The breaking and mending of porphyrins: Reductive coupling of secochlorin bisaldehydes

Article abstract of DOI:10.1016/j.tetlet.2012.04.137

The reaction of free base or Ni(II) complex secochlorin bisaldehydes 4H₂ and 4Ni regenerates the ultimate starting material of the bisaldehydes, meso-tetraphenylporphyrin 2H₂ and 2Ni, respectively. Depending on the reaction conditions employed (hydrazine hydrate in pyridine at reflux or hydrazine hydrate activated with sulfur in the presence of aqueous NaOH at ambient temperature), either porphyrin 2H₂ is formed together with known dihydroxymorpholinochlorin 9H₂ or known 2-hydroxychlorin 8H₂. Two different reaction pathways for the hydrazine reaction can be derived, either involving the formation of a meso-tetraphenyl-1,4,5- triazepinoporphyrin that loses spontaneously N₂ or a Wolff-Kishner-type pathway that also involves an intramolecular aldol-type reaction. Neither reaction is synthetically useful but both highlight in an impressive fashion the high thermodynamic stability of porphyrins. They also bring the 'breaking and mending of porphyrin' strategy to its ultimate conclusion by regenerating the starting porphyrin.

Full text of DOI:10.1016/j.tetlet.2012.04.137

Tetrahedron Letters 53 (2012) 3524–3526
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Tetrahedron Letters
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The breaking and mending of porphyrins: reductive coupling of secochlorin
bisaldehydes
⇑
Joshua Akhigbe , Lalith P. Samankumara , Christian Brückner
Department of Chemistry, University of Connecticut, Unit 3060, Storrs, CT 06269-3060, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of free base or Ni(II) complex secochlorin bisaldehydes 4H and 4Ni regenerates the ultimate
2
Received 14 April 2012
Revised 23 April 2012
Accepted 29 April 2012
Available online 3 May 2012
starting material of the bisaldehydes, meso-tetraphenylporphyrin 2H
on the reaction conditions employed (hydrazine hydrate in pyridine at reflux or hydrazine hydrate acti-
vated with sulfur in the presence of aqueous NaOH at ambient temperature), either porphyrin 2H is
formed together with known dihydroxymorpholinochlorin 9H or known 2-hydroxychlorin 8H . Two dif-
ferent reaction pathways for the hydrazine reaction can be derived, either involving the formation of a
meso-tetraphenyl-1,4,5-triazepinoporphyrin that loses spontaneously N or a Wolff–Kishner-type path-
way that also involves an intramolecular aldol-type reaction. Neither reaction is synthetically useful
but both highlight in an impressive fashion the high thermodynamic stability of porphyrins. They also
bring the ‘breaking and mending of porphyrin’ strategy to its ultimate conclusion by regenerating the
starting porphyrin.
2
and 2Ni, respectively. Depending
2
2
2
Keywords:
Porphyrins
Porphyrinoids
Pyrrole-modified porphyrins
Secochlorins
2
Reductive coupling
Ó 2012 Elsevier Ltd. All rights reserved.
The synthesis of porphyrin analogues, such as expanded por-
phyrins,1 porphyrin isomers,2 or porphyrin analogues in which
one (or, in selected cases, two) pyrrolic building blocks are re-
placed by a non-pyrrolic hetero- or carbacycle is one of the key
A single class of stable porphyrin analogues containing a seven-
membered ring in place of a pyrrole are the known tropiporphyrins,
such as example 7. This carbaporphyrin class was synthesized
along a 3+1 pathway, that is along a total synthesis route in which
a tripyrromethane and 1,3,5-cycloheptriene-1,6-dicarbaldehyde
were condensed to form the macrocycle.
1
5
3
areas of research in current porphyrin chemistry. The desire to
gain a deeper understanding of the aromatic nature of porphyrins
and the need for fine-tuned chromophores to be used in synthetic
light harvesting systems or as photo-chemotherapeutics are some
driving forces of this work.4
N
We contributed by synthesizing a range of porphyrinoids
5
6–8
containing non-pyrrolic heterocycles such as azetes, oxazoles,
9
8,10–12
13
N
N
imidazoles, morpholines,
or pyrazines along a ‘porphyrin
9
breaking and mending’ pathway. The synthesis of morpholino-
chlorin 1M illustrates this approach (Scheme 1). A meso-tetra-
arylporphyrin, 2M, is converted into the corresponding
7
1
0
diolchlorin 3M. Subsequent diol cleavage generates secochlorin
7
,14
10,11
bisaldehyde 4M,
that is subjected to a ring-closing reaction.
We showcase here an intriguing reaction that likely involves the
intermediacy of a porphyrinoid containing a seven-membered ring
that, however, cannot be isolated. Instead, it spontaneously frag-
ments to form a porphyrin. Our findings have no direct preparative
significance. However, they contribute to the understanding of the
physical and chemical properties of porphyrinoids containing
non-pyrrolic heterocycles in general, and nitrogen-rich seven-
membered rings in particular.
In one particular instance we used a bifunctional nucleophile,
9
hydroxylamine, to ring-close secochlorin 4H
ipated porphyrinoid 5H containing a seven-membered ring could
not be isolated. Instead, one of the products isolated (in 15%) at
2
. However, the antic-
2
9
that time was novel-imidazoloporphyrin 6H
mation was rationalized by the extrusion of CO
providing indirect evidence for the existence of oxadiazepinone-
derived porphyrinoid 5H
2
(Scheme 2). Its for-
2
from 5H , thus
2
2
.
Following our work on the reaction of secochlorin bisaldehyde
9
4
H
2
with hydroxylamine (Scheme 2), it seemed only logical to test
⇑
Corresponding author. Tel.: +1 860 486 2743; fax: +1 860 486 2981.
E-mail address: c.bruckner@uconn.edu (C. Brückner).
These authors contributed equally.
the reaction of bisaldehydes 4H
2
and 4Ni with hydrazine. Thus, the
bisaldehyde free base and its nickel(II) complex were heated to
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.137

J. Akhigbe et al. / Tetrahedron Letters 53 (2012) 3524–3526
3525
Ph
M
Ph
OH
The formation of the porphyrin can be rationalized: the reaction
of hydrazine with bisaldehyde 4 under imine-forming conditions
likely forms hydrazone I and subsequently the 1,4,5-triazepine-
containing porphyrinoid II. Porphyrin 2M is subsequently formed
by loss of nitrogen from this seven-membered ring intermediate.
OH
Ph
1
. OsO , py
4
2
N
N
N
N
N
2
. H S
Ph
Ph
M
From a thermodynamic point of view, this reaction certainly pos-
3M
ꢀ
sesses a greatly favorable
DH
because the likely non-planar
reaction
porphyrinoid with inherent strain is converted into very stable
products, the strain-free, planar porphyrin, and gaseous N . Mech-
anistically, a facile excision of N from 1,4,5-triazepine II is not sur-
2
M
Pb(OAc) (for 2Ni)
4
Ph
Ph
NaIO -silica (for 2H )
2
4
2
2
prising and several pathways are possible. Perhaps the most
elegant pathway involves a de facto disrotatory cyclization to form
III (alas, while electrocyclic reaction pathways are most appealing
for this reaction, this is the thermally disallowed reaction path-
OEt
M = 2H, NiII
EtOH, [H+]
Ph
CHO
O
CHO
OEt
Ph
N
N
18
way), followed by a retro-[2+2] cycloaddition of the rearrange-
M
M
Ph
ment product (Scheme 3). Interestingly, the analogous inverse
reaction steps are frequently utilized in the construction of
1
M
4M
1
9
0
seven-membered rings.
Likewise, porphyrin b,b -bonds are
Scheme 1. Synthesis of a morpholinochlorin along the ‘breaking and mending of a
20
susceptible to partake in electrocyclic reactions.
porphyrin’ strategy.
In none of the reactions were we able to isolate and directly ob-
serve the seven-membered ring product II. We reasoned that the
loss of nitrogen is assisted by the high temperature of the reaction
conditions (pyridine, reflux, 115 °C for several hours). However, a
reduction of the reaction temperature to ambient conditions also
Ph
Ph
N
H NOH,
2
N
O
oxidation
4H2
N
– CO
N
2
resulted in the formation of porphyrin 2H but accompanied by
O
2
Ph
Ph
some of the known dihydroxymorpholinochlorin 9H
product of bisaldehyde 4M with water.
2
, the reaction
7
5H2
6H2
Procedures to activate hydrazine toward hydrazone formation
were reported (H N–NH O activated with aq NaOH and ele-
mental S at elevated temperature). Using the activated hydra-
zine, a reaction at room temperature took place over the course
of two hours but one of the reaction products still proved to be por-
Scheme 2. Synthesis of imidazoloporphyrin 6H
2
via putative intermediate 5H .
2
2
2
ꢁH
2
2
1
reflux with a large stoichiometric excess hydrazine hydrate in pyr-
1
6
idine. The reaction produced a single, non-polar product in high
for the Ni(II) complex) and moderate (for the much more labile free
base bisaldehyde) yields. Much to our surprise, the products were
phyrin 2H
known b-hydroxylated chlorin 8H
2
(20% isolated yield) plus, much to our surprise, the
(
2
(in 50% isolated yield).22 Again,
the putative seven-membered ring product could not be directly
observed.
1
7
identified as porphyrins 2H
2
and 2Ni, respectively (Scheme 3).
Ph
Ph
Ph
N
N
N
N
N
N
N
N
N
N
Ph
M
Ph
M = 2H, Ni
M
M
Ph
Ph
II
III
2M
Ph
H N-NH ·H O,
2
2
2
Ph
py, Δ or r.t.
OH
Ph
Ph
CHO
N
NH2
CHO
O
CHO
N
N
N
N
N
OH
Ph
Ph
M
Ph
M
+
Ph
N
I
(observed for reaction of 4H2
9H2
at ambient temperature)
4M
H N-NH ·H O/
2 2 2
Ph
S/NaOH, r.t.
for M = 2H
Ph
H
H
N
H
OH
N
H
Ph
OH
OH
NH
N
N
H
C
Ph
Ph
+ 2H2
O
N
H
HN
Ph
IV
8
H2
Ph
Scheme 3. Formation of porphyrin 2M, b-hydroxychlorin 7H , and dihydroxymorpholinochlorin 9H by reaction of secochlorin 4M with hydrazine under varying reaction
2
2
conditions.

3
526
J. Akhigbe et al. / Tetrahedron Letters 53 (2012) 3524–3526
N
References and notes
CHO
N
CHO
1. Sessler, J. L.; Weghorn Expanded, S. Contracted & Isomeric Porphyrins; Pergamon
NH
N
N
NH
N
N
Press: New York, NY, 1997.
NH2NH2
2
.
.
Sessler, J. L.; Gebauer, A.; Vogel, E. In The Porphyrin Handbook; Kadish, K. M.,
Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, 2000; Vol. 2, pp
1–54.
(a) Lash, T. D. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R.,
Eds.; Academic Press: San Diego, 2000; Vol. 2, pp 125–200; (b) Latos-Grazynski,
L. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.;
Academic Press: San Diego, 2000; vol. 2, pp 361–416.
HN
HN
3
PrCOOH
PrCOOH
PrCOOH
PrCOOH
1
0
11
4.
Representative reviews of porphyrins in photomedicine: (a) Sternberg, E. D.;
Dolphin, D.; Brückner, C. Tetrahedron 1998, 54, 4151–4202; (b) O’Connor, A. E.;
Gallagher, W. M.; Byrne, A. T. Photochem. Photobiol. 2009, 85, 1053–1074;
Representative reviews of porphyrins in light harvesting applications: (c)
Aratani, N.; Kim, D.; Osuka, A. Acc. Chem. Res. 2009, 42, 1922–1934; (d) Gust, D.;
Moore, T. A.; Moore, A. L. Acc. Chem. Res. 2009, 42, 1890–1898.
Scheme 4. Synthesis of diazine-annulated porphyrin 11.25
2
The formation of hydroxy-chlorin 8H can also be rationalized
using a series of known reactions. Again, hydrazone I forms as a
first step. This undergoes a base-induced tautomerization to form
2
IV. Further deprotonation induces the release of N and, in effect,
a Wolff–Kishner type reduction of one aldehyde generates an anion
that undergoes an intramolecular aldol-type ring-closure reaction
with the neighboring aldehyde, thus forming hydroxychlorin 8H
Some variations in the order of reactions taking place are conceiv-
able. A loss of a water molecule from 8H –thus formally forming
the aldol condensation product–generates porphyrin 2H
Of course, we cannot exclude that the porphyrin 2H
reaction was not formed along a competing pathway involving
triazepine II. On the other hand, we assume that porphyrin 2H
5
6
.
.
Banerjee, S.; Hyland, M. A.; Brückner, C. Tetrahedron Lett. 2010, 51, 4505–4508.
(a) McCarthy, J. R.; Perez, M. J.; Brückner, C.; Weissleder, R. Nano Lett. 2005, 5,
2552–2556; (b) Ogikubo, J.; Brückner, C. Org. Lett. 2011, 13, 2380–2383.
7. Akhigbe, J.; Ryppa, C.; Zeller, M.; Brückner, C. J. Org. Chem. 2009, 74, 4927–4933.
8.
McCarthy, J. R.; Melfi, P. J.; Capetta, S. H.; Brückner, C. Tetrahedron 2003, 59,
137–9146.
9
2
.
9.
Akhigbe, J.; Peters, G.; Zeller, M.; Brückner, C. Org. Biomol. Chem. 2011, 9, 2306–
2313.
1
1
0. Brückner, C.; Rettig, S. J.; Dolphin, D. J. Org. Chem. 1998, 63, 2094–2098.
1. (a) McCarthy, J. R.; Jenkins, H. A.; Brückner, C. Org. Lett. 2003, 5, 19–22; (b)
Brückner, C.; Götz, D. C. G.; Fox, S. P.; Ryppa, C.; McCarthy, J. R.; Bruhn, T.;
Akhigbe, J.; Banerjee, S.; Daddario, P.; Daniell, H. W.; Zeller, M.; Boyle, R. W.;
Bringmann, G. J. Am. Chem. Soc. 2011, 133, 8740–8752.
2
2
.
2
in this
12. (a) Daniell, H. W.; Brückner, C. Angew. Chem., Int. Ed. 2004, 43, 1688–1691; (b)
2
Lara, K. K.; Rinaldo, C. K.; Brückner, C. Tetrahedron 2005, 61, 2529–2539.
formed under the pyridine/hydrazine hydrate conditions was
formed along the Wolff–Kishner-type pathway as the signature
conditions for Wolff–Kishner reductions are generally drastically
caustic (KOH, diethylene or ethylene glycol, 180 °C). It thus
seems plausible that the two different reaction paths delineated
lead to the products observed.
The formation of porphyrins 2 from the aldehydes 4 is formally
a reductive coupling. Interestingly, a McMurry reaction24 on seco-
chlorin bisaldehydes does not lead to the formation of a porphyrin,
a circumstance we attribute to steric effects.
13. Campbell, C. J.; Rusling, J. F.; Brückner, C. J. Am. Chem. Soc. 2000, 122, 6679–
685.
6
14. Brückner, C.; Sternberg, E. D.; MacAlpine, J. K.; Rettig, S. J.; Dolphin, D. J. Am.
Chem. Soc. 1999, 121, 2609–2610.
15. (a) Bergman, K. M.; Ferrence, G. M.; Lash, T. D. J. Org. Chem. 2004, 69,
23
7888–7897; (b) Lash, T. D.; Chaney, S. T. Tetrahedron Lett. 1996, 37,
8825–8828.
1
6. Free base or Ni(II) complex of meso-tetraphenylsecochlorin bisaldehyde 4H
4Ni (ꢂ20 mg), prepared according to literature procedures (Ref. 7,10,
respectively) was dissolved in pyridine (10 ml) in round-bottom flask
equipped with a magnetic stir bar. To this solution was added H N–NH
ꢁH
1.0 ml) and the mixture was heated to reflux for 3 h. When the starting material
2
or
a
2
2
2
O
(
was consumed (reaction control by TLC and UV–vis), the reaction mixture was
evaporated to dryness by rotary evaporation. The resulting mixture was
Perhaps the closest example of a hydrazine-induced ring-
closure reaction of a porphyrin bisaldehyde was presented by
Chaudhry and Clezy (Scheme 4).25 The b,b -bisaldehyde of the
separated on a preparative TLC plate (500
ether 30–60 1:1). Isolated yield for 2H and 2Ni after recrystallization, were up to
0% and 70%, respectively. Their spectroscopic properties were identical to those
2 2
lm silica gel–CH Cl /petroleum
2
0
5
b-octa-substituted porphyrin 10H
2
was converted into 1,2-dia-
of independently prepared materials (Ref. 17).
1
7. (a) Adler, A. D.; Longo, F. R.; Finarelli, J. D.; Goldmacher, J.; Assour, J.; Korsakoff,
L. J. Org. Chem. 1967, 32, 476; (b) Fleischer, E. B.; Miller, C. K.; Webb, L. E. J. Am.
Chem. Soc. 1964, 86, 2342–2347.
2
zine-annulated porphyrin 11H , with no report of the loss of
nitrogen from this entity.
In summary, the formation of a porphyrinoid containing a se-
ven-membered 1,4,5-triazapine moiety by reaction of a secochlo-
rin bisaldehyde is likely, but the product is unstable with respect
to the thermal excision of elemental nitrogen and concomitant for-
mation of a porphyrin. Depending on the reaction conditions em-
ployed during the reaction of the bisaldehyde secochlorin with
hydrazine, two different reaction pathways that produce some
identical products are likely. This reaction highlights the over-
whelming stability of the porphyrin framework.
18. Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. 1969, 8, 781–932.
1
2
2
2
9. (a) Hassenrück, K.; Martin, H. D. Synthesis 1988, 569–586; (b) Kantorowski, E.
J.; Kurth, M. J. Tetrahedron 2000, 56, 4317–4353.
0. Tome, A. C.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S. J. Porphyrins Phthalocyanines
2009, 13, 408–414.
1. Russavskaya, N. V.; Grabelnykh, V. A.; Levanova, E. P.; Sukhomazova, E. N. .;
Deryagina, E. N. Russ. J. Org. Chem. 2002, 38, 1551–1553.
2. An aqueous suspension of NaOH, sublimed S, and H
ratio) was heated to 80–85 °C and stirred for 2 h. The resulting solution was
cooled to ambient temperature. meso-Tetraphenylsecochlorin bisaldehyde 4H
2
N–NH
2
ꢁH
2
O (1:1:1 molar
2
(
(
ꢂ20 mg), synthesized in THF in a separate flask according to the literature
Ref. 7) shortly prior to when it was needed, was added. The mixture was
As the original porphyrin starting material was reconstituted,
our ‘porphyrin breaking and mending’ pathway has come to full
circle. Or, perhaps more correctly expressing the sentiments of
the synthetic chemist aiming at generating novel macrocycles,
our efforts were short-circuited.
stirred at ambient temperature for 2 h. The progress of the reaction was
monitored using TLC and UV–vis spectroscopy. Once the starting material was
consumed, the crude mixture was filtered (glass frit M), the filter cake
extracted with CH
using rotary evaporation. The product 8H
(silica–CH Cl ) in 40–50% yields.
2
Cl
2
, and the combined filtrates were evaporated to dryness
2
was isolated by preparative TLC
2
2
2
3. (a) Todd, D. Org. React. 1948, 4, 378–422; (b) Hutchins, R. O. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 8, pp 327–362; (c) Reusch, W. In Reduction; Augustine, R. L., Ed.; Dekker:
New York, 1968; pp 171–211.
Acknowledgments
2
2
4. Fürstner, A. In Transition Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.;
Wiley-VCH: Weinheim, 2004; Vol. 1, pp 449–468.
5. Chaudhry, I. A.; Clezy, P. S. Austr. J. Chem. 1982, 35, 1185–1201.
This work was supported by the NSF (CHE-0517782 and CHE-
058846). We thank Claudia Ryppa for the McMurry coupling
1
experiments of 4H /4Ni.
2