Synthesis, structure, and complexation properties of partially and completely reduced meso-octamethylporphyrinogens (calix[4]pyrroles)

Article abstract of DOI:10.1002/anie.200804937

(Figure Presented) New tricks for an old dog: Calixpyrroles bind anions efficiently and can be transformed into transition-metal complexes only under forcing conditions. Reducing the macrocycle creates a ligand that easily forms classical Werner complexes with copper, nickel, and palladium ions. The metal complexes present an array of four directed hydrogen bonds, which specifically bind the counterions (see picture; blue N, white H, green Cl, red Cu, Ni, or Pd).

Full text of DOI:10.1002/anie.200804937

Communications
DOI: 10.1002/anie.200804937
Porphyrinoids
Synthesis, Structure, and Complexation Properties of Partially and
Completely Reduced meso-Octamethylporphyrinogens
(Calix[4]pyrroles)**
Valeria Blangy, Christoph Heiss, Vsevolod Khlebnikov, Christophe Letondor, Helen Stoeckli-
Evans,* and Reinhard Neier*
Many organic ligands used by nature in important biological
processes[1–5] are formed by the condensation of simple
starting materials.[6–9] Uroporphyrinogen III, the biosynthetic
precursor of the “pigments of life”, forms metal complexes
only under specific reaction conditions.[10–12] Most uropor-
phyrinogens acquire this capacity by oxidation or by tauto-
merization of the ligand.[2,12,13]
As they have numerous applications, macrocyclic nitro-
gen-containing ligands and their metal complexes have been
thoroughly studied.[35–41] Reducing calixpyrroles might lead to
new nitrogen-containing ligands with interesting properties.
Here we report the synthesis and structures of partially and
total reduced meso-octamethylporphyrinogens and the com-
plexes formed with CuII, NiII, and PdII salts. To the best of our
knowledge the successful reduction of meso-octaalkylpor-
phyrinogens has not been described previously. Reductions of
pyrroles usually require relatively harsh conditions.[42] Most
efficient reductions of alkyl pyrroles require an acid as the
solvent or as a component of the solvent mixture. Acidic
conditions are also used to synthesize meso-octaalkylpor-
phyrinogens but at the same time these conditions trigger the
opening of the macrocycle. It was not apparent whether
experimental conditions could be found that would allow the
reduction of all pyrrole rings before the macrocycle would be
destroyed.[17]
The first meso-octaalkylporphyrinogen was synthesized
more than 120 years ago by Baeyer.[14] The correct structure
was proven by Rothemund in 1955.[15–17] Forty years later the
X-ray structure analysis of this class of compounds showed
alternating conformations of the pyrrole rings in the solid
state.[18] The X-ray structures of these macrocycles acting as
ion-pair receptors revealed a conelike conformation and
resembled the structures observed for calixarenes.[18–20] For
this reason the name calix[4]pyrroles was proposed as a trivial
name for the meso-octaalkylporphyrinogens.[18] Hydrogen
bonding, the dominating mode of interaction of neutral
calixpyrroles, allows these compounds to be used as anion
sensors.[21–23] Many interesting modifications of calixpyrroles
have been reported: calixphyrins,[24,25] hybrids between cal-
ixpyrroles and porphyrins, expanded calixpyrroles like the
calix[6]pyrroles,[26] and calixpyridines, hybrids containing
pyrroles and pyridines.[27–29] Many of these studies were
carried out with the aim to improve the anion-binding
properties.[19,30,31] To obtain Werner-type metal complexes
from calix[4]pyrroles the ligand must be deprotonated using
butyllithium.[10,32–34]
We started to screen reduction conditions with the hope of
finding an experimental procedure for the reduction of meso-
octamethylporphyrinogens (Scheme 1). First we avoided the
use of acids as we feared competition between acid-catalyzed
destruction and acid-catalyzed reduction. Our initial
attempts, where we varied the temperature (from 508C to
[*] Dr. V. Blangy, Dr. C. Heiss, V. Khlebnikov, Dr. C. Letondor,
Prof. Dr. R. Neier
Institut de Chimie, Universitꢀ de Neuchꢁtel
rue Emile-Argand 11, 2009 Neuchꢁtel (Switzerland)
Fax: (+41)327-182-511
E-mail: Reinhard.Neier@unine.ch
Homepage: http://www2.unine.ch/cho
Prof. Dr. H. Stoeckli-Evans
Institut de Physique, Universitꢀ de Neuchꢁtel
rue Emile-Argand 11, 2009 Neuchꢁtel (Switzerland)
Fax: (+41)327-182-511
E-mail: Helen.Stoeckli-Evans@unine.ch
[**] This work was supported by the Swiss National Science Foundation
(Grant No. 2000-067057.01) and the University of Neuchꢁtel. This
work is part of the thesis of V.B. We thank Dipl.-Chem. Michael
Schmid (Neuchꢁtel), Dr. Lydia Brelot (Neuchꢁtel), and Christopher
Jones (Cambridge) for preliminary experiments.
Scheme 1. Synthesis and catalytic hydrogenation of meso-octamethyl-
calix[4]pyrrole (1). a) H3CSO3H, EtOH, 35!458C, 15 min; b) H2
(100 atm), Pd/C, CH3COOH, 1008C, Pd/substrate 13.3:100, 24 h.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804937.
1688
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 1688 –1691

Angewandte
Chemie
2008C), the hydrogen pressure (from 80 to 150 atm) and the
catalyst (for example, Raney nickel and Rh on Al2O3), met
with no success. We isolated either recovered starting material
or reduced monopyrroles. We started to add increasing
amounts of acids in the hope of accelerating the reduction
process and avoiding as much as possible the competing ring-
opening.
Initially this approach was not successful, and only
reduced degradation products could be isolated. However,
when we used glacial acetic acid as the solvent, we could
isolate a product that a molecular-ion peak at m/z 437 [M +
H]+ in its electrospray ionization mass spectrum (ESI-MS).
This indicated that four of the eight double bonds of the meso-
octamethylporphyrinogen 1 had been reduced. Under these
unoptimized conditions (Pd/C, 85 atm H2 at 558C) the
partially reduced product was obtained as a mixture of two
diastereoisomers, as indicated in the 13C NMR spectrum of
the raw material. On refining the hydrogenation conditions
(higher temperatures and pressures) we obtained only the
major diastereoisomer 2 (Scheme 1). The 13C NMR spectrum
of 2 shows only seven signals indicating that the pyrrolidine
rings and pyrrole rings are alternating. The X-ray structure[43]
of the partially reduced meso-octamethylporphyrinogen 2
(Figure 1) confirmed this hypothesis.
also ref. [29]) and is responsible for the properties of this
compound, which is a weak base.
In isolating the 1,3-bis-reduced compound 2, we were
surprised not to find the 1,2-bis-reduced isomer. One
explanation is that the 1,3-regioisomer is protected against
the acid-catalyzed degradation, whereas the 1,2-bis-reduced
compound can still undergo acid-catalyzed ring-opening.
Compound 2 is water soluble in its diprotonated form,
whereas the monoprotonated ligand precipitates out of water.
The hydrogen-bonding network (vide supra) influences the
acid–base behavior and probably the solubility of this new
compound. Finally, it seems reasonable that once one of the
pyrrole rings had been reduced on the surface of the catalyst,
the second reduction should occur on the same face of the
molecule. So with hindsight the structure of compound 2 can
be rationalized. Attempts to reduce 2 further were not
successful even under optimized conditions.
In the ESI mass spectrum of the crude product we
detected a compound exhibiting a peak at m/z 445, which
corresponds to the monoprotonated form of the completely
reduced calixpyrrole 3 (Scheme 1). Isolating this compound in
pure form proved to be difficult. By careful chromatography
using neutral aluminum oxide we finally obtained small
quantities of the completely reduced compound 3 as a white
solid. The 13C NMR spectrum of 3 shows five signals, which
consistent with a structure in which all the hydrogen atoms at
the ring junctions point in the same direction. Despite
considerable efforts we have not been able to improve
significantly the yield of the completely reduced compound 3.
Currently the conditions given in Scheme 1 are the best
compromise we have found between the degradation of the
macrocycle and the formation of the completely reduced
product 3.
In order to test the ability of ligand 3 to chelate different
metals, we prepared complexes of CuII, NiII, and PdII
following a similar procedure by mixing one equivalent of 3
with one equivalent of the metal salt in an appropriate solvent
(Scheme 2). The complexation with CuII occurs smoothly
when copper(II) chloride is heated with the reduced com-
pound 3 in ethanol for 2 h. The complex formation can be
conveniently followed by UV absorption at 284 nm. The UV
spectra of the reaction mixture showed an isosbestic point at
248 nm. The nickel complex was prepared by the same
procedure. The PdII complex was prepared from palladi-
um(II) acetate in dichloromethane. In this case, according to
Figure 1. Molecular structure of 2 with thermal ellipsoids drawn at the
50% probability level. Atoms N1 and N1i and N2 and N2i are related
ꢀ
by the crystallographic twofold axis. N H···N hydrogen bonds are
shown as dashed lines.
The conformation of 2 is dramatically different from that
of the starting compound 1. The two pyrrole rings in 2 are
almost coplanar, and the two hydrogen atoms on the nitrogen
atoms point towards the center of the macrocycle. The two
pyrrolidine rings are almost orthogonal to the plane of the
macrocycle. The hydrogen atoms at the ring junctions as well
as those on N1i and N1 of the pyrrolidine residues point
towards the outside of the macrocycle. The protons of the
pyrroles are hydrogen-bonded to the basic nitrogen atoms of
the pyrrolidine rings. The hydrogen-bonding network deter-
mines the conformation of this compound in the crystal (see
Scheme 2. Synthesis of complexes 4–6. 4: CuCl2·H2O, EtOH, reflux,
2 h. 5: NiCl2·6H2O, EtOH, reflux, 24 h. 6: Pd(AcO)2, CH2Cl2, reflux,
24 h.
Angew. Chem. Int. Ed. 2009, 48, 1688 –1691
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1689

Communications
mass and NMR analyses, the acetate ligands were partially
hydrogen bonds arranged by two symmetry-related macro-
cycle units (Figure 2c). Two different X-ray structures of the
palladium complex have been obtained depending on the
solvent used for the recrystallization. By slow evaporation of
a solution of 6 in dichloromethane we obtained an ortho-
rhombic polymorph (structure in Figure 2c), while a mono-
clinic polymorph, with two independent molecules per
asymmetric unit, was obtained when a solution of 6 in
dichloromethane and chloroform was concentrated by slow
evaporation. The monoclinic and orthorhombic structures are
similar, except for the position of the chloride counterions
and solvent molecules of crystallization (structures and data
are shown in the Supporting Information).[43]
In conclusion, we have developed a procedure for the
partial or total reduction of meso-octaalkylporphyrinogens.
The product of partial reduction is surprisingly stable, and
only the regioisomer of the 1,3-reduction was isolated. The
completely reduced compound is a strong base and smoothly
forms metal complexes, as shown by the formation of the CuII,
NiII, and PdII complexes. The reduction of the meso-octaal-
kylporphyrinogen 1 has changed the properties of this
skeleton. The meso-octaalkylporphyrinogens are known to
be anion binders, but in their reduced form they behave like
normal nitrogen-containing macrocycles. Moreover, the
metal complexes of reduced calix[4]pyrrole may maintain
their anion-binding ability through the hydrogen-bond net-
work. As a result of the four five-membered rings the
conformational mobility of this ligand is rather limited. In the
metal chelate, the quasi-axial arrangement of the substituents
exchanged by chloride during the reaction. Chlorinated
solvents contain and continuously form small quantities of
hydrogen chloride. Remaining acetate ligands were smoothly
replaced by chloride when the complex was washed with a
brine solution.
Suitable crystals of complexes 4–6 were obtained
(Figure 2).[43] Interestingly, the X-ray structures of these
complexes are very similar. In all the complexes, the four
nitrogen atoms of the macrocycle are arranged nearly in a
plane, and four of the eight methyl groups bound to the
meso carbons are arranged in a quasi-axial arrangement,
whereas the four others point away from the macrocycle in a
quasi-equatorial position. The nickel and copper complexes
show a quasi-octahedral coordination sphere of the metal ion,
and two chloride ions are within bonding distance of the metal
ion (Figure 2a,b). In the copper complex 4, one chloride ion is
linked directly to the metal center, whereas the other is held
in place by the hydrogen network provided by the four NH
groups of the pyrrolidine residues. In the nickel complex 5
both chloride ions are within bonding distance to the metal.
The chloride labeled Cl2 is fixed through a hydrogen-bonding
network similar to that in the copper complex. In the solid-
state structure of the palladium complex 6 the Pd–Cl
distances, ranging from 3.05 to 3.11 ꢀ, are too long to be
interpreted as formal bonds. As with the NiII and CuII
complexes, hydrogen-bonding between one chloride ion and
the NH groups of the pyrrolidine residues was observed. In
this case, the central chloride ion is bound through four NH
Figure 2. Molecular structure of complexes 4, 5, and 6 with thermal ellipsoids drawn at the 50% probability level. Dotted lines indicate NH···Cl
interactions (solvent molecules and most hydrogen atoms have been removed for clarity). Selected distances (in ꢂ): a) Cu complex 4: Cu1–N
2.109–2.136, NH···Cl2 2.60–2.84, Cu1–Cl1 2.432(1) ꢂ; b) Ni complex 5: Ni1–N 2.139–2.153, NH···Cl2 2.65–2.76 ꢂ, Ni1–Cl1 2.359(1), Ni1–Cl2
2.550(1); c) Pd complex 6: Pd1–N 2.082–2.093; NH···Cl2b 2.68–2.93 ꢂ, Pd1–Cl1 3.115(2) ꢂ.
1690 www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 1688 –1691

Angewandte
Chemie
[22] J. L. Sessler, P. A. Gale in The Porphyrin Handbook, Vol. 6
at the meso positions may form a cavity. These structural and
chemical properties should allow the synthesis of interesting
new metal complexes.
(Eds.: K. M. Kadish, K. M. Smith, R. Guilard), Academic Press,
San Diego, 2000, p. 257.
[23] P. A. Gale, Coord. Chem. Rev. 2000, 199, 181.
[24] C. Bucher, D. Seidel, V. Lynch, V. Kral, J. L. Sessler, Org. Lett.
2000, 2, 3103.
[25] V. Krꢃl, J. L. Sessler, R. S. Zimmerman, D. Seidel, V. Lynch, B.
Andrioletti, Angew. Chem. 2000, 112, 1097; Angew. Chem. Int.
Ed. 2000, 39, 1055.
[26] B. Turner, M. Botoshansky, I. Eichen, Angew. Chem. 1998, 110,
2633; Angew. Chem. Int. Ed. 1998, 37, 2475.
[27] P. A. Gale, J. L. Sessler, V. Kral, Chem. Commun. 1998, 1.
[28] J. L. Sessler, W.-S. Cho, V. Lynch, V. Krꢄl, Chem. Eur. J. 2002, 8,
1134.
[29] V. Krꢃl, P. A. Gale, P. Anzenbacher, Jr., K. Jursꢅkovꢃ, V. Lynch,
J. L. Sessler, Chem. Commun. 1998, 9.
Received: October 9, 2008
Published online: December 30, 2008
Keywords: hydrogen bonds · hydrogenation · metal complexes ·
.
N ligands · porphyrinoids
[1] D. Voet, J. G. Voet, Biochemistry, Wiley, New York, 1990.
[2] H. Scheer, Chlorophylls, CRC Press, Boca Raton, 1991.
[3] B. Krꢁutler, Biochem. Soc. Trans. 2005, 33, 806.
[4] B. Krꢁutler, S. Ostermann in The Porphyrin Handbook, Vol. 11
(Eds.: K. M. Kadish, K. M. Smith, R. Guilard), Academic Press,
San Diego, 2003, p. 229.
[30] D.-W. Yoon, H. Hwang, C.-H. Lee, Angew. Chem. 2002, 114,
1835; Angew. Chem. Int. Ed. 2002, 41, 1757.
[31] K. A. Nielsen, W.-S. Cho, J. Lyskawa, E. Levillain, V. M. Lynch,
J. L. Sessler, J. O. Jeppesen, J. Am. Chem. Soc. 2006, 128, 2444.
[32] D. Jacoby, C. Floriani, A. Chiesi-Villa, C. Rizzoli, J. Chem. Soc.
Chem. Commun. 1991, 220.
[33] J. Jubb, D. Jacoby, C. Floriani, A. Chiesi-Villa, C. Rizzoli, Inorg.
Chem. 1992, 31, 1306.
[34] L. Bonomo, E. Solari, R. Scopelliti, C. Floriani, Chem. Eur. J.
2001, 7, 1322.
[35] M. Studer, A. Reisen, T. A. Kaden, Helv. Chim. Acta 1989, 72,
1253.
[36] E. Kimura, Y. Kodama, M. Shionoya, T. Koike, Inorg. Chim.
Acta 1996, 246, 151.
[37] P. Bryan, J. C. Dabrowiak, Inorg. Chem. 1975, 14, 296.
[38] Z. Guo, P. J. Sadler, Angew. Chem. 1999, 111, 1610; Angew.
Chem. Int. Ed. 1999, 38, 1512.
[5] B. Krꢁutler, Chimia 1987, 41, 277.
[6] H.-J. Kwon, W. C. Smith, A. J. Sharon, S. H. Hwang, M. J. Kurth,
B. Shen, Science 2002, 297, 1327.
[7] S. S. Lamb, G. D. Wright, Proc. Natl. Acad. Sci. USA 2005, 102,
519.
[8] A. R. Battersby, F. J. Leeper, Top. Curr. Chem. 1998, 195, 143.
[9] A. I. Scott, J. Org. Chem. 2003, 68, 2529.
[10] C. Floriani, Chem. Commun. 1996, 1257.
[11] C. Floriani, R. Floriani-Moro in The Porphyrin Handbook,
Vol. 3 (Eds.: K. M. Kadish, K. M. Smith, R. Guilard), Academic
Press, San Diego, 2000, p. 385.
[12] A. Eschenmoser, Angew. Chem. 1988, 100, 5; Angew. Chem. Int.
Ed. Engl. 1988, 27, 5.
[13] L. R. Milgrom, The Color of life, Oxford University Press,
Oxford, 1997.
[39] J. E. Hage, J. E. Iburg, J. Kerschner, J. H. Koek, E. L. M.
Lempers, R. J. Martens, U. S. Racherla, S. W. Russell, T. Swarth-
off, M. R. P. Van Vliet, J. B. Warnaar, L. Van der Wolf, B.
Krijnen, Nature 1994, 369, 637.
[40] D. De Vos, T. Bein, Chem. Commun. 1996, 917.
[41] D. E. De Vos, T. Bein, J. Organomet. Chem. 1996, 520, 195.
[42] R. A. Jones in Comprehensive Heterocyclic Chemistry, Vol. 4
(Eds.: C. W. Bird, G. W. H. Cheeseman), Pergamon Press,
Oxford, 1984, p. 255.
[43] CCDC 688525 (2), 688526 (4), 704348 (5), 702636 (6-ortho-
rhombic), and 702635 (6-monoclinic) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[14] A. Baeyer, Ber. Dtsch. Chem. Ges. 1886, 19, 2184.
[15] V. V. Chelintzev, B. V. Tronov, S. G. Karmanov, J. Russ. Phys.-
Chem. Soc. 1916, 48, 1210.
[16] V. V. Chelintzev, B. V. Tronov, Chem. Abstr. 1917, 11, 452.
[17] P. Rothemund, C. L. Gage, J. Am. Chem. Soc. 1955, 77, 3340.
[18] P. A. Gale, J. L. Sessler, V. Kral, V. Lynch, J. Am. Chem. Soc.
1996, 118, 5140.
[19] R. Custelcean, L. H. Delmau, B. A. Moyer, J. L. Sessler, W.-S.
Cho, D. Gross, G. W. Bates, S. J. Brooks, M. E. Light, P. A. Gale,
Angew. Chem. 2005, 117, 2593; Angew. Chem. Int. Ed. 2005, 44,
2537.
[20] V. Bꢂhmer, Angew. Chem. 1995, 107, 785; Angew. Chem. Int. Ed.
Engl. 1995, 34, 713.
[21] P. A. Gale, P. Anzenbacher, J. L. Sessler, Coord. Chem. Rev.
2001, 222, 57.
Angew. Chem. Int. Ed. 2009, 48, 1688 –1691
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1691