Dipyrromethane + dipyrromethanedicarbinol routes to an electron deficient meso-substituted phlorin with enhanced stability

Article abstract of DOI:10.1021/jo070216k

(Chemical Equation Presented) Two dipyrromethane + dipyrromethanedicarbinol routes to a meso-substituted phlorin bearing electron-withdrawing pentafluorophenyl substituents (TpFPPhl) were investigated in an attempt to obtain a phlorin with enhanced stabil

Full text of DOI:10.1021/jo070216k

Dipyrromethane + Dipyrromethanedicarbinol Routes to an Electron
Deficient meso-Substituted Phlorin with Enhanced Stability
Anna Y. O’Brien, John P. McGann, and G. Richard Geier, III*
Department of Chemistry, Colgate UniVersity, 13 Oak DriVe, Hamilton, New York 13346
ggeier@mail.colgate.edu
ReceiVed February 1, 2007
Two dipyrromethane + dipyrromethanedicarbinol routes to a meso-substituted phlorin bearing electron-
withdrawing pentafluorophenyl substituents (TpFPPhl) were investigated in an attempt to obtain a phlorin
with enhanced stability toward light and air and to explore the application of dipyrromethanecarbinol
chemistry to the preparation of phlorins. For each route, a systematic survey of reaction parameters for
the two-step, one-flask reaction leading to TpFPPhl was performed. The analytical-scale reactions were
monitored for yield of TpFPPhl by HPLC. Sharp differences were observed in the yield of TpFPPhl
afforded by the two synthetic routes. The most promising reaction condition (TFA catalysis, 100 mM)
was performed on a preparative scale providing TpFPPhl in a yield of 45% (189 mg). The stability of
the electron-deficient phlorin in dilute solution upon exposure to light and air was probed in a number
of solvents, and decomposition was monitored by UV-vis spectroscopy and HPLC. Many of the solutions
of TpFPPhl were found to be quite stable for periods of ∼8 h, with decomposition requiring exposure
periods of several days. Taken together, this work contributes an efficient synthesis of a meso-substituted
phlorin of practical stability and provides further insights toward the adaptation of dipyrromethanecarbinol
chemistry to the preparation of diverse porphyrinoids.
Introduction
and phlorins have been relevant in model studies of coenzyme
F430.7 The equilibrium between phlorin and chlorin tautomers
has been investigated.8 More recently, phlorins have garnered
interest for their anion binding properties.9 Phlorins have been
detected as side products in reactions intended to prepare other
porphyrinoids,9,10 N-confused phlorins have been reported,11 and
Phlorins are porphyrinic macrocycles that differ from por-
phyrins by the presence of an sp3-hybridized carbon atom at
one of the four meso-positions.1 Phlorins were first reported in
the course of Woodward’s landmark studies of macrocycles
related to chlorophyll a.2 Phlorins were later identified as
intermediates in syntheses of porphyrins,3 in studies of reduc-
tions of porphyrins,4 and in reactions of porphyrins with
nucleophiles.5 A phlorin structure has been implicated in the
catalytic cycle of heme P460 of hydroxylamine oxidoreductase,6
(4) (a) Mauzerall, D. J. Am. Chem. Soc. 1962, 84, 2437-2445. (b) Closs,
G. L.; Closs, L. E. J. Am. Chem. Soc. 1963, 85, 818-819. (c) Fuhrhop,
J.-H.; Mauzerall, D. J. Am. Chem. Soc. 1968, 90, 3875-3876. (d) Lanese,
J. G.; Wilson, G. S. J. Electrochem. Soc. 1972, 119, 1039-1043. (e) Harel,
Y.; Meyerstein, D. J. Am. Chem. Soc. 1974, 96, 2720-2727. (f) Langhus,
D. L.; Wilson, G. S. Anal. Chem. 1979, 51, 1139-1144. (g) Marrese, C.
A.; Carrano, C. J. Inorg. Chem. 1983, 22, 1858-1862. (h) Marrese, C. A.;
Carrano, C. J. Inorg. Chem. 1984, 23, 3961-3968. (i) Baral, S.; Hambright,
P.; Neta, P. J. Phys. Chem. 1984, 88, 1595-1600. (j) Harriman, A. J.
Photochem. 1985, 29, 139-150. (k) Abou-Gamra, Z.; Harriman, A.; Neta,
P. J. Chem. Soc., Faraday Trans. 2 1986, 82, 2337-2350. (l) Sutter, T. P.
G.; Rahimi, R.; Hambright, P.; Bommer, J. C.; Kumar, M.; Neta, P. J. Chem.
Soc., Faraday Trans. 1993, 89, 495-502.
(1) Sessler, J. L.; Zimmerman, R. S.; Bucher, C.; Kral, V.; Andrioletti,
B. Pure Appl. Chem. 2001, 73, 1041-1057.
(2) Woodward, R. B. Ind. Chim Belg. 1962, 27, 1293-1308.
(3) (a) Rocha Gonsalves, A. M. d’A.; Pereira, M. M. J. Heterocycl. Chem.
1985, 22, 931-933. (b) Lash, T. D. J. Porphyrins Phthalocyanines 1997,
1, 29-44. (c) Lash, T. D.; Gandhi, V. J. Org. Chem. 2000, 65, 8020-
8026.
10.1021/jo070216k CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/27/2007
4084
J. Org. Chem. 2007, 72, 4084-4092

An Electron-Deficient meso-Substituted Phlorin
there has been interest in syntheses of phlorins from building
block precursors in analogy to stepwise syntheses of meso-
substituted porphyrins.12,13
recently (vide infra), the use of peripheral substituents to
improve the stability of phlorins had only been demonstrated
in Woodward’s work involving a phlorin stabilized by the steric
bulk of â-pyrrole substituents adjacent to the sp3-hybridized
carbon atom.2 The use of peripheral substituents to enhance
phlorin stability is attractive as such substituents are less
perturbing than metal insertion or N-substituents to the mac-
rocycle structure and to the central core. Our earlier observations
on the effect of meso-substituents on corrole stability18 inspired
our attempts to obtain stable phlorins via the judicious selection
of meso-substituents. Sterically bulky substituents (e.g., mesityl)
were expected to shield the meso-positions from oxidation, and
electron-withdrawing substituents (e.g., pentafluorophenyl) were
expected to render the macrocycle electron deficient and
therefore less prone to oxidation.
The presence of an sp3-hybridized meso-carbon atom has a
profound effect on the structure and properties of phlorins. The
sp3-hybridized carbon atom disrupts the conjugation of the
macrocycle, and it renders the ring nonplanar. Additionally, the
inner core of the phlorin macrocycle contains three N-H-type
nitrogen atoms compared to the two found in porphyrins. Thus,
the phlorin ligand upon deprotonation and metal insertion is
trianionic compared to the dianionic nature of porphyrins.
Finally, phlorins are generally unstable toward ambient light
and air. Phlorins bearing a hydrogen atom at the sp3-hybridized
position readily undergo oxidation to the corresponding aromatic
porphyrins. Phlorins for which this pathway is blocked by
substituents at the sp3-hybridized carbon atom are still subject
to oxidation, leading to ring-opened biladienone species.14 The
poor stability of phlorins complicates their preparation and study.
The handful of phlorins sufficiently stable for isolation and
characterization have generally possessed either an electro-
negative central metal ion15 or structurally distorting substituents/
tethers on one or more of the core nitrogen atoms.16,17 Until
Our initial efforts to explore the effect of peripheral meso-
substituents on the stability of phlorins considered the effect of
sterically bulky mesityl substituents, as the methodology of
Krattinger and Callot for the preparation of phlorins via
alkylation of a porphyrin precursor19 provided an attractive route
for the preparation of meso-mesityl substituted phlorins.
Encouragingly, we found that phlorin stability could be enhanced
by the incorporation of mesityl substituents at the three sp2-
hybridized meso-positions, increasing the half-life of dilute
solutions of phlorin exposed to light and air from <15 to
>90 min.20 Importantly, we found that steric protection was
required at all three sp2-hybridized meso-positions, not just the
two positions adjacent to the sp3-hybridized carbon atom (posi-
tions 10 and 20). The favorable outcome of this study provided
motivation for the investigation of electron-withdrawing sub-
stituents, and the recent report of stable phlorin-dipyrrin
conjugates possessing sterically bulky and electron-withdrawing
meso-substituents provided further encouragement.10 Our efforts
to prepare a phlorin bearing pentafluorophenyl substituents and
studies of its stability are described herein. The targeted phlorin
species, 5,5-dimethyl-10,15,20-tris(pentafluorophenyl)phlorin 3
(TpFPPhl), was selected as the two methyl groups prevent
oxidation of the sp3-hybridized meso-carbon atom and the
pentafluorophenyl groups would render the sp2-hybridized meso-
positions electron deficient.
(5) (a) Setsune, J.; Yazawa, T.; Ogoshi, H.; Yoshida, Z. J. Chem. Soc.,
Perkin Trans. I 1980, 1641-1645. (b) Pandian, R. P.; Chandrashekar, T.
K.; Chandrasekhar, V. Ind. J. Chem. 1991, 30A, 579-583. (c) Segawa, H.;
Azumi, R.; Shimidzu, T. J. Am. Chem. Soc. 1992, 114, 7564-7565. (d)
Jiang, X; Nurco, D. J.; Smith, K. M. Chem. Commun. 1996, 1759-1760.
(e) Collman, J. P.; Boulatov, R. J. Am. Chem. Soc. 2000, 122, 11812-
11821. (f) Senge, M. O.; Kalisch, W. W.; Bischoff, I. Chem.sEur. J. 2000,
6, 2721-2738. (g) Feng, X.; Bischoff, I.; Senge, M. O. J. Org. Chem. 2001,
66, 8693-8700.
(6) Arciero, D. M.; Hooper, A. B. Biochem. Soc. Trans. 1998, 26, 385-
389.
The preparation of TpFPPhl required an approach different
from alkylation of the corresponding porphyrin as the penta-
fluorophenyl groups are reactive toward strong nucleophiles.
Thus, we elected to explore dipyrromethanecarbinol chemistry
initially reported for the preparation of meso-substituted por-
phyrins21,22 and later extended to the preparation of other por-
phyrinoids such as heteroatom modified porphyrins,23 chlorin,24
(7) (a) Stolzenberg, A. M.; Stershic, M. T. Inorg. Chem. 1987, 26, 3082-
3083. (b) Stolzenberg, A. M.; Stershic, M. T. J. Am. Chem. Soc. 1988,
110, 6391-6402.
(8) Whitlock, H. W.; Oester, M. Y. J. Am. Chem. Soc. 1973, 95, 5738-
5741.
(9) Ka, J. W.: Lee, C. H. Tetrahedron Lett. 2001, 42, 4527-4529.
(10) Gryko, D. T.; Koszarna, B. Eur. J. Org. Chem. 2005, 3314-3318.
(11) (a) Li, X.; Chmielewski, P. J.; Xiang, J.; Xu, J.; Li, Y.; Liu, H.;
Zhu, D. Org. Lett. 2006, 8, 1137-1140. (b) Li, X.; Chmielewski, P. J.;
Xiang, J.; Xu, J.; Jiang, L.; Li, Y.; Liu, H.; Zhu, D. J. Org. Chem. 2006,
71, 9739-9742.
(18) Geier, G. R., III; Chick, J. F. B.; Callinan, J. B.; Reid, C. G.;
Auguscinski, W. P. J. Org. Chem. 2004, 69, 4159-4169.
(19) (a) Krattinger, B.; Callot, H. J. Tetrahedron Lett. 1996, 37, 7699-
7702. (b) Krattinger, B.; Callot, H. J. Eur. J. Chem. 1999, 1857-1867.
(20) LeSaulnier, T. D.; Graham, B. W.; Geier, G. R., III. Tetrahedron
Lett. 2005, 46, 5633-5637.
(12) Bucher, C.; Seidel, D.; Lynch, V.; Kral, V.; Sessler, J. L. Org. Lett.
2000, 2, 3103-3106.
(13) Hong, S. J.; Ka, J. W.; Won, D. H.; Lee, C. H. Bull. Korean Chem.
Soc. 2003, 24, 661-663.
(14) Jeandon, C.; Krattinger, B.; Ruppert, R.; Callot, H. J. Inorg. Chem.
2001, 40, 3149-3153.
(21) (a) Lee, C. H.; Li, F.; Iwamoto, K.; Dadok, J.; Bothner-By, A. A.;
Lindsey, J. S. Tetrahedron 1995, 51, 11645-11672. (b) Rao, P. D.;
Dhanalekshmi, S.; Littler, B. J.; Lindsey, J. S. J. Org. Chem. 2000, 65,
7323-7344. (c) Geier, G. R., III; Callinan, J. B.; Rao, D. P.; Lindsey, J. S.
J. Porphyrins Phthalocyanines 2001, 5, 810-823.
(15) Sugimoto, H. J. Chem. Soc., Dalton. Trans. 1982, 1169-1171.
(16) (a) Setsune, J.-i.; Ikeda, M.; Iida, T.; Kitao, T. J. Am. Chem. Soc.
1988, 110, 6572-6574. (b) Setsune, J.-i.; Ishimaru, Y.; Kitao, T. Chem.
Lett. 1990, 1351-1354. (c) Setsune, J.-i.; Yamaji, H.; Kitao, T. Tetrahedron
Lett. 1990, 31, 5057-5060. (d) Setsune, J.-i.; Wada, K.-i.; Higashino, H.
Chem. Lett. 1994, 213-216. (e) Setsune, J.-i.; Kashihara, K.; Wada, K.-i.
Chem. Lett. 2001, 608-609.
(22) Wallace, D. M.; Leung, S. H.; Senge, M. O.; Smith, K. M. J. Org.
Chem. 1993, 58, 7245-7257.
(23) Cho, W. S.; Kim, H. J.; Littler, B. J.; Miller, M. A.; Lee, C. H.;
Lindsey, J. S. J. Org. Chem. 1999, 64, 7890-7901.
(17) (a) Krattinger, B.; Callot, H. J. Chem. Commun. 1996, 1341-1342.
(b) Ruppert, R.; Jeandon, C.; Sgambati, A.; Callot, H. J. Chem. Commun.
1999, 2123-2124. (c) Ishimaru, Y.; Sumida, S.; Iida, T. Tetrahedron Lett.
2001, 42, 419-421.
(24) (a) Strachan, J. P.; O’Shea, D. F.; Balasubramanian, T.; Lindsey, J.
S. J. Org. Chem. 2000, 65, 3160-3172. (b) Balasubramanian, T.; Strachan,
J. P.; Boyle, P. D.; Lindsey, J. S. J. Org. Chem. 2000, 65, 7919-7929.
J. Org. Chem, Vol. 72, No. 11, 2007 4085

O’Brien et al.
SCHEME 1. Complementary Dipyrromethane +
Dipyrromethanedicarbinol Routes for the Preparation of a
Phlorin Bearing Electron-Withdrawing Pentafluorophenyl
Substituents
the reaction outcome, and the as yet unknown diacyl dipyr-
romethane precursor 2b to 2b-OH might be obtained more
efficiently than 2a.
To explore the preparation of TpFPPhl, the required precur-
sors were prepared and a systematic survey of key reaction
parameters (acid catalyst, acid concentration, reaction time, and
oxidant quantity) was performed for each route. The yield of
TpFPPhl in these analytical-scale reactions was assessed by
HPLC. Preparative-scale reactions were performed using the
best condition identified from the analytical-scale reactions, and
TpFPPhl was isolated and characterized. The stability of
TpFPPhl in dilute solution toward light and air was examined
in a number of solvents by monitoring changes in UV-vis
spectra and HPLC chromatograms as a function of time.
Results and Discussion
Preparation of Dipyrromethanes, Diacyl Dipyrromethanes,
and Dipyrromethanedicarbinols. Dipyrromethanes 1a,b27 and
the diacyl dipyrromethane 2a21b (precursor to 2a-OH) were
prepared according to the literature. Diacyl dipyrromethane 2b
(precursor to 2b-OH) was a new compound, and it was prepared
from dipyrromethane 1a (eq 1) in accordance with typical
conditions for the preparation of other diacyl dipyrromethanes21b
s
with one notable exception. We found that 2b could be isolated
and purified by multiple precipitations from CH2Cl2/hexanes
rather than requiring chromatography. In this fashion, 2b was
obtained in yields ranging from 13-29% (370-830 mg). This
compares favorably with our preparations of 2a in yields of
5-13%. Dipyrromethanedicarbinol species 2a-OH and 2b-OH
were prepared immediately before use by NaBH4 reduction of
the appropriate diacyl dipyrromethane and were used without
purification as reported in the literature.21b
corrole,18,25 and an octaphyrin.26 We are aware of only one other
attempt to prepare meso-substituted phlorins via a dipyrro-
methanecarbinol approach.13 In this work of Lee and co-workers,
a pair of reactions were explored with one providing a phenyl-
substituted phlorin in a yield of 2% and the other failing to
provide phlorin. It was not clear whether these results were
due to fundamental problems with the overall approach, the
selection of reaction conditions, or poor stability of the targeted
phlorins. Thus, we felt that a further investigation of a dipyrro-
methanecarbinol route might add clarity to the feasibility of
preparing phlorins in this fashion while also providing further
insights toward the general application of dipyrromethane-
carbinol species to syntheses of diverse porphyrinoids.
Toward that end, two dipyrromethane + dipyrromethanedi-
carbinol routes leading to TpFPPhl were explored (Scheme 1).
The route involving the condensation of dipyrromethane 1a with
dipyrromethanedicarbinol 2a-OH was attractive as both precur-
sors are known in the literature, although the diacyl dipyr-
romethane precursor 2a to 2a-OH is challenging to obtain in
high yield.21b The route involving the condensation of 1b and
2b-OH was of interest as the selection of the dipyrromethane
and dipyrromethanedicarbinol partners may have an effect on
Survey of Reaction Conditions in Two-Step, One-Flask
Reactions of a Dipyrromethane and a Dipyrromethanedi-
carbinol Leading to TpFPPhl. Studies of the two reaction
routes leading to TpFPPhl involved the isolation of authentic
TpFPPhl, the development of an analytical method for monitor-
ing the production of TpFPPhl in analytical-scale reactions, a
survey of acid catalysis conditions, an investigation of oxidation
conditions, and reaction time course experiments.
1. Isolation of TpFPPhl. As the preparation of the target
phlorin had not been previously reported, reactions of 1a and
2a-OH and reactions of 1b and 2b-OH were performed using
Dy(OTf)3 (10 mM) as the acid catalyst so as to obtain a small
quantity of TpFPPhl for preliminary characterization and for
use in the development of an HPLC method for monitoring the
production of TpFPPhl in analytical-scale reactions. The distinc-
tive green appearance and the characteristic UV-vis spectrum
of phlorins helped to guide the search for TpFPPhl. Further
analysis of promising pigments by laser desorption mass
spectrometry (LD-MS) led to the provisional identification
of TpFPPhl. Additional characterization was performed on
(25) (a) Guilard, R.; Gryko, D. T.; Canard, G.; Barbe, J.-M.; Koszarna,
B.; Brandes, S.; Tasior, M. Org. Lett. 2002, 4, 4491-4494. (b) Gryko, D.
T.; Tasior, M.; Koszarna, B. J. Porphyrins Phthalocyanines 2003, 7, 239-
248. (c) Decreau, R. A.; Collman, J. P. Tetrahedron Lett. 2003, 44, 3323-
3327.
(26) Geier, G. R., III; Grindrod, S. C. J. Org. Chem. 2004, 69, 6404-
6412.
(27) (a) 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. (b)
Laha, J. K.; Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.; Lindsey, J.
S. Org. Process Res. DeV. 2003, 7, 799-812.
4086 J. Org. Chem., Vol. 72, No. 11, 2007

An Electron-Deficient meso-Substituted Phlorin
TABLE 1. Reaction Conditions Providing the Highest Yield of
TpFPPhl for Each Acid Catalysta
TpFPPhl prepared later in the study after methods for its
synthesis and purification were further refined.
% yield of
2. HPLC Method for Monitoring the Production of
TpFPPhl in Analytical-Scale Reactions. To perform a large
number of analytical-scale reactions in parallel, methodology
for the efficient monitoring of the yield of TpFPPhl was
required. UV-vis spectroscopy is often employed to monitor
reactions leading to porphyrinoids due to the strong absorbance
of these species.28 Unfortunately, the absorbance of phlorins is
much weaker; thus, we found it difficult to detect TpFPPhl by
UV-vis spectroscopy in the presence of other pigments. Passing
an aliquot of the crude reaction mixture through a silica pad to
remove polar pigments as performed in our earlier studies of
corrole18 and an octaphyrin26 was still not sufficient to allow
accurate spectrophotometric detection of TpFPPhl in the pres-
ence of remaining byproducts. As a result, an HPLC method
originally developed for the quantitation of porphyrin, N-
confused porphyrin, and sapphyrin29 was adapted to this study
(see the Supporting Information for a discussion of the HPLC
method development, control experiments, reproducibility,
calibration, and representative chromatograms). In short, the
adapted method entailed the oxidation of an aliquot of the
condensation reaction mixture with DDQ, basification by the
addition of triethylamine, filtration of the oxidized reaction
mixture through a silica pad to remove insoluble and strongly
polar species, and analysis by HPLC.
entry
reactants
acid
TFA
[acid], mMb
TpFPPhlc
1
2
3
4
5
6
7
8
9
1a + 2a-OH
1a + 2a-OH
1a + 2a-OH
1a + 2a-OH
1a + 2a-OH
1b + 2b-OH
1b + 2b-OH
1b + 2b-OH
1b + 2b-OH
1b + 2b-OH
100
3.2
32
10
32
100
3.2
100
0.32
0.32
19
17
15
4
InCl3
Sc(OTf)3
Yb(OTf)3
Dy(OTf)3
TFA
4
44
32
40
19
20
InCl3
Sc(OTf)3
Yb(OTf)3
Dy(OTf)3
10
a The reactions were performed with the indicated reactants (2.5 mM
each) on a 5-10 mL scale in CH2Cl2 at room temperature. The reactions
were monitored at 0.25, 1, and 4 h. b The lowest acid concentration that
provided a near-maximum yield of TpFPPhl. Higher quantities of some
acids provided yields of TpFPPhl similar to those reported here. c The
highest yield (HPLC) of the three time points is reported.
3. Survey of Acid Catalysis Conditions. Two-step, one-flask
syntheses of porphyrinoids involve an acid-mediated condensa-
tion step, where starting materials are converted to various linear
and cyclic oligomers, and a subsequent oxidation step, where
appropriate oligomers are converted to the oxidized porphyrinoid
species. It is well-established that key reaction parameters in
the condensation step (e.g., the choice of acid catalyst, acid
concentration, and reaction time) can have a profound effect
on the outcome of the reaction.28,30 In this study, five acid
catalysts [TFA, InCl3, Sc(OTf)3, Yb(OTf)3, and Dy(OTf)3] at
five concentrations (0.32, 1.0, 3.2, 10, and 32 mMsand in some
cases 100 and 320 mM)31 were investigated. Each reaction was
monitored for the yield of TpFPPhl at 0.25, 1, and 4 h. TFA is
a benchmark acid for condensations leading to porphyrinoids,28
and the four mild Lewis acids have been found to be well-
suited for dipyrromethanecarbinol routes to porphyrin21c and
other porphyrinoids.18,26
The conditions providing the highest yield of TpFPPhl for
each acid catalyst in reactions of 1a with 2a-OH or 1b with
2b-OH are summarized in Table 1. Representative plots of the
yield of TpFPPhl as a function of acid catalyst concentration
for the reaction of 1b with 2b-OH are provided in Figure 1
(see the Supporting Information for a complete set of plots).
The highest yields of TpFPPhl (40-44%) were obtained from
the reaction of 1b with 2b-OH using TFA (100 mM) or
Sc(OTf)3 (100 mM) catalysis (Table 1, entries 6 and 8). These
FIGURE 1. Yield of TpFPPhl as a function of (A) [TFA] and (B)
[Dy(OTf)3] for reactions of 1b and 2b-OH (2.5 mM each) at room
temperature. The reactions were monitored by HPLC.
maximal yields of TpFPPhl are within the range of yields
typically obtained in porphyrinoid syntheses from dipyr-
romethanedicarbinols. Other key observations are as follows.
(1) The reaction of 1a with 2a-OH provided markedly lower
yields of TpFPPhl than the complementary reaction of 1b with
2b-OH. The difference in yield of TpFPPhl between the two
routes is most pronounced with the mildest acid catalysts (e.g.,
Table 1, entries 4 and 9). While it is not clear why the reaction
of 1b with 2b-OH provides a higher yield of TpFPPhl, it is
clear that the positioning of substituents on the dipyrromethane
and dipyrromethanedicarbinol precursors can significantly im-
pact the outcome of the reaction. (2) The lowest concentration
of acid catalyst affording the maximal yield of TpFPPhl was
quite similar for the two reaction routes in the case of TFA,
InCl3, and Sc(OTf)3 catalysis (e.g., Table 1, entries 1 and 6 for
TFA) and quite different in the case of Yb(OTf)3 and Dy(OTf)3
(e.g., Table 1, entries 4 and 9). Yb(OTf)3 and Dy(OTf)3 are
(28) Lindsey, J. S.; Schreiman, I. C.; Hsu, H. C.; Kearney, P. C.;
Marguerettaz, A. M. J. Org. Chem. 1987, 52, 827-836.
(29) Geier, G. R., III; Lindsey, J. S. J. Org. Chem. 1999, 64, 1596-
1603.
(30) (a) Geier, G. R., III; Lindsey, J. S. J. Chem. Soc., Perkin Trans. 2
2001, 677-686. (b) Geier, G. R., III; Lindsey, J. S. J. Chem. Soc., Perkin
Trans. 2 2001, 687-700. (c) Geier, G. R., III; Lindsey, J. S. J. Porphyrins
Phthalocyanines 2002, 6, 159-185.
(31) The quantity of acid is reported in concentration units of molarity
for convenience of comparison of reaction conditions; however, InCl3, Sc-
(OTf)3, Yb(OTf)3, and Dy(OTf)3 are poorly soluble in CH2Cl2, and the
reaction mixtures were heterogeneous as reported previously.21c
J. Org. Chem, Vol. 72, No. 11, 2007 4087

O’Brien et al.
reasonable catalysts for the reaction of 1b with 2b-OH but poor
catalysts for the other route. (3) The acid concentration providing
the highest yield of TpFPPhl is generally quite high (with the
exceptions found in Table 1, entries 9 and 10). This observation
is consistent with a previous study of reactions of pyrrole with
pentafluorobenzaldehyde leading to the corresponding meso-
substituted porphyrin that found that a 10-fold higher concentra-
tion of acid was required compared to reactions not involving
an electron-deficient aldehyde.32 (4) The effect of acid concen-
tration on the yield of TpFPPhl is similar to that which we have
observed previously in the synthesis of other porphyrinoids.18,26
Stronger acids (e.g., TFA) require more exacting conditions,
whereas the milder acids provided a similar yield of TpFPPhl
regardless of the acid concentration (Figure 1). The concentra-
tion of the milder acids had more of an impact on the rate of
obtainment of the maximal yield of TpFPPhl than on the value
of the maximal yield. (5) The effect of acid concentration on
the yield of TpFPPhl is similar between the two reaction routes,
despite the overall lower yield of TpFPPhl obtained from the
reaction of 1a with 2a-OH. (6) Reaction reversibility was probed
by HPLC and TLC monitoring of the crude reaction mixtures
for the presence of pentafluorophenylporphyrin. The presence
of porphyrin could only come about through reversible processes
(i.e., scrambling). Both reaction routes were found to be resistant
toward reversible processes as only reactions employing high
concentrations of the stronger acids [e.g., TFA (320 mM), InCl3
(32 mM), Sc(OTf)3 (32 and 100 mM)] afforded trace levels of
porphyrin. This finding is consistent with previous studies of
reversibility in porphyrin synthesis which found that oligomers
possessing electron-withdrawing substituents are resistant to
reversible processes.32 There was little difference between the
two reaction routes in regards to the detection of porphyrin
byproduct. The catalysis conditions noted in Table 1 generally
provided TpFPPhl devoid of porphyrin byproduct (exceptions
are entries 3 and 8). In summary, the survey of acid catalysts
revealed conditions affording TpFPPhl in good yield, found that
the reaction route involving 1b and 2b-OH is superior, and
showed that in many respects the reaction of a dipyrromethane
and dipyrromethanedicarbinol leading to TpFPPhl is similar to
analogous reactions leading to other porphyrinoids.
4. Investigation of Oxidation Conditions. While the two-
step, one-flask syntheses of some porphyrinoids are quite
tolerant of a wide range of oxidation conditions (e.g., meso-
aryl substituted porphyrins), others require more exacting
conditions (e.g., meso-aryl substituted corroles18). Thus, to
appropriately monitor reactions leading to TpFPPhl in the survey
of acid catalysis conditions and in subsequent experiments, we
investigated conditions for the oxidation of reaction aliquotss
the effect of the quantity of DDQ oxidant and its application as
a neat, solid or in solution (10 mM in toluene). We initially
explored oxidation conditions prior to performing the survey
of acid catalyst conditions. The reactions of 1a with 2a-OH
and 1b with 2b-OH mediated by Dy(OTf)3 (10 mM) were
performed, and aliquots (1.2 mL) of the reaction mixture were
transferred to quantities of DDQ (0.5, 1.0, 2.0, 4.0, 8.0, 16, or
32 mg) or to quantities of DDQ in solution (equivalent to 0.25,
0.5, and 1.0 mg of DDQ). The oxidized reaction mixtures were
assessed by HPLC and TLC. Later, once the reaction of 1b
with 2b-OH mediated by TFA (100 mM) was found to provide
the highest yield of TpFPPhl, a condensation reaction of 1b
with 2b-OH under TFA catalysis was performed and aliquots
(1.2 mL) were transferred to quantities of DDQ (0.25, 0.5, 1.0,
2.0, 4.0, 8.0, 16, and 32 mg).
For both reaction routes and under either condensation
condition, the highest yield of TpFPPhl was obtained using
1.0 mg of solid DDQ. At both higher and lower quantities of
DDQ, the yield of TpFPPhl decreased and the presence of other
pigments increased. At DDQ quantities of g16 mg, only trace
levels of TpFPPhl were observed. The use of DDQ in toluene
solution afforded TpFPPhl yields about half that obtained from
the use of an equivalent amount of solid DDQ (after adjusting
for dilution due to the toluene). The stoichiometric quantity of
DDQ for the 1.2 mL aliquot is 1.36 mg (2 equiv per reduced
phlorin precursor).33 Thus, the best oxidation conditions identi-
fied from these experiments utilized a little less than the
stoichiometric quantity of DDQ (1.5 equiv). Care was taken in
the survey of acid catalysis conditions and subsequent experi-
ments to dispense 1.00 ( 0.05 mg of DDQ for oxidation of
reaction aliquots prior to HPLC and TLC analysis.
5. Reaction Time Course Experiments. Promising reaction
conditions identified from the survey of acid catalysis condi-
tions34 were performed for the reaction of 1a with 2a-OH and
1b with 2b-OH with monitoring by HPLC and TLC at time
points ranging from 1 min to 24 h. A summary of reaction
conditions investigated and the highest yield of TpFPPhl
observed is provided in Table 2. Representative plots of the
yield of TpFPPhl as a function of condensation time are
provided in Figure 2 (see the Supporting Information for the
complete set of plots).
As with the survey of acid catalysis conditions, the reaction
of 1b with 2b-OH with TFA catalysis (100 mM) provided the
highest yield of TpFPPhl (56%). In this reaction, the maximum
yield of TpFPPhl was obtained quite quickly (∼2 min), and it
remained fairly steady throughout the duration of the experiment
(Figure 2A). The steady yield of TpFPPhl as a function of time
is of practical significance, as it suggests that this reaction need
not be monitored closely to obtain a maximum yield of TpFPPhl.
Other key observations are as follows. (1) The reaction of 1a
with 2a-OH again provided much lower yields of TpFPPhl than
the corresponding reactions of 1b with 2b-OH. (2) Despite the
difference in yield of TpFPPhl between the two reaction routes,
the yield trajectories were quite similar. TFA and InCl3 catalysis
afforded fairly rapid obtainment of the maximum yield of
TpFPPhl, with only a slight decline in yield at long reaction
times. Sc(OTf)3 catalysis provided a more gradual increase in
the yield of TpFPPhl followed by a sharp turnover after the
maximum yield was obtained (Figure 2B). It is interesting that
the two reaction routes had similar reaction yield trajectories,
but ultimately provided very different yields of TpFPPhl. It is
also interesting that the milder acid Sc(OTf)3 provided a more
pronounced turnover in yield than TFA catalysis involving a
(33) This is the same as 2 equiv of DDQ relative to the dipyrromethane
or dipyrromethanedicarbinol starting materials.
(34) The condensation reaction conditions selected from the acid survey
experiments were chosen based on both the yield of TpFPPhl and the
condensation reaction time required to obtain the highest yield of TpFPPhl.
As a result, in some cases, a higher concentration of acid catalyst was
employed in the time course experiments than the minimal concentration
identified in Table 1. For example, reactions of 1b with 2b-OH mediated
by Dy(OTf)3 afforded a similar yield of TpFPPhl regardless of the acid
concentration; however, reactions employing a higher concentration of the
acid proceeded more quickly (Figure 1B). Thus, Table 1 reports 0.32 mM
as the lowest concentration of Dy(OTf)3 providing a near-maximal yield
of TpFPPhl, whereas a concentration of 10 mM was employed in the time
course experiment so that the reaction would be faster.
(32) Geier, G. R., III; Lindsey, J. S. Tetrahedron 2004, 60, 11435-
11444.
4088 J. Org. Chem., Vol. 72, No. 11, 2007

An Electron-Deficient meso-Substituted Phlorin
TABLE 2. Summary of Results from Reaction Time Course
Experimentsa
observed in a subset of the reactions. InCl3 and Sc(OTf)3
catalysis conditions (Table 2, entries 3, 5, and 6) provided trace
levels of porphyrin. This observation is consistent with the
results of the survey of acid catalysis conditions. The best
condition in terms of yield of TpFPPhl (Table 2, entry 4)
afforded TpFPPhl devoid of porphyrin.
% yield of
[acid], mM time, hb TpFPPhl c
entry
reactants
acid
1
2
3
4
5
6
7
8
1a + 2a-OH TFA
100
10
32
100
10
32
0.25
0.5
1
0.033
0.5
0.5
20
14
18
56
45
41
23
21
1a + 2a-OH InCl3
1a + 2a-OH Sc(OTf)3
1b + 2b-OH TFA
Preparative-Scale Synthesis of TpFPPhl. To confirm find-
ings of the analytical-scale experiments and to obtain a sufficient
quantity of TpFPPhl for characterization and stability studies,
preparative-scale reactions were performed. The best reaction
route and condition identified from the analytical-scale reactions
was utilized for the preparative-scale reactions [reaction of 1b
with 2b-OH (2.5 mM each), TFA catalysis (100 mM), in
CH2Cl2 at room temperature followed by oxidation with DDQ
(1.5 equiv)33]. A discussion of an investigation of oxidation
conditions for preparative-scale reactions may be found in
the Supporting Information. Reaction of 1b with 2b-OH on a
0.500 mmol scale was carried out for 15 min prior to the addition
of DDQ. Consistent with analytical-scale reactions, an HPLC
yield of TpFPPhl of 55% was obtained from an aliquot of the
condensation reaction mixture removed immediately prior to
DDQ oxidation of the bulk reaction mixture. After DDQ
addition, triethylamine (5 equiv relative to acid) was added and
the mixture was allowed to stir for 30 min at room temperature.
Analysis of an aliquot of the oxidized reaction mixture by HPLC
provided a yield of TpFPPhl of 48%, indicating fairly effective
oxidation of the bulk reaction mixture. TpFPPhl was isolated
from polar and insoluble byproducts by passage through a silica
pad, washing with CH2Cl2. TpFPPhl was further purified by a
short silica gel column [CH2Cl2/hexanes (1:3) to CH2Cl2]
followed by a short neutral alumina column [CH2Cl2/hexanes
(1:4)] to afford 189 mg, 45% yield. The isolated yield of
TpFPPhl was similar to the yield determined by HPLC after
oxidation of the reaction mixture. The isolated yield of 45%
compares favorably to syntheses of other porphyrinoids via
dipyrromethanecarbinol routes as well as to the recent report
of phlorin-dipyrrin conjugates.10 To obtain TpFPPhl in a form
more easily dispensed, attempts were made to crystallize the
phlorin. This proved to be challenging as TpFPPhl displayed
good solubility in solvents of a wide range of polarities. The
best conditions identified utilized CH2Cl2 and pentane, affording
TpFPPhl as dark green, needle-like crystals (110 mg).
1b + 2b-OH InCl3
1b + 2b-OH Sc(OTf)3
1b + 2b-OH Yb(OTf)3
1b + 2b-OH Dy(OTf)3
3.2
10
0.25
0.25
a The reactions were performed with the indicated reactants (2.5 mM
each) on a 15-18 mL scale in CH2Cl2 at room temperature. The reactions
were monitored from 1 min to 24 h. b The reaction time that first provided
the highest yield of TpFPPhl. c The highest yield of TpFPPhl (HPLC) is
reported.
FIGURE 2. Yield of TpFPPhl as a function of condensation time for
reaction of 1b and 2b-OH (2.5 mM each) in CH2Cl2 at room
temperature under catalysis with (A) TFA (100 mM) or (B) Sc(OTf)3
(32 mM). The reactions were monitored by HPLC. Note the log scale
for time.
Characterization of TpFPPhl. UV-vis spectra characteristic
of phlorins were obtained from the isolated sample of TpFPPhl,
and satisfactory LD-MS and high-resolution FAB-MS data were
1
fairly high concentration of TFA (100 mM).35 (3) The yield
trajectories for the reaction of 1b with 2b-OH with Yb(OTf)3
and Dy(OTf)3 show a gradual increase in the yield of TpFPPhl
with no turnover at long reaction times (Supporting Information).
These trajectories are similar to those observed in dipyr-
romethanecarbinol routes to porphyrins21c and corroles.18 (4)
The yields of TpFPPhl observed in these experiments were
generally similar to those obtained at equivalent time points in
the survey of acid catalysis conditions. Thus, the reactions and
HPLC monitoring were reproducible. (5) Reaction reversibility
as indicated by the presence of porphyrin byproduct was only
obtained. The H NMR spectrum recorded in CDCl3 was in
accordance with expectations with four doublets in the region
of 6.78-7.36 ppm corresponding to the four pairs of nonequiva-
lent â-pyrrole protons, a sharp singlet at 1.47 ppm corresponding
to the six equivalent methyl protons, and a very broad singlet
centered at ∼2.7 ppm corresponding to the N-H protons
(Supporting Information). The downfield location of the N-H
signals relative to aromatic porphyrinoids is consistent with the
absence of overall macrocycle aromaticity as would be expected
1
for a phlorin. The H NMR spectrum recorded in DMSO-d6
again revealed signals for the pairs of nonequivalent â-pyrrole
protons (6.73-7.61 ppm) and the six equivalent methyl protons
(1.63 ppm) (Supporting Information). Interestingly, the signals
for the N-H protons appeared as a pair of much sharper signals
at 6.10 (1H) and 6.89 (2H) ppm, and the N-H protons at 6.89
(35) The cause of the turnover in yield of TpFPPhl under catalysis by
Sc(OTf)3 is not clear. In two-step, one-flask reactions of pyrrole and
benzaldehyde leading to tetraphenylporphyrin, it has been shown that a
turnover in yield of porphyrin is accompanied by the formation of truncated
oligomers.30a Whether similar shunt processes are involved in the Sc(OTf)3-
mediated condensation reaction leading to TpFPPhl is not presently clear.
1
ppm showed coupling in the H NMR and COSY spectra to
two of the pairs of nonequivalent â-pyrrole protons (Supporting
J. Org. Chem, Vol. 72, No. 11, 2007 4089

O’Brien et al.
FIGURE 3. Plots of absorbance as a function of time of exposure to
light for solutions of TpFPPhl in (A) THF (655 nm) and (B) hexanes
(643 nm). Note the difference in time scale for the inset plots.
Information). The assignment of the N-H protons was sup-
ported by the absence of correlations to carbon atoms in the
HMQC spectrum (Supporting Information). The presence of two
distinct N-H signals and coupling with â-pyrrole protons
suggests preference among the possible N-H tautomers of
TpFPPhl when in DMSO solution.
Stability of TpFPPhl. The stability toward light and air of
TpFPPhl in dilute solution was investigated. Similar to our
previous studies of the stability of meso-substituted corroles,18
octaphyrins,26 and phlorins bearing mesityl substituents,20 solu-
tions of TpFPPhl in solvents of varying polarity (hexanes,
toluene, CH2Cl2, THF, ethyl acetate, acetone, acetonitrile, and
methanol) were prepared, and changes in UV-vis spectra were
followed as a function of time of exposure to ambient room
light (i.e., light from conventional overhead fluorescent lighting).
The solutions were monitored closely for 8 h of exposure,
followed by monitoring once a day for a period of 2 weeks.
Plots of TpFPPhl absorbance (∼650 nm) as a function of time
for 8 h and 14 days are shown in Figure 3 for the most stable
solution (THF) and the least stable solution (hexanes) (see
Supporting Information for the complete set of plots). Plots of
overlaid UV-vis spectra for the same solutions at 8 h and 14
days are shown in Figure 4 (see Supporting Information for
the complete set of overlaid spectra).
As shown by the illustrative data, the dilute solutions of
TpFPPhl are quite stable over 8 h of exposure to light and air.
The most stable solution in THF provided better than 99% of
its initial absorbance at 655 nm after 8 h, and even the least
stable solution in hexanes provided 82% of its initial absorbance
at 643 nm (Figure 3). When exposed to light continuously for
longer periods of time, all solutions of TpFPPhl showed gradual
decomposition. Decomposition was generally more rapid in
solvents of lower polarity, though the correlation is not perfect.
The changes observed in the UV-vis spectra of each solution
of TpFPPhl during decomposition were similar but not identical.
FIGURE 4. UV-vis spectra of solutions of TpFPPhl recorded after
exposure to light and air in (A) THF, 0-8 h; (B) hexanes, 0-8 h; (C)
THF, 0-14 days; and (D) hexanes, 0-14 days. The arrows indicate
the direction of the change.
Generally, the overlaid spectra provided fairly clean isobestic
points (e.g., Figure 4D) as was observed in our previous studies
of phlorins bearing mesityl substituents. Light is required for
the observed changes in the UV-vis spectra, as dilute solutions
stored in the dark showed little change in their UV-vis spectra.
In the course of these experiments, the absorbance at the
wavelength selected for monitoring (∼650 nm) did not fall to
zero as degradation products also absorb in this region. Thus,
in some cases, it was difficult to determine exactly when
decomposition of TpFPPhl was complete. To confirm the results
of UV-vis monitoring, fresh solutions were prepared in
hexanes, CH2Cl2, or THF, exposed to light, and the disappear-
ance of TpFPPhl was monitored by HPLC for a period of 2
weeks (see the Supporting Information for plots of peak area
of TpFPPhl as a function of time of exposure to light).
Consistent with the UV-vis monitoring, no change was
observed in the THF or CH2Cl2 solutions in the first 8 h of
4090 J. Org. Chem., Vol. 72, No. 11, 2007

An Electron-Deficient meso-Substituted Phlorin
drying over Na2SO4. The crude product mixture was concentrated,
yielding a reddish solid. Multiple precipitations (3-6 times) of the
crude mixture from CH2Cl2/hexanes afforded purified 2b as a white
crystalline solid (13-29%, 370-830 mg). The range in isolated
yield is largely related to the number of precipitations required for
exposure to light and only a decrease in peak area of 6% was
observed for the hexanes solution. At the end of 2 weeks, the
THF solution contained ∼80% of the original level of TpFPPhl,
the CH2Cl2 solution contained ∼25%, and the hexanes solution
had no detectable TpFPPhl. The half-lives of the TpFPPhl in
CH2Cl2 and hexanes in these experiments were ∼5 and 2.5 days,
respectively.
1
purification of 2b: mp 225 °C decomp; H NMR (DMSO-d6) δ
12.24 (s, 2H), 6.81 (d, J ) 4.0 Hz, 2H), 6.09 (d, J ) 4.0 Hz, 2H),
1.76 (s, 6H); 13C NMR (DMSO-d6) δ 27.3, 36.4, 109.4, 114.3 (t,
J ) 22 Hz), 123.0, 131.3, 137.4 (d, J ) 253 Hz), 141.6 (d, J )
245 Hz), 143.3 (d, J ) 244 Hz), 150.1, 170.9; CI-MS obsd 563
(MH+), calcd 563 (MH+); νmax (thin film)/cm-1 1621. Anal. Calcd
for C25F10O2H12N2: C, 53.40; H, 2.15; N, 4.98. Found: C, 53.53;
H, 2.09; N, 5.06.
The stability of TpFPPhl compares exceptionally well to the
phlorins prepared in our previous study probing the effects of
meso-mesityl substituents.20 The most stable phlorin in that study
underwent noticeable decomposition in all solvents in less than
90 min, and in nonpolar solvents, its half-life was about 10 min.
It is more difficult to compare the stability of TpFPPhl to other
phlorins reported in the literature. In most instances, phlorins
are simply described as being stable or unstable without
elaboration. An investigation of the stability of phlorin-dipyrrin
conjugates bearing sterically bulky and electron-withdrawing
substituents was reported by Gryko and Koszarna.10 However,
decomposition was monitored qualitatively by TLC and ESI-
MS analysis of solutions exposed to light for only up to 10 h.
The solvents employed in their experiments were not specified.
Thus, it is difficult to draw comparisons to TpFPPhl. Overall,
the stability of TpFPPhl is quite good. Under conditions of
normal handling, TpFPPhl is quite stable and no precautions to
avoid exposure to light are required.
HPLC Determination of the Yield of TpFPPhl. Analytical-
scale reactions of 1a with 2a-OH and 1b with 2b-OH were
monitored for the yield of TpFPPhl by adaptation of a literature
method for the analysis of porphyrin, N-confused porphyrin, and
sapphyrin in crude reaction mixtures.29 An aliquot (1.2 mL) of a
condensation reaction mixture was transferred by adjustable pipet
to a 1.8 mL microcentrifuge tube containing DDQ (1.00 mg,
0.00441 mmol), and the mixture was vortex mixed for 2-5 s.
Triethylamine (5 equiv relative to acid) was added. A portion of
the oxidized reaction mixture (1.0 mL) was transferred via
adjustable pipet to a Pasteur pipet filled two-thirds full with silica
gel (∼1.5 g). The sample was eluted with three 1 mL portions of
CH2Cl2, and solvent was driven off the column with a handheld
pipet tool. The eluant was transferred to an autosampler vial and
capped. HPLC analysis was performed with an injection volume
of 1 µL, a normal phase silica column (Alltech, Altima, 4.6 mm ×
250 mm), using an isocratic solvent mixture of 92% hexanes and
8% acetone. The hexanes solvent was water saturated by storing
over water prior to use. The solvent flow rate was controlled as
follows: T ) 0-8 min, 1 mL/min; T ) 8-9 min, linear increase
to 2 mL/min; T ) 9-14 min, 2 mL/min; T ) 14-15 min, linear
decrease to 1 mL/min TpFPPhl eluted at 8.4 min. Detection was
performed at 417 and 435 nm. The limit of detection at either
wavelength was ∼1% yield of TpFPPhl. The yield of TpFPPhl was
determined from the peak area by calibration of the detector
response to TpFPPhl. Representative chromatograms and further
details on the analysis method development, control and reproduc-
ibility experiments, and HPLC calibration may be found in the
Supporting Information.
Survey of Acid Catalysis Conditions. Immediately prior to the
condensation reactions, the diacyl dipyrromethane [2a (175 mg,
0.250 mmol) or 2b (141 mg, 0.250 mmol)] was reduced to the
corresponding dipyrromethanedicarbinol (2a-OH or 2b-OH) with
NaBH4 (0.475 g, 12.5 mmol) in THF/methanol (20 mL, 3:1)
following a literature procedure.21b The reduction reactions were
monitored by TLC [2a, alumina, EtOAc/hexanes (1:1); 2b alumina,
EtOAc/CH2Cl2 (1:1)]. After being dried under vacuum for 30 min,
the dicarbinol was dissolved in CH2Cl2 and transferred to a
100 mL volumetric flask. Dipyrromethane 1a (43.6 mg, 0.250
mmol) or 1b (78.1 mg, 0.250 mmol) was added to the flask, and
volume was brought to the mark by adding CH2Cl2. Reactions were
performed at room temperature in tightly capped 20 mL vials that
were stirred with a micro stir bar. Solid acids were weighed into
all reaction vials prior to the beginning of the reaction sequence
for the day, and each reaction was initiated by the addition of 5-
10 mL of the reactant solution via volumetric pipet. Reactions
involving TFA were initiated by the addition of TFA to reaction
vials already containing 5 mL of the reactant solution. The reactions
were monitored by HPLC at 0.25, 1, and 4 h as described above.
TLC was performed on the crude, oxidized mixture [silica,
CH2Cl2/hexanes (1:1)].
Conclusions
Two complementary dipyrromethane + dipyrromethanedi-
carbinol routes to a meso-substituted phlorin bearing electron-
withdrawing pentafluorophenyl substituents were investigated.
Although the reaction routes were similar in regards to the best
conditions for acid catalysis and the reaction time course
trajectories, they were quite different in terms of the maximum
yield of TpFPPhl. The substantially different yields of TpFPPhl
provided by the two routes demonstrate that the placement of
substituents in the precursors can have a profound effect on the
outcome of the reaction. Using the superior route of the reaction
of 1b with 2b-OH under TFA catalysis (100 mM), TpFPPhl
could be obtained relatively efficiently on a good scale. Dilute
solutions of TpFPPhl were found to be quite resistant toward
degradation upon exposure to light and air, with solutions in
polar solvents being generally more stable than solutions in
nonpolar solvents. The preparation of a phlorin of practical
stability provides encouragement for further studies of the
stabilization of phlorin via peripheral meso-substituents, and the
efficient synthesis of TpFPPhl will facilitate the detailed study
of additional properties and coordination chemistry of meso-
substituted phlorins.
Experimental Section
5,5-Dimethyl-1,9-bis(pentafluorobenzoyl)dipyrromethane (2b).
Following a general diacylation procedure from the literature,21b
ethyl magnesiumbromide (25.0 mL, 250 mmol, 1 M in THF) was
added dropwise over 15 min to a solution of 5,5-dimethyldipyr-
romethane 1a (0.871 g, 5.00 mmol) in dry toluene (100 mL) under
argon. The reaction mixture was stirred for 30 min at room
temperature, and a solution of pentafluorobenzoylchloride (1.80 mL,
12.5 mmol) in dry toluene (12.5 mL) was added dropwise over
10 min. The reaction mixture was stirred for 30 min at room
temperature. The reaction was quenched by addition of saturated
aqueous NH4Cl (75 mL). The organic layer was separated and
washed with water (50 mL) and then brine (50 mL) followed by
Reaction Time Course Experiments. Reaction monitoring as
a function of time was performed as described above for the survey
of acid catalysis conditions with the exception of using a 15-
18 mL reaction volume. The reactions were monitored by HPLC
as described above for yield of TpFPPhl at 1, 2, 4, 8, 15, and
J. Org. Chem, Vol. 72, No. 11, 2007 4091

O’Brien et al.
30 min, and 1, 2, 4, 8, and 24 h. TLC was performed on the crude,
oxidized mixture [silica, CH2Cl2/hexanes (1:1)].
the intensity of the visible band (642-655 nm). Data were
normalized with respect to the maximum absorbance in the visible
range prior to exposure to light. As a control, an analogous
experiment was performed with solutions of TpFPPhl (CH2Cl2 and
hexanes) maintained in the dark.
TpFPPhl Stability Experiments (HPLC). In a darkened lab,
solutions of TpFPPhl were prepared in hexanes, CH2Cl2, and THF.
The concentration of each solution was adjusted so that the initial
peak area was between 150 and 300 area units. The samples were
analyzed in the dark by HPLC using the same analysis parameters
as described above for analysis of oxidized reaction mixtures, and
then the solutions were exposed to light (conventional overhead
fluorescent lighting). Chromatograms were recorded at 15 min, 1,
2, 4, 6, and 8 h, and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13, and 14 days
of continuous exposure to room lights. Decomposition of TpFPPhl
was inferred by a decline in the peak area.
5,5-Dimethyl-10,15,20-tris(pentafluorophenyl)phlorin,
TpFPPhl (3). The reduction of 2b (281 mg, 0.500 mmol) with
NaBH4 (946 mg, 25.0 mmol) in THF/methanol (40 mL, 3:1)
afforded the corresponding dicarbinol 2b-OH which was used
without purification. The dicarbinol was dried under vacuum for
30 min and then immediately subjected to condensation with 1b
(156 mg, 0.500 mmol) in the presence of TFA (1.54 mL, 20.0
mmol) in CH2Cl2 (200 mL) for 15 min at room temperature.
Immediately before oxidation, an aliquot (1.2 mL) of the condensa-
tion reaction was removed for HPLC analysis. Oxidation of the
remainder of the reaction was carried out by the addition of DDQ
(167 mg, 0.730 mmol) at room temperature. After 5 min, triethyl-
amine (14 mL, 100 mmol) was added and the mixture was stirred
at room temperature for a further 30 min. An aliquot (1.2 mL) of
the oxidized reaction mixture was removed for HPLC analysis. The
remaining reaction mixture was filtered through a pad of silica gel
and eluted with CH2Cl2 until the eluant was no longer green. The
filtrate was concentrated and adsorbed onto silica gel (10 g),
concentrated to dryness, and purified by chromatography [silica,
CH2Cl2/hexanes (1:3, 1:2, 1:1, 3:2, 2:1, and 3:1)]. To remove a
low level of residual impurities, the sample was adsorbed onto
alumina (15 g) and purified by chromatography [alumina, CH2Cl2/
hexanes (4:1)] affording TpFPPhl, 3 (189 mg, 45%) that was
subsequently crystallized from CH2Cl2/pentane providing dark green
crystals (110 mg): λabs (toluene, ꢀ × 103) 358 (33.3), 417 (46.2),
Acknowledgment. Support for this work was provided by
the National Science Foundation under Grant Nos. 0517882 and
0310521. Acknowledgment is made to the donors of The
Petroleum Research Fund, administered by the American
Chemical Society, for partial support of this research. We thank
Tim LeSaulnier for performing preliminary experiments. High-
resolution FAB mass spectra were obtained at the Mass
Spectrometry Laboratory for Biotechnology at North Carolina
State University. Partial funding for the facility was obtained
from the North Carolina Biotechnology Center and the National
Science Foundation.
1
438 (52.7), 654 (30.4); H NMR (CDCl3) δ 1.47 (s, 6H), 2.70 (br
s, 3H), 6.78 (d, J ) 3.9 Hz, 2H), 6.95 (d, J ) 3.9 Hz, 2H), 7.12 (d,
J ) 5.0 Hz, 2H), 7.36 (d, J ) 5.0 Hz, 2H); (DMSO-d6) δ 1.63 (s,
6H), 6.10 (s, 1H), 6.73 (dd, J ) 2.3, 3.6 Hz, 2H), 6.89 (s, 2H),
7.09 (dd, J ) 2.0, 3.4 Hz, 2H), 7.35 (d, J ) 5.0 Hz, 2H), 7.61 (d,
J ) 5.0 Hz, 2H); LD-MS obsd 838.1 (M+); HRMS (FAB) 838.1236
(M+), calcd 838.1214 (M+) (C40H17F15N4).
Supporting Information Available: General experimental
methods; discussion of the HPLC method development, control
experiments, reproducibility, and calibration; representative chro-
matograms of reaction mixtures; plots of yield of TpFPPhl as a
function of acid concentration; plots of yield of TpFPPhl as a
function of condensation reaction time; investigation of oxidation
conditions for preparative-scale syntheses of TpFPPhl; plots of
absorbance of TpFPPhl as a function of exposure to light; overlaid
UV-vis spectra recorded from solutions of TpFPPhl exposed to
light, plots of HPLC peak area of TpFPPhl as a function of time of
exposure to light; 1H NMR spectrum of 2b; and 1H NMR, COSY,
and HMQC spectra of TpFPPhl 3. This material is available free
of charge via the Internet at http://pubs.acs.org.
TpFPPhl Stability Experiments (UV-Vis).20 In a darkened lab,
solutions of TpFPPhl were prepared in hexanes, toluene, CH2Cl2,
THF, ethyl acetate, acetone, acetonitrile, and methanol. The
concentration of each solution was adjusted so that the maximum
absorbance in the visible range (642-655 nm) was between 0.5
and 0.9. UV-vis spectra were recorded in the dark, and then the
solutions were exposed to room lights (conventional overhead
fluorescent lighting). Spectra were recorded at 15, 30, and 45 min,
1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 h, and 1, 1.5, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, and 14 days of continuous exposure to room
lights. Decomposition of TpFPPhl was inferred from changes in
JO070216K
4092 J. Org. Chem., Vol. 72, No. 11, 2007