485 mmol) containing piperidine (958 µL,
9.69 mmol) was refluxed for 8 h under argon. The reaction
mixture was cooled to room temperature, quenched with 2 N
HCl (∼250 mL), and extracted with ether. The extracts were
washed with water, base (NaHCO3), and water. The organic
solution was dried (Na2SO4), concentrated, and chromato-
graphed (silica, CH2Cl2) to give a colorless oil (14.6 g, 79%):
1H NMR δ 1.33 (t, J ) 7.2 Hz, 3H), 2.37 (s, 3H), 4.26 (q, J )
7.2 Hz, 2H), 6.39 (d, J ) 15.8 Hz, 1H), 7.18 (d, J ) 8.2 Hz,
2H), 7.42 (d, J ) 8.2 Hz, 2H), 7.66 (d, J ) 15.8 Hz, 1H); 13C
NMR δ 14.5, 21.6, 60.6, 117.4, 128.2, 129.8, 131.9, 140.8, 144.8,
167.4. Anal. Calcd for C12H14O2: C, 75.76; H, 7.42. Found: C,
75.76; H, 7.44.
3-(Ethoxycarbonyl)-4-(4-methylphenyl)pyrrole (3).20 A
suspension of TosMIC (15.7 g, 80.5 mmol) and 2 (14.6 g, 76.7
mmol) in dry ether/DMSO (2:1) (154 mL) was added dropwise
under argon to a stirred suspension of NaH (2.39 g, 99.7 mmol)
in ether (70 mL). The mixture started to reflux due to the
exothermic reaction. After 3 h, water (200 mL) was cautiously
added to the mixture, and the aqueous phase was extracted
with ether and CH2Cl2. The combined organic extracts were
5484 J. Org. Chem., Vol. 70, No. 14, 2005

De Novo Synthesis of Stable Tetrahydroporphyrinic Macrocycles
dried (Na2SO4), concentrated, and chromatographed [silica,
CH2Cl2/ethyl acetate (9:1)] to give a light brown solid (13.1 g,
74%): mp 154-155 °C (lit.20 mp 135-137 °C); 1H NMR δ 1.25
(t, J ) 7.2 Hz, 3H), 2.36 (s, 3H), 4.22 (q, J ) 7.2 Hz, 2H), 6.75-
6.77 (m, 1H), 7.16 (d, J ) 7.8 Hz, 2H), 7.38 (d, J ) 7.8 Hz,
2H), 7.46-7.48 (m, 1H), 8.38-8.54 (br, 1H); 13C NMR δ 14.5,
21.4, 59.8, 113.9, 118.3, 125.4, 126.8, 128.6, 129.4, 132.0, 136.3,
165.2. Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59; N, 6.11.
Found: C, 73.11; H, 6.59; N, 6.12.
mesityl oxide (18.0 mL, 160 mmol), diphenyl diselenide (5.00
g, 16.0 mmol), and ammonium peroxydisulfate (109 g, 480
mmol) in anhydrous MeOH (1.20 L) was refluxed for 4 h under
argon. The progress of the reaction was monitored by TLC.
The reaction mixture was poured into water (1.20 L) and
extracted with CHCl3. The organic layer was washed with
water, dried (Na2SO4), and concentrated to give a dark brown
oil. Bulb-to-bulb distillation of the oil at 50 °C/0.04-0.05
mmHg gave a yellow oil. The 1H NMR spectrum of the oil
showed the presence of unknown impurities. The oil was
chromatographed [silica, hexanes/ethyl acetate (3:1)] to give
a pale yellow oil (7.37 g, 29%). Characterization data were
consistent with the literature25 for the title compound: 1H
NMR δ 1.96 (d, J ) 1.2 Hz, 3H), 2.21 (d, J ) 1.2 Hz, 3H), 3.42
(s, 6H), 4.49 (s, 1H), 6.36-6.38 (m, 1H); 13C NMR δ 21.3, 28.2,
54.5, 104.5, 119.1, 160.2, 194.2; FAB-MS obsd 159.1020, calcd
159.1021 (C8H14O3) [M + H]+. Note: The use of reagent-grade
methanol resulted in a slow reaction (>26 h for completion)
in comparison to the relatively fast reaction (<4 h) when
anhydrous methanol was used.
3-(4-Methylphenyl)pyrrole (4).21-23 Following a standard
procedure,16 a mixture of 3 (6.81 g, 29.7 mmol) and ethylene
glycol (76.0 mL) in a 250 mL Claisen flask was flushed with
argon for 10 min, and then powdered NaOH (3.05 g, 76.2
mmol) was added. The flask was placed in an oil bath at 120
°C, and the temperature was raised to 160 °C. After 2.5 h, the
flask was cooled to room temperature, and 10% aqueous NaCl
(150 mL) was added. The aqueous layer was extracted with
CH2Cl2. The organic extract was washed with 10% aqueous
NaCl, dried (Na2SO4), concentrated, and chromatographed
(silica, CH2Cl2) to give a light brown solid (3.33 g, 71%): mp
92-93 °C (lit.21 mp 93-95 °C; lit.22 mp 80-82 °C; lit.23 mp
1,1-Dimethoxy-4,4-dimethyl-6-[3-(4-methylphenyl)pyr-
rol-2-yl]-5-nitro-2-hexanone (8). Following a general pro-
cedure,15,16 CsF (1.82 g, 12.0 mmol, 3.00 mol equiv, freshly
dried by heating to 100 °C under vacuum for 1 h) was placed
in a flask under argon. A mixture of 6 (921 mg, 4.00 mmol)
and 7 (6.33 g, 40.0 mmol, 10 mol equiv) in dry acetonitrile (40
mL) was transferred by cannula to the flask containing CsF.
The mixture was heated at 65 °C for 1.2 h, whereupon TLC
analysis showed the reaction to be complete. The reaction
mixture was filtered through a bed of silica (ethyl acetate),
and the filtrate was concentrated. The resulting oil was
subjected to bulb-to-bulb distillation at room temperature/
0.04-0.05 mmHg for 3 h, affording recovery of the acetal 7
(∼2 g) as the distillate and the desired product in the crude
undistilled residue. Purification of the residue by column
chromatography [alumina, ethyl acetate/hexanes (1:3)] gave
a light brown solid (626 mg, 40%): mp 98-100 °C; 1H NMR δ
1.09 (s, 3H), 1.19 (s, 3H), 2.37 (s, 3H), 2.53, 2.71 (AB, 2J )
18.8 Hz, 2H), 3.21 (ABX, 3J ) 2.4 Hz, 2J ) 15.4 Hz, 1H), 3.39
1
85-87 °C); H NMR δ 2.34 (s, 3H), 6.51-6.54 (m, 1H), 6.82-
6.84 (m, 1H), 7.05-7.08 (m, 1H), 7.15 (d, J ) 7.8 Hz, 2H), 7.43
(d, J ) 7.8 Hz, 2H), 8.15-8.32 (br, 1H); 13C NMR δ 21.3, 106.7,
114.4, 119.0, 125.1, 125.4, 129.5, 133.1, 135.2; FAB-MS obsd
157.0885, calcd 157.0891 (C11H11N).
2-Formyl-3-(4-methylphenyl)pyrrole (5). Following a
standard procedure,16 a solution of 4 (472 mg, 3.00 mmol) in
DMF (0.96 mL) and CH2Cl2 (30 mL) under argon was cooled
to 0 °C, and then POCl3 (340 µL, 3.60 mmol) was added
dropwise. After 1 h, the flask was warmed to room temperature
and stirred overnight (∼18 h). The reaction was quenched at
0 °C with 2.5 M aqueous NaOH (25 mL). The mixture was
poured into water (50 mL) and extracted with CH2Cl2. The
combined organic layers were washed with water and brine,
dried (Na2SO4), and concentrated. The residue was chromato-
graphed [silica, CH2Cl2/ethyl acetate (9:1)] to give a brown
solid. 1H NMR spectroscopy showed two regioisomers in a ca.
13:1 ratio. Cooling of the solution (ethyl acetate/hexanes) at
ca. -16 °C resulted in precipitation of an orange solid, which
proved to be a single regioisomer (354 mg, 64%): mp 149-
150 °C; 1H NMR δ 2.41 (s, 3H), 6.42-6.44 (m, 1H), 7.10-7.13
(m, 1H), 7.26 (d, J ) 8.0 Hz, 2H), 7.40 (d, J ) 8.0 Hz, 2H),
9.63-9.64 (m, 1H), 9.52-9.78 (br, 1H); 13C NMR δ 21.4, 111.6,
126.2, 128.9, 129.3, 129.7, 130.9, 137.7, 137.9, 180.2; FAB-MS
obsd 186.0907, calcd 186.0919 (C12H11NO).
3
2
(ABX, J ) 11.6 Hz, J ) 15.4 Hz, 1H), 3.41 (s, 6H), 4.34 (s,
1H), 5.22 (ABX, 3J ) 2.4 Hz, 3J ) 11.6 Hz, 1H), 6.22-6.24 (m,
1H), 6.66-6.68 (m, 1H), 7.19 (d, J ) 8.0 Hz, 2H), 7.24 (d, J )
8.0 Hz, 2H), 8.06-8.14 (br, 1H); 13C NMR δ 21.3, 24.1, 24.3,
25.3, 36.8, 45.1, 55.20, 55.22, 95.0, 104.7, 109.5, 117.7, 122.1,
123.7, 128.4, 129.4, 133.5, 135.6, 203.7. Anal. Calcd for
C21H28N2O5: C, 64.93; H, 7.27; N, 7.21. Found: C, 65.02; H,
7.34; N, 7.14.
3-(4-Methylphenyl)-2-(2-nitroethyl)pyrrole (6). Follow-
ing a standard procedure,16 a mixture of 5 (3.93 g, 21.2 mmol),
KOAc (2.29 g, 23.3 mmol), methylamine hydrochloride (1.72
g, 25.4 mmol), and nitromethane (190 mL) under argon was
stirred at room temperature. The mixture slowly yielded an
orange-red precipitate. After the mixture was stirred for 2.5
h, TLC showed the appearance of a new component and the
disappearance of 5. The reaction was quenched with brine and
extracted with ethyl acetate. The organic layer was dried (Na2-
SO4) and concentrated. The residue was dissolved in THF/
MeOH (210 mL, 3:7) at 0 °C. NaBH4 (2.41 g, 63.6 mmol) was
added in portions at 0 °C. Then, the mixture was stirred for
0.5 h at room temperature. The reaction mixture was neutral-
ized with acetic acid (pH ) 7); then, water (150 mL) was added,
and the mixture was extracted with ethyl acetate. The organic
extract was washed with water and brine, dried (Na2SO4),
concentrated, and chromatographed [silica, hexanes/ethyl
acetate (3:1)] to give a light brown solid (3.61 g, 74%): mp
Conversion of 1 f Tetrahydroporphyrinic Macro-
cycles: Preparation to Obtain MeO-BC (5 mM 1 and 50
mM BF3‚OEt2). A solution of 1 (93 mg, 0.27 mmol) in CH3CN
(54 mL) was treated with neat BF3‚OEt2 (350 µL, 2.7 mmol,
50 mM). The reaction mixture was stirred at room temperature
without deaeration for 15 h. The reaction was monitored by
absorption spectroscopy. TEA (1.0 mL) was added to the
reaction mixture. The reaction mixture was concentrated, and
the residue was dissolved in CH2Cl2. The solution was washed
(water), dried (Na2SO4), concentrated, and chromatographed
[silica, CH2Cl2/hexanes (1:1)]. The first band (green) was
collected (H-BC, 8.1 mg, 11%), and then the second band
(green) was collected (MeO-BC, 24 mg, 30%).
Preparation to Obtain TDC (11 mM 1 and 10 mM BF3‚
OEt2). BF3‚OEt2 (18 µL, 0.14 mmol) in CH3CN (1.6 mL) was
slowly added to a solution of 1 (50. mg, 0.15 mmol) in CH3CN
(12 mL). The reaction mixture was stirred at room temperature
without deaeration for 24 h. TEA (20 µL, 0.14 mmol) was
added to the reaction mixture. The reaction mixture was
concentrated, and the residue was chromatographed [silica,
CH2Cl2/hexanes (1:1)]. The first green band was collected (H-
BC, ,0.1 mg, ,0.1%). Some pinkish material then eluted (not
identified). The second green band was collected (MeO-BC,
2.7 mg, 6.3%). Further elution with CH2Cl2 afforded the third
green band (TDC, 30. mg, 66%).
1
81-82 °C; H NMR δ 2.37 (s, 3H), 3.44 (t, J ) 6.8 Hz, 2H),
4.54 (t, J ) 6.8 Hz, 2H), 6.27-6.29 (m, 1H), 6.73-6.75 (m, 1H),
7.18-7.25 (m, 4H), 8.19-8.36 (br, 1H); 13C NMR δ 21.2, 24.4,
75.2, 109.6, 117.7, 121.9, 123.2, 128.0, 129.5, 133.4, 135.8; FAB-
MS obsd 230.1060, calcd 230.1055 (C13H14N2O2).
1,1-Dimethoxy-4-methyl-3-penten-2-one (7). The follow-
ing procedure employs the approach of Tiecco et al.25 but at
80-times larger scale and with altered workup. A mixture of
J. Org. Chem, Vol. 70, No. 14, 2005 5485

Kim and Lindsey
Preparation to Obtain H-BC (18 mM 1 and 140 mM
BF3‚OEt2). A solution of 1 (50. mg, 0.15 mmol) in CH3CN (8.3
mL) was treated with BF3‚OEt2 (150 µL, 1.2 mmol). The
reaction mixture was stirred at room temperature without
deaeration for 24 h. TEA (167 µL, 1.2 mmol) was added to the
reaction mixture. The reaction mixture was concentrated, and
the residue was chromatographed [silica, CH2Cl2/hexanes (1:
1)]. The first green band was collected (H-BC, 20. mg, 49%).
The second green band was collected (MeO-BC, 0.80 mg,
1.9%). Further elution with CH2Cl2 did not afford any TDC.
Data for 8,8,18,18-Tetramethyl-2,12-bis(4-methylphen-
yl)bacteriochlorin (H-BC): 1H NMR δ -2.00 (br, 2H), 1.93
(s, 12H), 2.61 (s, 6H), 4.56 (s, 4H), 7.59 (d, J ) 8.0 Hz, 4H),
8.13 (d, J ) 8.0 Hz, 4H), 8.73 (d, J ) 2.0 Hz, 2H), 8.81 (s, 2H),
8.86 (s, 2H); λabs (toluene)/nm 351 (ꢀ ) 130 000 M-1 cm-1), 374
(120 000), 499 (35 000), 737 (130 000, fwhm 20 nm); λem (λexc
499 nm) 744 nm (fwhm 21 nm), Φf ) 0.14; LD-MS obsd 550.0;
FAB-MS obsd 550.3068, calcd 550.3096 (C38H38N4).
Data for 1H,22H,24H-7,8,17,18-Tetradehydro-1-(1,1-
dimethoxymethyl)-3,3,13,13-tetramethyl-7,17-bis(4-meth-
ylphenyl)corrin (TDC): 1H NMR δ 1.04 (s, 3H), 1.24 (s, 3H),
2
1.26 (s, 3H), 1.33 (s, 3H), 1.82 (d, J ) 13.2 Hz, 1H), 2.38 (s,
3H), 2.42 (s, 3H), 2.49 (d, 2J ) 13.2 Hz, 1H), 2.65, 2.71 (AB, 2J
) 18.8 Hz, 2H), 3.37 (s, 3H), 3.40 (s, 3H), 4.26 (s, 1H), 5.42 (s,
1H), 5.43 (s, 1H), 6.02 (s, 1H), 6.25 (d, J ) 2.8 Hz, 1H), 6.57
(d, J ) 1.6 Hz, 1H), 7.20 (d, J ) 8.0 Hz, 2H), 7.29 (d, J ) 8.0
Hz, 2H), 7.38 (d, J ) 8.0 Hz, 2H), 8.42 (d, J ) 8.0 Hz, 2H),
11.34-11.40 (br, 1H), 11.89-11.96 (br, 1H); λabs (toluene)/nm
343 (ꢀ ) 24 000 M-1 cm-1), 437 (7400), 640 (4300), 703 (5400);
LD-MS obsd 612.7; FAB-MS obsd 612.3447, calcd 612.3464
(C40H44N4O2).
Acknowledgment. This work was funded by the
NIH (GM36238).
Data for 5-Methoxy-8,8,18,18-tetramethyl-2,12-bis(4-
methylphenyl)bacteriochlorin (MeO-BC): 1H NMR δ
-1.90 (br, 1H), -1.78 (br, 1H), 1.91 (s, 6H), 1.92 (s, 6H), 2.61
(s, 6H), 4.40 (s, 2H), 4.41 (s, 2H), 4.49 (s, 3H), 7.58 (two d, J )
8.0 Hz, 4H), 8.10 (d, J ) 8.0 Hz, 2H), 8.14 (d, J ) 8.0 Hz, 2H),
8.66-8.69 (m, 2H), 8.78 (s, 1H), 8.81 (s, 1H), 8.95 (d, J ) 2.0
Hz, 1H); λabs (toluene)/nm 356 (ꢀ ) 110 000 M-1 cm-1), 374
(130 000), 511 (39 000), 732 (120 000); λem (λexc 511 nm) 739
nm, Φf ) 0.18; LD-MS obsd 580.1; FAB-MS obsd 580.3232,
calcd 580.3202 (C39H40N4O).
Supporting Information Available: Experimental pro-
cedure for determination of fluorescence quantum yields of
bacteriochlorins; NMR data and assignments for H-BC,
MeO-BC, and TDC; spectral data for selected compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO050467Y
5486 J. Org. Chem., Vol. 70, No. 14, 2005