Siamese-twin porphyrin: A pyrazole-based expanded porphyrin of persistent helical conformation

Article abstract of DOI:10.1002/chem.201204296

The 3+3-type synthesis of a pyrazole-based expanded porphyrin 22 H ₄, a hexaphyrin analogue named Siamese-twin porphyrin, and its homobimetallic diamagnetic nickel(II) and paramagnetic copper(II) complexes, 22 Ni₂ and 22 Cu₂

Full text of DOI:10.1002/chem.201204296

FULL PAPER
DOI: 10.1002/chem.201204296
Siamese-Twin Porphyrin: A Pyrazole-Based Expanded Porphyrin of
Persistent Helical Conformation
Lina K. Blusch,[a] Yasmin Hemberger,[b] Kevin Prçpper,[a] Birger Dittrich,[a]
Franziska Witterauf,[b] Michael John,[a] Gerhard Bringmann,*[b]
Christian Brꢀckner,*[c] and Franc Meyer*[a]
Abstract: The 3 +3-type synthesis of a
pyrazole-based expanded porphyrin
22H4, a hexaphyrin analogue named
Siamese-twin porphyrin, and its homo-
bimetallic diamagnetic nickel(II) and
paramagnetic copper(II) complexes,
22Ni2 and 22Cu2, are described. The
structure of the macrocycle composed
of four pyrroles and two pyrazoles all
linked by single carbon atoms, can be
interpreted as two conjoined porphyr-
in-like subunits, with the two opposing
pyrazoles acting as the fusion points.
Variable-temperature 1D and 2D
NMR spectroscopic analyses suggested
a conformationally flexible structure
for 22H4. NMR and UV/Vis spectro-
scopic evidence as well as structural pa-
rameters proved the macrocycle to be
non-aromatic, though each half of the
molecule is fully conjugated. UV/Vis
and NMR spectroscopic titrations of
the free base macrocycle with acid
showed it to be dibasic. In the com-
plexes, each metal ion is coordinated in
a square-planar fashion by a dianionic,
porphyrin-like {N4} binding pocket.
The solid-state structures of the dica-
tion and both metal complexes were
elucidated by single-crystal diffractom-
etry. The conformations of the three
structures are all similar to each other
and strongly twisted, rendering the
molecules chiral. The persistent helical
twist in the protonated form of the free
base and in both metal complexes per-
mitted resolution of these enantiomeric
helimers by HPLC on a chiral phase.
The absolute stereostructures of
22H62+, 22Ni2, and 22Cu2 were as-
signed by a combination of experimen-
tal electronic circular dichroism (ECD)
investigations and quantum-chemical
ECD calculations. The synthesis of the
first member of this long-sought class
of expanded porphyrin-like macrocy-
cles lays the foundation for the study
of the interactions of the metal centers
within their bimetallic complexes.
Keywords: copper
nickel · pH titration · porphyrins ·
AHCTUNGTRENNpGUN yrazole
·
chirality
·
AHCTUNGTRENNUNG
Introduction
issues such as anion binding[2] or aromaticity.[3] Hꢀckel aro-
matic, anti-aromatic, non-aromatic, and Mçbius aromatic ex-
panded-porphyrin systems have been realized.[4] Also, a ple-
thora of useful compounds were introduced, among them
macrocycles with actinide coordination capabilities,[5] effica-
cy in the photodynamic therapy of tumors[6] or as MRI
agents,[7] or compounds possessing pronounced non-linear
optical properties.[8] Particularly the reports by the groups of
Sessler, Osuka, Kim, Latos-Grazynski, and Chandrashekar
Expanded porphyrins are higher analogues of porphyrins,
that is, porphyrinoids with more ring atoms than a porphyr-
in. Since the time they were serendipitously discovered,[1]
the field has become a multi-faceted area of research that
has had broad impact on our understanding of fundamental
over the past decade have lent distinction to the field.[9]
A
[a] Dr. L. K. Blusch,+ Dipl.-Chem. K. Prçpper, B. Dittrich, Dr. M. John,
Prof. Dr. F. Meyer
number of recent reports deal with the fusion of multiple
porphyrins or porphyrin-like macrocycles into larger sys-
tems, the formation of their multi-metallic complexes, and
the study of their physical properties.[10]
Institute of Inorganic Chemistry, University of Gçttingen
Tammannstr. 4, 37077 Gçttingen (Germany)
Fax : (+49)551-39-3063
E-mail: Franc.Meyer@chemie.uni-goettingen.de
The conformational diversity among expanded porphyrins
is vast because of their enormous structural variability: For
instance, expanded porphyrins may contain pyrroles or
other heterocycles (furans, thiophenes, etc.), the pyrrolic
building blocks may be directly connected, linked by single
atoms or multi-carbon chains (of varying hybridization),
imine linkages may be present, and the pyrroles may be in-
verted or present in an N-confused fashion (2,4-linked
rather than the traditional 2,5-linkage),[11] or coordinated
metal ions can be present in the porphyrinoid centers.[12] In
addition, the macrocycle conformation is controlled by tem-
[b] Dipl.-Chem. Y. Hemberger, Dipl.-Chem. F. Witterauf,
Prof. Dr. Dr. h.c. mult. G. Bringmann
Institute of Organic Chemistry, University of Wꢀrzburg
Am Hubland, 97074 Wꢀrzburg (Germany)
E-mail: bringman@chemie.uni-wuerzburg.de
[c] Prof. Dr. C. Brꢀckner
Department of Chemistry, University of Connecticut
Storrs, Connecticut 06269-3060 (USA)
E-mail: c.bruckner@uconn.edu
[+] nꢁe Frensch.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204296.
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perature, solvent, degree of oxidation, and/or protonation
levels.[9a] The conformation of hexaphyrin 1, one of the
older and best-studied example of an expanded porphyrin,
for instance,[13] is mainly planar, with two pyrroles inverted,
but variation of the substitution pattern and/or oxidation
state introduces dumbell-shaped or figure-eight conforma-
tions (Scheme 1).[9c] Free-base heptaphyrin 2[14] and octa-
phyrin 3[15] generally adopt figure-eight conformations.
Scheme 1. Selected expanded porphyrins; b-substituents of octaphyrin
omitted for clarity.
It is well-established that pyrazoles with chelating side-
arms can act as bridging ligands in highly preorganized dinu-
clear transition metal complexes.[16] Such pyrazole-based
chelates proved to be versatile and useful building blocks in
bioinorganic coordination chemistry as they offer a good
compromise for mimicking the bridging carboxylate donors
frequently found in bimetallic enzymes in Nature and be-
cause they could be readily incorporated into compartmen-
talized ligand frameworks.[17] In these complexes, the pyra-
zoles are monoanionic donors supporting a range of metal–
metal distances.[18]
The integration of pyrazole moieties (or other heterocy-
cles such as imidazoles,[19] oxazoles,[20] thiadiazoles, or tria-
zoles[21]) in porphyrinoid macrocyclic compounds is, howev-
er, little developed. Only one family of porphyrin analogues
incorporating a pyrazole, carbaporphyrins 4, recently intro-
duced by the group of Lash, is known.[22] One other multi-
dentate cyclic pyrazole–pyrrole hybrid ligand was reported,
compound 5,[23] but this macrocycle cannot be categorized as
a true porphyrinoid, that is, containing a fully conjugated
framework.
Scheme 2. The Siamese-twin porphyrin framework structure as derived
from the hexaphyrin structure, simultaneously highlighting the fusion of
two porphyrin-like halves of the molecule.
named it the “Siamese-twin porphyrin”.[24] This naming is
descriptive of the framework structure but shall not evoke
any implications about the presence of aromatic conjugation
pathways. One of the goals of this target structure was to in-
corporate two metal ions in these highly preorganized bind-
ing pockets in close proximity to each other and to study
the resulting metal–metal cooperativity.
We are not the first to conceive the twin-porphyrin frame-
work structure. Lind, in a 1987 dissertation,[25] described sev-
eral approaches towards this expanded porphyrin. Invaria-
bly, however, they were unsuccessful. With the benefits of
hindsight, this can be attributed to a number of factors: The
key intermediate for the 3+3-MacDonald-type strategies
pursued was a pyrazole analogue to a tripyrrane, bispyrrolyl-
pyrazole 10 (Scheme 3). It was synthesized by the acylation
of dimethylpyrrole 8 by the activated pyrazole diester 7,
itself obtained from well-known pyrazole diester 6. Reduc-
tion of bisketone 9 generated compound 10. However, its
synthesis succeeded only as the pyrazole-N-substituted de-
A formal replacement of the two inverted pyrroles in hex-
aphyrin by pyrazoles gives rise to the scaffold structure
shown in Scheme 2. The resulting expanded porphyrin, con-
sisting of four pyrroles and two pyrazoles, merges the struc-
tural characteristics of pyrazoles bearing chelating side-arms
with those of porphyrins; it can also be interpreted as the
fusion of two porphyrin-like coordination sites. We thus
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Siamese-Twin Porphyrin
FULL PAPER
Scheme 3. Lindꢃs attempted synthesis of the twin porphyrin 13.
rivative. Whereas 10 could be successfully diformylated to
provide 11, and the 3+3 condensation of 10 and 11 led to
macrocycle 12, the pyrazole benzyl protection group (Bn)
could not be removed. This, however, may have been the
crucial factor in Lindꢃs inability to convert framework 12 to
the fully conjugated (planar) twin-porphyrin framework
structure 13. Particularly problematic was the oxidation of
the pyrrole–pyrazole bridging meso-carbon atoms.
When we embarked on the synthesis of the twin-porphyr-
in framework, we also decided to pursue a 3+3 strategy
similar to Lindꢃs. Based on our experience with the function-
alization of pyrroles and pyrazoles, we devised an alterna-
tive strategy towards the assembly of the key building block,
bis(pyrrolyl-methylene)-pyrazoles 14, which was based on
an alkylation of an a-unsubstituted pyrrole with a pyra-
zole.[23] We thus directly delivered sp3-linkages between the
pyrazole and pyrroles. A double Vilsmeyer–Haak formyla-
tion of 14 generated bisaldehydes 15. This strategy requires
fewer steps than Lindꢃs synthesis of the equivalent building
block, but most importantly, it avoids the use of a pyrazole
protecting group.
3 macrocyclization of the pyrrolyl–pyrazole building blocks
had likely taken place, their conformational flexibility and
the large number of stereoisomers formed posed great tech-
nical difficulties. As a result, the macrocycles could not be
isolated or spectroscopically unambiguously characterized.
Even more damaging, our inability to reliably oxidize any
sp3-carbon atoms attached to the pyrazoles hampered any
progress. Thus, even though we avoided the need of pyra-
zole protecting groups, we still faced the same oxidation
problem that Lind described. Notably, Lash et al. also de-
scribed their difficulties in oxidizing the equivalent positions
in their attempts to synthesize carbaporphyrin 4, thus point-
ing to a general problem when incorporating pyrazoles into
porphyrinoids.[22]
Guided by these experiences, our renewed efforts were fi-
nally successful and the twin porphyrin and its homobime-
tallic 22Cu2 complex were described in a preliminary
report.[24] Following up on this, we provide here the details
of the design and synthesis of the free-base twin porphyrin
22H4 and the formation and structure of its dicopper(II)
complex 22Cu2. Furthermore, we will firstly report the syn-
thesis and crystal structure of the homobimetallic diamag-
netic dinickel(II) complex 22Ni2, as well as the crystal struc-
ture of the protonated form of free-base twin porphyrin
22H62+, revealing the highly twisted chiral conformations al-
ready observed for the dicopper complex.[24] A series of
NMR and UV/Vis spectroscopic investigations allowed con-
clusions to be drawn on the protonation- and temperature-
dependent conformational characteristics of the macrocycles
and the prevailing conjugation pathways. Importantly, the
helimeric conformations of the macrocycles were found to
be persistent. We will thus also describe the resolution of
the enantiomers by HPLC on a chiral phase and the investi-
gation of the respective helical stereoisomers by online LC-
ECD measurements. A comparison of their experimental
ECD spectra with the quantum-chemically calculated ones
permitted assignment of their absolute stereostructures.
Unfortunately, the 3+3-type syntheses of the target mac-
rocycles could not be achieved at the time, though other in-
teresting, non-conjugated macrocycles, such as 5, were pre-
pared and studied.[23] Three major obstacles became evident
in our work, some of which mirrored the problems in Lindꢃs
work: Whereas mass spectrometry (MS) indicated that a 3+
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G. Bringmann, C. Brꢀckner, F. Meyer et al.
Results and Discussion
linked macrocycle, was isolated as a mixture of stereoisom-
ers (as indicated by the presence of multiple peaks for its di-
agnostic signals in the NMR spectra). Similarly to the octa-
b-alkyl, meso-tetraarylporphyrinogen, the steric hindrance
between the meso- and the b-substituents stabilizes this
leuco compound against rapid aerial oxidation.[27] However,
heating the light-yellow solution of 21 with four equivalents
of DDQ in toluene for 12 min resulted in the formation of a
deep-green solution. This reaction time should not be ex-
ceeded to minimize decomposition reactions. Column chro-
matography on silica gel with n-hexane and ethyl acetate (in
a 2:1 ratio) provided the green product 22H4 as the first
major fraction. Evaporation of
Synthesis of the twin porphyrin 22H4: We hypothesized that
the substitution of all meso-positions with phenyl groups
would facilitate the oxidation of the macrocycle by offering
additional conjugation. We further assumed that the decora-
tion of all b-positions of the pyrroles and the pyrazole b-
carbon atoms would enforce a conformation of the macrocy-
clic, non-conjugated precursor that places all substituents on
the outside, further facilitating its oxidation and formation
of the target structure. Indeed, this strategy proved to be
successful (Scheme 4).
the solvent and taking up the
crude green solid in a minimal
amount of acetone, and subse-
quent solvent removal of the
filtrate provided spectroscopi-
cally pure 22H4. The HR-MS
(m/z=1301.6895) data suggest-
ed a composition of C92H85N8
(for [MH+]), as expected for
the (monoprotonated) target
free-base twin porphyrin 22H4.
UV/Vis spectroscopic proper-
ties of twin porphyrin 22H4 in
its neutral, mono-, and diproto-
nated states: The UV/Vis spec-
trum of the neutral macrocycle
22H4 shows two relatively
broad main absorption bands at
390 and 639 nm in a ꢀ2:1 ratio
(plus a shoulder at 734 nm).
The bands are characterized by
extinction coefficients of, or
under,
105 Lmolꢁ1 cmꢁ1
(Figure 1, Table 1). In compari-
son, porphyrins exhibit extinc-
tion coefficients for their Soret
bands that are frequently
Scheme 4. Synthesis of the twin porphyrin 22H4 and its homobimetallic complexes.
higher.[28] Thus, the spectrum
resembled much more those of
The key building block in the 3+3 synthesis of 22H4 is
the all-b- and meso-substituted pyrrole–pyrazole hybrid 20.
Its synthesis started from our previously reported precursor
3,5-dibenzoyl-4-phenyl-1H-pyrazole (16).[26] The reaction
series (reduction to give 17, followed by halogenation to
provide 18 and subsequent substitution with 3,4-diethylpyr-
role 19 to form compound 20) was modeled after the syn-
thesis of the pyrrole–pyrazole hybrid 14 reported by us ear-
lier.[23a] This pyrazole analogue of a tripyrrane was isolated
as a mixture of stereoisomers. The spectroscopic signatures
of 20 confirmed its connectivity. The acid-catalyzed 3+3-
type condensation of two equivalents of the pyrrole–pyra-
zole hybrid 20 with two equivalents of benzaldehyde pro-
ceeded smoothly, providing 21. This compound, an all-sp3-
linear oligopyrrolic pigments,[29] indicating the presence of
extensive conjugation but not of an aromatic porphyrin-like
p-system. A UV/Vis titration of 22H4 with trifluoroacetic
acid (TFA) in CH2Cl2 allowed the characterization of the
macrocycle as dibasic. Upon protonation, only a subtle color
change was observed (Figure 1). Addition of one equivalent
of TFA caused only a minor intensity increase and redshift
of the long-wavelength shoulder (to 753 nm), whereas the
intensity of the band at 390 nm decreased only a little. Addi-
tion of a second equivalent of TFA resulted in a slight shift
of the band at 390 nm (to 400 nm) but the band at 639 nm
increased to ꢀ80% of the intensity of the high-energy band.
No further changes were observed beyond the addition of
two equivalents of acid. This spectral behavior upon proto-
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Siamese-Twin Porphyrin
FULL PAPER
(or four signals if NH tautomerism was slow). Also, the CH3
protons appeared as four distinct triplets (see the also low-
1
temperature H1H-COSY spectrum in the Supporting Infor-
mation, Figure S2). This indicated the presence of a structur-
al property that reduces the overall symmetry of the macro-
cycle. Vogel and co-workers observed the diastereotopic
splitting of the methylene protons for 3 as a consequence of
its twisted geometry.[30] In the case of 22H4, the appearance
of the diastereotopic methylene signals can also be rational-
ized by assuming that a similar conformational effect leads
to the formation of a chiral molecule. This assumption was
confirmed by single-crystal diffractometry (see below).
1
One other diagnostic feature in the H NMR spectrum of
22H4 at 248 K was the presence of low-field signals (at d=
11.38 and 13.34 ppm) assigned to the inner NH protons. As
expected, these protons were readily exchanged with
[D4]MeOD. The low-field chemical shifts of the NH protons
were a clear indication for the absence of any macrocyclic
diatropic ring current induced by a macrocyclic p-aromatic
system that would have shifted the signals significantly
below d=1 ppm. Alternatively, low-field-shifted pyrrole and
pyrazole NH signals may be attributed to the presentation
of the NH groups pointing towards the outside of an aro-
matic macrocycle. However, NOESY experiments showed a
correlation of the NH signals with each other (the Support-
ing Information, Figure S5), indicating that they are all ori-
ented inwards. Thus, NMR spectroscopy provided evidence
that the presence of the b- and meso-substituents had the
desired conformational consequences.
Figure 1. UV/Vis spectroscopic titration of 22H4 in CH2Cl2 with 0 to
2.25 equivalents of TFA.
Table 1. UV/Vis spectral data of the compounds 22H4, 22H62+, 22Ni2,
and 22Cu2.
l/nm (e /104 Lmolꢁ1 cmꢁ1
)
2+
22H4
22H6
22Ni2
22Cu2
390 (11)
639 (4.9)
734 (1.7)
400 (10)
668 (8.7)
795 (1.8)
377 (6.2)
547 (2.6)
765 (1.4)
391 (4.6)
629 (2.2)
nation is untypical of p-aromatic porphyrinoid macrocycles
but is reminiscent of bilindiones and related linear oligopyr-
rolic pigments.[29]
The presence of two distinct, relatively sharp NH signals
of equal intensity in the 1H NMR spectrum of 22H4 at
248 K again indicated an overall two-fold symmetry of the
1
NMR spectroscopic characterization of free-base twin por-
free base in solution (Figures 2 and 3). The diagnostic NH J
1
phyrin 22H4: The H NMR spectrum of 22H4 in CD2Cl2 at
coupling constants observed in the 1H15N-HMBC NMR
spectrum of 22H4 permitted an assignment of the two sig-
nals (Figure 4; for a more detailed discussion of this spec-
trum, see below).[31] The signal at d=11.38 ppm was attrib-
uted to the pyrrole NH proton (Npyr at d=ꢁ244 ppm;
1J(NH)=95 Hz) and the signal at d=13.34 ppm to the pyra-
ambient temperature is broadened and of marginal diagnos-
tic value (Figure 2). Apart from the presence of signal clus-
ters assigned to the phenyl and the ethyl substituents, not
much more can be interpreted. Cooling to 248 K significant-
ly sharpened the peaks, indicating that much of the signal
broadening can be attributed to dynamic processes. At this
temperature, macrocycle 22H4 exhibited more signals as-
signed to methylene protons than the two signals anticipated
for the highly symmetric constitution of the twin porphyrin
1
zole NH (Npz at d=ꢁ168 ppm; J(NH)=107 Hz).
Protonation of 22H4 and its analysis by using NMR spectro-
scopy: The structure of 22H4 implied the presence of two
Figure 2. 1H NMR spectrum (500 MHz, CD2Cl2) of 22H4 under the indicated conditions. The residual solvent signal is marked with an asterisk (*).
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G. Bringmann, C. Brꢀckner, F. Meyer et al.
Figure 3. Downfield region of the 1H NMR spectrum (500 MHz, CD2Cl2,
248 K) highlighting the changes assigned to the NH proton signals upon
stepwise protonation (cf. also to Figure S4, the Supporting Information).
Signal set a was assigned to 22H4, signal set b to 22H5+, and signal set c
2+
to 22H6
.
Scheme 5. Spectroscopically derived structures and H-bond patterns in
the three protonation states of 22H4.
temperatures) implied that the basicity of the free base a,
monoprotonated species b, and diprotonated species c are
relatively close to each other. This indicated the presence of
two essentially independent electronic systems. In case of a
strong electronic coupling (through, for instance, conjuga-
tion), one would have expected the basicity of the monopro-
tonated species to be much more reduced compared with
that of the neutral species, such that no significant quantities
of the diprotonated species would have been formed before
the vast majority of the neutral species would have been
monoprotonated.
Figure 4. 1H15N-HMBC spectrum (500 MHz, CD2Cl2, 243 K) of 22H4 +1
equivalent TFA. A mixture of three differently protonated species is
+
2+
present: 22H4 (a), 22H5 (b and b’) and 22H6 (c and c’).
A 1H15N-HMBC spectrum of the mixture of the three spe-
+
2+
basic imine-type pyrroles and two significantly less-basic
pyrazole imine nitrogens. Protonation studies confirmed
this. NMR titrations of 22H4 with TFA were performed,
showing diagnostic changes (Figure 3). Particularly the low-
field region of the spectra warranted a closer inspection as
they permitted conclusions to be drawn on the protonation
site and the existence of distinct mono- and diprotonated
species. Addition of a single equivalent of TFA generated a
number of additional signals. Next to a substantial portion
of unaltered 22H4 (indicated species a), two more species (b
and c) became apparent. Upon addition of the second
equivalent of TFA, species c became the major product and
only traces of b remained. Thus, the higher-symmetry spe-
cies, 22H4 (a), 22H5 (b) and 22H6 (c) after the addition
of one equivalent of TFA was recorded at 243 K (Figure 4).
This, and the NOESY spectroscopy (the Supporting Infor-
mation, Figure S5), also allowed us the assignment of the lo-
cation of the protons and the resulting intramolecular H-
bond pattern (Scheme 5). As predicted, based on the gener-
al basicity of the pyrrolic imine nitrogens and pyrazoles, the
protons were found to be located on the pyrrole imine nitro-
gens, and each half of the molecule to be sequentially mo-
noprotonated. 13C NMR spectra also confirmed these assign-
ments based on the symmetry elements visible (the Support-
ing Information, Figures S3 and S7). Addition of an excess
of TFA led to a fast scrambling of all pyrazole protons and
the number of signals was reduced to one quarter (the Sup-
porting Information, Figures S8–S10).
2+
cies c is the diprotonated molecule 22H6 and, consequent-
ly, species b can be assigned as the low-symmetry monopro-
+
1
2
pz
pz
ꢁ
ꢁ
N
tonated species 22H5 carrying five non-equivalent NH pro-
Besides the J couplings, J interactions for the H N
1
tons (Scheme 5).
hydrogens were also detectable in the H15N-HMBC spec-
trum (Figure 4). Further, cross-peaks provided evidence for
the presence of H-bonds between the NHpz and NHpyr pro-
tons to the neighboring imine-type Npyr/pz atoms, thus fully
defining the H-bond patterns within the macrocycle
The existence of a temperature-dependent equilibrium be-
tween the neutral, monoprotonated, and diprotonated spe-
cies in the presence of a single equivalent of protons (equili-
brium shifted towards the monoprotonated species at lower
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Siamese-Twin Porphyrin
FULL PAPER
2+
(Scheme 5). Somewhat surprisingly, macrocycle 22H6 fea-
tures four protons in one {N4} compartment, but only two in
the other {N4} compartment.
resent the fusion points of two porphyrin-like {N4} chelation
pockets, they also insulate the two p-systems from cross-talk
with each other. In fact, the replacement of a pyrrolic build-
ing block in a porphyrin by a pyrazole in compound 4 also
inhibits the aromatic conjugation pathway.[22a]
2+
Solid-state conformation of the twin porphyrin 22H6
:
Crystals suitable for investigation by single crystal X-ray dif-
Importantly, the crystal structure demonstrates that the
conformation of the macrocycle is severely twisted, mirror-
ing the solution-state data. The helical twist along the long
axis of the molecule (the mesopyr/pyr to mesopyr/pyr axis) ren-
ders it chiral. Given the non-chiral space group, the crystals
fraction of 22H62+·2TFAꢁ·x
AHCTUNGTRENNUNG
slow solvent evaporation from a saturated solution of the
macrocycle in acetone and TFA. The compound crystallized
in the non-chiral space group P1 (with about 800 atoms per
asymmetric unit; for further details see the Supporting In-
formation). The resolution of the diffraction data did not
provide decisive evidence of the protonation state of each
relevant site in the macrocycle. However, UV/Vis and NMR
spectroscopic solution-state investigations confirmed it to be
present as a dication under the crystallization conditions.
Hence this diprotonated species is likely also present in the
crystal as well.
The molecular structure confirmed the connectivity of the
free-base twin porphyrin structure (Figure 5A). The chro-
mophore bond lengths showed an alternating short-long pat-
tern (Figure 5B), providing further evidence for the pres-
ence of two essentially independent p-conjugation pathways
that are each restricted to their half of the macrocycle (Fig-
ure 5C), thus excluding the presence of a 26-p system analo-
gous to that found in hexaphyrins. While the pyrazoles rep-
2+
of 22H6 must therefore be a racemic mixture of the P-
and M-helimers. The helimer torsion angle t (defined in Fig-
ure 5D as the a-Cpyr–meso-Cpyr/pyr–meso-Cpyr/pyr–a-Cpyr tor-
sion angle) is approximately ꢂ868; the angle between the
two N4 mean planes is ꢀ418.
The origin of the non-planarity of twin porphyrins 22H4 and
22H62+: Solution and solid-state investigations of the free
base in neutral and protonated forms showed that the mac-
rocycle adopts a drastically non-planar conformation. How-
ever, a DFT molecular model[32] of the macrocycle in the ab-
sence of any peripheral substituents suggests the macrocycle
to be perfectly planar (Figure 6). Once the substituents were
introduced or the macrocycle was diprotonated, the compu-
tations revealed non-planar conformations (see Supporting
Information, Figure S20).
The conformational plasticity
of porphyrinoids is well-
known.[9c,d] Which particular
conformation is favored de-
pends on several factors, includ-
ing intrinsic structural con-
straints, intramolecular hydro-
gen-bonding, the aromatic or
anti-aromatic character of the
conjugated p-system, and the
presence and nature of periph-
eral substituents. In particular,
[26]hexaphyrins were observed
to assume a non-planar confor-
mation upon introduction of
bulky substituents.[33] This be-
havior is also observed in “reg-
ular” porphyrins. For instance,
b-octaalkyl-meso-tetrakisaryl-
substituted porphyrins are non-
planar, whereas porphyrins with
either b-octaalkyl- or meso-tet-
rakisaryl-substitution are rela-
tively planar.[34] The computa-
tions of our twin porphyrin sug-
Figure 5. Molecular solid-state structure of 22H62+: A) front view and labeling of atoms. B) side view and se-
lected bond lengths in ꢄ. Structure of 22H6 (C) in which the two independent p-conjugation pathways are
gest that the introduction of
only b-ethyl groups does not
cause any distortion, but as
soon as the meso-phenyl groups
are introduced, it causes steric
interactions that force the mac-
2+
highlighted and the mesopyr/pyr positions are marked. D) schematic representation of the P-enantiomer, the no-
menclature of these helimers and the view along both mesopyr/pyr carbon atoms (long axis of the molecule) of
the framework of 22H62+, highlighting the torsion angle t. All hydrogen atoms and residual solvent molecules
were omitted for clarity, as were the phenyl and ethyl groups in B and D. In the solid-state structures arbitrari-
ly, only the P-helical enantiomers are shown.
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G. Bringmann, C. Brꢀckner, F. Meyer et al.
was already proven successful for the assignment of the ab-
solute configurations of other chiral porphyrinoid systems
with all kinds of stereogenic elements such as axes,[39] cen-
ters, and helices.[36] All calculations were performed by using
the Gaussian 09 software package.[40] During the investiga-
2+
tion of the conformational space of 22H6 by the B3LYP/6-
31GACHTNUTGRNEUNG
(d,p)[41] method, we discovered that only two strain-free
conformations of the backbone existed, each with all possi-
ble combinations of the different orientations of the ethyl
substituents (Figure 7).
Figure 6. Molecular model (DFT, BP86 level)[32] of the twin-porphyrin
framework in the absence of any substituents: free base (blue) and its
protonated dicationic form (gray).
rocycle into a non-planar, twisted conformation (the Sup-
porting Information, Figure S20). Experiments directed at
relieving the steric congestion within the twin porphyrin
framework are in progress.
2+
Chiral resolution of the diprotonated species 22H6
by
using HPLC on a chiral stationary phase and assignment of
the absolute stereostructures: Figure-eight and twisted con-
formations of expanded porphyrins are intrinsically chiral
but in most cases the two helical enantiomers interconvert
rapidly. However, Vogel et al. showed that b-hexadecaethy-
loctaphyrin 3 is conformationally stable enough to allow the
separation of the two enantiomers by HPLC on a chiral sta-
tionary phase.[30] Osuka et al. also demonstrated the chiral
resolution of a quadruply N-fused heptaphyrin.[35] Smaller
porphyrinoids assuming stable twisted conformations were
also chirally resolved.[36]
2+
Figure 7. Comparison of conformations of 22H6 of the same absolute
configuration (here M), but with different chromophoric backbones (blue
and pink; left), and with completely oppositely orientated ethyl substitu-
ents (blue and green, right) and the predicted CD spectra for these con-
formations.
Attempts to separate any enantiomers of the neutral mac-
rocycle 22H4 failed but the HPLC separation of a racemic
2+
mixture of 22H6 on a chiral phase (Chiralpak IA column)
succeeded in the presence of TFA (0.05% in ethyl acetate).
Even though the retention times of the two stereoisomers
2+
(P-22H6 and M-22H62+) were so similar to each other
Even the slight change in the chromophore conformation
of 22H6 resulted in a significant blueshift (>40 nm) of the
2+
that, according to its HPLC-UV/Vis spectral trace, no reso-
lution had taken place, HPLC-ECD showed a good resolu-
tion (see later, Figure 9), demonstrating once more the ad-
vantages of this technique.[37]
first excited states in the CD spectrum predicted for Conf-2
in comparison with the one calculated for the global mini-
mum, represented by Conf-1 (Figure 7, left). This can be ex-
plained by the larger difference in the HOMO–LUMO gap
of DE=1.97 eV computed for Conf-2 in contrast to DE=
1.82 eV simulated for Conf-1 and the fact that the
HOMO!LUMO transition accounts for more than 70% of
the very first excited state (Conf-1: l=852.6 nm, HOMO!
LUMO 76%; Conf-2: l=779.7 nm, HOMO!LUMO
71%). The frontier molecular orbitals also show a strong
overlap over the whole macrocyclic framework (Figure 8),
Since therefore no significant charge-transfer effects were
expected, TDDFT was the method of choice to describe the
chiroptical properties of these Siamese-twin porphyrins.
Moreover, due to the larger steric repulsion of the phenyl
and ethyl substituents, the enthalpy of formation for Conf-2
was so much increased that this conformer was already out
of the energetically relevant range (DE>3 kcalmolꢁ1 above
By using NOESY, a minimum level for racemization en-
thalpies DG =100 kJmolꢁ1 for 22H4 and of 105 kJmolꢁ1
¼
2+
for 22H6 could be estimated with the assumption of tem-
¼
perature-independent DG (details in the Supporting Infor-
mation). Lifetimes were projected to be 12 h and 4 d, re-
spectively. Thus, even though the diprotonated macrocycle is
slighty more stable, the inability to separate the enantiomers
of 22H4 points to a separation problem rather than a fast
enantiomeric interconversion considering the timescale of
the resolution experiment.
A lack of precedents precluded an empirical assignment
of the absolute stereostructure of the helical enantiomers of
22H62+. We therefore determined their absolute configura-
tion by quantum-chemical calculation of the CD spectra and
comparison with the experimental ones.[38] This approach
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Siamese-Twin Porphyrin
FULL PAPER
the corresponding mono-cati-
ons, which either are mixed-va-
lence MIIMIII species or feature
non-innocent ligand radicals;
this distinction is currently
under investigation.
The UV/Vis spectra of the
metal complexes displayed hy-
pochromic but otherwise only
moderately
shifted
spectra
when compared with the free-
base ligand (Figures 1 and 10).
Again, the broad bands of near-
equal intensity resembled the
spectra of the metal complexes
of linear oligopyrrolic li-
gands.[29]
The dicopper complex is par-
amagnetic.[24] We previously re-
ported the unusual, yet substan-
tial ferromagnetic coupling be-
tween the two idealized square-
Figure 8. Frontier orbitals obtained from B3LYP/6-31GACTHNUTRGENUGN(d,p) calculations (plotted with an isovalue of 0.0208)
showing a strong overlap for both conformations, Conf-1 and Conf-2, and the calculated energies of their
HOMO!LUMO transition.
the global minimum). The orientation of the ethyl substitu-
ents by contrast had no significant effect on the calculated
CD spectrum, as long as the conformers considered pos-
sessed the same backbone conformation (Figure 7, right).
Due to this fortunate circumstance, the TD B3LYP/6-
planar d9 copper centers.[24] The d8 Ni2+ ion in a square-
planar coordination sphere is expected to be diamagnetic
and, indeed, the 1H NMR spectrum of 22Ni2 showed no
signs of any paramagnetic broadening or shifting of the
spectrum (see Supporting Information, Figure S13); it re-
sembled the spectrum of 22H62+·excess TFA (see Support-
ing Information, Figures S8–S10). The absence of any broad-
ening of the spectra recorded for 22Ni2 was also an indica-
tion for the presence of a conformationally rigid structure.
Like in the free-base ligand, the diastereotopic splitting of
the methylene signals of the b-ethyl groups suggested a non-
planar (twisted) conformation and the two distinct methyl
signals indicate an overall D2 symmetry (Figure 11).
31GACHTUNGTRENNUNG(d,p) calculation to provide the UV/Vis and CD data
needed to be carried out solely for the global minimum con-
formation of 22H62+. After a small UV/Vis correction[39] of
only 5 nm (see Supporting Information, Figure S18), com-
2+
parison of the simulated CD curve for M-22H6 with the
experimental CD spectrum of the more rapidly eluting ster-
eoisomer showed an excellent agreement (peak 1, Figure 9),
2+
whereas the CD curve calculated for P-22H6
matched
well with the one measured for the more slowly eluting
enantiomer (peak 2, Figure 9). This permitted not only the
unambiguous assignment of the absolute configuration of
the two enantiomers of 22H6 but also provided additional
proof for the existence of the diprotonated species (see Sup-
porting Information, Figures S17 and S19).
Crystal structures of the dinickel(II) and dicopper(II) com-
plexes 22Ni2 and 22Cu2: Crystals of 22Ni2 suitable for X-
ray diffraction were obtained by slow solvent evaporation of
a saturated solution of 22Ni2 in toluene. The compound
crystallized in the non-chiral monoclinic space group C2/c.
Its molecular structure showed the twist along the long axis
also seen in the structure of the diprotonated free-base (and
the dicopper complex; see below).[24] It thus again crystal-
lized as a racemic mixture of two enantiomeric helimers.
The compound exhibited crystallographic two-fold symme-
try (D2 molecular symmetry). The absence of any counter-
ions to each of the nickel(II) centers confirmed the dianion-
ic nature of each metal-binding pocket that was formed by
deprotonation of one pyrazole and one pyrrole per binding
site. The {N4}-coordination sphere of the nickel ions was not
entirely planar but slightly twisted towards tetrahedral coor-
dination, with alternating deviations of the nitrogen atoms
2+
Synthesis of the homobimetallic complexes 22Ni2 and
22Cu2: Stirring the deep-green free-base 22H4 with Cu-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
in the formation of a blue-green (copper) and burgundy
(nickel) complex, respectively (Scheme 4). The relatively
low polarity of the isolated materials suggested the forma-
tion of neutral complexes. The HR-ESI(+) of the nickel
complex indicated the composition C92H80N8Ni2 (for [M+]),
that is, the successful synthesis of the dinickel(II) complex
22Ni2 (see Supporting Information, Figure S11 and S12). In
a similar way, the formation of the dicopper complex 22Cu2
was shown by HR-MS (C92H80N8Cu2). The observation of
M+ parent ions in both cases suggested that the dinickel(II)
and dicopper(II) complexes can be readily oxidized to give
from the mean plane by ꢂ0.23 ꢄ (angle between the Npyr
-
Ni-Npyr and the Npz-Ni-Npz planes was 19.28; Figure 12).
This, however, was not enough to cause a fundamental
change of metal ion d-orbital splitting from that expected
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G. Bringmann, C. Brꢀckner, F. Meyer et al.
Figure 11. High-field portion (alkyl region) of the 1H1H COSY spectrum
of 22Ni2 (500 MHz, CD2Cl2, ambient temperature).
ꢁ
for an idealized planar coordination sphere. The Ni N bond
lengths varied from 1.90 to 1.93 ꢄ with the longer bonds to
the pyrazole nitrogen atoms. Owing to the small size of the
low-spin nickel(II) ion (0.69 ꢄ),[10c] porphyrins and chlorins
ꢁ
also tend to be twisted (ruffled), thus providing short Ni N
bond lengths (1.96 ꢄ were observed for only slightly ruffled
nickel(II) porphyrins; strongly ruffled nickel(II) porphyri-
noids achieved bond distances as short as 1.89 ꢄ). In con-
trast to the present case, however, the twist axis in the ruf-
fled nickel(II) porphyrinoids is along the meso-Cpyr/pyr–meso-
Cpyr/pyr axis. Therefore, the ruffling does not distort the coor-
dination sphere of the central metal from planarity. The di-
copper complex 22Cu2 also crystallized as a racemic mixture
in the space group C2/c, and also had a similarly twisted
conformation as the dinickel complex 22Ni2, although some
metric differences were notable (Figure 12). Each copper(II)
ion is coordinated in a severely distorted square-planar fash-
ion (the angle between the Npyr-Cu-Npyr and the Npz-Cu-Npz
2+
Figure 9. Results of the HPLC separation of a racemic mixture of 22H6
on a chiral phase (Chiralpak IA; ambient temperature; ethyl acetate/n-
hexane (v/v) 30:70, isocratic flow rate: 0.8 mLminꢁ1) and elucidation of
the absolute configuration of the two helical enantiomers by comparison
of the experimental CD spectra with the calculated CD curves.
ꢁ
planes is 16.88). The Cu N distances are significantly longer
ꢁ
than the Ni N distances in 22Ni2 and range from 1.96 to
2.01 ꢄ, with the longer bonds to the Npz atoms. The differen-
ces in the bond lengths between 22Ni2 and 22Cu2 reflect the
d9 electronic structure of the copper(II) with its unpaired
electron in the antibonding dx2ꢁy2 orbital. Overall, each bind-
ing pocket is more distorted than in, for instance, [b-octaeth-
yl-meso-tetraphenylporphyrinato]-copper(II),[42] highlighting
the influence of the twist intrinsic to the ligand. The twist is,
with a helimer torsion angle of ꢂ788, in between that of the
nickel complex and the protonated free-base. The Cu···Cu
distance of 3.88 ꢄ falls within the range of metal–metal sep-
arations found in pyrazolate-bridged binuclear systems.[16]
The overall lengths of the macrocyclic frameworks along
their long axes (the mesopyr/pyr to mesopyr/pyr distances) de-
2+
creased from the protonated macrocycle 22H6 (10.72 ꢄ)
to 22Cu2 (10.61 ꢄ) to 22Ni2 (10.48 ꢄ), tracking, as expect-
ed, with the magnitude of the helimeric twist angles (Fig-
ure 12D).
Figure 10. UV/Vis spectra of 22Ni2 (magenta solid trace) and 22Cu2
(blue broken trace) in CH2Cl2.
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Siamese-Twin Porphyrin
FULL PAPER
cantly, the helimeric conforma-
tions were persistent and did
not racemize (within the time-
frame of our observations). We
conclude this conformational
stability from the straightfor-
ward separation of the enantio-
meric helimers of both com-
plexes by HPLC on a chiral
phase (Figure 13 and the Sup-
porting Information, S14). Ex-
cellent resolution was achieved
with a 50:50 ratio of ethyl ace-
tate and n-hexane on a Chiral-
pak IB column. For both com-
plexes 22Ni2 and 22Cu2, a clear
separation was observed in the
LC-UV band. DFT optimiza-
tion of the global minima of
22Ni2 and 22Cu2 and the UV/
Vis and CD spectra calculations
were again carried out with the
B3LYP functional in combina-
Figure 12. Molecular solid-state structure of A) 22Ni2 (symmetry transformation to generate equivalent atoms
(’): 0.5ꢁx, 0.5+y, 1.5ꢁz) and of B) 22Cu2 (symmetry transformation to generate equivalent atoms (’): 1ꢁx, y,
0.5ꢁz). C) schematic representation of the P-enantiomer, the nomenclature of these helimers and the view
tion with the 6-31ACTHNUGRTNEUNG(d,p) basis set
2+
along the mesopyr/pyr axis highlighting the torsion angle. D) overlay of the macrocyclic core structures of 22H6
for all elements except for the
transition metals, for which the
larger 6-311G*[46] basis set was
applied. Comparison of the ex-
perimental CD spectra with the
CD curves calculated for the
enantiomers of the two dimeta-
(gray), 22Ni2 (olive-green) and 22Cu2 (light blue). All hydrogen atoms and residual solvent molecules were
omitted for clarity, as were phenyl and ethyl groups in C and D. Exemplarily only the P-helices are shown
throughout. The torsion angle t of ꢂ738 found for 22Ni2 was significantly smaller than that angle observed in
2+
ꢁ
the diprotonated free-base 22H6 . Based on the relatively short N Ni bond lengths, the stronger twist of the
macrocycle seems to be induced by the nickel ions. The Ni···Ni distance of 3.81 ꢄ is similar to metal–metal
separations in pyrazolate-bridged binuclear systems (3.3–4.5 ꢄ).[16]
It has been pointed out that the outcomes of metalation
experiments of expanded porphyrins are not always predic-
table.[9c] On account of their flexibility and oxidation sensi-
tivity, this is particularly true for the metalation of hexaphyr-
ins and their N-confused congeners.[9c,11] For instance, meso-
arylhexaphyrin 1 forms a monometallic complex with AgIII
and homobimetallic complexes with AgIII and HgII and a
range of AuIIIM heterobimetallic complexes. The metals are
located in plane and each is coordinated by N2C2 donor
sets.[43] However, the reactions with first-row transition-
metals are more complex. For example, treatment of 1 with
CuII or CuI leads to entirely unanticipated meso-position ox-
idation and dearomatization of the macrocycle or to frame-
work rearrangements to form the C-oxidized version of the
doubly N-confused hexaphyrin.[44] One other reaction type
lated complexes revealed an excellent match for the CD
spectra of the faster eluting isomers (peak 1, Figure 13) with
the one predicted for M-22Ni2 and in the case of 22Cu2
with that of the P-enantiomer (the Supporting Information,
Figure S14); this led to the unambiguous stereochemical as-
signment of the helical enantiomers of both dimetalated
species.
Conclusion
We have achieved the synthesis of the long sought-after pyr-
azole-based expanded porphyrin 22H4 and its homobimetal-
lic nickel(II) and copper(II) complexes 22Ni2 and 22Cu2.
This macrocycle merges the architecture of two porphyri-
noid {N4} coordination sites, but neither of the individual co-
ordination sites, nor the entire macrocycle, showed porphyri-
noid aromaticity. The neutral free base was deduced to be
conformationally dynamic at the NMR timescale. The proto-
nation behavior of the free base was elucidated by NMR
and UV/Vis spectroscopy. These investigations also provided
numerous indications for the rigid and twisted conformation
of the diprotonated species. The solid-state conformations of
the diprotonated free base and the bimetallic complexes
were shown to be helimeric. HPLC on a chiral stationary
phase allowed us the resolution of 22H62+, 22Ni2, and
induced by PdII includes the formation of Pd C bonds with
ꢁ
concomitant macrocycle dearomatization.[45] The smooth
and predictable outcome of the metalation of twin porphyr-
in 22H4, on the other hand, demonstrates the conformation-
al and chemical stability of this ligand and its potential to
serve as scaffold for the targeted formation of bioinspired
bimetallic complexes.
Chiral resolution of 22Ni2 and 22Cu2: The solid-state heli-
meric conformations of the metal complexes 22Ni2 and
22Cu2 were also maintained in solution and, most signifi-
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G. Bringmann, C. Brꢀckner, F. Meyer et al.
Acknowledgements
Financial support from the Fonds der Chemischen Industrie and the
DAAD (fellowships to L.K.B) as well as the NSF (CHE-0517782 and
1058846, both to C.B.) is gratefully acknowledged.
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22Cu2 into their enantiomers and the unambiguous determi-
nation of their absolute configurations by a combination of
experimental and quantum-chemical ECD investigations.
Thus, the twin porphyrin and its metal complexes provide
another, and new, example of the class of porphyrins with
persistent chirality. Moreover, their metal-binding pocket
permits the formation of bimetallic complexes in which the
metals are close enough to interact with each other and po-
tentially also with a range of bridging axial ligands. Thus,
these macrocycles provide a new scaffold for the study of bi-
metallic multi-electron processes or the biomimetic activa-
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Siamese-Twin Porphyrin
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Received: December 3, 2012
Published online: && &&, 2013
Chem. Eur. J. 2013, 00, 0 – 0
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www.chemeurj.org
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G. Bringmann, C. Brꢀckner, F. Meyer et al.
Expanded Porphyrins
L. K. Blusch, Y. Hemberger,
K. Prçpper, B. Dittrich, F. Witterauf,
M. John, G. Bringmann,*
C. Brꢀckner,* F. Meyer* . . . . &&&& — &&&&
Siamese-Twin Porphyrin: A Pyrazole-
Based Expanded Porphyrin of Persis-
tent Helical Conformation
The chiral twist: The first pyrazole-
based expanded porphyrin is highly
twisted, which implies helical chirality.
Besides the separation of the helical
enantiomers of the free base, a thor-
ough understanding of the origin of
the twist and its pH dependency was
obtained (see figure). First bimetallic
nickel and copper complexes were syn-
thesized, in which each metal is
embedded in a porphyrin-like {N4}
pocket. The complexes were fully char-
acterized, including the resolution of
helimers.
Expanded porphyrins
The synthesis of the long sought-after pyrazole-based
expanded porphyrin and its homobimetallic nickel(II) and
copper(II) complexes is described in the Full Paper by G.
Bringmann, C. Brꢀckner, F. Meyer et al. on page && ff.
Spectroscopic evidence as well as structural parameters of
this hexaphyrin analogue (named the Siamese-twin
porphyrin) proved it to be non-aromatic, though each half
of the molecule is fully conjugated. In the complexes, each
metal ion is coordinated in a square-planar fashion by a
dianionic, porphyrin-like {N4} binding pocket. The confor-
mations of the diprotonated macrocycle and its metal
complexes are all strongly twisted. The persistent helical
twist permitted resolution of the enantiomeric helimers by
HPLC on a chiral phase.
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ÝÝ
These are not the final page numbers!