Efficient Biomimetic Hydroxylation Catalysis with a Bis(pyrazolyl)imidazolylmethane Copper Peroxide Complex

Article abstract of DOI:10.1002/chem.201501685

Bis(pyrazolyl)methane ligands are excellent components of model complexes used to investigate the activity of the enzyme tyrosinase. Combining the N donors 3-tert-butylpyrazole and 1-methylimidazole results in a ligand that is capable of stabilising a (μ-η²:η²)-dicopper(II) core that resembles the active centre of tyrosinase. UV/Vis spectroscopy shows blueshifted UV bands in comparison to other known peroxo complexes, due to donor competition from different ligand substituents. This effect was investigated with the help of theoretical calculations, including DFT and natural transition orbital analysis. The peroxo complex acts as a catalyst capable of hydroxylating a variety of phenols by using oxygen. Catalytic conversion with the non-biological phenolic substrate 8-hydroxyquinoline resulted in remarkable turnover numbers. In stoichiometric reactions, substrate-binding kinetics was observed and the intrinsic hydroxylation constant, k_ox, was determined for five phenolates. It was found to be the fastest hydroxylation model system determined so far, reaching almost biological activity. Furthermore, Hammett analysis proved the electrophilic character of the reaction. This sheds light on the subtle role of donor strength and its influence on hydroxylation activity.

Full text of DOI:10.1002/chem.201501685

DOI: 10.1002/chem.201501685
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&
Structure–Activity Relationships |Hot Paper|
Efficient Biomimetic Hydroxylation Catalysis with
a Bis(pyrazolyl)imidazolylmethane Copper Peroxide Complex
Claudia Wilfer,[a, b] Patricia Liebhäuser,[b] Alexander Hoffmann,[b] Hannes Erdmann,[a]
Oleg Grossmann,[a] Leander Runtsch,[a] Eva Paffenholz,[b] Rahel Schepper,[c] Regina Dick,[c]
[c]
[d]
[d]
´
´
Matthias Bauer, Maximilian Dürr, Ivana Ivanovic-Burmazovic, and Sonja Herres-
Pawlis*[a, b]
Dedicated to Prof. Dr. Heinz Decker on the occasion of his 65th birthday
Abstract: Bis(pyrazolyl)methane ligands are excellent com-
ponents of model complexes used to investigate the activity
of the enzyme tyrosinase. Combining the N donors 3-tert-bu-
tylpyrazole and 1-methylimidazole results in a ligand that is
capable of stabilising a (m-h2:h2)-dicopper(II) core that resem-
bles the active centre of tyrosinase. UV/Vis spectroscopy
shows blueshifted UV bands in comparison to other known
peroxo complexes, due to donor competition from different
ligand substituents. This effect was investigated with the
help of theoretical calculations, including DFT and natural
transition orbital analysis. The peroxo complex acts as a cata-
lyst capable of hydroxylating a variety of phenols by using
oxygen. Catalytic conversion with the non-biological phenol-
ic substrate 8-hydroxyquinoline resulted in remarkable turn-
over numbers. In stoichiometric reactions, substrate-binding
kinetics was observed and the intrinsic hydroxylation con-
stant, kox, was determined for five phenolates. It was found
to be the fastest hydroxylation model system determined so
far, reaching almost biological activity. Furthermore,
Hammett analysis proved the electrophilic character of the
reaction. This sheds light on the subtle role of donor
strength and its influence on hydroxylation activity.
belongs to the class of type-III copper enzymes.[3,4] In its active
centre, each copper atom is surrounded by three histidine
moieties.[3]
Introduction
A major part of research in the field of bioinorganic chemistry
revolves around the development of model complexes that
imitate the catalytic centre of enzymes. With these, chemists
investigate reaction mechanisms or recreate the catalytic
reactions of enzymes.[1]
Reactions catalysed by tyrosinase include the ortho-hydroxyl-
ation of phenols to catechols and subsequent oxidation to
quinones.[3–6] After X-ray crystallographic characterisation of
Streptomyces castaneoglobisporus tyrosinase by Matoba et al. in
Tyrosinase is a widespread enzyme in mammals, birds,
plants and fungi.[2] Comprising a dicopper(II) peroxide core, it
2006, it has been accepted that
peroxide core is present in tyrosinase.[3]
a
(m-h2:h2)-dicopper(II)
For the formation of the peroxide core in model chemistry,
a copper(I) species is reacted with O2. In general, this reaction
can result in several products,[4–6] but most frequently the
(m-h2:h2)-peroxide copper(II) core (SP core) and the isomeric
bis(m-oxo)dicopper(III) core (O core) are found; these are nearly
isoenergetic and exist in equilibrium at low temperatures.[7–9]
The steric properties and, more importantly, the basicity of the
[a] Dr. C. Wilfer, H. Erdmann, O. Grossmann, L. Runtsch,
Prof. Dr. S. Herres-Pawlis
Department für Chemie und Pharmazie
Ludwig-Maximilians-Universität München
Butenandtstraße 5–13, 81377 München (Germany)
[b] Dr. C. Wilfer, P. Liebhäuser, Dr. A. Hoffmann, E. Paffenholz,
Prof. Dr. S. Herres-Pawlis
S
Institut für Anorganische Chemie
ligands used determine whether the P or the O core is gener-
Rheinisch-Westfälische Technische Hochschule Aachen
Landoltweg 1, 52074 Aachen (Germany)
E-mail: sonja.herres-pawlis@ac.rwth-aachen.de
ated preferably. Therefore, many ligand families have been in-
vestigated as building blocks of tyrosinase and related hemo-
cyanin models, including tris(pyrazolyl)borates,[10] tris(pyrazo-
lyl)methanes,[11] alkyl amines,[12] pyridines,[13,14] ketiminates[15]
and guanidines.[16,17] Changing the ligand class can result in
the formation of another Cu2O2 species, but can also vary
within a ligand class, for example, by changing one donating
substituent. We have investigated donor competition be-
tween pyridinyl and pyrazolyl moieties in the HC(3-tBuPz)2(Py)
ligand (3-tBuPz=3-tert-butylpyrazolyl, Py=pyridyl) and shown
[c] R. Schepper, R. Dick, Prof. Dr. M. Bauer
Department Chemie, Universität Paderborn
Warburger Straße 100, 33098 Paderborn (Germany)
´
´
[d] M. Dürr, Prof. Dr. I. Ivanovic-Burmazovic
Department Chemie und Pharmazie
Friedrich-Alexander-Universität Erlangen-Nürnberg
Egerlandstraße 1, 91058 Erlangen (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501685.
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that nucleophilicity and basicity have to be taken into ac-
count.[18–20]
followed in 2009 with an imidazolyl-containing tris(2-pyridyl-
methyl)amine (TMPA) derivative,[40] and in 2012 Limberg et al.
presented a tripodal ligand containing sterically demanding
imidazolyl moieties for the stabilisation of CuI and CuII spe-
cies.[41] Those species were also capable of oxygen activation.
Earlier this year, they demonstrated the hydroxylation of 2,4-di-
tert-butylphenol (DTBP) to the
After the first examples of stoichiometric hydroxylations
mediated by a peroxo species,[21–23] few ligand systems have
been able to achieve significant catalytic phenol hydroxylation
so far. In 1990 RØglier et al. presented a model containing a
corresponding quinone with this
system.[42] In parallel, Stack et al.
showed that a P species with
simple methylimidazoles could
be stabilised at extremely low
temperatures of À1208C and
also displayed hydroxylation ac-
tivity.[43]
Remarkably, these previous
Figure 1. Ligands used for catalytic tyrosinase modelling.
imidazolyl-containing
systems
did not show the catalytic activi-
biphenyl spacer (Figure 1).[24] Casella et al. were later able to
achieve the first monophenolase reaction by using a Cu2O2
complex.[25] Since then, the group has made significant contri-
butions concerning hydroxylation reactions in particular.[26–29]
In 2010, Tuczek et al. followed with a mononuclear copper(I)
complex that consisted of pyridine and/or imine moieties as
precursors (Figure 1).[30] Recently, we presented the first room-
temperature-stable, catalytic tyrosinase model that consisted
of bis(pyrazolyl)methanes (Figure 1),[31] whereas Tuczek et al.
published catalytic systems with ligands that consisted of
imine and benzimidazole and imine and pyrazolyl moieties, re-
spectively.[32,33] In the next step, they could prove that an auxili-
ary base, such as NEt3, was not always necessary for the con-
version of phenolic substrates. Thereby, the phenol was at-
tached to a pyridine-containing ligand and its proper position-
ing in close proximity to the copper dioxygen unit was suffi-
cient to convert the phenol into an ortho-quinone.[34] Lumb
et al. made use of catalytic Cu/O2 chemistry to generate valua-
ble organic products from simple substituted phenols.[35,36]
They could also oxidise primary and secondary alcohols by
using a tyrosinase mimic as a catalyst, which made the
oxidising agent 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO)
unnecessary.[37]
Scheme 1. Synthesis of L, C1 and C2.
ty demonstrated herein with the novel bis(pyrazolyl)imidazolyl-
methane ligand HC(3-tBuPz)2(1-MeIm) (L).
We developed a new bis(pyrazolyl)methane ligand as part of
a functional tyrosinase model. In addition to catalytic studies, Results and Discussion
DFT and natural transition orbital (NTO) calculations were
Ligand and complex syntheses
performed to further investigate the electronic structure of the
complex and to gain an insight into electron transitions that
Ligand L was prepared by using a synthetic procedure analo-
S
occurred during the formation of the P core.
gous to that reported previously (Scheme 1).[44] The substituted
pyrazole is deprotonated and treated with thionylchloride,
resulting in the sulfoxide. In the following step, 1-methyl-2-imi-
dazolecarboxaldehyde is added to the mixture and, under
CoCl2 catalysis and reflux conditions, the bis(pyrazolyl)methane
ligand L is formed (Scheme 1 and Figure 2). Upon reaction of L
with CuCl2, single crystals of [CuCl2{HC(3-tBuPz)2(1-MeIm)}] (C1)
could be obtained from the reaction mixture. Furthermore, the
reaction of CuBr2 with L afforded single crystals of [CuBr2{HC(3-
tBuPz)2(1-MeIm)}]·MeCN (C2; Scheme 1 and Figure 2).
By keeping the 3-tBuPz units because their bulky alkyl group
prevents the formation of bisfacial complexes, pyridinyl was
substituted by 1-methylimidazolyl (1-MeIm; Scheme 1). The
use of imidazolyl as a N-donating ligand is obvious because it
is the key building block of the amino acid histidine.[38] Thus,
ligands containing imidazolyl moieties have already been ap-
plied in the field of copper-oxygen chemistry. In 1995, Sorrell
et al. used a substituted tris(imidazolyl)phosphine ligand to
stabilise a peroxo dicopper(II) adduct.[39] Karlin and co-workers
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not as accurate as those for C1;
however, the bond lengths are
predicted well. Bond angles are
predicted to be either too large
or too small, but overall result in
a predicted t4 value that is simi-
lar to the experimental one.
With regard to possible conform-
ers with tridentate or bis(pyra-
zolyl) coordination, we tried to
obtain other conformer struc-
tures. It should be noted that all
attempts failed and yielded the
experimentally found conform-
ers. However, the observed pyra-
zolyl–imidazolyl coordination is
not caused by steric hindrance
of the large tert-butyl groups,
since we already have structural-
ly characterised comparable cop-
per(II) halide complexes with the
sterically similar ligand HC(3-
tBuPz)2(Py).[19] We interpret this
finding as an indication of the
slightly stronger donor strength
of imidazolyl groups, as already
discussed by others.[46–48] Hence,
compared with pyridinyl units,
the imidazolyl unit is the
strongest donor in the series
Py<Pz<Im.[46]
Figure 2. Molecular structures of L, C1 and C2.
Table 1. Selected experimental and calculated (Gaussian 09, TPSSh, 6-31g(d))[51] bond lengths [Š] and angles [8]
of L, C1 and C2.
Bond lengths [Š]
L exptl
C1 exptl
(X=Cl)
C1 calcd
(X=Cl)
C2 exptl
(X=Br)
C2 calcd
(X=Br)
CapÀNPz
CapÀCIm
NPzÀNPz
1.450(2) 1.451(2) CuÀX(1)
2.225(1)
2.251(1)
2.044(3)
1.957(3)
2.240
2.218
2.000
1.961
2.404(1)
2.353(1)
2.073(4)
1.964(4)
2.316
2.316
2.036
1.977
1.507(2)
CuÀX(2)
1.358(2) 1.367(2) CuÀNPz
CuÀNIm
CapÀNPz
CapÀCIm
1.455(4) 1.462(4) 1.457 1.459 1.467(5) 1.452(6) 1.461 1.456
1.502(5)
1.502
1.493(6)
1.501
Bond angles [8]
NPz-Cap-NPz 111.4(1)
X(1)-Cu-X(2) 97.3(1)
103.3
95.5
137.4
146.8
94.8
94.5(1)
100.6(1)
152.6(1)
142.0(1)
93.5(1)
88.9(2)
102.6
93.9
144.6
146.3
95.1
NPz-Cap-CIm 109.9(1) 110.7(1) X(1)-Cu-NPz
98.8(1)
150.8(1)
141.7(1)
93.4(1)
89.3(1)
X(1)-Cu-NIm
X(2)-Cu-NPz
X(2)-Cu-NIm
NPz-Cu-NIm
89.3
87.6
[45]
t4
0.48
0.54
0.46
0.49
For a more detailed under-
standing of donation effects in
Table 1 displays key bond lengths and angles for the four-
coordinate copper(II) complexes C1 and C2 and ligand L itself.
Ligand L is a substituted methane and as such crystallises as
complexes C1, C2 and the peroxo complex P, which includes
the ligand L, natural bond orbital (NBO) analysis was per-
formed, yielding NBO charges and charge-transfer (CT) ener-
gies related to donation from the pyrazolyl and imidazolyl moi-
eties to the copper atom. NBO charges are not absolute charg-
es, but can help in the understanding of electronic effects in
complexes.[49–52] The NBO charges and CT energies are summar-
ised in Table 2.
¯
an almost perfect tetrahedron in the triclinic space group P1.
Bond lengths are in the common range known for bis(pyrazo-
lyl)methanes.[44] In both molecular structures of C1 and C2, one
pyrazolyl moiety is pushed out of the coordination sphere
around the copper atom, which suggests that the imidazolyl
moiety has a stronger donor ability towards the central metal.
The CuÀNIm bond length is shorter than the CuÀNPz bond in
C1 and C2. The t4 values indicate a distorted coordination
geometry, which can neither be assigned to a distorted tetra-
hedron nor to square-planar geometry.[45] The CuÀNPz, CuÀNIm
and CuÀX bond lengths are shorter in C1 than those in C2.
Based on the molecular structures of C1 and C2, we conducted
DFT structural optimisations. The results are also displayed in
Table 1. By comparing experimental and calculated bond
lengths for C1, a proper accordance is found because the only
bond length predicted to be too short is the CuÀCl(2) one. For
bond angles, the calculations show the same dispersion as in
the molecular structure of C1. For example, the NPz-Cu-NIm and
Cl(2)-Cu-NIm angles are predicted almost correctly, whereas all
others deviate by not more than 68, excluding the Cl(1)-Cu-NIm
angle. For C2, the calculated angles at the copper atom are
Table 2. NBO charges [eÀ units] and CT energies [kcalmolÀ1] for C1, C2
and P. (Gaussian 09, TPSSh/6-31g(d) and NBO 6.0).[49–51]
C1
C2
P
NBO charges
NIm
NPz (coord.)
NPz
À0.57
À0.37
À0.35
0.86
À0.56
À0.36
À0.30
0.70
À0.61
À0.46
À0.46
1.38
Cu
X(1)
X(2)
CT energies
NIm!Cu
NPz!Cu
À0.57
À0.48
À0.55
À0.48
22.4
21.1
22.6
19.9
23.7/23.9
36.8/38.6
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The results in Table 2 reveal that NIm donor atoms possess
a more negative charge than the NPz donor atoms, and that
the NBO charge at the non-coordinating NPz atom is less nega-
tive than that on the coordinating one. However, the pKa
values and partial charges on the coordinating N atoms mostly
do not give conclusive indications, as shown earlier.[18,20] Analy-
sis of the CT energies suggests a slightly larger donor ability of
the nitrogen lone pair of imidazolyl to the central metal. This
might be related to the shorter CuÀNIm bond length. For the P
species, the NBO calculations show higher CT energies for pyr-
azolyl. This seems to be the case when the imidazolyl units are
located at the axial positions, which lie at a slightly longer dis-
tance from the copper centre. This conformer (Scheme 2) was
Figure 3. UV/Vis spectrum of the formation of P(SbF6)2 at 195 K (DFT:
BS-TPSSh/6-31g(d)).
this region, separated by 200 nm, clearly show the formation
of a peroxide complex. It is known from other copper(II) perox-
ide complexes that their UV/Vis spectra exhibit intense oxygen
to copper charge-transfer (LMCT) absorptions, which are con-
sistent with the presence of highly covalent CuÀO bonds.[7]
The real metalloproteins oxytyrosinase and oxyhemocyanin
also show similar UV/Vis transitions.[54,55] A striking difference,
however, is the blueshift of the UV/Vis bands in comparison to
those at l=350 and 550 nm for other known bis(pyrazolyl)me-
thane peroxo complexes.[27,31] To understand this phenomenon,
NTO calculations were performed; the results are analysed
below.[56]
Scheme 2. Top: Preparation of the side-on peroxide species P. Bottom:
Calculated structure of the P species after geometry optimisation with
TPSSh/6-31g(d).
The species P(SbF6)2 could be generated in >95% yield at
195 K and was stable at that temperature for several days. Its
half-life at 273 K is 3.5 min. Further analyses included cryo-ul-
trahigh resolution (cryo-UHR) ESI mass spectrometry (Figure 4),
which also confirmed the formation of a (m-h2:h2)-copper(II)
peroxide core. The peroxo complex appears here as the mono-
cationic species P(SbF6)+.
used for all theoretical investigations because it was the ener-
getically favourable one. Moreover, due to the mirror plane,
the orbitals of this conformer appear more symmetrical and
therefore clearer. We found that all possible conformers lay
within 2 kcalmolÀ1. In the other conformers, the CT energy also
depends on the corresponding CuÀN distances, which makes
analysis more complicated. The reasons behind this are
currently under investigation by Herres-Pawlis et al.[53]
Peroxo complex formation and characterisation
The copper(I) precursor was generated in situ from the starting
compounds by following the synthetic route described by
Herres-Pawlis et al.[31] It should be noted that the direct synthe-
sis of a CuI complex from [Cu(MeCN)4]SbF6 is possible, but this
species does not activate dioxygen, since acetonitrile blocks
the coordination site.[11] The precursor [Cu{HC(3-tBuPz)2(1-
MeIm)}][SbF6] was then injected into an O2-saturated solution
in dichloromethane at 195 K (Scheme 2). The formation of the
resulting peroxide complex [Cu2O2{HC(3-tBuPz)2(1-MeIm)}2]
[SbF6]2 (P(SbF6)2) was monitored by UV/Vis spectroscopy
(Figure 3).
The spectrum shows absorption bands at l=334 and
534 nm. Time-dependent (TD) DFT calculations predict the po-
sitions of these bands perfectly. Moreover, the deep violet
colour of the solution and the existence of UV/Vis bands in
Figure 4. Cryo-UHR-ESI mass spectrum of P(SbF6)2 at 193 K.
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Figure 5. NTO analysis of P (Gaussian 09, BS-TPSSh/6-31g(d)).
LUNTO=lowest unoccupied natural transition orbital
Figure 6. Copper K-edge XANES spectrum of P(SbF6)2.
NTO calculations on the geometry-optimised coordinates
were performed by using the TPSSh functional with broken
symmetry combined with the 6-31g(d) basis set. Figure 5
shows the results of this calculation. LUNTO symbolises the
orbital that accepts electrons in the transition process under
investigation. NTO analysis was performed for the four major
electronic transitions.
Consequently, CuIII can also be excluded and a CuII state is
unequivocally concluded. The white-line morphology was
similarly found by Solomon et al.[63] and Meyer et al.[64] for
dinuclear (m-h2:h2) side-on complexes.
The extended X-ray absorption fine structure (EXAFS)
spectrum and corresponding Fourier-transformed function of
P(SbF6)2 are given in Figure 7, and the extracted structural pa-
rameters are given in Table 3. The first contribution at an aver-
Those at l=326, 329 and 374 nm correspond to the transi-
tion at l=334 nm in the experimental spectrum, which is very
accurate (see the Supporting Information for details). The
second transition is also predicted very well because deviation
from the experimental value is only 4 nm. Each NTO consists of
fractions of several orbital types of copper and the oxygen per-
oxide unit. The LUNTO, for example, is composed of ps* orbital
parts at the oxygen atoms and dxy orbitals at the copper
atoms. The less intensive transition at l=534 nm originates
from a NTO that shows oxygen pv* and Cu dxy characteristics
(NTO 4). For NTO 1–3, it is not as easy to see the components
that contribute to the transition orbital. The NTO 1 shows ele-
ments of ps* at the oxygen atoms and those of dxz at copper.
In NTO 2, the same applies, with an additional peroxide–s*
fraction. The NTO 3 does not incorporate any peroxide-orbital
parts, but shows participation of the p system of the ligand.
The TD-DFT calculations already predict blueshifted LMCT tran-
sitions. These can be explained by the strong donor ability of
the imidazolyl moiety at the ligand. As Stack et al. reported in
2014, increased donation of the ligand to copper leads to an
increase of the LUMO orbital energy, and therefore, results in
a higher energetic transition, which appears blueshifted.[57]
As a further characterisation method, we performed X-ray
absorption experiments (XAS) at the copper K-edge.
Figure 7. Fourier-transformed Cu K-edge EXAFS spectrum (black solid line:
experimental data; grey dashed line: fitted function) of P(SbF6)2.
Table 3. Structural parameters obtained by fitting the experimental
EXAFS functions with theoretical models.
Figure 6 shows the Cu K-edge X-ray absorption near-edge
structure (XANES) spectrum of P(SbF6)2. Only a low-intensity
pre-edge signal at 8978 eV is found in the spectrum. This ex-
cludes an oxidation state of CuI because the intensity is typical
for a dipole-forbidden 1s!3d quadrupole transition character-
istic of CuII.[58–60] The 1s!4p+LMCT shake-down transition at
8987 eV[61] is only present as a weak shoulder. It should be
noted that CuIII in related compounds is characterised by
a sharp signal around this energy value,[61] and a higher pre-
peak intensity due to more available empty d states.[62]
Abs-Bs[a] N(Bs)[b]
P(SbF6)2 Cu-N/O
r(Abs-Bs)[c] [Š] s[d] [Š]
R[e] [%]
5.4Æ0.5 1.99Æ0.02
0.063Æ0.006 15.05
0.032Æ0.003
Cu-C/N
Cu-C/N
Cu-Cu
1.4Æ0.2 2.92Æ0.03
4.6Æ0.9 3.37Æ0.03
1.3Æ0.4 3.69Æ0.06
0.112Æ0.012
0.110Æ0.033
[a] Abs=X-ray absorbing atom. Bs=backscattering atom (neighbour).
[b] Number of neighbour atoms. [c] Distance between Abs and Bs.
[d] Debye–Waller-like factor to account for disorder. [e] Quality of fit.
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age distance of 1.99 Š is composed of the two oxygen atoms
from the side-on peroxo group and nitrogen atoms from the li-
gands. The next two shells at 2.92 and 3.37 Š are also com-
bined C/N shells from the ligand and are in reasonable agree-
ment with the DFT model. However, it should be noted that
carbon and nitrogen at distances of around 3 Š are subjected
to a rather large error in coordination numbers due to the low
back-scattering amplitude.[65] A CuÀCu contribution at 3.69 Š
with one back-scatterer within the error bar could be detected,
which additionally proved the dimeric character of the com-
plex in solution. This value is 0.12 Š larger than that in the DFT
model of P. Considering the high noise level of the unfiltered
spectra, which is caused by the low concentration of the
copper species and the dichloromethane solvent, the agree-
ment is quite good. Higher distance multiple scattering shells
were removed by Fourier filtering.[60,63]
Figure 8. UV/Vis spectra of P(SbF6)2 (dashed) and of the formation of the
quinone (black).
Stoichiometric and catalytic hydroxylation
To investigate the kinetics of the hydroxylation step, we
studied the stoichiometric hydroxylation reaction of P with var-
ious sodium phenolates. Excess oxygen was removed by N2
purging before the substrate was added. All five substrates are
quantitatively converted into the corresponding catechol
within 20 min (see the Supporting Information). We detected
a strong dependence of the reaction speed on the amount of
substrate added. This typical substrate binding kinetics, depict-
ed in Figure 9, has also been observed for the parent peroxo
species.[31] We assume that a phenolate–peroxo species forms
as an intermediate.[31] The related bis(m-oxo) species was found
to be energetically less favourable.[52] Measuring the hydroxyl-
ation velocity at different substrate concentrations enables us
to resolve the intrinsic hydroxylation constant, kox, and the
binding constant, Keq.
Functional enzymatic models not only need to incorporate
a model of the active centre of the enzyme, but also be able
to execute the catalytic reactions of those enzymes. As men-
tioned above, the catalytic reactivity of tyrosinase models is
rare. We performed experiments to show both efficient stoi-
chiometric oxidation of phenolates to catecholates at 193 K
and catalytic oxidation of phenols to quinones at room tem-
perature with triethylamine, through a reaction pathway con-
sistent with the generally accepted enzymatic mechanism.[5,31]
Following a standard protocol,[24,30,66] the combination of
25 equivalents of 8-hydroxyquinoline and 50 equivalents of
triethylamine under an oxygen pressure of 1 atm leads to the
formation of 14 equivalents of the quinone in 20 min
(Figure 8). With prolonged reaction time, the yield of the qui-
none decreases, presumably due to consecutive reac-
tions of the highly reactive quinones, leading to
a yield of 9 equivalents after 1 h and 7 equivalents
after 16 and 18 h. The formation of the quinone was
followed by UV/Vis spectroscopy, due to the strong
UV/Vis band at l=413 nm (e=1000 LmolÀ1 cmÀ1).[67]
This reaction proceeds on a millimolar scale and con-
verts 80% of the added hydroxyquinoline into the
quinone, which makes it synthetically useful. The ad-
dition of triethylamine or 8-hydroxyquinoline sepa-
rately does not affect the lifetime of the P species.
Only in combination does the hydroxylation reaction
occur. Moreover, the formation of the P species can
be observed when either triethylamine or 8-hydroxy-
quinoline is present. When both components are
present, the P species does not appear, but the same
catalytic hydroxylation reaction is observable by its
strong quinone absorption as those observed when
the components are added after P formation. This
type of self-assembly has been observed previously
for related P species.[19,68] We also studied the poten-
tial influence of silver ions, but retrieving all AgCl by
Figure 9. Top: Scheme of the substrate-binding kinetics. Left: Substrate binding and
hydroxylation of p-carbomethoxyphenolate by P(SbF6)2; right: Hammett plot for the
stoichiometric hydroxylation reaction with various p-substituted phenolates at 195 K.
means of a syringe filter (0.45 mm) did not change
the results.
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for the parent pyridinyl–peroxo species. Analysis of the sub-
strate-binding kinetics quantitatively proves that the electron-
deficient substrate p-carbomethoxyphenolate is hydroxylated
approximately six times faster. This possibility of efficiently
tuning catalytic activity by donor exchange opens up new di-
rections for industrial applications of this mild, selective and
atom-economic hydroxylation chemistry.
Table 4. Hydroxylation constant, kox [sÀ1], of both P species with p-X-
phenolates.
X
ImPz-P
PyPz-P[31]
OMe
Me
F
4.27
3.36
2.84
2.83
2.28
1.33
0.87
0.73
0.65
0.36
H
CO2Me
Table 4 provides a summary of the data for kox for the pres-
ent P species and the parent species PyPz-P. It is remarkable
that the intrinsic hydroxylation constant, kox, of P for carbome-
thoxyphenolate could be determined as 2.28 sÀ1 (pyridinyl–
peroxo: 0.36 sÀ1) and the equilibrium constant, Keq, as
0.066 LmolÀ1 (pyridinyl–peroxo: 1.00 LmolÀ1). For the same
substrate, Itoh et al. reported a hydroxylation constant of
0.083 sÀ1 with a P species stabilised by a tridentate bis(pyridi-
Experimental Section
General
All experiments involving moisture- and air-sensitive compounds
were carried out by using standard Schlenk techniques. All chemi-
cals were purchased from Sigma-Aldrich, Alfa-Aesar, Acros Organ-
ics, Applichem, Fluka or ABCR and were used as received without
further purification. The solvents used were dried by standard liter-
ature procedures.[70] The starting materials 3-tert-butylpyrazole,[71]
1-methyl-2-imidazolecarboxaldehyde[72] and CuCl[73] were synthes-
ised according to procedures reported in the literature. For the cat-
alytic conversion of phenolates, the substituted phenols were de-
protonated with a solution of NaOH, according to a procedure re-
ported in the literature.[74]
nyl)benzylamine ligand, LPy2Bz [23]
For fluorophenolate, they re-
.
ported a value of 0.63 sÀ1. For a m-h1:h1-peroxo species, stoi-
chiometric hydroxylation reactivity was reported with hydroxyl-
ation constants that were at least one magnitude smaller.[25]
With regard to real tyrosinase, Garcia-Canovas et al. reported
kcat. values for 258C in a buffer solution that were five times
larger.[69] Taking into account that the biological reaction pro-
ceeds at a temperature 100 K higher than that of biomimetic
systems, it is clear that the new system comes very close to
the biological reaction speed.
Physical methods
Cryospray-ionisation MS (CSI-MS) measurements were performed
on a UHR-TOF Bruker Daltonik (Bremen, Germany) maXis plus 5G
instrument, which was an ESI-TOF mass spectrometer capable of
a resolution of at least 60000 full-width at half-maximum (FWHM),
coupled to a Bruker Daltonik Cryospray unit. Detection was in posi-
tive-ion mode and the source voltage was 4.5 kV. The flow rates
were 250 mLhÀ1. The drying gas (N2), to aid solvent removal, was
held at 198 K and the spray gas was held at 193 K. The machine
was calibrated prior to every experiment through direct infusion of
the Agilent ESI-TOF low concentration tuning mixture, which pro-
vided an m/z range of singly charged peaks up to 2700 Da in both
ion modes. Fast-atom bombardment (FAB) mass spectra were ob-
tained with a Thermo Finnigan MAT 95 or a Jeol MStation sector
field mass spectrometer. Ionisation was achieved with accelerated
xenon atoms (8 kV) in a glycerin or 2-nitrobenzylalcohol matrix on
a copper target. For low-resolution measurements, the resolution
was about 1000 and for high resolution at about 5000. Depending
on the method, areas between 40 and 3040 u were recorded. ESI
mass spectra were obtained on a Thermo Finnigan LTQ Ultra Fouri-
er-transform ion cyclotron resonance mass spectrometer. Resolu-
tion was adjusted to 100000 at m/z 400. Depending on the
method, areas between 50 and 2000 u were recorded. ESI meas-
urements were performed at an IonMax ionic source with an ESI
head. The source voltage was 4 kV with a spray capillary tempera-
ture of 523 K, a sheath-gas flow rate of 25 and a sweep-gas flow
rate of 5 units. IR spectra were recorded with a Jasco FTIR 460
spectrophotometer in the range of 650–3500 cmÀ1. Measurements
took place at room temperature in the ATR measurement mode.
UV/Vis spectra were recorded with a Varian Cary 60 spectropho-
tometer from Agilent Technologies in combination with a fibre-
optic quartz glass immersion probe (Hellma, 1 mm) in a customised
Schlenk measurement cell. Elemental analyses were performed
with a Vario EL or Vario MICRO CHNS analyser.
Furthermore, a correlation of the obtained kox values against
the corresponding Hammett parameters (Figure 9) gave a
reaction constant, 1, of À0.5, which proved that the reaction
proceeded electrophilically, as mediated by tyrosinase with
a 1 value of À1.75.[69] The parent peroxo species possesses
a 1 of À1.[31]
Moreover, it shows the superior hydroxylation reactivity of P
in comparison to the pyridinyl–peroxo species, which is direct-
ly related to exchange of the third donor function pyridinyl
against the imidazolyl moiety. The stronger donor ability
enhances the oxidative force of P, which leads to faster hydrox-
ylation in the catalytic mode, but also to the observed
subsequent reactions.
Conclusion
We have reported that fine-tuning of biomimetic ligands leads
to enhanced catalytic activity of a catalytic tyrosinase model.
We have provided syntheses and structural characterisation of
a new bis(pyrazolyl)imidazolylmethane ligand and its copper(II)
halide complexes. The reaction of dioxygen with its copper(I)
hexafluoridoantimonate complex gives a peroxo species that
has been characterised by UV/Vis and XAS spectroscopy as
well as cryo-UHR-ESI mass spectrometry. The classical CT ab-
sorptions are strongly blueshifted and have been analysed by
TD-DFT and NTO analysis. They show the special role of the
third donor function. The new peroxo species displays stoichio-
metric and catalytic hydroxylation activity. The catalytic activity
towards 8-hydroxyquinoline is more rapid than that observed
Chem. Eur. J. 2015, 21, 17639 – 17649
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Full Paper
CCDC-1057372 L, 1057370 C1 and 1057371 C2 contain the supple-
mentary crystallographic data for this paper. These data are provid-
ed free of charge by The Cambridge Crystallographic Data Centre.
X-ray absorption measurements
Measurements at the Cu K-edge were carried out at beamline
BM23 of the European Synchrotron Radiation Facility ESRF (Greno-
ble, France) in fluorescence mode by making use of a hyperpure
solid-state Ge detector. The sample was measured as a frozen solu-
tion at liquid nitrogen temperature by using CH2Cl2 as a matrix.
Due to the low concentration of 0.01 molLÀ1, several scans were
conducted and averaged to increase the signal to noise ratio. Data
reduction followed standard procedures given in ref. [59]. Due to
the high residual noise, Fourier filtering was applied in the range
Dr=3–11.5 Š.
Computational details
DFT calculations were performed with the program suite Gaussi-
an 09.[49] The geometries of L, C1, C2 and the peroxo species were
optimised (Table 1) by using the nonlocal hybrid meta GGA TPSSh
functional[79] and the double-zeta basis set 6-31g(d), as implement-
ed in Gaussian 09 on all atoms. The starting geometries for L and
complexes C1 and C2 were generated from the molecular struc-
tures. The P conformer geometries were derived from those of the
parent pyrazolyl–pyridinyl P species. Energetic evaluation of the P
conformers was also done with TPSSh/def2-TZVP. Frequency calcu-
lations did not show imaginary values. NBO calculations for the
complexes were accomplished by using the program suite
NBO 6.0.[50,51,80] Continuous spectra were plotted with the AOMix
program.[81,82] The intensities were normalised to the experimental
spectrum. For the P species, we searched for energetically low-
lying unrestricted Kohn–Sham (UKS) wavefunctions with broken
spin and spatial symmetry (“broken-symmetry” wavefunctions) by
using the “guess=mix” keyword.
X-ray diffraction analyses
The crystal data for L, C1 and C2 are presented in Table 5. The
data for L and C2 were collected with an Oxford KM4 XCalibur2
diffractometer and for C1 with a Bruker D8 Venture diffractometer
with graphite monochromated MoKa radiation (l=0.71073 Š). Data
reduction and absorption correction was performed with the pro-
grams CRYSALIS (Oxford, 2008) and CRYSALIS RED (Oxford, 2008; L
and C2) or with SAINT and SADABS (C1).[75] The structure was
solved by direct and conventional Fourier methods and all non-hy-
drogen atoms were refined anisotropically with full-matrix least-
squares based on F2 (XPREP,[76] SHELXS[77] and ShelXle[78]). Hydrogen
atoms were derived from difference Fourier maps and placed at
idealised positions, riding on their parent C atoms, with isotropic
displacement parameters of Uiso(H)=1.2Ueq(C) and 1.5Ueq(C
methyl). All methyl groups were allowed to rotate, but not tip.
HC(3-tBuPz)2(1-MeIm) (L)
3-tert-Butylpyrazole (5.00 g, 0.40 mol, 2 equiv) was added in small
portions to a slurry of NaH (1.00 g, 0.42 mol, 2.1 equiv) in freshly
distilled, dry THF (50 mL) at 273 K under vigorous stirring, until no
more gas evolution was visible. Next, thionylchloride (1.50 mL,
0.20 mol, 1 equiv) was added dropwise to the yellow suspension at
273 K and stirred first at 273 K for 30 min and afterwards at room
temperature for another 45 min. 1-Methylimidazole-2-carboxalde-
hyde (2.20 g, 0.20 mol, 1 equiv) and catalytic amounts of CoCl2
were added before the mixture was heated at reflux overnight and
the evolution of SO2 gas was visible. The solution changed colour
to red–orange. After cooling the reaction mixture to room temper-
ature, water (50 mL) and diethyl ether (50 mL) were added, fol-
lowed by 2 h of stirring. Lastly, the combined organic phases were
extracted with diethyl ether (3”45 mL) and washed with water
(2”50 mL) and brine (2”50 mL). The combined organic phases
were dried over Na2SO4 and the solvent was reduced in vacuo. The
product was obtained by vacuum distillation (313 K, 1.4”10À2 bar)
in the second fraction in good yield (4.7 g, 0.14 mol, 70%). Single
crystals obtained from the mixture were characterised by XRD anal-
ysis. 1H NMR (400 MHz, CDCl3, 298 K): d=1.26 (s, 18H; 3-tBuPz),
Table 5. Crystallographic data and parameters of L, C1 and C2.
L
C1
C2
formula
Mr [gmolÀ1
C19H28N6
340.47
C19H28Cl2CuN6 C21H31Br2CuN7
474.91 604.89
]
crystal size [mm]
0.37”0.31”0.10 0.0”0.04”0.04 0.26”0.24”0.19
T [K]
173(2)
173(2)
triclinic
¯
P1
173(2)
monoclinic
Cc
12.5876(4)
14.4039(6)
14.6325(5)
90
103.298(4)
90
2581.89(16)
4
crystal system
space group
a [Š]
b [Š]
c [Š]
triclinic
¯
P1
6.3373(4)
10.2663(4)
14.8859(7)
84.201(4)
87.172(4)
88.343(3)
961.53(7)
2
1.176
0.074
0.71073
368
7.6934(6)
8.0918(7)
18.1881(15)
89.787(2)
88.0722(2)
84.734(2)
1126.85(16)
2
1.400
1.223
0.71073
494
a [8]
b [8]
3
3.45 (s, 3H; MeIm), 6.15 (d, J(H,H)=2.5 Hz, 2H; 4H-tBuPz), 6.87 (d,
g [8]
3J(H,H)=1.2 Hz, 1H; 5H-MeIm), 7.04 (d, 3J(H,H)=1.2 Hz, 1H; 4H-
MeIm), 7.44 (d, 3J(H,H)=2.5 Hz, 2H; 5H-tBuPz), 7.64 ppm (s, 1H;
CH); 13C NMR (100 MHz, CDCl3, 298 K): d=30.6 (CH3-tBuPz), 32.2 (C-
tBuPz), 33.1 (CH3-MeIm), 71.5 (CH(ap.)), 103.5 (4C-tBuPz), 122.8 (5C-
MeIm), 128.0 (4C-MeIm), 129.4 (5C-tBuPz), 142.0 (2C-MeIm),
163.1 ppm (3C-tBuPz); IR (ATR): n˜ =2959 (w, CHarom), 2928 (w,
CHarom), 2902 (w, CHarom), 2866 (vw, CHaliph), 1531 (w), 1519 (m),
1501 (w), 1478 (w), 1461 (w), 1400 (w), 1362 (w), 1335 (m), 1317
(w), 1281 (w), 1244 (m), 1225 (w), 1206 (w), 1189 (w), 1153 (m),
1135 (w), 1046 (m), 1022 (w), 993 (w), 927 (w), 852 (w), 818 (m),
805 (s), 762 (vs), 724 (m), 698 (m), 664 cmÀ1 (w); MS (ESI+, acetone):
m/z (%): 364 (17) [M+H+Na]+, 363 (100) [M+Na]+, 341 (42) [M+
H]+, 218 (10) [C10H19N4 +Na]+, 217 (96) [C12H17N4]+, 214 (1)
[C13H16N3]+; HRMS (ESI+; acetone): m/z calcd for C19H28N6Na [M+
Na]+: 363.2273; found: 363.2273; elemental analysis calcd (%) for
C19H28N6 (340.48 gmolÀ1): C 67.0, H 8.3, N 24.7; found: C 67.1, H
8.3, N 24.3.
V [Š3]
Z
1calcd. [gcmÀ3
]
1.556
3.963
0.71073
1220
m [mmÀ1
l [Š]
]
F(000)
hkl range
reflns collected
À6/7, À12/10,
Æ18
Æ9, Æ10, Æ22 À15/14, À16/17,
À17/16
5216
20053
4623
0.0511
4623
6403
3583
0.0286
3583
288
0.0295
0.0648
1.068
independent reflns 3882
Rint.
0.0149
reflns observed
no. parameters
R1 [Iꢀ2s(I)]
wR2 (all data)
goodness-of-fit
3882
233
0.0499
0.1350
1.037
260
0.0460
0.1128
1.085
largest diff. peak,
À0.213, 0.229
À0.512, 0.882 À0.431, 0.405
À3
hole [eŠ
]
Chem. Eur. J. 2015, 21, 17639 – 17649
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(25 equiv) and NEt3 (50 equiv) in CH2Cl2 (200 mL) was added. The re-
action solution was warmed to room temperature, stirred over-
night and monitored by means of UV/Vis spectroscopy through-
out; an intense feature at l=413 nm owing to the formation of
the corresponding quinone was observed.[67] After 16–18 h, the re-
action was quenched with 0.5m HCl (3 mL). The aqueous solution
was extracted with CH2Cl2 (3”3 mL) and the combined organic
phases were dried over MgSO4. The solvent was reduced in vacuo,
followed by NMR spectroscopic characterisation.[31] The quantity of
the quinone formed was determined from the extinction coeffi-
cient of the quinone, yielding 14 turnovers per dinuclear copper
peroxide species after 20 min. The 7,8-dione of quinoline was de-
tected by HRMS (EI): m/z calcd for C9H5O2N: 159.0319; found:
159.0310, which corresponded to the quinone with the appropri-
[CuCl2{HC(3-tBuPz)2(1-MeIm)}] (C1)
Copper(II) chloride (0.17 g, 1.00 mmol) was suspended in methanol
(5 mL), resulting in a green–brown slurry. A solution of L (0.34 g,
1.00 mmol) dissolved in methanol (5 mL) was added dropwise to
the copper-salt mixture and after stirring for 16 h at room temper-
ature a deep-green solid precipitated. Storage of the mixture at
room temperature resulted in single crystals suitable for XRD analy-
sis (0.14 g, 0.29 mmol, 30%). IR (ATR): n˜ =3100 (vw, CHarom), 2902
(w, CHarom), 2865 (w, CHaliph), 1518 (m), 1474 (w), 1459 (w), 1417 (w),
1350 (m), 1229 (m), 1204 (w), 1152 (w), 1081 (w), 1054 (w), 970 (w),
861 (m), 831 (w), 811 (m), 803 (vs), 782 (vs), 770 (vs), 756 (m), 728
(w), 699 (m), 669 (w), 634 (w), 627 (w), 614 (m), 603 cmÀ1 (m); MS
(FAB+): m/z (%): 440 (16) [63Cu37ClL]+ and [65Cu35ClL]+, 438 (20)
[63Cu35ClL]+, 405 (20) [65CuL]+, 403 (40) [63CuL]+, 342 (15) [L]+, 217
(100) [HC(3-tBuPz)(1-MeIm)]+; elemental analysis calcd (%) for
C19H28Cl2CuN6 (474.92 gmolÀ1): C 48.1, H 5.9, N 17.7; found: C 47.9,
H 6.0, N 17.7.
1
ate calculated isotope. H NMR (400 MHz, CD3OD): d=6.90 (m, 1H),
7.80 (m, 1H), 7.92 (m, 1H), 8.20 (m, 1H), 8.54 ppm (m, 1H).
Stoichiometric reaction of P(SbF6)2
The reactions of P(SbF6)2 with sodium p-X-phenolates (X=H,
CO2Me, OMe, Me, F) at 195 K ([P(SbF6)2]=1 mm, [substrate]=1, 2,
5, 10, 15 and 20 equiv per dimer) were optically monitored by fol-
lowing the decay of the peroxide species until no change in the
absorption spectrum was evident. In all reactions, solutions of
P(SbF6)2 were prepared by the “injection” method at 195 K to give
a final volume of 10 mL. After stabilisation of the optical spectrum,
excess O2 was removed by five cycles of vacuum/N2 purging and
five min of purging the solution with N2. The substrate solutions
were added quickly in one portion. The data for each reaction
were reasonably fitted with a single exponential to obtain the
pseudo-first-order rate constant, kobs. The saturation behaviour of
kobs with respect to [phenolate] was fitted to the equation in
Figure 9 to obtain the rate constant for the oxidation reaction, kox,
and the association constant, Keq. Substrate characterisation was
performed as described previously.[31] The resulting NMR spectra
are given in the Supporting Information.
[CuBr2{HC(3-tBuPz)2(1-MeIm)}]·MeCN (C2)
An orange solution of L (0.17 g, 0.50 mmol) dissolved in THF (1 mL)
was added dropwise to a deep-green solution of copper(II) bro-
mide (0.11 g, 0.50 mmol) dissolved in acetonitrile (2 mL). The solu-
tion was stirred at room temperature for 3 h, which resulted in the
precipitation of a brown solid. The solid was recrystallised from
acetonitrile (4 mL) by making sure to cool the solution slowly (over
5 h). Storage of the solution at 241 K resulted in small brown crys-
tals suitable for XRD analysis after 4 d (0.21 g, 0.35 mmol, 70%). IR
(ATR): n˜ =3118 (w, CHarom.), 3101 (w, CHarom.), 2966 (m, CHarom.), 2908
(w, CHarom.), 2867 (w, CHaliph.), 1737 (vw), 1639 (w), 1552 (w), 1523
(m), 1516 (m), 1484 (m), 1459 (m), 1415 (m), 1362 (m), 1345 (m),
1335 (w), 1286 (w), 1232 (vs), 1207 (m), 1156 (m), 1084 (m), 1067
(m), 1030 (w), 1018 (w), 986 (w), 971 (m), 928 (vw), 861 (m), 833
(m), 804 (vs), 774 (vs), 725 (m), 699 (s), 669 cmÀ1 (w); MS (FAB+):
m/z (%): 744 (11) [C38H56N1263Cu]+, 487 (3) [C1813CH28N665Cu81Br]+,
486 (12) [C19H28N665Cu81Br]+, 485 (10) [C1813CH28N663Cu81Br]+,
[C1813CH28N665Cu79Br]+,
484
(37)
[C19H28N663Cu81Br]+,
[C19H28N665Cu79Br]+, 483 (8) [C1813CH28N663Cu79Br]+, 482 (26)
[C19H28N663Cu79Br]+, 403 (76) [C19H28N663Cu]+, 341 (100) [C19H29N6]+,
217 (100) [C12H17N4]+; elemental analysis calcd (%) for
C19H28N6CuBr2 (563.83 gmolÀ1): C 40.47, H 5.01, N 14.91; found: C
40.52, H 5.17, N 14.28.
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft
(DFG) (DFG-FOR1405 and SFB749-B10) is gratefully acknowl-
edged. Calculation time is gratefully acknowledged from the
OCuLUS Cluster at the PC2 Paderborn and the Leibniz-Rechen-
zentrum München. M.B. gratefully acknowledges provision of
beamtime by the European Radiation Synchrotron Facility
(ESRF, Grenoble, France), and we also thank Olivier Maton and
Dr. Suresh Gatla for help during the measurements. I.I.-B. and
M.D. gratefully acknowledge support through the “Solar Tech-
nologies Go Hybrid” initiative of the State of Bavaria. S.H.-P.
and C.W. thank Ulrich Herber for help with NMR spectroscopy
measurements.
[Cu2O2{HC(3-tBuPz)2(1-MeIm)}2][SbF6]2 (P(SbF6)2)
A solution of L (0.16 mmol, 54 mg) dissolved in CH2Cl2 (5 mL) was
added in one portion to CuCl (0.17 mmol, 17 mg). The resulting
suspension was stirred for 45 min to 1 h. With vigorous shaking,
a solution of AgSbF6 (0.17 mmol, 61 mg) dissolved in THF (250 mL)
was added and AgCl precipitated to produce the precursor solu-
tion. This solution could be filtered through a syringe filter (VWR,
130 mm, 0.45 mm). CH2Cl2 (10 mL) was added to a UV/Vis measure-
ment cell and cooled to 195 K. Oxygen was bubbled through the
solvent for 5 min to generate an oxygen-saturated solution before
the precursor solution (1 mL) was added, resulting in an immediate
colour change to deep violet. Formation of the peroxide complex
was followed by UV/Vis spectroscopy.
Keywords: copper
· biomimetic synthesis · kinetics · N
ligands · structure–activity relationships
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Chem. Eur. J. 2015, 21, 17639 – 17649
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17647
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Chem. Eur. J. 2015, 21, 17639 – 17649
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