Effect of carbinol group placement on complementary reactions of dipyrromethane+bipyrrole species leading to corrole and/or an octaphyrin

Article abstract of DOI:10.1016/j.tet.2008.08.025

Complementary reactions of a dipyrromethanedicarbinol+2,2′-bipyrrole and a 2,2′-bipyrroledicarbinol+a dipyrromethane were investigated to determine the effect of carbinol group placement on the product distribution and on the broader reaction course. Analytical-scale reactions were performed for both reactions to explore the interplay of acid catalyst, acid concentration, and solvent on the yield of corrole and an octaphyrin. The two reaction routes were further compared under representative conditions by assessing acid-catalyzed decomposition of the dicarbinol species affording benzaldehyde (TLC and GC-MS) and by performing time course experiments monitoring macrocycle yield (UV-vis), presence of benzaldehyde (TLC), and oligomer composition (LD-MS). The complementary reactions were generally found to be quite different. Key to this work was the refinement of a method for the acylation of 2,2′-bipyrrole.

Full text of DOI:10.1016/j.tet.2008.08.025

Tetrahedron 64 (2008) 9828–9836
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Effect of carbinol group placement on complementary reactions
of dipyrromethaneþbipyrrole species leading to corrole
and/or an octaphyrin
*
Kara C. Braaten, Darcy G. Gordon, Michael M. Aphibal, G. Richard Geier, III
Department of Chemistry, Colgate University, Hamilton, NY 13346, USA
a r t i c l e i n f o
a b s t r a c t
Complementary reactions of a dipyrromethanedicarbinolþ2,20-bipyrrole and a 2,20-bipyrroledicarbinolþa
dipyrromethane were investigated to determine the effect of carbinol group placement on the product
distribution and on the broader reaction course. Analytical-scale reactions were performed for both
reactions to explore the interplay of acid catalyst, acid concentration, and solvent on the yield of corrole and
an octaphyrin. The two reaction routes were further compared under representative conditions by
assessing acid-catalyzed decomposition of the dicarbinol species affording benzaldehyde (TLC and GC–MS)
and by performing time course experiments monitoring macrocycle yield (UV–vis), presence of benzal-
dehyde (TLC), and oligomer composition (LD-MS). The complementary reactions were generally found to
be quite different. Key to this work was the refinement of a method for the acylation of 2,20-bipyrrole.
Ó 2008 Elsevier Ltd. All rights reserved.
Article history:
Received 9 May 2008
Received in revised form 5 August 2008
Accepted 7 August 2008
Available online 12 August 2008
Keywords:
Dipyrromethanedicarbinol
Bipyrroledicarbinol
Corrole
[34]Octaphyrin(1.1.1.0.1.1.1.0)
1. Introduction
octaphyrin is an interesting molecule given its chiral, figure eight
structure and the presence of two metal binding sites.6
Porphyrinoids with core structures altered relative to porphyrin
are of interest.1 Such species offer synthetic challenges and display
interesting and potentially useful properties. One core alteration of
particular note is the presence of one or more direct bipyrrole
linkage(s) as exemplified in porphyrinoids such as corrole, sap-
phyrin, rubyrin, and rosarin (Fig. 1). Within this family of macro-
cycles, the core dimensions, planarity, and extent of conjugation
varydaffording molecules with distinct properties. For example,
corrole is known to stabilize metal ions in high oxidation states,2
and sapphyrin in its diprotonated form binds anions.3 Continued
progress in studies of porphyrinoids with bipyrrole linkages is
aided by the further development of synthetic methodology. This
effort is in turn assisted by insights into the reactivity of potential
building block molecules and a further understanding of the effect
of reaction parameters.
The motivations for our prior study were to determine whether
reactions involving unsubstituted 2,20-bipyrrole also predominately
afforded the octaphyrin, to examine whether the product distribu-
tion could be influenced by the choice of solvent, acid catalyst, cat-
alyst quantity, and reaction time, and to develop a practical method
for the preparation of meso-substituted corrole and/or the octa-
phyrin. We found that under nearlyall reaction conditions surveyed,
N
H
NH
N
N
N
NH HN
sapphyrin
NH HN
corrole
Previously, we investigated the reaction of a dipyrromethane-
dicarbinol 2-OH with a b
-unsubstituted 2,20-bipyrrole 3 leading to
meso-triphenylcorrole (TPC, 5) or meso-hexaphenyl[34]octa-
phyrin(1.1.1.0.1.1.1.0) (HPO, 6) (Scheme 1, reaction of 2-OHþ3).4 This
work was inspired, in part, by an earlier report by Vogel and co-
NH
N
N
H
N
H
N
N
N
HN
workers on the reaction of a
b
-substituted 2,20-bipyrrole species,
H
H
N
H
N
which led to a
b
-substituted octaphyrin rather than corrole.5 The
N
N
rubyrin
rosarin
* Corresponding author. Tel.: þ1 315 228 6795; fax: þ1 315 228 7935.
E-mail address: ggeier@mail.colgate.edu (G.R. Geier III).
Figure 1. Structures of porphyrinoids bearing bipyrrole linkages.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.025

K.C. Braaten et al. / Tetrahedron 64 (2008) 9828–9836
9829
H
Ph
about the bipyrrole linkage in polar solvents. Additionally, in-
vestigation of the complementary reactions would provide further
insight toward the application of bipyrroledicarbinol species in
porphyrinoid synthesis.
HN
NH
2-OH
Ph
Ph
OH
HO
In the present work, we performed a comparative study of the
reaction of a dipyrromethanedicarbinol 2-OHþ2,20-bipyrrole 3 and
the complementary reaction of a 2,20-bipyrroledicarbinol 4-OHþa
dipyrromethane 1. The interplay of acid catalyst, acid concentra-
tion, and solvent was compared in a survey of catalysis conditions.
Under representative conditions identified from the survey, the
propensity of each dicarbinol species to undergo acid-catalyzed
decomposition leading to benzaldehyde was examined. Using the
same representative conditions, the two reaction routes were fur-
ther compared in time course experiments with monitoring for
macrocycle yield (UV–vis), presence of benzaldehyde (TLC), and
overall oligomer composition (laser desorption mass spectrometry,
LD-MS). Taken together, the comparison of the two reaction routes
provides insights toward the reactivity of building block molecules
with complementary carbinol group placement.
+
H
N
H
N
3
1. acid
2. [O]
Ph
NH
N
TPC
5
Ph
Ph
NH HN
+
Ph
Ph
Ph
2. Results and discussion
HN
HN
NH
NH
N
N
2.1. Preparation of building block molecules
HPO
6
Ph
Ph
N
N
5-Phenyldipyrromethane 1,8 1,9-bis(benzoyl)-5-phenyldipyrro-
methane 2,9 and 2,20-bipyrrole 39 were prepared in accordance
with the literature procedures. Dipyrromethanedicarbinol 2-OH
was prepared freshly via reduction of 2 with NaBH4 and used
without purification.9
Ph
1. acid
2. [O]
To prepare the required bipyrroledicarbinol 4-OH, we sought to
diacylate 3 to afford the diacylbipyrrole 4, which would then be
reduced with NaBH4 to the dicarbinol (Scheme 2). Key to this approach
was the identification of a method for the diacylation of 3. While
there are many examples of the diacylation of 2,20-bipyrroles bear-
H
Ph
1
NH HN
+
ing
b
-substituents,10 there are fewer examples of diacylation of 3.11
OH
HO
The acylation of unsubstituted 2,20-bipyrrole 3 is potentially prob-
H
N
H
N
Ph
Ph
lematic as acylation may take place at the available
a
and
b
positions.
4-OH
Scheme 1. Complementary reactions of dipyrromethaneþbipyrrole species leading to
NaBH4
corrole and/or an octaphyrin.
Ph
Ph
N
H
N
H
4-OH
3
O
O
HPO was obtained over TPC. A number of conditions were identified
in analytical-scale reactionsthat affordedHPO inyields of w20%. The
best of these conditions provided an isolated yield of 25% on a pre-
parative scale. The production of the octaphyrin over corrole in the
work of Vogel and co-workers and in our own is consistent with the
known energetic preference for the anti conformation of 2,20-
bipyrrole (Fig. 2).7 The lower energy anti orientation is found in both
bipyrrole units of the octaphyrin whereas corrole requires a syn
orientation about the bipyrrole linkage. Although the anti and syn
conformations of 2,20-bipyrrole differ in their net dipole moments,
we found that the distribution of the corrole and octaphyrin prod-
ucts was not impacted by solvent polarity.
Given the results of our previous study, we wondered how the
complementary reaction of a 2,20-bipyrroledicarbinol 4-OH with
a dipyrromethane 1 might compare to the reaction of 2-OHþ3 in
terms of product distribution and the broader reaction course
(Scheme 1, reaction of 4-OHþ1). Placement of the polar carbinol
groups on the bipyrrole species might perturb the conformation
4
Scheme 2. Synthesis of 2,20-bipyrroledicarbinol 4-OH.
Of the various acylation methods previously applied to bipyr-
roles,10,11 dipyrromethanes,12 and/or pyrrole,13 we explored Friedel–
Crafts, Grignard, and Vilsmeier–Haack conditions. Analytical-scale
reactions were performed and the crude reaction mixtures were
assessed by 1H NMR spectroscopy. Vilsmeier–Haack condi-
tions (POCl3, N,N-dimethylbenzamide) employed by Vogel and co-
workers11 for the diacetylation of 3 to yield diacetyl, dipropionyl,
and dibutyryl 2,20-bipyrroles gave the best result. Direct application
of their method afforded 4 and a monoacyl bipyrrole (5-benzoyl-
2,20-bipyrrole) in a ratio of 1.0:5.7. Further refinement (increase of
reaction time and equivalents of POCl3 and amide) improved the
ratio to 1.0:0.031 (Supplementary data). 1H NMR analysis of the
crude reaction mixture revealed only the presence of a low level of
monoacyl bipyrrole and unreacted N,N-dimethylbenzamide in
addition to 4. Nevertheless, purification of 4 was complicated by its
poor solubility in most common organic solvents. Addition of a hot
DMSO solution of the crude reaction mixture to hot iPrOH was
found to precipitate 4 in good purity. 1H NMR analysis of purified 4
revealed only a low level of DMSO and iPrOH solvent impurity that
could not be removed by prolonged heating under vacuum.
H
N
N
H
N
H
N
H
syn
anti
The poor solubility of 4 was expected to complicate the re-
duction of 4 to 4-OH. Indeed, 4 was only partially soluble in the
Figure 2. syn and anti conformations of 2,20-bipyrrole.

9830
K.C. Braaten et al. / Tetrahedron 64 (2008) 9828–9836
THF/MeOH solvent mixture customarily used in the reduction of
diacyl species.12a Fortunately, 4-OH displayed good solubility in the
solvent mixture so that by extending the reaction time and pro-
viding additional NaBH4 the reduction went to completion as
judged by TLC, IR, and 1H NMR analyses. As is customary in related
dipyrromethanedicarbinol chemistry,12a 4-OH was used without
extensive purification.
complementary reactions under identical conditions were different
(the exception being a small number of conditions that failed to
provide TPC or HPO from either reaction route). Most commonly,
reaction conditions that afforded HPO or HPO and TPC from
2-OHþ3 failed to provide HPO or TPC from 4-OHþ1 (e.g., entries 3,
5, and 7). Conditions that did afford HPO from both reaction routes
generally provided a lower level of HPO from 4-OHþ1 (e.g., entries
1, 4, and 6). Interestingly, a subset of conditions afforded HPO from
2-OHþ3 and TPC from 4-OHþ1 (e.g., entries 2, 8–10). TPC was most
commonly observed from reactions of 4-OHþ1 carried out in the
most polar solvent, acetonitrile. No reaction of 4-OHþ1 in aceto-
nitrile produced HPO and no reaction of 2-OHþ3 in acetonitrile
produced TPC. Yields of HPO similar to the highest values obtained
in CH2Cl2 from our previous study of 2-OHþ3 could be obtained
from toluene/THF (4:1) and CH2Cl2/THF (9:1) under appropriate
catalytic conditions (e.g., entry 1). A number of reaction conditions
produced low levels of TPP from both reaction routes, though about
twice as many reactions of 4-OHþ1 provided detectable TPP. TPP
was typically observed at the longest time point of 4 h, after HPO
and/or TPC had already been observed. Reversible processes lead-
ing to the formation of TPP were most prevalent in acetonitrile and
least prevalent in THF.
2.2. Solubility of the 2,20-bipyrroledicarbinol 4-OH
Given the poor solubility of 4, the solubility of 4-OH was ex-
amined in the solvent systems employed in our prior study of the
reaction of 2-OHþ3 (toluene, CH2Cl2, THF, and acetonitrile).4
Solutions of 4-OH at the required concentration of 2.5 mM could be
obtained from THF and acetonitrile, but not from toluene and
CH2Cl2. Thus, the solubility of 4-OH in toluene and CH2Cl2
containing a minimal level of THF or acetonitrile was explored.
Solutions could be obtained in toluene/THF (4:1) and CH2Cl2/THF
(9:1) mixtures. A small number of trial reactions of 2-OHþ3 were
carried out in toluene/THF (4:1) and CH2Cl2/THF (9:1) mixtures, and
meaningful results were obtained in terms of yields of TPC and HPO
relative to reactions previously carried out in toluene, CH2Cl2, or
THF. Thus, for the comparative study of 2-OHþ3 and 4-OHþ1, tol-
uene/THF (4:1), CH2Cl2/THF (9:1), THF, and acetonitrile were used.
Overall, the survey of catalyst conditions revealed that place-
ment of the carbinol groups on the bipyrrole rather than on the
dipyrromethane and choice of solvent have a profound effect on the
product distribution. In particular, conditions were identified
where the two reaction routes provided entirely different macro-
cyclic products.
2.3. Survey of catalysis conditions
The effect of key reaction parameters (acid catalyst, acid con-
centration, and solvent) on the complementary reactions of
2-OHþ3 (dipyrromethanedicarbinol route) and 4-OHþ1 (bipyrro-
ledicarbinol route) was examined in a survey of catalysis conditions.
Analytical-scale reactions were performed using five different acid
catalysts [TFA, InCl3, Sc(OTF)3, Yb(OTf)3, and Dy(OTf)3], at five dif-
ferent concentrations (0.32, 1.0, 3.2, 10, and 32 mM),14 in the four
different solvents stated above. The acids selected for this study
were those examined in our prior investigation of the reaction of
2-OHþ3.4 These acids have also been previously employed in
the syntheses of a variety of porphyrinoids from dicarbinol
species.9,15–17 Solvents were selected to afford a range of polarities
while considering the solubility of 4-OH. Each reaction was moni-
tored for the yield of TPC and HPO (UV–vis) at reaction times of 0.25,
1, and 4 h in accordance with our earlier study.4 In addition, UV–vis
analysis was also used to detect tetraphenylporphyrin (TPP), which
could arise from reversible processes.
2.4. Acid-catalyzed decomposition of dicarbinol species
leading to benzaldehyde
The contrasting yields of HPO and TPC provided by the com-
plementary reactions in the survey of catalysis conditions may have
a variety of underlying causes. Previously, Setsune and Maeda
reported acid-catalyzed decomposition of
a
b-substituted
bipyrroledicarbinol leading to benzaldehyde (Scheme 3).18 To the
best of our knowledge, such decomposition of dipyrromethane-
carbinol species has not been reported. Furthermore, detailed studies
of pyrroleþaldehyde reactions leading to tetraarylporphyrins did not
detect reversion of oligomeric species to benzaldehyde.19 Thus, it
occurred to us that the contrasting yields of HPO and TPC noted in
the survey of catalysis conditions could stem from differential
acid-catalyzed decomposition of 2-OH and 4-OH. An assessment of
acid-catalyzed decomposition of 2-OH and 4-OH leading to benzal-
dehyde would provide insight into the generality of this
phenomenon.
The survey of catalysis conditions revealed sharp differences
between the two complementary reactions. Representative data
are provided in Table 1 (see Supplementary data for additional
results). Generally, the yields of TPC and HPO provided by the
Table 1
Comparison of macrocycle yields from the reactions of 2-OHþ3 (dipyrromethanedicarbinol route) and 4-OHþ1 (bipyrroledicarbinol route) from representative conditions
examined in the survey of catalysis conditionsa
Entry
Solvent
Acid
[Acid], mM
2-OHþ3
% Yield of HPOb
4-OHþ1
% Yield of HPOb
% Yield of TPCb
% Yield of TPPb
% Yield of TPCb
% Yield of TPPb
1
2
3
4
5
6
7
8
9
10
CH2Cl2/THF (9:1)
CH2Cl2/THF (9:1)
THF
THF
THF
TFA
Sc(OTf)3
TFA
Sc(OTf)3
Dy(OTf)3
Dy(OTf)3
TFA
Yb(OTf)3
Dy(OTf)3
Dy(OTf)3
10
1.0
1.0
1.0
0.32
32
0.32
1.0
0.32
1.0
18
7.4
15
8.6
8.1
7.0
11
7.5
7.5
6.7
dc
d
8.4
d
d
d
d
d
d
d
d
1.4
d
d
d
d
d
d
d
d
1.8
d
d
2.1
d
2.3
d
d
d
d
d
d
1.8
d
3.0
d
d
d
d
d
THF
d
d
MeCN
MeCN
MeCN
MeCN
d
d
8.6
4.8
8.7
5.2
3.2
5.7
a
The reactions were performed with the indicated reactants (2.5 mM each) on a 5–10 mL scale at room temperature. The reactions were monitored at 0.25, 1, and 4 h.
The highest yield (UV–vis) at any of the three time points is reported.
Not detected.
b
c

K.C. Braaten et al. / Tetrahedron 64 (2008) 9828–9836
9831
levels of benzaldehyde from the decomposition of 2-OH generally
afforded the highest yields of HPO in reactions of 2-OHþ3 (entries
1, 3, and 7). Conditions that gave rise to some decomposition of 4-
OH provided the highest yield of TPC from the reaction of 4-OHþ1
(entries 8–10).
O
acid
+
Ph
Ph
N
H
N
H
N
H
N
H
Ph
H
OH
HO
Given the importance of dipyrromethanedicarbinol species
in the preparation of a variety of porphyrinoids,15–17,20 the sus-
ceptibility of dipyrromethanedicarbinol 2-OH to acid-catalyzed
decomposition was examined under additional conditions of rele-
vance to porphyrinoid synthesis. Reactions were performed in
CH2Cl2 with catalysis by InCl3 (0.32 mM), Sc(OTf)3 (0.32, 1.0 mM),
Yb(OTf)3 (3.2, 10 mM), or Dy(OTf)3 (1.0, 10 mM), or in acetonitrile
with TFA (30 mM). Under all conditions involving CH2Cl2, uniformly
moderate levels of benzaldehyde (30–40%) were detected. The re-
action in acetonitrile provided a lower level of benzaldehyde (8%). It
is interesting that a moderate level of decomposition of 2-OH was
observed in the reactions carried out in CH2Cl2 as these conditions
generally provide good yields of porphyrin when applied to the
Scheme 3. Acidolysis of a bipyrroledicarbinol leading to benzaldehyde.
To investigate the acid-catalyzed decomposition of 2-OH or 4-
OH, the dicarbinol species were treated under the conditions of
Table 1 and monitored from 5 min to 4 h. This subset of reaction
conditions captures the major trends observed from the broader
survey of catalysis conditions. At each time point, the level of
benzaldehyde was estimated by TLC analysis as described by
Lindsey and co-workers.19 A subset of samples were also assessed
by GC–MS. TLC and GC–MS results were generally in good agree-
ment. Control samples of 2-OH or 4-OH were monitored in the
absence of acid catalyst, and low levels of benzaldehyde (ꢀ5%) were
detected by TLC and GC–MS analyses (presumably from de-
composition on the silica TLC plate or in the GC injector). Data
obtained from the dicarbinol species treated with acid were cor-
rected for the low level of benzaldehyde detected in the control
samples.
The results of this study are summarized in Table 2. A low level
of benzaldehyde was detected from both dicarbinol species. How-
ever, benzaldehyde was detected in larger quantity and under
a wider range of reaction conditions from 2-OH. When observed,
acid-catalyzed decomposition occurred rapidly. The maximum
level of benzaldehyde was obtained by reaction times of 5–15 min,
and there was little additional change at longer time points.
Interpretation of these results is complicated as benzaldehyde
generated from acid-catalyzed decomposition may, under some
conditions, react further with other species generated during the
reaction. Thus, the level of benzaldehyde detected in these exper-
iments may understate the actual level of decomposition of 2-OH
and 4-OH. Minimally, it is clear that acid-catalyzed decomposition
takes place for both dicarbinol species under some reaction con-
ditions. Additionally, differential decomposition does not appear to
account for the generally higher macrocycle yields obtained from
the reaction of 2-OHþ3 in the survey of catalysis conditions as
2-OH rather than 4-OH was found to be more susceptible to
decomposition. The level of dicarbinol decomposition did correlate
with some aspects of the macrocycle yield data from the survey of
catalysis conditions. Reaction conditions that provided the lowest
reactions of a dipyrromethaneþa dipyrromethanedicarbinol.15
A
subset of these conditions also provide good yields of HPO from the
reaction of 2-OHþ3.4 It is clear that the potential for a reaction
condition to facilitate decomposition of the dicarbinol species does
not preclude application of the reaction condition toward macro-
cycle formation. There are likely multiple factors at play such as the
relative rate of decomposition compared to the rates of reactions
leading to the desired product. Nevertheless, the potential for at
least a low level of dicarbinol decomposition should be considered
in attempts to more fully understand porphyrin forming reactions
that make use of carbinol speciesdeven when mild acid catalysts
are employed.
2.5. Reaction time course experiments
To broadly compare the reactions 2-OHþ3 and 4-OHþ1 so as to
further investigate the contrasting yields of HPO and TPC observed
from the complementary reactions in the survey of catalysis
conditions, time course experiments were performed under the
representative reaction conditions of Table 1. Reactions were
monitored from 1 min to 24 h for yield of HPO, TPC, and TPP (UV–
vis), yield of benzaldehyde from acid-catalyzed decomposition
(TLC), and the overall oligomer composition (LD-MS). Detailed
monitoring as a function of time facilitates further examination of
conclusions drawn from the more limited sampling utilized in the
survey of catalysis conditions. The monitoring of species in addition
to HPO, TPC, and TPP allows correlation of macrocycle yields with
the presence of other byproducts.
The yield of HPO, TPC, and TPP observed from the time course
experiments (Table 3) mirrored results from the survey of catalysis
conditions. Thus, trends in macrocycle yields noted from the survey
of catalysis conditions were not artifacts of the selection of time
points. Again, three general scenarios were observed: (1) reaction
of 2-OHþ3 provided HPO or both HPO and TPC whereas neither
were obtained from reaction of 4-OHþ1 (entries 3, 5, and 7), (2)
both reactions provided HPO, albeit at a lower level for reaction of
4-OHþ1 (entries 1, 4, and 6), and (3) reaction of 2-OHþ3 provided
HPO whereas TPC was obtained from the reaction of 4-OHþ1
(entries 2, 8–10). It is again interesting that in the most polar sol-
vent, reaction of 2-OHþ3 provided HPO whereas 4-OHþ1 provided
TPC. This observation is consistent with the polar carbinol groups of
the bipyrroledicarbinol impacting the conformation about the
bipyrrole linkage in polar solvents.
Table 2
Comparison of the level of benzaldehyde from acidolysis of dipyrromethane-
dicarbinol 2-OH and bipyrroledicarbinol 4-OHa
Entryc
% Yield of benzaldehydeb
From 2-OH
From 4-OH
1
2
3
4
5
6
7
8
9
10
dd
12
d
10
10
10
4
18
18
18
d
d
d
d
d
d
d
4
4
4
a
The reactions were performed with the indicated dicarbinol species (2.5 mM
each) on a 3 mL scale at room temperature. The reactions were monitored at 0.083,
0.25, 0.5, 1, 2, and 4 h.
The reaction conditions for each entry are the same as those found in Table 1.
The highest yield (TLC) at any of the time points is reported. The yield values are
corrected for the low level of benzaldehyde observed in control samples not treated
with acid catalyst.
b
Representative yield trajectories as a function of time are shown
in Figure 3 for a condition that afforded HPO from the reaction of 2-
OHþ3 and TPC from the reaction of 4-OHþ1 (see Supplementary
data for the complete set of plots). In both reactions, the yield of
HPO (2-OHþ3) or TPC (4-OHþ1) increased, reached a maximum,
c
d
The level of benzaldehyde did not exceed the background level detected in the
control.

9832
K.C. Braaten et al. / Tetrahedron 64 (2008) 9828–9836
Table 3
Summary of macrocycle yields from the reaction time course experiments of 2-OHþ3 (dipyrromethanedicarbinol route) and 4-OHþ1 (bipyrroledicarbinol route)a
Entry
Solvent
Acid
[Acid], mM
2-OHþ3
% Yield of HPOb
4-OHþ1
% Yield of HPOb
% Yield of TPCb
% Yield of TPPb
% Yield of TPCb
% Yield of TPPb
1
2
3
4
5
6
7
8
9
10
CH2Cl2/THF (9:1)
CH2Cl2/THF (9:1)
THF
THF
THF
TFA
Sc(OTf)3
TFA
Sc(OTf)3
Dy(OTf)3
Dy(OTf)3
TFA
Yb(OTf)3
Dy(OTf)3
Dy(OTf)3
10
1.0
1.0
1.0
0.32
32
0.32
1.0
0.32
1.0
18
4.9
15
9.2
8.7
5.7
12
6.7
7.3
6.6
dc
d
7.5
d
d
d
d
d
d
d
d
2.1
d
d
1.9
d
1.7
d
d
d
d
d
d
1.8
d
3.1
d
4.7
d
d
d
d
d
d
d
THF
d
d
d
MeCN
MeCN
MeCN
MeCN
d
d
d
1.8
0.7
1.4
9.3
9.8
8.7
5.5
5.4
4.9
a
The reactions were performed with the indicated reactants (2.5 mM each) on a 5–10 mL scale at room temperature. The reactions were monitored from 1 min to 24 h.
The highest yield (UV–vis) at any of the time points is reported.
Not detected.
b
c
A
The level of benzaldehyde was generally low (4–10%) for both
25
reaction routes under all conditions. The low level of benzaldehyde
was typically obtained by 1 min time point and maintained at
a similar level throughout the rest of the reaction. There were no
sharp differences between the amount of benzaldehyde detected
from the reactions of 2-OHþ3 and 4-OHþ1 performed under
identical conditions. This result contrasts somewhat with obser-
vations from the examination of the acid-catalyzed decomposition
of 2-OH and 4-OH, which found that 2-OH generally gave higher
levels of benzaldehyde (Table 2). It appears that the difference in
the propensity of 2-OH and 4-OH to undergo acid-catalyzed
decomposition is less important when the additional reactant (2,20-
bipyrrole 3 or 5-phenyldipyrromethane 1) is present. Again, it
appears that differential acid-catalyzed decomposition of the
dicarbinol species is not an important factor in the obtainment of
different macrocycle yields in the reactions of 2-OHþ3 and
4-OHþ1.
2-OH + 3
MeCN
20
15
10
5
Dy(OTf)3 (0.32 mM)
HPO
TPC
TPP
0
0.01
0.1
1
time (h)
10
100
B
25
20
15
10
5
The overall oligomer composition from aliquots of crude, oxi-
dized reaction mixtures was assessed at each time point by LD-MS.
This methodology has been previously applied to the study of
reactions leading to meso-tetraarylporphyrins21 and other por-
phyrinoids.22 The assignment of LD-MS spectra obtained from the
reactions of 2-OHþ3 and 4-OHþ1 was carried out in analogous
fashion to previous studies of the reaction of pyrroleþaldehyde.21a
Sequential condensation of carbinol species with bipyrrole or
dipyrromethane followed by oxidation with DDQ would lead to
three oligomer series that differ in the nature of the groups ter-
minating the oligomer chain. The oligomer series for the reaction of
2-OHþ3 is shown in Scheme 4, and the calculated weights for the
first four members of each series are shown in Table 4. The calcu-
lated weights are for the fully unsaturated form of each open-chain
oligomer assuming loss of any terminal carbinol –OH group(s). A
peak was considered to be a member of an oligomer series if the
m/z value fell within ꢁ2 of the calculated value. TPC belongs to the
n¼1 member of the (BC)n series and HPO belongs to the n¼2
member of the same series. In some instances, oligomers were
detected at m/z values 18 or 36 units higher than the calculated
value, indicating the presence of one or two intact –OH groups from
terminal carbinol units. Oligomers arising from reversible pro-
cesses (i.e., scrambling) were recognized by their peaks falling at
m/z values correlating with calculated weights of oligomers
expected to arise from the reaction of pyrroleþbenzaldehyde rather
than the calculated weights of Table 4 (see Supplementary data for
further discussion). Assignments were made in a similar fashion for
4-OHþ1 (see Supplementary data).
4-OH + 1
MeCN
Dy(OTf)3 (0.32 mM)
HPO
TPC
TPP
0
0.01
0.1
1
time (h)
10
100
Figure 3. Yield of HPO, TPC, and TPP as a function of condensation time for (A) 2-
OHþ3 and (B) 4-OHþ1 (2.5 mM each) at room temperature under the indicated
conditions. The reactions were monitored spectrophotometrically. Note the log scale
for time.
and then declined over time. In both cases TPP was observed late in
the reaction, indicating that reversible processes developed over
time. A variety of trajectories were observed from the other re-
action conditions, but they also generally showed an obtainment of
a maximum yield of HPO or TPC followed by a decline in the yield at
longer reaction times. In reactions where TPP was observed, it
always appeared after the yield of HPO or TPC had substantially
declined from its maximum value. Reactions of 2-OHþ3 carried out
in CH2Cl2/THF (9:1) were fast, affording the maximum yield of HPO
by a reaction time of 1 min followed by a gradual decline in the
yield of HPO. The complementary reaction of 4-OHþ1 under
identical conditions was much slower.
Trends in oligomer composition provided insight into the gen-
eral scenarios noted for macrocycle yield. Under conditions where
the reaction of 2-OHþ3 provided HPO, and neither HPO nor TPC
were obtained from the reaction of 4-OHþ1 (Table 3, entries 5 and

K.C. Braaten et al. / Tetrahedron 64 (2008) 9828–9836
9833
2-OH + 3
1. acid
2. DDQ
Ph
Ph
Ph
nH
H
N
N
N
N
H
(BC)n
Ph
Ph
Ph
H
n
N
N
N
N
H
N
N
(BC)nB
Ph
Ph
nH
Ph
Ph
Ph
Ph
H
N
N
N
N
N
N
C(BC)n
Scheme 4. Expected oligomers present in crude, oxidized reaction mixtures from
2-OHþ3 (B¼bipyrrole and C¼dipyrromethanedicarbinol).
Table 4
Calculated molecular weights of oligomers from 2-OHþ3a
Figure 4. LD-MS spectra of crude, oxidized reaction mixtures from the reaction of (A)
2-OHþ3 and (B) 4-OHþ1 (2.5 mM each). The reactions were carried out with Dy(OTf)3
(0.32 mM) in THF at room temperature for 30 min. The yield of HPO, TPC, and TPP (UV–
vis) and yield of benzaldehyde (TLC) are shown for each reaction (ND¼not detected).
B¼(BC)n or (DC)n series, 6¼(BC)nB or (DC)nD series, ,¼C(BC)n or C(DC)n series,
DPM¼dipyrromethene, and R¼oligomer from reversible process.
n
(BC)n
(BC)nB
C(BC)n
1
2
3
4
526
1050
1574
2098
654
1178
1702
2226
920
1440
1968
2492
a
The oligomer masses increase with n according to (MWnþ1¼MWnþ524). The
oligomers are fully unsaturated.
under some reaction conditions, the reaction of 4-OHþ1 still pro-
ceeded more sluggishly and resulted in a lower yield of HPO.
Under the interesting set of reaction conditions where 2-OHþ3
provided HPO while 4-OHþ1 gave TPC (Table 3, entries 2, 8–10), the
oligomer compositions were somewhat different from those ob-
served under the other reaction conditionsdespecially for the
reaction of 4-OHþ1. Representative spectra from the condition of
entry 9 are provided in Figure 6 (see Supplementary data for the
complete set of spectra for this condition). Both reactions afforded
a number of oligomers, with the oligomer composition from the
reaction of 4-OHþ1 being more complex in this case. Both reactions
proceeded slowly at first, with primarily starting materials and
short oligomers bearing –OH groups from the carbinol units
(including the acyclic precursor to TPC) present at early reaction times.
The reaction of 4-OHþ1 continued to provide a peak corresponding
to dipyrromethene at all time points. At long reaction times, both
reactions were more subject to reversible processes than was the
case under the other reaction conditions. Thus, the conditions that
best facilitated oligomerization in the reaction of 4-OHþ1 were also
sufficiently vigorous to increase reversible processes at longer re-
action times. However, it is important to note that TPC was detected
prior to the detection of oligomers formed by reversible processes.
Thus, the production of TPC does not appear to be due to an ad-
vantageous recombination of fragments generated from the origi-
nal building block molecules through reversible processes. In fact,
the emergence of oligomers produced through reversible processes
correlated with the decline in the yield of TPC at longer reaction
times.
7), 2-OHþ3 showed much richer oligomer compositions. Repre-
sentative spectra from the condition of entry 5 are provided in
Figure 4 (see Supplementary data for the complete set of spectra for
this condition). Compared to the reaction of 2-OHþ3, the reaction
of 4-OHþ1 proceeded very sluggishly. Throughout the reaction,
4-OHþ1 displayed few oligomers, a strong peak corresponding to
5-phenyldipyrromethene (arising from the oxidation of unreacted
dipyrromethane upon treatment with DDQ), and oligomers that
retained –OH groups from carbinol units. Interestingly, a peak was
detected at m/z¼544, consistent with an oligomer the size of TPC
but still possessing a –OH group. Thus, it appears that the failure of
the reaction of 4-OHþ1 under these conditions to provide detect-
able levels of HPO or TPC lies in poor oligomer formation and
cyclization rather than in other possibilities such as over oligo-
merization or undesired reversible processes. LD-MS spectra
obtained under conditions that afforded both HPO and TPC from
the reaction of 2-OHþ3, but neither product from the reaction of
4-OHþ1 (Table 3, entry 3) showed similar trends (see Supple-
mentary data for the complete set of spectra).
Under conditions where both reactions provided HPO albeit at
a lower level for 4-OHþ1 (Table 3, entries 1, 4, and 6), the oligomer
compositions were more similar for the two complementary
reactions. Representative spectra from the condition of entry 4 are
provided in Figure 5 (see Supplementary data for the complete set
of spectra for this condition). Although the oligomer compositions
were more similar in this scenario, they were not identical. The
spectra from the reaction of 4-OHþ1 still showed a peak corre-
sponding to dipyrromethene at all time points, and the oligomer
composition took a longer time to develop. So while it appears that
the complementary reactions can follow a similar reaction pathway
The time course experiments along with the results from the
survey of catalysis conditions revealed that more exacting condi-
tions are required for the reaction of 4-OHþ1 than for 2-OHþ3. The

9834
K.C. Braaten et al. / Tetrahedron 64 (2008) 9828–9836
Figure 6. LD-MS spectra from crude, oxidized reaction mixtures from the reaction of
(A) 2-OHþ3 and (B) 4-OHþ1 (2.5 mM each). The reactions were carried out with
Dy(OTf)3 (0.32 mM) in MeCN at room temperature for 1.5 h (2-OHþ3) or 1 h (4-OHþ1).
The yield of HPO, TPC, and TPP (UV–vis) and yield of benzaldehyde (TLC) are shown for
each reaction (ND¼not detected). B¼(BC)n or (DC)n series, 6¼(BC)nB or (DC)nD series,
,¼C(BC)n or C(DC)n series, DPM¼dipyrromethene, and R¼oligomer from reversible
process.
Figure 5. LD-MS spectra of crude, oxidized reaction mixtures from the reaction of (A)
2-OHþ3 and (B) 4-OHþ1 (2.5 mM each). The reactions were carried out with Sc(OTf)3
(1.0 mM) in THF at room temperature for 4 h. The yield of HPO, TPC, and TPP (UV–vis)
and yield of benzaldehyde (TLC) are shown for each reaction (ND¼not detected).
B¼(BC)n or (DC)n series, 6¼(BC)nB or (DC)nD series, ,¼C(BC)n or C(DC)n series,
DPM¼dipyrromethene, and R¼oligomer from reversible process.
reaction of 4-OHþ1 provided low to modest yields of HPO or TPC
under only a subset of reaction conditions. The generally poor
macrocycle yields obtained from this reaction route were found to
stem from a combination of sluggish oligomer formation, poor
cyclization, incomplete utilization of starting material, and/or re-
versible processes. These issues could not be readily solved through
the adjustment of reaction parameters such as acid catalyst con-
centration, solvent, or reaction time. In contrast, the reaction of
2-OHþ3 gave modest to moderate levels of HPO across a fairly wide
range of reaction conditions. The improved yields of HPO were
accompanied by an oligomer distribution centered on the m/z of
HPO and largely devoid of oligomers arising from reversible pro-
cesses (except at long reaction times).
Given the widespread use of CH2Cl2 in porphyrin forming
reactions, time course experiments were also carried out for the
reaction of 2-OHþ3 in CH2Cl2. The complementary reaction of
4-OHþ1 could not be compared for these conditions due to the
poor solubility of 4-OH in CH2Cl2. The results of these experiments
are provided in Supplementary data.
directed to some extent by the choice of dicarbinol species and
solvent. However, there are certainly more efficient routes to
the preparation of meso-substituted corroles.9,23 The bipyrrole-
dicarbinol species behaves in distinctive ways relative to the
complementary dipyrromethanedicarbinol. In other contexts,
bipyrroledicarbinol species may be interesting building block
molecules.
3. Conclusions
Complementary reactions of a dipyrromethanedicarbinolþ2,20-
bipyrrole (2-OHþ3) and a 2,20-bipyrroledicarbinolþa dipyrro-
methane (4-OHþ1) leading to TPC and/or HPO were investigated to
establish the impact of carbinol group placement and key reaction
parameters on the distribution of products and on the broader
reaction course. In addition, we sought to explore the chemistry of
a bipyrroledicarbinol speciesda building block molecule that has
not been as extensively studied as dipyrromethanedicarbinols. The
complementary reactions were compared in a survey of catalysis
conditions, in an examination of the susceptibility of the dicarbinol
species to acid-catalyzed decomposition, and in time course
experiments. Supporting the overall study was the refinement of
conditions for the acylation of 2,20-bipyrrole.
Key findings of the work include: (1) The complementary
reactions of 2-OHþ3 and 4-OHþ1 afforded different quantities of
HPO and/or TPC across a range of acid catalysts, acid concentra-
tions, and solvents. (2) Conditions were identified such that the
reaction of 2-OHþ3 provided HPO and the reaction of 4-OHþ1
2.6. Practical implications
By investigating the impact of carbinol group placement and the
effect of key reaction parameters on the distribution of products
and the broader reaction course, observations were made with
relevance toward the preparation of porphyrinoids bearing bipyr-
role linkages. The reaction of 2-OHþ3 is the better route to HPO.
This route provides good yields of HPO under a variety of reaction
conditions. The reaction pathway leading to HPO or TPC can be

K.C. Braaten et al. / Tetrahedron 64 (2008) 9828–9836
9835
instead provided TPC. This scenario was most commonly observed
in the solvent of highest polarity. (3) Both dicarbinol species
underwent acid-catalyzed decomposition under some reaction
conditions, with the 2-OH being somewhat more susceptible.
However, in the presence of the other reactant, the differences in
the level of benzaldehyde formation were less pronounced in the
reactions of 2-OHþ3 and 4-OHþ1. Differential extent of acidolysis
of 2-OH and 4-OH does not account for the differing yields of
macrocycles. (4) Time course experiments supported the trends
observed in the survey of catalysis conditions. (5) The examination
of oligomer compositions facilitated further comparison of the
complementary reactions, providing insight into the contrasting
yields of HPO and TPC. In reactions of 4-OHþ1, oligomer formation
proceeded sluggishly and, in some cases, with a good deal of
reversibility. Identifying appropriate conditions for the reaction of
4-OHþ1 are more challenging than for the complementary re-
action. In summary, the placement of the carbinol groups on the
bipyrrole species rather than on the dipyrromethane has a pro-
found effect on the reaction course. Complementary reaction routes
can give rise to quite different results, and therefore, may have
unique utilities.
IR (thin film): 3273 (NH), 1594 (C]O). HRMS (FAB) m/z calcd for
22H17N2O2 [MHþ]: 341.1290; found: 341.1303.
C
4.3. Survey of catalysis conditions
Immediately prior to the condensation reactions, 2 (161 mg,
0.375 mmol) was reduced to the corresponding dicarbinol species
2-OH with NaBH4 (0.71 g, 19 mmol) in THF/methanol (30 mL, 3:1)
following a literature procedure.9,12a The reduction was monitored
by TLC [alumina, EtOAc/hexanes (3:2)]. For reactions involving 4-
OH, 4 (128 mg, 0.375 mmol) was reduced in a similar fashion ex-
cept that three portions of NaBH4 (0.71 g, 19 mmol) were added at
reaction times of 0, 30, and 60 min. The reduction of 4 proceeded
better if the mixture was sonnicated for w10 min prior to the first
addition of NaBH4 (4 does not initially dissolve entirely). The re-
duction was monitored by TLC [alumina, CH2Cl2/EtOAc (2:1)]. Crude
4-OH was characterized by 1H NMR and IR. 1H NMR (400 MHz,
DMSO-d6):
d
5.63 (m, 4H), 5.76 (s, 2H), 6.07 (t, J¼2.8 Hz, 2H), 7.21 (t,
J¼7.2 Hz, 2H), 7.30 (t, J¼7.5 Hz, 4H), 7.39 (d, J¼7.7 Hz, 4H), 10.7 (s,
2H). IR (thin film): 3450 (OH), 3264 (NH).
After drying under vacuum for 30 min, the dicarbinol species (2-
OH or 4-OH) was dissolved in the desired solvent and transferred to
a 50-mL volumetric flask. A solution of 3 (49.5 mg, 0.375 mmol) or
1 (83.3 mg, 0.375 mmol) was prepared in the desired solvent in
a 100-mL volumetric flask. The contents of the two volumetric
flasks were mixed, thereby providing a stock solution of 2-OH and 3
or 4-OH and 1 (2.5 mM each). Reactions were performed at room
temperature in tightly capped 20-mL vials stirred with a micro stir
bar. Solid acids were weighed into all reaction vials prior to
beginning the reaction sequence for the day, and each reaction was
started 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 stock solution. The reactions were monitored spectro-
photometrically for yield of HPO, TPC, and TPP at 0.25, 1, and 4 h as
described previously.4 TLC was performed on the crude, oxidized
mixture [silica, CH2Cl2/ethyl acetate (25:1)].
4. Experimental section
4.1. General
1H NMR (400 MHz) and absorption spectra were collected
routinely. Melting points are uncorrected. Chromatography was
performed on silica (Merck, 230–400 mesh, 60 Å). CHCl3 used in the
preparation of 4 was distilled from CaH2. THF used in the reduction
of 2 and 4 was stored over 4-Å Linde molecular sieves. CH2Cl2 used
in analytical-scale reactions of 2-OHþ3 and 4-OHþ1 was distilled
from potassium carbonate and stored over 4-Å Linde molecular
sieves. THF and toluene used in analytical-scale reactions of
2-OHþ3 and 4-OHþ1 were obtained from a Braun MB-SPS solvent
purification system. CH2Cl2 used in spectrophotometric de-
termination of the yield of TPC and HPO was passed through a pad
of basic alumina prior to use. Dipyrromethane 1,8 diacyl dipyrro-
methane 2,9 and 2,20-bipyrrole 39 were prepared as described in
the literature. All other chemicals were reagent grade and were
used as received.
4.4. Acid-catalyzed decomposition of dicarbinol species
leading to benzaldehyde
Immediately prior to the reactions, 2 (16.1 mg, 0.0375 mmol) or
4 (12.8 mg, 0.0375) was reduced to the corresponding dicarbinol
species 2-OH or 4-OH as described above in the survey of catalysis
conditions. After drying under vacuum for 30 min, the dicarbinol
species (2-OH or 4-OH) was dissolved in the desired solvent to
afford a solution of 2-OH or 4-OH (2.5 mM). Reactions were per-
formed at room temperature in tightly capped 20-mL vials stirred
with a micro stir bar. Solid acids were weighed into all reaction vials
prior to beginning the reaction sequence for the day, and each
reaction was started by the addition of 3 mL of the dicarbinol solution
via volumetric pipet. Reactions involving TFA were initiated by the
addition of TFA to reaction vials already containing 3 mL of the
dicarbinol stock solution. The reactions were monitored by TLC and
GC/MS analyses at 5 min, 15 min, 30 min, 1 h, 2 h, and 4 h.
4.2. 5,50-Dibenzoyl-2,20-bipyrrole (4)
Following a refined published procedure,11 2,20-bipyrrole 3
(250 mg, 1.89 mmol) was combined with N,N-dimethylbenzamide
(3.66 g, 24.5 mmol) in dry CHCl3 (2.3 mL) under argon. The slurry
was cooled to 0 ꢂC in an ice bath, and POCl3 (2.28 mL, 24.5 mmol)
was added over 30 s. The ice bath was replaced by a water bath
heated to 50 ꢂC, and the clear, brown reaction mixture was stirred
at 50 ꢂC under argon for 6 h. The reaction mixture was transferred
to a solution of sodium acetate (13 g) in water (55 mL). The mixture
was heated at 70 ꢂC for w10 min to drive off the CHCl3. The mixture
was further heated at 90 ꢂC for 1 h. The reaction was cooled to room
temperature, sonnicated for w15 min, and placed in a refrigerator
overnight. Vacuum filtration, followed by rinsing with water, and
drying under vacuum (60 ꢂC for 2 h) afforded crude product as a tan
powder (563 mg). The crude product was dissolved in hot DMSO
(w7 mL) and then dripped slowly into hot iPrOH (w21 mL). A
yellow precipitate formed quickly. The mixture was stored in
a freezer for 2 h. Vacuum filtration followed by rinsing with iPrOH
and drying under vacuum (150 ꢂC for 2 h) afforded 4 as a yellow
solid (410 mg, 64%). Mp¼329–331 ꢂC. 1H NMR (400 MHz, DMSO-
TLC analysis: following a published procedure,19 aliquots (2
of each reaction mixture were spotted using a micropipet on a silica
TLC plate alongside spots of aliquots (2 L) of solutions of benzal-
mL)
m
dehyde (0.1, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0 mM). Plates were developed in
CH2Cl2/hexanes (1:1) and visualized by short wavelength UV light.
The intensity of spots due to benzaldehyde was visually compared.
Control experiments found that residual acid catalyst or other
byproducts did not impact the detection of benzaldehyde.
GC–MS analysis: an aliquot (150 mL) of each reaction mixture
was transferred to a microfuge tube. Triethylamine (5 equiv relative
to acid) was added and the mixture was passed through a filter
d6):
d
6.87 (m, 2H), 6.92 (m, 2H), 7.54 (t, J¼7.6 Hz, 4H), 7.63 (t,
J¼7.1 Hz, 2H), 7.84 (d, J¼7.4 Hz, 4H), 12.4 (s, 2H). 13C NMR (100 MHz,
DMSO-d6): d 110.4,121.0,128.8,128.9,131.3,131.7,132.1,138.7,183.5.

9836
K.C. Braaten et al. / Tetrahedron 64 (2008) 9828–9836
pipet into an autosampler vial. The solution (0.5
mL) was analyzed
Supplementary data
with the following GC conditions: VF-5ms column; 30 mꢃ
0.25 mmꢃ0.25
m
m; inlet temperature 260 ꢂC; temperature gradi-
Supplementary data associated with this article can be found in
the oSnline version, at doi:10.1016/j.tet.2008.08.025.
ent: temperature 1, 60 ꢂC (2 min); temperature 2, 270 ꢂC (1 min);
rate 30 ꢂC/min, total runtime 10 min; helium constant flow of
1.0 mL/min. The retention time for benzaldehyde was 4.4 min. The
MS response was calibrated with benzaldehyde solutions of known
concentration (0.1, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0 mM) and the response
was found to be linear. Control experiments found that the addition
of triethylamine and sample filtration did not alter the detection
of benzaldehyde. Analysis reproducibility was found to be
satisfactory.
References and notes
1. (a) Sessler, J. L.; Weghorn, S. Expanded, Contracted, and Isomeric Porphyrins;
Elsevier: Oxford, 1997; (b) Jasat, A.; Dolphin, D. Chem. Rev. 1997, 97, 2267–2340;
(c) Sessler, J. L.; Gebauer, A.; Vogel, E. In The Porphyrin Handbook; Kadish, K. M.,
Smith, K., Guilard, R., Eds.; Academic: San Diego, CA, 2000; Vol. 2, pp 1–54; (d)
Sessler, J. L.; Gebauer, A.; Weghorn, S. J. In The Porphyrin Handbook; Kadish, K.
M., Smith, K., Guilard, R., Eds.; Academic: San Diego, CA, 2000; Vol. 2, pp 55–
124; (e) Sessler, J. L.; Seidel, D. Angew. Chem., Int. Ed. 2003, 42, 5134–5175; (f)
Misra, R.; Chandrashekar, T. K. Acc. Chem. Res. 2008, 41, 265–279.
2. (a) Vogel, E.; Will, S.; Schulze-Tilling, A.; Neumann, L.; Lex, J.; Bill, E.; Trautwein,
A. X.; Wieghardt, K. Angew. Chem., Int. Ed. Engl. 1994, 33, 731–735; (b) Erben, C.;
Will, S.; Kadish, K. M. In The Porphyrin Handbook; Kadish, K. M., Smith, K.,
Guilard, R., Eds.; Academic: San Diego, CA, 2000; Vol. 2, pp 233–300; (c) Gross,
Z. J. Biol. Inorg. Chem. 2001, 6, 733–738.
3. (a) Sessler, J. L.; Cyr, M. J.; Burrell, A. K. Synlett 1991, 127–134; (b) Sessler, J. L.;
Davis, J. M. Acc. Chem. Res. 2001, 34, 989–997.
4. Geier, G. R., III; Grindrod, S. C. J. Org. Chem. 2004, 69, 6404–6412.
5. Vogel, E.; Bro¨ring, M.; Fink, J.; Rosen, D.; Schmickler, H.; Lex, J.; Chan, K. W. K.;
Wu, Y.-D.; Plattner, D. A.; Nendel, M.; Houk, K. N. Angew. Chem., Int. Ed. Engl.
1995, 34, 2511–2514.
6. (a) Gisselbrecht, J.-P.; Bley-Escrich, J.; Gross, M.; Zander, L.; Michels, M.; Vogel,
E. J. Electroanal. Chem. 1999, 469, 170–175; (b) Werner, A.; Michels, M.; Zander,
L.; Lex, J.; Vogel, E. Angew. Chem., Int. Ed. 1999, 38, 3650–3653; (c) Bley-Escrich,
J.; Gisselbrecht, J.-P.; Vogel, E.; Gross, M. Eur. J. Inorg. Chem. 2002, 2829–2837;
(d) Bley-Escrich, J.; Gisselbrecht, J.-P.; Michels, M.; Zander, L.; Vogel, E.; Gross,
M. Eur. J. Inorg. Chem. 2004, 492–499.
7. (a) Orti, E.; Tomas, F.; Sanchez-Marin, J. J. Mol. Struct. (Theochem.) 1983, 104,
197–206; (b) Orti, E.; Sanchez-Marin, J.; Tomas, F. Theor. Chim. Acta 1986, 69,
41–49; (c) Orti, E.; Sanchez-Marin, J.; Tomas, F. J. Chim. Phys. 1987, 84, 729–734;
(d) Kofranek, M.; Kovar, T.; Karpfen, A.; Lischka, H. J. Chem. Phys. 1992, 96, 4464–
4473; (e) Padilla-Campos, L.; Toro-Labbe, A. J. Mol. Struct. (Theochem.) 1995, 330,
223–229; (f) Duarte, H. A.; Duani, H.; De Almeida, W. B. Chem. Phys. Lett. 2003,
369, 114–124.
4.5. Reaction time course experiments
Immediately prior to the reactions, 2 (37.6 mg, 0.0875 mmol) or
4 (29.8 mg, 0.0875) was reduced to the corresponding dicarbinol
species 2-OH or 4-OH as described above in the survey of catalysis
conditions. After drying under vacuum for 30 min, the dicarbinol
species (2-OH or 4-OH) was dissolved in the desired solvent and 3
(11.6 mg, 0.0875 mmol) or 1 (19.4 mg, 0.0875 mmol) was added to
afford a stock solution of 2-OH and 3 or 4-OH and 1 (2.5 mM each).
Reactions were performed at room temperature in tightly capped
20-mL vials stirred with a micro stir bar. Solid acids were weighed
into all reaction vials prior to beginning the reaction sequence for
the day, and each reaction was started by the addition of 8 mL of the
reactant solution via volumetric pipet. Reactions involving TFA
were initiated by the addition of TFA to reaction vials already
containing 8 mL of the reactant stock solution. The reactions were
monitored for yield of HPO, TPC, TPP spectrophotometrically as
described previously,4 for yield of benzaldehyde, and for oligomer
composition by LD-MS at 1 min, 4 min, 8 min, 15 min, 30 min,
45 min, 1 h, 1.5 h, 2 h, 4 h, 8 h, and 24 h.
8. Laha, J. K.; Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.; Lindsey, J. S. Org.
Process Res. Dev. 2003, 7, 799–812.
TLC analysis: an aliquot (100
transferred to microfuge tube containing DDQ (0.34 mg,
0.0015 mmol). The sample was vortex mixed and allowed to stand
for at least 5 min. An aliquot (2 L) of the crude, oxidized reaction
m
L) of crude reaction mixture was
9. Geier, G. R., III; Chick, J. F. B.; Callinan, J. B.; Reid, C. G.; Auguscinski, W. P. J. Org.
Chem. 2004, 69, 4159–4169.
a
10. (a) Bro¨ring, M. Synthesis 2000, 1291–1294; (b) Bro¨ring, M.; Griebel, D.; Hell, C.;
Pfister, A. J. Porphyrins Phthalocyanines 2001, 5, 708–714; (c) Setsune, J.; Tanabe,
A.; Watanabe, J.; Maeda, S. Org. Biomol. Chem. 2006, 4, 2247–2252.
11. Vogel, E.; Ko¨cher, M.; Lex, J.; Ermer, O. Isr. J. Chem. 1989, 29, 257–266.
12. (a) Rao, P. D.; Dhanalekshmi, S.; Littler, B. J.; Lindsey, J. S. J. Org. Chem. 2000, 65,
7323–7344; (b) Gryko, D. T.; Tasior, M.; Koszarna, B. J. Porphyrins Phthalocya-
nines 2003, 7, 239–248; (c) Tamaru, S.; Yu, L.; Youngblood, W. J.; Muthuku-
maran, K.; Taniguchi, M.; Lindsey, J. S. J. Org. Chem. 2004, 69, 765–777.
13. (a) White, J.; McGillivray, G. J. Org. Chem. 1977, 42, 4248–4251; (b) Kakushima,
M.; Hamel, P.; Frenette, R.; Rokach, J. J. Org. Chem. 1983, 48, 3214–3219; (c)
Barbero, M.; Cadamuro, S.; Degani, I.; Fochi, R.; Gatti, A.; Regondi, V. J. Org.
Chem. 1988, 53, 2245–2250; (d) Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.;
Tidwell, T. T.; Artis, D. R.; Muchowski, J. M. J. Org. Chem. 1990, 55, 6317–6328; (e)
Cadamuro, S.; Degani, I.; Dughera, S.; Fochi, R.; Gatti, A.; Piscopo, L. J. Chem. Soc.,
Perkin Trans. 1 1993, 273–283; (f) Wallace, D. M.; Leung, S. H.; Senge, M. O.;
Smith, K. M. J. Org. Chem. 1993, 58, 7245–7257.
14. The quantity of acid is reported in concentration units of molarity for conve-
nience of comparison of reaction conditions. However, InCl3, Sc(OTf)3, Yb(OTf)3,
and Dy(OTf)3 are poorly soluble in some of the solvents, and the reaction
mixtures were heterogeneous as reported previously.15
15. Geier, G. R., III; Callinan, J. B.; Rao, D. P.; Lindsey, J. S. J. Porphyrins Phthalocya-
nines 2001, 5, 810–823.
16. O’Brien, A. Y.; McGann, J. P.; Geier, G. R., III. J. Org. Chem. 2007, 72, 4084–4092.
17. Setsune, J.; Tsukajima, A.; Watanabe, J. Tetrahedron Lett. 2007, 48, 1531–1535.
18. Setsune, J.; Maeda, S. J. Am. Chem. Soc. 2000, 122, 12405–12406.
19. Li, F.; Yang, K.; Tyhonas, J. S.; MacCrum, K. A.; Lindsey, J. S. Tetrahedron 1997, 53,
12339–12360.
20. (a) 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; (b) Strachan, J. P.; O’Shea, D. F.; Balasubramanian,
T.; Lindsey, J. S. J. Org. Chem. 2000, 65, 3160–3172; (c) Balasubramanian, T.;
Strachan, J. P.; Boyle, P. D.; Lindsey, J. S. J. Org. Chem. 2000, 65, 7919–7929.
21. (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; Littler, B. J.; Lindsey, J. S. J. Chem. Soc., Perkin Trans. 2 2001, 701–
711; (d) Geier, G. R., III; Littler, B. J.; Lindsey, J. S. J. Chem. Soc., Perkin Trans. 2
2001, 712–718.
m
mixture was analyzed by TLC as described above for the acidolysis
of dicarbinol species affording benzaldehyde.
LD-MS analysis: following a published procedure,21a an aliquot
(1 mL) from the same crude, oxidized reaction mixtures used in TLC
analysis was spotted onto a MALDI target. The crude, oxidized
samples were analyzed in the absence of added matrix. LD-MS
spectra were recorded using a TOF instrument in reflector mode
equipped with a nitrogen laser (337 nm), 1.2 m flight tube, MCP
detector, and a 2 GHz digitizer. Mass accuracy is <100 ppm with
external standards. Spectra were averaged over 200–300 shots
taken from at least four locations on the target. Samples were an-
alyzed after all reactions for 1 day were completed. Samples spent
between 2 and 8 h on the target prior to LD-MS analysis. Control
experiments found that samples were stable on the MALDI target
while awaiting analysis. LD-MS analysis was found to be insensitive
the quantity of DDQ used in the oxidation of the crude reaction
mixtures. Very similar spectra were obtained upon oxidizing the
reaction aliquot (100
to 2.3 mg.
mL) with quantities of DDQ ranging from 0.14
Acknowledgements
Support for this work was provided by the National Science
Foundation under grant No. 0517882. We thank Tiffany Chu for her
assistance with 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.
22. Krivokapic, A.; Cowley, A. R.; Anderson, H. L. J. Org. Chem. 2003, 68, 1089–1096.
23. (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. Eur. J. Org. Chem. 2002,
1735–1743; (c) Nardis, S.; Monti, D.; Paolesse, R. Mini-Rev. Org. Chem. 2005, 2,
355–374.