Effects of aldehyde or dipyrromethane substituents on the reaction course leading to meso-substituted porphyrins

Article abstract of DOI:10.1016/j.tet.2004.09.081

To better understand the effects of diverse substituents on reactions leading to porphyrins, pyrrole+aldehyde condensations and related reactions of dipyrromethanes were examined. The course of pyrrole+aldehyde condensations was investigated by monitoring the yield of porphyrin (by UV-Vis spectroscopy), reaction of aldehyde (by TLC), and changes in the composition of oligomers (by laser desorption mass spectrometry). Reaction reversibility was examined via exchange experiments. Reversibility of reactions leading to porphyrin was further probed with studies of dipyrromethanes. The reaction course was found to depend on the nature of the substituent and the acid catalyst. Alkyl or electron-donating substituents displayed levels of reversibility (exchange/scrambling) on par or greater than that of the phenyl substituent, whereas electron-withdrawing or sterically bulky substituents exhibited little to no reversibility. The results obtained provide insight into the electronic and steric effects of different substituents and should facilitate the design of synthetic plans for preparing porphyrinic macrocycles. Graphical abstract.

Full text of DOI:10.1016/j.tet.2004.09.081

Tetrahedron 60 (2004) 11435–11444
Effects of aldehyde or dipyrromethane substituents on the
reaction course leading to meso-substituted porphyrins
†
G. Richard Geier, III and Jonathan S. Lindsey
*
Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8204, USA
Received 22 February 2004; revised 19 September 2004; accepted 21 September 2004
Available online 18 October 2004
Abstract—To better understand the effects of diverse substituents on reactions leading to porphyrins, pyrroleCaldehyde condensations and
related reactions of dipyrromethanes were examined. The course of pyrroleCaldehyde condensations was investigated by monitoring the
yield of porphyrin (by UV–Vis spectroscopy), reaction of aldehyde (by TLC), and changes in the composition of oligomers (by laser
desorption mass spectrometry). Reaction reversibility was examined via exchange experiments. Reversibility of reactions leading to
porphyrin was further probed with studies of dipyrromethanes. The reaction course was found to depend on the nature of the substituent and
the acid catalyst. Alkyl or electron-donating substituents displayed levels of reversibility (exchange/scrambling) on par or greater than that of
the phenyl substituent, whereas electron-withdrawing or sterically bulky substituents exhibited little to no reversibility. The results obtained
provide insight into the electronic and steric effects of different substituents and should facilitate the design of synthetic plans for preparing
porphyrinic macrocycles.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
A key finding was that the condensation entails a
combination of reversible and irreversible reactions, thereby
often causing the yield of porphyrinogen to pass through a
The one-flask reaction of pyrrole and an aldehyde provides a
direct approach for the synthesis of meso-substituted
porphyrins.1 The reaction is performed in two stages: (1)
maximum and then decline. The overall rate of reaction and
acid catalyzed condensation of pyrroleCaldehyde forming
predominantly polypyrromethane oligomers and the cyclic
porphyrinogen; (2) addition of an oxidant (e.g., DDQ or
p-chloranil) to give the corresponding polypyrromethenes
and porphyrin (Scheme 1). We previously carried out a
series of experiments to gain insight into the course of the
condensation.2–5 A battery of analytical techniques was
employed, which allowed determination of the yields of
porphyrinic macrocycles such as the porphyrin, N-confused
porphyrin and sapphyrin (by UV–Vis and HPLC),6
consumption of the aldehyde (by TLC),7 change in the
composition of the mixture of oligomers (by laser
desorption mass spectrometry, LD-MS),2,3 and formation
of dipyrrin chromophores (by UV–Vis).8 These studies,
performed with the benchmark reaction of benzaldehyde
and pyrrole under a variety of conditions, revealed the
complexity of the overall reaction.
Keywords: Porphyrin; Porphyrinogen; Dipyrromethane; Polypyrro-
methane; Pyrrole; Laser desorption mass spectrometry.
* Corresponding author. Tel.: C1 919 515 6406; fax: C1 919 513 2830;
e-mail: jlindsey@ncsu.edu
† Current address: Department of Chemistry, Colgate University, Hamil-
ton, NY 13346, USA.
Scheme 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.081

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G. R. Geier III, J. S. Lindsey / Tetrahedron 60 (2004) 11435–11444
ultimate yield of porphyrin is dependent on the concen-
tration of the reactants, the nature of the acid catalyst, and
on the concentration of the acid. Obtaining a maximal yield
of porphyrin requires careful monitoring of the reaction
‘trajectory’ so that oxidation, the second step of the
porphyrin-forming process (which terminates all conden-
sation processes), can be initiated at the appropriate time.
The decline in porphyrinogen yield that occurs under some
conditions is accompanied by a shift of the oligomer
composition to shorter species (‘oligomer truncation’).
with TFA or BF3-etherate for reaction with 10 mM each of
aldehyde and pyrrole in CH2Cl2 at room temperature. Under
refined conditions, the consumption of aldehyde, changes in
the oligomer composition, and the yield of porphyrin were
investigated as a function of time for each aldehyde. The
reversibility of the condensation was investigated via
exchange experiments. Studies of a set of dipyrromethanes
examined the propensity for reversible processes leading to
scrambling. Taken together, these studies provide a
foundation for understanding the effects of structural and
electronic changes in the aldehyde or dipyrromethane
moiety on the course of reaction leading to porphyrins.
In related experiments, we examined the reversibility of
dipyrromethaneCaldehyde condensations leading to trans-
A2B2-porphyrins. Dipyrromethanes are valuable building
blocks in diverse routes to porphyrins.9–13 However, the
successful use of dipyrromethanes requires the reaction to
proceed without acidolysis of the dipyrromethane and
recombination of the resulting dipyrromethane fragments
yielding undesired porphyrin products (i.e., scrambling).14
Again, the phenyl group was the predominant substituent
employed.4,5
2. Results and discussion
2.1. Reactions of aldehydes
Two specific aldehydes of a given type were selected for
comparison to benzaldehyde in reactions leading to meso-
substituted porphyrins. In each case, the two aldehydes that
comprise a pair have similar structures but different
molecular weights in anticipation of the exchange
experiments. The selected aldehydes are as follows:
benzaldehyde and p-tolualdehyde (benchmark case),
p-anisaldehyde and 4-ethoxybenzaldehyde (electron donat-
ing), pentafluorobenzaldehyde and 2,3,5,6-tetrafluoro-
benzaldehyde (electron withdrawing), mesitaldehyde and
2,6-dimethylbenzaldehyde (sterically bulky), and hexanal
and heptanal (alkyl). Three general types of experiments
were performed: investigation of acid catalyst requirements,
reaction time course studies, and examination of reaction
reversibility.
A present objective has been to determine the generality of
the observations for substituents that differ markedly from
that of the phenyl group. Of particular interest are the effects
of electron-withdrawing, electron-releasing, sterically
bulky, and non-aryl groups on the catalytic requirements,
the trajectory of the reaction, the oligomer composition and
its change over time, and the reversibility of the reaction.
Improved understanding of these issues is important for the
rational refinement of reaction conditions, for suppressing
undesired reversible processes, and for the design of
synthetic plans so as to avoid potentially problematic
reactions.
2.1.1. Acid catalysis requirements. The catalytic require-
ments for each aldehyde were examined by reacting an
aldehyde and pyrrole (10 mM each) at room temperature
in CH2Cl2 over a range of concentrations of TFA or
BF3-etherate. After condensation for 15 min, 1 h, or 4 h, an
aliquot of the reaction mixture was oxidized with DDQ
and the yield of porphyrin was determined
In this paper, we report studies of condensations of a
representative set of aldehydes with pyrrole, and conden-
sations involving dipyrromethanes. Diverse aryl sub-
stituents were employed (electron donating, electron
withdrawing, and sterically bulky) as well as alkyl groups.
The studies first identified appropriate catalytic conditions
Table 1. The acid catalysis conditions identified for each aldehydea
Entry
Substituent type
R group in RCHO
Acid
[Acid], mMb
% Yield of porphyrinc
1
2
3
4
5
6
7
8
Benchmark
Benchmark
Benchmark
Benchmark
e-rich
e-rich
e-rich
e-rich
e-deficient
e-deficient
e-deficient
e-deficient
Alkyl
Alkyl
Alkyl
Alkyl
Phenyl
Phenyl
p-Tolyl
p-Tolyl
4-MeO-phenyl
4-MeO-phenyl
4-EtO-phenyl
4-EtO-phenyl
C6F5
TFA
BF3-etherate
TFA
BF3-etherate
TFA
BF3-etherate
TFA
BF3-etherate
TFA
BF3-etherate
TFA
BF3-etherate
TFA
BF3-etherate
TFA
BF3-etherate
22
1.0
22
41
23
41
17
29
NDd
28
NDd
11
23
13
22
14
8
1.0
22
d
—
22
d
—
9
215
10
215
10
10
1.0
10
10
11
12
13
14
15
16
C6F5
2,3,5,6-F4-phenyl
2,3,5,6-F4-phenyl
Pentyl
Pentyl
Hexyl
Hexyl
16
12
1.0
a The reactions were performed with 10 mM each of pyrrole and aldehyde at a 10 ml scale in CH2Cl2 at room temperature. The reactions were monitored at
15 min, 1 h, and 4 h.
b The optimal acid concentration in terms of yield of porphyrin and reaction time.
c The highest yield (UV–Vis) at any of the three timepoints is reported.
d No porphyrin was detected at any concentration of BF3-etherate (limit of detection is 0.5%).

G. R. Geier III, J. S. Lindsey / Tetrahedron 60 (2004) 11435–11444
11437
Figure 1. Percent yield of porphyrin (filled symbols) and percent unreacted
aldehyde (open symbols) as a function of condensation time for reactions of
pyrroleCaldehyde (10 mM each) in CH2Cl2 at room temperature.
Reactions were monitored by removing an aliquot of the reaction mixture,
oxidizing with DDQ, and analyzing spectrophotometrically for yield of
porphyrin and by TLC for unreacted aldehyde. Note the log scale for time.
Figure 2. LD-MS spectra showing the oligomer composition at selected
timepoints for the reaction of pyrroleCp-anisaldehyde (10 mM each) under
TFA catalysis (20 mM) in CH2Cl2 at room temperature. Reactions were
monitored by removing an aliquot of the reaction mixture, oxidizing with
DDQ, and directly analyzing the crude, oxidized reaction mixture. The
percent yield of porphyrin (UV–Vis) and percent unreacted aldehyde (TLC)
are reported for each timepoint. Three oligomer series are defined based on
the groups present at the oligomer chain termini: (1) a pyrrole and an
aldehyde terminus, (PA)n series, B; (2) pyrrole units at both termini,
(PA)nP series, 6; and (3) aldehyde units at both termini, A(PA)n series, ,.
A fourth oligomer series has an internal bipyrrole group, and pyrrole groups
at both termini, P(PA)nP series, +. Significant peaks that could not be
assigned to one of the four oligomer series are denoted with a ‘?’. The
number (n) of repeating pyrrole-aldehyde (PA) units is given by the number
above the symbol.
spectrophotometrically. All aldehydes were examined in
this manner with the exception of mesitaldehyde and 2,6-
dimethylbenzaldehyde, which are known not to react under
these conditions and were instead condensed with pyrrole
using the established conditions of BF3-etherate/ethanol
cocatalysis.15
The rate of formation (and possible decay) of the
porphyrinogen is dependent on the concentration of a

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G. R. Geier III, J. S. Lindsey / Tetrahedron 60 (2004) 11435–11444
given type of acid. Such a phenomenon, which is well
documented for the reaction of benzaldehyde and pyrrole,
was observed to varying degrees with the aldehydes
examined herein (see the Supplementary data for plots of
the yield of porphyrin as a function of acid concentration).
For example, for p-anisaldehyde, the reaction with 46 mM
TFA afforded a yield of 26% at 15 min, 5% after 1 h, and
0% after 4 h. However, the reaction with 22 mM TFA
provided a yield of 29% after 1 h and w17% after 4 h. For
the reaction at 10 mM TFA, the reaction at 4 h afforded the
highest yield (24%), with less than a 10% yield obtained at
the earlier timepoints.
the maximum yield of porphyrin obtained under any acid
concentration. Nearly identical yields of porphyrin were
obtained from each member of a pair of aldehydes under a
given reaction condition. The lone exception involved
benzaldehyde and p-tolualdehyde. Under BF3-etherate
catalysis, p-tolualdehyde provided less porphyrin (1.4 to
five times lower) than did benzaldehyde at equivalent
reaction times. The acid catalyst concentrations identified
for subsequent use herein are summarized in Table 1. Note
that the yields obtained are not fully optimized. Investi-
gation of other reaction conditions known to give improved
yields in some cases such as use of clays,16–20 cocatalysis
(BF3-etherateCsalt,7 BF3-etherateCTFA21), or other cata-
lysts,22–24 as well as variation in the concentration of the
aldehyde and pyrrole were not within the scope of the
present study.
These results concerning the interplay of acid concentration
and reaction rate illustrate the complexity of identifying a
single best set of conditions for a given aldehyde. A range of
acid concentration afforded a good yield of porphyrin at one
of the three timepoints for each type of aldehyde. This range
varied from the extremes of w50-fold for reactions of
aldehydes with electron-withdrawing groups under BF3-
etherate catalysis to w5-fold for aldehydes with electron-
donating groups under TFA catalysis. In addition, aldehydes
bearing electron-withdrawing groups required w10 times
higher acid concentration to obtain the maximum yield of
porphyrin than the other aldehydes examined herein. It is
noteworthy that despite the subtleties of the conditions
affording the highest yield of porphyrin, application of one
or both of the standard reaction conditions [20 mM TFA or
1.0 mM BF3-etherate] to all aldehydes (except those bearing
bulky substituents in the 2- and 6-positions) provided a yield
of porphyrin at some point in the reaction that was close to
2.1.2. Reaction time course. The time course for the
pyrroleCaldehyde reactions was examined in greater detail
by following the formation of the porphyrin (UV–Vis),
disappearance of the aldehyde (TLC), and change in
oligomer composition (LD-MS) as a function of time from
1 min to 24 h. The reactions were performed under the
catalytic conditions identified from the acid catalysis
examination, as well as BF3-ethanol cocatalysis conditions
previously reported for mesitaldehyde.15 The latter
conditions also were employed for p-anisaldehyde, as
p-alkoxybenzaldehydes are known to condense poorly
with pyrrole in the presence of BF3-etherate alone.8
Representative plots of the percent yield of porphyrin and
percent unreacted aldehyde as a function of condensation
Table 2. Effects of aldehyde structure on the reaction course leading to porphyrina
Entry
R in RCHO
Acid
[Acid],
mM
Timeb
%
% Unreacted
aldehyded
Yield
turnovere
Oligomer
truncationf
Porphyrinc
1
2
3
4
5
6
7
8
Phenyl
Phenyl
p-Tolyl
TFA
BF3-etherate
TFA
BF3-etherate
TFA
BF3/EtOH
TFA
BF3/EtOH
TFA
BF3-etherate
TFA
BF3-etherate
BF3/EtOH
BF3/EtOH
TFA
BF3-etherate
TFA
BF3-etherate
20
1.0
20
1.0
20
3.3/130
20
3.3/130
215
10
215
10
3.3/130
3.3/130
10
1.0
10
1.0
1–4 h
1–8 h
30 min–1 h
4–24 h
1 h
40
25
39
17
34
38
32
36
12
23
13
25
19
19
16
9
!5
30
15
35
High
Low
High
High
Trace
High
None
High
Low
p-Tolyl
None
4-MeO-phenyl
4-MeO-phenyl
4-EtO-phenyl
4-EtO-phenyl
C6F5
10
Near total
Near total
Near total
Near total
Low
Low
Low
Low
Low
Low
Low
None
Low
None
15 min–1 h
1 h
!5
10
High
Low
15 min–1 h
8 min–4 h
8 min–24 h
4 min–8 h
15 min–8 h
1–4 h
NDg
5
9
Lowh
None
Lowh
Trace
Lowh
Lowh
Nonei
Nonej
Nonej
Nonej
10
11
12
13
14
15
16
17
18
C6F5
!5
10
2,3,5,6-F4-phenyl
2,3,5,6-F4-phenyl
2,4,6-Me3-phenyl
2,6-Me2-phenyl
Pentyl
NDg
10
1–8 h
10
i
15 min–8 h
8 min–24 h
15 min–8 h
8 min–24 h
—
—
—
—
i
Pentyl
Hexyl
Hexyl
i
16
9
i
a The reactions were performed with 10 mM each of pyrrole and aldehyde at a 15 ml scale at room temperature in CH2Cl2 (for mesitaldehyde and 2,6-
dimethylbenzaldehyde, ethanol cocatalysis was carried out in CHCl3 stabilized with amylenes or in CH2Cl2). The reactions were monitored at 1 min,
4 min, 8 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h.
b The range of time during the condensation reaction where the yield of porphyrinogen was maximal (as inferred from the yield of porphyrin in aliquots of the
oxidized reaction mixture).
c The maximum yield of porphyrin (UV–Vis).
d The level of unreacted aldehyde at the time that the maximum yield of porphyrin was first obtained.
e Yield turnover refers to a decline in the yield of porphyrin after the maximum has been obtained.
f
Oligomer truncation refers to disappearance of larger oligomers, and appearance of shorter oligomers that were not present at early reaction times.
g Below the limits of detection (!1%).
h The changes in oligomer composition occurred between the 8 h and 24 h timepoints.
i
Alkyl aldehydes could not be detected readily by TLC analysis.
The intensity and resolution of peaks of higher m/z than the porphyrin were poor for all spectra; nevertheless, the appearance of the spectra remained
consistent once the maximum yield of porphyrin was obtained.
j

G. R. Geier III, J. S. Lindsey / Tetrahedron 60 (2004) 11435–11444
11439
time are provided in Figure 1 (see the Supplementary data
for the complete set of plots for all aldehydes). The quantity
of unreacted aldehyde was not determined for the alkyl
aldehydes, which are poorly detected upon TLC analysis.
A representative set of LD-MS spectra showing changes in
the oligomer composition as a function of time are shown in
Figure 2 (see the Supplementary data for the complete set of
spectra). Observations from the time course experiments are
summarized in Table 2.
occur. Three premixing times were examined: a time close
to when the maximum yield of porphyrinogen is initially
attained and the concentration of unreacted aldehyde is
!10% of the original concentration, a later timepoint when
porphyrinogen yield was still high, and a long timepoint
when the porphyrinogen yield had in some cases declined.
(The objective of !10% unreacted aldehyde was achieved
in every case with the exception of p-tolualdehyde under
BF3-etherate catalysis.) Duplicate mixtures were prepared
at each premixing time. One mixture was allowed to react
with no additional acid catalyst, and the second mixture was
Two key features concerning the trajectory of the pyrroleC
aldehyde reaction are (1) the extent to which the yield of
porphyrinogen declines after reaching a maximum, and (2)
the extent to which the oligomers undergo truncation. The
turnover in porphyrinogen yield is readily established by
monitoring the condensation over time. In some cases, the
turnover was near total while in other cases the porphyrino-
gen yield reached a maximum and then plateaued. Reactions
of aldehydes with electron-donating substituents showed a
substantial turnover in the yield of porphyrinogen under
TFA or BF3-etherate/EtOH catalysis (Fig. 1B), much more
than previously observed with benzaldehyde under TFA or
BF3-etherate catalysis. Examination of crude, oxidized
reaction samples by LD-MS reveals the composition of
the oligomers.2 Studies of the reaction with benzaldehydeC
pyrrole under TFA catalysis showed that the oligomeric
composition continues changing over a period well beyond
the peak in porphyrinogen yield. The composition becomes
enriched in shorter oligomers that were not originally
present in the LD-MS spectra, a phenomenon we have
referred to as oligomer truncation.2 Oligomer truncation
can result from reactions giving reversible formation/
disassembly of polypyrromethanes in conjunction with
irreversible side reactions, and/or irreversible side reactions
that cause fragmentation of polypyrromethanes. In the
present work, reactions of aldehydes with electron-donating
substituents showed significant levels of oligomer trunca-
tion (Fig. 2), while other reactions provided little to no
truncation. It is noteworthy that continued formation of long
oligomers at prolonged reaction times was not observed,
even for aldehydes that react poorly or in a non-reversible
manner.
The two members of a given pair of aldehydes generally
provided identical results. The lone exception was the
benchmark pair of benzaldehyde and p-tolualdehyde.
Benzaldehyde was consumed faster under BF3-etherate or
TFA catalysis and provided a higher yield of porphyrin
under BF3-etherate than p-tolualdehyde (Fig. 1A). There
were no sharp differences in the oligomer compositions
provided by the two aldehydes. The disparities are not due
to inappropriate acid concentrations, as the acid catalysis
study found both aldehydes to require similar acid
concentrations.
Figure 3. LD-MS spectra of crude, oxidized reaction mixtures from
exchange experiments involving hexanal (RZpentyl) and heptanal (RZ
hexyl) that illustrate the assignment of the level of exchange. The region
corresponding to the m/z ratio of the possible porphyrin products is shown.
The peaks are labeled as follows: PZoligomer containing only pentyl
substituents, HZoligomer containing only hexyl substituents, and MZ
oligomers containing a mixture of pentyl and hexyl substituents. The
conditions that provide each spectrum are as follows: (A) BF3-etherate
(1.0 mM), no acid pulse, premixingZ15 h, postmixingZ4 h; (B) BF3-
etherate (1.0 mM), no acid pulse, premixingZ15 min, postmixingZ1 h;
(C) BF3-etherate (1.0 mM), acid pulse, premixingZ4 h, postmixingZ4 h;
(D) BF3-etherate (1.0 mM), acid pulse, premixingZ15 min, postmixingZ
4 h.
2.1.3. Reaction reversibility. The reversibility of the
condensations was examined by double-labeling crossover
(i.e., ‘exchange’) studies.7,8 Reactions of two aldehydes of a
given type (e.g., p-anisaldehyde and 4-ethoxybenzaldehyde)
were performed side-by-side under the conditions used in
the reaction course studies. After a defined ‘premixing
time’, an aliquot from each reaction was transferred to a
common flask and the exchange processes were allowed to

11440
G. R. Geier III, J. S. Lindsey / Tetrahedron 60 (2004) 11435–11444
treated with fresh acid catalyst (acid pulse) at the time of
mixing. At the time of mixing, the oligomer composition
(LD-MS) and the level of unreacted aldehyde (TLC
analysis) were examined. After mixing, the porphyrin
yield and oligomer composition of the combined reactions
were monitored from 4 min to 4 h. As the two aldehydes of a
given pair are of different mass, oligomers containing the
two different substituents could be distinguished by LD-MS.
The peak assignments were made as described previously.2
In the limit of no reversibility, the LD-MS spectrum would
be identical to the superimposed spectra of separate
reactions of pyrrole with each aldehyde. In the limit of
total reversibility, the oligomer composition (and thus the
LD-MS spectrum) would be identical to that obtained from
a mixed condensation of pyrrole and the two aldehydes.
Illustrative LD-MS spectra for the case of hexanal and
heptanal are shown in Figure 3. The results of all of the
exchange experiments are summarized in Table 3.
The present experiments investigated wider reaction
conditions and mixing times, and the LD-MS analysis
allows detection of exchange in all oligomer species
produced in the reaction. Thus, it is now clear that at least
some aspects of condensations of alkyl aldehydes exhibit
reversibility under some reaction conditions.
There was no strong correlation between yield of porphyrin
and extent of exchange, indicating that porphyrinogen
formation does not depend on reaction reversibility
(recovery from unproductive oligomers). The extent of
exchange was greatest at the shortest premixing times,
regardless of the addition of an acid pulse. Thus, in all cases
there appears to be gradual, irreversible damage to the
oligomers that prevents exchange processes. In all cases
where exchange was detected, the exchange occurred
gradually upon mixing the individual reactions and did
not reach a statistical level. These results indicate that while
initial oligomer formation is reversible to varying degrees
depending on the aldehyde and acid, the reversibility is
sluggish, declines over time, and cannot be overcome by
adding fresh acid catalyst.
The results led to an approximate rank ordering of aldehyde
substituents in terms of reversibility in the pyrroleC
aldehyde condensation: phenyl/p-tolylR4-alkoxyphenylO
alkyl[pentafluorophenyl/tetrafluorophenylOmesityl/2,6-
dimethylphenyl. The rank order is somewhat dependent on
the conditions of the exchange experiment as evidenced by
entries 1–4 in Table 3 that pertain to the benchmark
aldehydes. Previously, we reported observing a low level of
exchange in reactions involving alkyl aldehydes and
concluded that reactions involving such aldehydes are
largely irreversible.8 Those previous experiments were
restricted to a single reaction condition and premixing
period, and only exchange manifested in the distribution of
porphyrins upon oxidation and TLC analysis was detected.
2.2. Reactions of dipyrromethanes
5-Substituted dipyrromethanes possessing substituents
analogous to those employed in the reactions of aldehydes
were selected: phenyl (benchmark case), 4-methoxyphenyl
(electron donating), pentafluorophenyl (electron withdraw-
ing), mesityl (sterically hindered), and pentyl (alkyl). Two
general types of experiments were performed: acidolysis
and oligomerization of the dipyrromethane in the absence of
Table 3. Results of porphyrinogen exchange experimentsa
Entry
Substituent type
Acidb
Premixing
timesc
Acid pulsed
Level of exchangee
Short premixing
time
Intermediate
premixing time
Long premixing
time
1
2
3
4
5
6
7
8
Benchmark
Benchmark
Benchmark
Benchmark
e-rich
e-rich
e-rich
e-rich
e-deficient
e-deficient
e-deficient
e-deficient
Bulky
TFA
TFA
BF3-etherate
BF3-etherate
TFA
1, 4, 15 h
1, 4, 15 h
1, 4, 15 h
1, 4, 15 h
1, 2, 6 h
1, 2, 6 h
0.5, 2, 6 h
0.5, 2, 6 h
0.25, 2, 15 h
0.25, 2, 15 h
0.25, 2, 15 h
0.25, 2, 15 h
2, 4, 24 h
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
Trace-low
Medium-high
High
High-statistical
Medium
High-statistical
Medium
Medium-high
Trace
Trace
Low
Low
Trace
Trace
Low-medium
Low
Medium-high
Low
Medium-high
Low
Medium
Not detected
Trace
Trace
Trace
Not detected
Trace-low
Trace
Trace
Trace-low
Medium
Trace
Trace
Trace-low
Medium
Trace
Trace
Trace
Trace
Not detected
Not detected
Not detected
Not detected
Not detected
Not detected
Trace
TFA
BF3/EtOH
BF3/EtOH
TFA
9
10
11
12
13
14
15
16
17
18
TFA
BF3-etherate
BF3-etherate
BF3/EtOH
BF3/EtOH
TFA
TFA
BF3-etherate
BF3-etherate
Bulky
Alkyl
Alkyl
Alkyl
Alkyl
2, 4, 24 h
Low
Low
Medium
Medium
High
0.5, 4, 15 h
0.5, 4, 15 h
0.25, 4, 15 h
0.25, 4, 15 h
Trace
Trace
Low
Yes
a The reactions were performed with 10 mM each of pyrrole and aldehyde at room temperature in CH2Cl2 (for mesitaldehyde and 2,6-dimethylbenzaldehyde,
CHCl3 stabilized with amylenes was used instead of CH2Cl2). At the conclusion of the premixing time, an equal volume (7.5 mL) of each pair of reaction
mixtures was mixed in a common flask. The combined mixture was monitored for exchange at 4 min, 15 min, 1 h, and 4 h by LD-MS.
b Refer to Table 2 for acid concentrations.
c The three values refer to the short, intermediate, and long premixing times listed in the final three columns of this table. A level of unreacted aldehyde of
!10% was present in each exchange experiment except with benzaldehyde and p-tolualdehyde under BF3-etherate (1.0 mM) catalysis. Both aldehydes
react slowly under BF3-etherate catalysis. The level of unreacted aldehyde at the three premixing times are as follows: 1 h: w30% benzaldehyde and
w70% p-tolualdehyde, 4 h: w15% benzaldehyde and w35% p-tolualdehyde, and 15 h: !5% benzaldehyde and w20% p-tolualdehyde.
d The acid pulse provided a quantity of fresh acid catalyst equal to that initially present (i.e., the overall acid concentration is doubled).
e The level of exchange by 4 h after mixing ranges from not detected/trace/low/medium/high/statistical.

G. R. Geier III, J. S. Lindsey / Tetrahedron 60 (2004) 11435–11444
11441
in Table 4, and representative LD-MS spectra are provided
in the Supplementary data.
5-Mesityldipyrromethane was found to be stable towards
all conditions investigated (Table 4, entries 13–15), and
5-pentafluorophenyldipyrromethane only underwent signifi-
cant, albeit slow reaction under BF3-etherate catalysis
(entries 9 and 12). The other dipyrromethanes generally
underwent rapid reaction (except under the low scrambling
conditions). Interestingly, 5-(4-methoxyphenyl)dipyrro-
methane underwent significant reaction in the presence of
1.0 mM BF3-etherate (entry 5) even though the same
condition fails to cause pyrroleCp-anisaldehyde to produce
detectable porphyrin. Accordingly, the failure of the
p-anisaldehydeCpyrrole reaction with 1.0 mM BF3-
etherate to give porphyrin must originate in the initial
condensation rather than subsequent steps of oligomer or
porphyrinogen formation. With the exception of 5-mesityl-
dipyrromethane, each dipyrromethane provided a yield of
porphyrin and oligomer composition similar to the reaction
of pyrroleCaldehyde under at least one of the conditions
investigated. Thus, the extent of reversibility from the
starting point of pure dipyrromethane is greater than that
obtained from the mixing of diverse species in the exchange
experiments (where statistical exchange was not observed).
Scheme 2.
added aldehyde, and reaction of a dipyrromethane and an
aldehyde.
2.2.1. Acidolysis and oligomerization. Each dipyrro-
methane (10 mM) was treated with acid catalysis conditions
in the absence of any added aldehyde (Scheme 2). The acid
catalysis conditions include (a) those identified herein for
porphyrin formation in the corresponding pyrroleCalde-
hyde reaction, (b) the standard condition of TFA (20 mM),
(c) the standard condition of BF3-etherate (1.0 mM), and (d)
our previously reported ‘low scrambling’ condition for the
condensation of sterically unhindered dipyrromethanes and
an aldehyde leading to trans-A2B2-porphyrins (1.0 mM
BF3-etherate, 100 mM NH4Cl, in MeCN at 0 8C).14 The
latter condition was employed to better discriminate among
those dipyrromethanes that are particularly susceptible
toward acidolysis. The reactions were monitored from
4 min to 4 h for yield of porphyrin (UV–Vis) and oligomer
composition (LD-MS). Observation of peaks in the LD-MS
spectrum due to the porphyrin and to oligomers of mass
greater than the dipyrromethane imply scrambling pro-
cesses, as their formation requires acidolysis of the
dipyrromethane and further reaction of the resulting
fragments. The results of the experiments are summarized
2.2.2. Reaction of a dipyrromethane and an aldehyde.
Reactions of a dipyrromethane with an aldehyde bearing a
complementary substituent (e.g., 5-pentafluorophenyl-
dipyrromethaneC2,3,5,6-tetrafluorobenzaldehyde; 5 mM
each; Scheme 3) were performed under conditions identified
for the corresponding pyrroleCaldehyde reaction. The
Table 4. Results upon treatment of dipyrromethanes with acid (in the absence of added aldehyde)
Entry
R in R-dipyrro-
methane
Reaction conditiona
Detection of
porphyrinb
Maximum
porphyrinc
% Porphyrind
Oligomer
formatione
1
2
3
4
5
6
7
Phenyl
Phenyl
Phenyl
4-MeO-phenyl
4-MeO-phenyl
4-MeO-phenyl
4-MeO-phenyl
TFA, 20 mM
15 min
30 min
NDf
!4 min
15 min
4 h
1 h
4 h
35
33
NDf
36
41
6
Yes
Yes
Trace
Yes
Yes
BF3-etherate, 1.0 mM
Low scrambling
TFA, 20 mM
BF3-etherate, 1.0 mM
Low scrambling
BF3-etherate/EtOH, 3.3/
130 mM
NDf
15 min
1 h
4 h
Yes
Yes
!4 min
15 min
38
8
9
C6F5
C6F5
C6F5
C6F5
C6F5
Mesityl
Mesityl
Mesityl
TFA, 20 mM
NDf
1 h
NDf
4 h
NDf
15
Trace
Yes
Yes
Yes
Yes
Trace
Trace
Trace
BF3-etherate, 1.0 mM
Low scrambling
TFA, 215 mM
BF3-etherate, 10 mM
TFA, 20 mM
BF3-etherate, 1.0 mM
BF3-etherate/EtOH, 3.3/
130 mM
10
11
12
13
14
15
NDf
NDf
4 h
NDf
3
30 min
30 min
NDf
4 h
13
NDf
NDf
NDf
NDf
NDf
NDf
NDf
NDf
16
17
18
19
Pentyl
Pentyl
Pentyl
Pentyl
TFA, 20 mM
!4 min
!4 min
!4 min
1 h
15 min
4 h
30 min
4 h
23
25
25
10
Yes
Yes
Yes
Yes
BF3-etherate, 1.0 mM
TFA, 10 mM
Low scrambling
a The reactions were performed with 10 mM of dipyrromethane. With the exception of the low scrambling condition, reactions were performed at room
temperature in CH2Cl2 (for mesitaldehyde and 2,6-dimethylbenzaldehyde, CHCl3 stabilized with amylenes was used instead of CH2Cl2). The low
scrambling conditions are as follows: BF3-etherate (1.0 mM), NH4Cl (100 mmol lK1), in MeCN at 0 8C. The reactions were monitored at 4 min, 15 min,
30 min, 1 h, and 4 h.
b The time at which porphyrin was first detected (UV–Vis) in an oxidized aliquot of the reaction mixture (limit of detection is 0.5%).
c The time at which the highest yield of porphyrin was observed.
d The highest yield of porphyrin observed. The yield is based on the stoichiometry of 1 equiv of porphyrinogen per 4 equiv of dipyrromethane.
e Detection of oligomers (LD-MS) of m/z greater than that of the dipyrromethane. ‘Trace’ means that only a small number of peaks of intensity close to the limit
of detection were observed.
f
No porphyrin was detected at any timepoint (limit of detection is 0.5%).

11442
G. R. Geier III, J. S. Lindsey / Tetrahedron 60 (2004) 11435–11444
reactions were monitored from 4 min to 8 h for yield of
porphyrin (UV–Vis) and oligomer composition (LD-MS).
Acidolysis and scrambling were assessed by examination of
the LD-MS spectra,4 where peaks due to expected
oligomers, oligomers formed by acidolysis, and oligomers
produced by scrambling are readily identified. The results of
these experiments are summarized in Table 5, and
illustrative LD-MS spectra are provided in Figure 4. Similar
reactions and analyses were performed for the reaction of
each dipyrromethaneCbenzaldehyde (see Supplementary
data).
With the exception of 5-mesityldipyrromethane and
5-pentafluorophenyldipyrromethane, condensations per-
formed in the presence of a complementary aldehyde or
benzaldehyde generally exhibited scrambling very early in
the reaction and the level of scrambling reached statistical
levels by the time the maximum yield of porphyrinogen was
obtained. 5-(4-Methylphenyl)dipyrromethane was found to
undergo scrambling more rapidly than 5-phenyldipyrro-
methane, even under the ‘low scrambling’ conditions (see
Supplementary data for LD-MS spectra). Thus, differences
between benzaldehyde and p-tolualdehyde observed during
the studies of pyrroleCaldehyde condensations may also
stem from different stability of oligomers bearing phenyl vs.
p-tolyl substituents. Although in this study aldehydes of
related structure generally behaved similarly, the contrast-
ing behavior of benzaldehyde and p-tolualdehyde does show
that small electronic differences can alter the course and
outcome of the reaction.
3. Outlook
The ability to prepare porphyrinic macrocycles bearing
diverse substituents is essential for a broad range of
applications. The objectives of this study were to examine
the catalytic requirements of a range of aldehydes, to better
understand the effects of diverse substituents on the reaction
course in terms of yield of porphyrin, reaction of aldehyde,
composition of the oligomers, and reversibility of poly-
pyrromethane and porphyrinogen formation, and to better
Scheme 3.
Table 5. Results of reactions of dipyrromethanes with their partner aldehydesa
Entry
R in R-dipyrro- Aldehyde
methane
Reaction
condition
Timeb
% Porphyrin
Scramblingc
Onset of
scramblingd
substituent
1
2
3
4
Phenyl
Phenyl
4-MeO-phenyl
4-MeO-phenyl
p-Tolyl
p-Tolyl
4-EtO-phenyl
4-EtO-phenyl
TFA, 20 mM
BF3-etherate, 1.0 mM
TFA, 20 mM
BF3-etherate/EtOH, 3.3/
130 mM
TFA, 215 mM
BF3-etherate, 10 mM
BF3-etherate/EtOH, 3.3/
130 mM
15 min
30 min
15 min
4 min
45
33
34
38
Statistical
Statistical
Statistical
Statistical
!4 min
15 min
!4 min
!4 min
5
6
7
C6F5
C6F5
Mesityl
2,3,5,6-F4-phenyl
2,3,5,6-F4-phenyl
2,6-Me2-phenyl
4 min
15 min
4 h
15
20
35
Low level
Statistical
Nonee
!4 min
!4 min
NA
8
9
Pentyl
Pentyl
Hexyl
Hexyl
TFA, 10 mM
BF3-etherate, 1.0 mM
4 min
15 min
22
31
Statistical
Statistical
!4 min
!4 min
a Thereactionswereperformedwith5 mMeachofdipyrromethane and aldehyde at the 15 ml scale at room temperature in CH2Cl2 (for 5-mesityldipyrromethane
and 2,6-dimethylbenzaldehyde, CHCl3 stabilized with amylenes was used instead of CH2Cl2). The reactions were monitored at 4 min, 15 min, 30 min, 1 h,
4 h, and 8 h.
b The time at which the yield of porphyrin reached its maximum value.
c Level of scrambling (LD-MS) at the time of maximum yield of porphyrin. Refer to Figure 4 for representative LD-MS spectra.
d The time at which scrambling was first detected (LD-MS).
e Peaks were observed that may be assigned to oligomers produced by acidolysis, but no scrambling was detected.

G. R. Geier III, J. S. Lindsey / Tetrahedron 60 (2004) 11435–11444
11443
a medium to high level of reversibility. The same aldehydes
with TFA catalysis generated a higher level of turnover in
porphyrinogen with a commensurate increase in level of
oligomer truncation. Turnover in porphyrinogen level and
extent of oligomer truncation were not always correlated.
For example, the reaction of p-anisaldehyde gave near-
total turnover (w35% yield of porphyrin at 1 h; !4% at
24 h) with both TFA and BF3-ethanol catalysis, but the
oligomer truncation was pronounced in the former yet low
in the latter. The condensations with mesitaldehyde and
pentafluorobenzaldehyde were generally irreversible, as
evidenced by the lack of porphyrinogen and
oligomer exchange. This finding illustrates that reversibility
is not a prerequisite for achieving a good yield of the
porphyrin.
The level of scrambling observed with various 5-substituted
dipyrromethanes is somewhat dependent on the reaction
conditions. Nevertheless, dipyrromethanes bearing phenyl,
alkyl, and electron-donating aryl groups were generally
prone to scrambling, while 5-pentafluorophenyldipyrro-
methane was very insensitive and 5-mesityldipyrromethane
was essentially inert toward scrambling. This order is
largely in agreement with the results of the porphyrinogen
exchange experiments, although the extent of scrambling
was often much greater than the level of exchange produced
in the corresponding pyrroleCaldehyde reaction. These
observations provide guidance for the design of synthetic
plans that minimize the potential for undesired scrambling.
Acknowledgements
This work was supported by the NIH (GM36238). 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 NSF.
Figure 4. LD-MS spectra of crude, oxidized reaction mixtures from
condensation of a dipyrromethane (R1-DPM) with an aldehyde bearing a
complementary substituent (R2-CHO). The yield of porphyrin was
determined by UV–Vis analysis. The panels illustrate the following: (A)
a low level of scrambling, and (B) statistical scrambling. The peaks are
labeled as follows: EZexpected oligomers, AZoligomers formed by
acidolysis, and SZoligomers produced by scrambling. The peaks were
assigned as described previously.4
Supplementary data
delineate the propensity for reversible processes leading to
scrambling in reactions of dipyrromethanes.
Complete experimental section, plots of the yield of
porphyrin as a function of acid concentration, and plots of
the yield of porphyrin and the percent unreacted aldehyde as
a function of condensation time for all aldehydes examined;
LD-MS spectra showing the oligomer composition at each
timepoint for all reactions of pyrroleCaldehyde examined;
data pertaining to studies of 5-substituted dipyrromethanes
bearing diverse substituents.
Examination of the catalytic requirements of the pyrroleC
aldehyde condensations revealed that quite a broad range of
acid concentrations can be employed as long as the differing
reaction trajectories resulting from the various aldehydes
are taken into account. Application of one or both of the
standard catalysis conditions [TFA (20 mM) or BF3-
etherate (1.0 mM)] results in reasonable yields of porphyrin
for most aldehydes (except sterically bulky aldehydes such
as mesitaldehyde) provided that the condensation is
monitored so that the oxidant is added at the time of
maximum yield of porphyrinogen.
Supplementary data associated with this article can be found
at doi:10.1016/j.tet.2004.09.081
References and notes
The reaction course of the pyrroleCaldehyde condensations
showed dependence on reaction conditions and aldehyde
substituent. The reactions of the phenyl, p-tolyl, and alkyl
aldehydes using BF3-etherate generally afforded little
turnover in porphyrinogen, little oligomer truncation, and
1. Lindsey, J. S. In The Porphyrin Handbook; Kadish, K. M.,
Smith, K. M., Guilard, R., Eds.; Academic: San Diego, CA,
2000; Vol. 1, pp 45–118.

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G. R. Geier III, J. S. Lindsey / Tetrahedron 60 (2004) 11435–11444
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