Tyrosinase Model Systems Supported by Pyrazolylmethylpyridine Ligands: Electronic and Steric Factors Influencing the Catalytic Activity and Impact of Complex Equilibria in Solution

Article abstract of DOI:10.1002/ejic.201800319

Two new copper(I) complexes supported by pyrazolylmethylpyridine (PMP) ligands are synthesized and investigated regarding their ability to catalyze the oxygenation of several monophenolic substrates. The PMP ligands containing a pyridine and a pyrazole donor group represent hybrids between dipyridylmethane (DPM) and bis(pyrazolyl)methane (BPM) ligands. The catalytic activity of the two new [Cu(MeCN)₂PMP]PF₆ complexes is found to be intermediate between that of catalytically inactive [Cu(MeCN)₂DPM]PF₆ and highly active [Cu(MeCN)₂BPM]PF₆, suggesting that the electronic properties of a multidentate ligand can be designed in a modular fashion. DFT calculations are used to explore the differences in reactivity between the two systems. Regarding the behavior of these complexes in solution, evidence for an equilibrium between homoleptic and heteroleptic forms is presented. The crystal structure of a dinuclear complex exhibiting two homoleptic Cu^II units bridged by a fluorido ligand is obtained, which might represent one of the decay products of PMP-type catalysts after prolonged reaction times.

Full text of DOI:10.1002/ejic.201800319

A Journal of
Accepted Article
Title: Tyrosinase model systems supported by pyrazolylmethylpyridine
ligands: electronic and steric factors influencing the catalytic
activity and impact of complex equilibria in solution
Authors: Benjamin Herzigkeit, Benedikt Maria Flöser, Tobias Adrian
Engesser, Christian Näther, and Felix Tuczek
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To be cited as: Eur. J. Inorg. Chem. 10.1002/ejic.201800319
Link to VoR: http://dx.doi.org/10.1002/ejic.201800319

European Journal of Inorganic Chemistry
10.1002/ejic.201800319
FULL PAPER
Tyrosinase model systems supported by pyrazolylmethylpyridine
ligands: electronic and steric factors influencing the catalytic
activity and impact of complex equilibria in solution
[
a]
[a]
[a]
[a]
Benjamin Herzigkeit, Benedikt M. Flöser, Tobias A. Engesser, Christian Näther and Felix
Tuczek*[a]
Dedicated to Prof. Dr. Peter Comba on the occasion of his 65th anniversary
Abstract: Two new copper(I) complexes supported by pyrazolyl-
methylpyridine (PMP) ligands are synthesized and investigated
regarding their ability to catalyze the oxygenation of several mono-
phenolic substrates. The PMP ligands containing a pyridine and a
pyrazole donor group represent hybrids between dipyridylmethane
(
DPM) and bispyrazolylmethane (BPM) ligands. The catalytic activity
of the two new [Cu(MeCN) PMP]PF complexes is found to be inter-
mediate between that of catalytically inactive [Cu(MeCN) DPM]PF
and highly active [Cu(MeCN) BPM]PF , suggesting that the electronic
2
6
2
6
2
6
properties of a multidentate ligand can be designed in a modular
fashion. DFT calculations are used to explore the differences in react-
ivity between the two systems. Regarding the behaviour of these
complexes in solution, evidence for an equilibrium between
homoleptic and heteroleptic forms is presented. The crystal structure
of a dinuclear complex exhibiting two homoleptic Cu(II) units bridged
by a fluorido ligand is obtained, which might represent one of the
decay products of PMP-type catalysts after prolonged reaction times.
Scheme 1. Reactions performed by tyrosinase (TY) and catechol oxidase (CO).
Centre: Schematic drawing of the oxy-form of the active site.
which bind dioxygen as peroxide between the copper centers in a
2
2
[7-9]
typical side-on bridging geometry (- : ) (oxy, Scheme 1).
This characteristic feature was also confirmed by the first X-ray
crystal structure of tyrosinase from the bacterium Streptomyces
castaneoglobisporus.[ 10 ] Since then, more and more crystal
structures of polyphenol oxidases (PPOs) were obtained from
bacteria, insects and plants, revealing subtle structural
differences between the various organisms.[11-13]
Small changes in the structure of the active site often have a
major impact on the function of the enzyme. The same applies to
the numerous and diverse small-molecule models of tyrosinase
and catechol oxidase (Scheme 2).[6-9,14-17] One of the first model
Introduction
Melanin, an ubiquitous biopolymer, is involved in many
[1]
pigmentation processes. It plays a major role in skin protection
[
2]
from UV light or ionizing radiation , in wound healing, immune
systems capable of catalytically oxygenating 2,4-di-tert-
butylphenol (2,4-DTBP-H) to 3,5-di-tert-butylquinone (3,5-DTBQ)
[
3]
[4]
response , the coloring of hair and skin and browning of fruits
and vegetables.[5] In melanogenesis tyrosinase (TY) catalyzes the
conversion of the amino acid L-tyrosine to L-DOPAquinone
through a two-step reaction combining a hydroxylation and a
subsequent two-electron oxidation.[6-8] Catechol oxidase (CO),
with a very similar active site, is only able to perform the oxidation
step (Scheme 1).[6-9] TY and CO are both copper type 3 enzymes
2 4 6 2
2
was the complex [Cu (MeCN) BiPh(impy) ](PF ) developed by
Réglier et al.[18] Since then the number of model systems has
significantly increased, showing that small variations in ligand
[19-22]
design can give rise to large differences in catalytic activity.
2 6
In 2010, our group presented the complex [Cu(MeCN) Lpy1]PF
supported by the mononucleating pyridine-imine ligand Lpy1 as a
catalyst for the tyrosinase-like ortho-oxygenation of 2,4-DTBP-H
to 3,5-DTBQ.[18,23] Afterwards, we exchanged the pyridine moiety
of Lpy1 for different heterocyclic groups (i.e. pyrazoles or
benzimidazole). In comparison to the parent complex, the Cu(I)
complexes derived from the resulting ligands showed similar and
even enhanced (up to a turnover number of 31) catalytic
activities.[ By replacing the imine and pyridine function with two
pyrazoles, leading to the BPM, mBPM, dmBPM systems
[
a]
Institut für Anorganische Chemie,
Christian-Albrechts-Universität zu Kiel,
Max-Eyth-Straße 2, 24118 Kiel, Germany
E-mail: ftuczek@ac.uni-kiel.de
http://www.ac.uni-kiel.de/tuczek
24]
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Inorganic Chemistry
10.1002/ejic.201800319
FULL PAPER
[
2 6 2 6
Cu(PMP) ]PF (3a) and [Cu(dmPMP) ]PF (3b) regarding the
oxygenation of 2,4-DTBP-H are examined. The results are
discussed and compared with those obtained on previous small-
molecule models of tyrosinase supported by bidentate ligands.
Results and Discussion
Synthesis of the ligands and their copper(I) complexes
The two ligands 1a and 1b were synthesized according to the
procedure of House et al.[29] In a phase-transfer catalysis with
Bu NOH 2-picolyl chloride hydrochloride was alkylated with the
4
corresponding pyrazole (Scheme 4). For the work-up of the
respective ligands we deviated from the original procedure (see
Exp. Sect.). Both ligands were converted to their corresponding
hetero- (2a, 2b) and homoleptic (3a, 3b) copper(I) complexes
under anaerobic conditions employing tetrakis(acetonitrile)-
copper(I) hexafluorophosphate (for more details see Exp. Sect.).
Scheme 2. Mono- and binucleating ligands included in model complexes for
the oxygenation of various substrates in a tyrosinase-like fashion.[
8, 18, 26, 27]
(
Scheme 2), the same catalytic activities as in the case of the Lpy1
containing system were observed.[ 25 ] On the other hand,
replacement of an imine with an oxazoline as a second donor led
to
catecholoxidase activity remaining.
tyrosinase activity was observed with a dipyridylmethane system
a total loss of catalytic tyrosinase activity, with only
[
26 ]
Likewise, no catalytic
(
(
DPM).[23] In view of the catalytically active BPM systems and the
equally active) HC(3-tBuPz) (Py) complex developed 2013 by
2
Herres-Pawlis et al., which is supported by a ligand containing
one pyridine and two tert-butyl-substituted pyrazoles per copper
center, the presence of one or more pyrazole moieties seems to
positively influence the catalytic activity of the derived Cu(I)
complexes.[25, 27 ] Therefore, we decided to replace the imine
function in Lpy1 with a pyrazole to obtain the new ligands 1a
Scheme 4. Syntheses of the ligands (PMP, 1a and dmPMP, 1b) and the
hetero- (2a, 2b) and homoleptic (3a, 3b) copper(I) complexes. Pz = 1H-
pyrazole; dmpz = 3,5-dimethylpyrazole.
(
PMP) and 1b (dmPMP) (Scheme 2), which had already shown
interesting properties when coordinated to several transition
metals, but have not been investigated with regard to copper
oxygenation chemistry yet.[28-30] The influence exerted by this
bidentate ligand combining a soft (pyridine N) and hard (pyrazole
N) donor on the coordination chemistry and the catalytic activity
of derived copper complexes should provide useful information for
further ligand and catalyst design.
Tyrosinase activity of 2a and 2b
For the detection of a catalytic tyrosinase activity of the
heteroleptic complexes 2a and 2b we chose the three
monophenolic substrates 2,4-DTBP-H, 3-TBP-H and 4-MeOP-H
exhibiting different structural and electronic properties. The
sterically most demanding monophenol 2,4-DTBP-H was used
because of the formation of its stable ortho-quinone 3,5-DTBQ
(Scheme 5), whereas the less congested monophenols 3-TBP-H
and 4-MeOP-H form characteristic secondary products (see
below).
Herein we present the synthesis of cationic hetero- and
+
+
homoleptic complexes of the type [Cu(MeCN)
2
2
L] and [CuL ] (L
=
PMP, dmPMP; Scheme 3). Detailed structural and theoretical
studies are performed in order to elucidate the physicochemical
properties and the coordination behavior of the obtained
compounds in solution. Furthermore, the catalytic activities of the
heteroleptic copper(I) complexes [Cu(MeCN)
Cu(MeCN) dmPMP]PF (2b) regarding the oxygenation of
,4-DTBP-H, 3-tert butylphenol (3-TBP-H) and 4-methoxyphenol
4-MeOP-H) as well as the activity of the homoleptic complexes
2 6
PMP]PF (2a) and
[
2
6
First, we checked the catalytic tyrosinase activity of 2a and
2b with the substrate 2,4-DTBP-H (Scheme 5). The oxygenation
2
(
was carried out under Bulkowski/Réglier conditions in all
cases.[
18,31]
To this end, a 500 µM solution of the copper(I) catalyst
in dichloromethane was prepared and 50 equivalents 2,4-
Scheme 3. Pyrazolylmethylpyridine ligands (1a, 1b) and their heteroleptic (2a,
b) and homoleptic Cu(I) complexes (3a, 3b) investigated in this study.
Scheme 5. Catalytic reaction of the phenolic substrate 2,4-DTBP-H to ortho-
quinone 3,5-DTBQ.
2
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European Journal of Inorganic Chemistry
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FULL PAPER
Figure 2. UV/vis spectra measured during the catalytic oxygenation of a 500 μM
solution of [Cu(MeCN) PMP]PF (2a) in dichloromethane in the presence of 3-
2 6
Figure 1. UV/vis spectra measured during the catalytic oxygenation of a 500
μM solution of [Cu(MeCN) PMP]PF (2a) in dichloromethane in the presence
2 6
TBP-H (50 equiv.) and triethylamine (100 equiv.) during the first 6 h at room
temperature; quartz cell length l =1 mm; inset: Turnover number per dicopper
unit (black squares) and turnover frequency per minute (gray triangles) as a
function of time.
of 2,4-DTBP-H (50 equiv.) and triethylamine (100 equiv.) during the first 6 h
at room temperature; quartz cell length l =1 mm; inset: Turnover number per
dicopper unit (black squares) and turnover frequency per minute (gray
triangles) as a function of time.
DTBP-H and 100 equivalents triethylamine per mononuclear
complex were added. Oxygenation of the reaction mixture led to
the formation of 3,5-DTBQ which was monitored by in situ UV/vis
spectroscopy based on the absorption band at 407 nm ( = 1830
hydroxy function and the remaining tert-butyl group is located in
meta position, which reduces the stability of the ortho-quinone
product towards further reactions. Correspondingly, after initial
formation of an absorption band at ~400 nm for 4-tert-butyl-
quinone, an oxidative coupling to 4-(tert-butyl)-5-(3-(tert-
butyl)phenoxy)cyclohexa-3,5-diene-1,2-dione occurs, as evident
from to the shift of the absorption band to 425 nm.[22, 32 ] For
complex 2a a TON of 25 for the oxidatively coupled product ( =
-1
-1 [18,23,25]
L mol cm ).
Both complexes are catalytically active with a
turnover number (TON) of 14 after 6 h for 2a and 11 after 7 h per
dicopper unit for 2b (Figure 1, Figure S1). The reaction proceeds
fast at the beginning with a high turnover frequency (TOF), but
-1
-1
nearly comes to a halt after 4 h for both complexes (Figure 1, inset, 898 L mol cm ) was achieved after 6 h of oxygenation at room
temperature (Figure 2).[26] Sterically more encumbered 2b led to
a TON of 13 after 4 h; afterwards no further increase of the
absorption band was observable (Figure S6). Regarding the TOF
of both complexes the fastest rate was observed directly at the
start of the oxygenation after which it rapidly decreased (Figure 2,
inset). 1H-NMR of an quenched aliquot of the reaction mixture
after 1 h hour revealed the ratio between starting material 3-TBP-
H and coupled ortho-quinone to be 82:18 for 2a (Figure S7, S8,
Table S1) and 89:11 for 2b (cf. Figure S9, S10, Table S1).
As a third, more electron-rich substrate 4-methoxyphenol
(4-MeOP-H) was examined (Scheme 7). This substrate is already
known to be oxidized by tyrosinase to 4-methoxy-1,2-
benzoquinone.[33] The electron-donating methoxy group causes
an increase of the electron density in the aromatic system and
therefore promotes the electrophilic attack of the peroxo core.[
Moreover, the formed quinone is quite reactive, forming the
coupled product 4-methoxy-5-(4-methoxyphenoxy)cyclohexa-
3,5-diene-1,2-dione at room temperature which can be monitored
Figure S1).
After one hour of oxygenation an aliquot was removed from
the reaction mixture and diluted to a 100 µM solution in
dichloromethane, which was treated with 6 M hydrochloric acid to
remove any copper species. After extraction and removal of
solvent H- and 13C-NMR spectra were measured (cf. Figure S2,
S3) in order to identify the organic catalysis products. According
1
1
to the H-NMR spectrum of the aliquot of 2a 79% of the starting
material 2,4-DTBP-H, 11% of the C-C coupling product 3,3’,5,5’-
tetra-tert-butyl-2,2’-biphenol (biphenol) and 10% of 3,5-DTBQ are
present after 1 h of oxygenation (Table S1), which is also in
agreement with the UV/vis spectra (TON = 9) after 1 h (cf.
Figure 1). Application of the same protocol to the methyl-
substituted system 2b resulted in a distribution of 87% 2,4-DTBP-
H, 7% biphenol and 6% 3,5-DTBQ (cf. Figure S4, S5, Table S1).
These results indicate that both heteroleptic copper(I) complexes
are catalytically active towards the conversion of 2,4-DTBP-H to
25,26]
3,5-DTBQ.
-1
-1
To investigate a sterically less crowded substrate 3-tert-
butylphenol (3-TBP-H) was employed (Scheme 6). In comparison
by UV/vis (418 nm band,  = 524 L mol cm ) throughout the
catalytic reaction.[
22, 26, 34]
After some time water formed during the
with 2,4-DTBP-H it has no tert-butyl group in direct vicinity of the
reaction hydrolyzes the coupled ortho-quinone, converting it into
Scheme 7. Catalytic reaction of the substrate 4-MeOP-H to 4-methoxy-5-(4-
methoxyphenoxy)cyclohexa-3,5-diene-1,2-dione and 2-hydroxy-5-methoxy-
Scheme 6. Catalytic reaction of the substrate 3-TBP-H to 4-(tert-butyl)-5-(3-
(tert-butyl)phenoxy)cyclohexa-3,5-diene-1,2-dione.
[
1,4]-benzoquinone.
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European Journal of Inorganic Chemistry
10.1002/ejic.201800319
FULL PAPER
Figure 3. UV/vis spectra measured during the catalytic oxygenation of a 500
μM solution of [Cu(MeCN) PMP]PF (2a) in dichloromethane in the presence
2 6
of 4-MeOP-H (50 equiv.) and triethylamine (100 equiv.) during the first 3.5 h at
room temperature; quartz cell length l =1 mm; inset: Turnover number per
dicopper unit (black squares) and turnover frequency per minute (gray
triangles) as a function of time.
-hydroxy-5-methoxy-[1,4]-benzoquinone and 4-MeOP-H.[26] For
Scheme 8. Proposed catalytic cycle for PMP-based systems in analogy to our
2
previous model systems with the substrate 2,4-DTBP-H.
A possible
2a a TON of 34 for the oxidatively coupled product 4-methoxy-5-
equilibrium prior to the used catalyst 2a is investigated in this work.
(
4-methoxyphenoxy)-cyclohexa-3,5-diene-1,2-dione was obser-
ved after 3 h of oxygenation at room temperature (Figure 3),
whereas 2b reached a TON of 33 after 1.5 h (Figure S11). The
TOF decreases significantly after 1.5 h of oxygenation for both
complexes 2a and 2b (Figure 3 inset, S11).
the 349 nm band). This might be attributed to a possible blocking
of the coordination site by the two acetonitrile co-ligands.[
37, 36]
For
an assignment of the absorption bands we performed time-
dependent density functional theory (TD-DFT) calculations
(Figure S20).
In conclusion it could be shown that the two new heteroleptic
complexes 2a and 2b are catalytically active towards the three
substrates 2,4-DTBP-H, 3-TBP-H and 4-MeOP-H.
An aliquot of the oxygenation mixture was quenched after 1
and 3 h of reaction time, and the organic products were analysed
1
13
1
via H- and C-NMR (Figure S12-S15, Table S1). The H-NMR
spectrum of 2a after 1 h showed the coupled ortho-quinone and
1
unreacted substrate in a ratio of 22 : 78. The H-NMR spectrum
recorded after 3 h indicated a notable increase of coupled ortho-
quinone. Additionally, the formation of para-quinone became
measureable, whereby a ratio of 13 % para-quinone : 35 %
coupling product : 52 % unreacted substrate was determined (cf.
Electronic and steric factors influencing catalytic activity
In the past years the range of copper complexes mediating a
catalytic tyrosinase-like reaction has been significantly
1
[8, 22-27, 37 ]
Figure S12-S15). For 2b the H-NMR spectrum recorded after 1
extended.
For an assessment of the new systems
h showed that para-quinone was already present, resulting in a
ratio of 7 : 38 : 55 (cf. Figure S16, S17). After 3 h the proceeding
reactions to the para-quinone and presumably the formation of
several not identified side-products led to a decrease of coupled
ortho-quinone (9 : 29 : 62) (cf. Figure S18, S19).
presented herein, we compare their catalytic activities with a
number of similar copper complexes supported by bidentate
ligands (Table 1; Scheme 2 and 9). Although not every single
system was examined with all substrates, comparison of the data
provides some clues that may be relevant for the future design of
such systems.
The catalytic cycle of the heteroleptic copper(I) complexes
2
a and 2b should be similar to the proposed cycle with previously
Most of our work focused on the substrate 2,4-DTBP-H.
Comparing the new complexes 2a (14) and 2b (11) it is notable
that 2b achieves a lower TON. This is analogous to the symmetric
pyrazole systems BPM and dmBPM where the TON is lowered
published model systems (Scheme 8).[
23-26]
For both complexes
2
2
2a and 2b we were able to detect a  : -peroxo intermediate
at low temperatures by UV/vis spectroscopy (Figure S20, S21).
However, the yield of the peroxo adduct was rather low (2.5% for
by introducing a methyl group in the vicinity of the heterocyclic
-1
-1
[25]
2a and 3.3% for 2b based on an  value of 20000 L mol cm for
N-donor.
Generally a lowering of the TON is observed if the
Table 1. Turnover numbers (TON) for the conversion of several substrates for model systems with a bidentate ligand design.
System
L
[
py
1
23]
DPM
[23]
BPM
[25,35]
dmBPM
[25,35]
L
imz
1
BIMZ
[26]
PMP
this work
14
dmPMP
this work
11
[26]
2
3
4
,4-DTBP-H
22
-
0
-
21
22
35
11
12
15
16
20
34
9
6
6
-TBP-H
25
34
13
33
-MeOP-H
-
-
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European Journal of Inorganic Chemistry
10.1002/ejic.201800319
FULL PAPER
data are available.[41, 42] However, determination of the molecular
structure from crystals grown from a solution of 2a showed that
the homoleptic complex 3a has formed (Figure 4, top). For 2b, no
crystals could be obtained. To further investigate the unexpected
formation of 3a and to also determine the structure of the missing
analog 3b, both 3a and 3b were directly synthesized by changing
the ligand:metal stoichiometry to 2:1 (Scheme 4). By slow
evaporation of the solvent suitable crystals for XRD were obtained,
which allowed to determine the structure of the homoleptic
complex 3b (Figure 4, bottom).
Scheme 9. Structure of the imidazole based ligands Limz1 and BIMZ.[26]
copper peroxo adduct is shielded by bulky groups, e.g. in the
t
HC(3-tBuPz)
2
(Py)-system by Herres-Pawlis or in the Bu
3
tacn-
The yellow copper(I) complex 3a crystallizes in the
monoclinic spacegroup C2/c with four formula units per unit cell.
The copper(I) cation is coordinated by two ligands of 1a in a
tetrahedrally-distorted geometry. N3-Cu1-N2 angles are 93.6(7)°/
93.2(3)° within the chelating ligands and 108.4(5)°/ 111.7(10)°
between the ligands. The average N-Cu-N angle is 110.0°. Metal-
ligand bond distances are 1.993(18) Å for Cu-Npy (Cu1-N3) and
2.078(17) Å for Cu-Npz (Cu1-N2), respectively. The second
homoleptic copper(I) complex 3b crystallizes in the monoclinic
1
system by Scarborough.[27, 38] On the other hand, both 2a and 2b
achieve lower TONs than [Cu(MeCN) py1]PF (22) and
Cu(MeCN) (16; cf Scheme 9) containing combinations
2
L
6
[
2 6
Limz1]PF
of imine and pyridine or imidazole groups, respectively.
Regarding copper complexes supported by symmetric ligands, 2a
ranges
Cu(MeCN)
between [Cu(MeCN)
2
BPM]PF
6
(21)
and
[
2
DPM]PF (0). This indicates that pyrazole groups
6
induce a higher catalytic activity than pyridine moieties in derived
Cu(I) complexes and, by mixing these units, an intermediate
activity results. As indicated by a TON of 9 exhibited by
spacegroup P2 /n with four formula units per unit cell. The
copper(I) cation is coordinated by two ligands 1b in
a
[
Cu(MeCN)
an intermediate position between pyrazole and pyridine (cf.
Table 1). Comparison of the asymmetric Lpy1 and the Limz
2
BIMZ]PF
6
(cf Scheme 9), imidazole appears to have
tetrahedrally-distorted geometry. N-Cu-N angles are 94.22(7)°
(N2-Cu1-N3) and 92.99(7)° (N23-Cu1-N22; both within chelating
ligands) whereas the angles between ligands are 111.43(8)°
(N23-Cu1-N2) and 126.66(7)° (N2-Cu1-N22). The average N-Cu-
N angle is 119.0°. Metal-ligand bond distances are 2.0648(17) Å
(Cu1-N3) and 2.0623(18) Å (Cu1-N23) for Cu-Npy as well as
2.0646(18) Å (Cu1-N2) and 2.0774(18) Å (Cu1-N22) for Cu-Npz.
The increase of the average N-Cu-N angle between two ligands
from 110.0° in the PMP system (3a) to 119.0° in the methylated
dmPMP system (3b) most likely derives from the increased steric
hindrance. In comparison, the catalytic activity of the
corresponding heteroleptic complexes 2a and 2b decreases with
the introduction of the methyl groups.
1
systems, on the other hand, indicates that replacement of pyridine
by imidazole may also decrease the activity of a derived copper(I)
complex regarding the monooxygenation of 2,4-DTBP-H (see
above).
Regarding the two other substrates, 3-TBP-H and 4-MeOP-
H, comparison between the different catalysts is less straightfor-
ward due to the fact that oxygenation of these substrates is
followed by an oxidative coupling reaction. The latter can also be
copper-catalyzed;[39, 40] the Cu(II) complex would thereby facilitate
nucleophilic attack of the substrate (phenolate) onto the
coordinated ortho-quinone and/or mediate the two-electron
oxidation of the resulting catechol intermediate. Regarding the
substrate 3-TBP-H we observed the so far highest TON (25) for
2a, whereas that of 2b (13) only reached about half of this value.
This is again due to the steric hindrance of its methyl-substituted
pyrazole unit. With the substrate 4-MeOP-H, on the other hand,
both complexes 2a and 2b nearly reached the same TON (34 and
3
3, respectively) which in turn equals that of the most active
catalysts [Cu(MeCN) (34) and [Cu(MeCN) BPM]PF
35). The other systems dmBPM (15) and BIMZ systems (6)
achieve significantly lower TONs compared to 2a and 2b.
2
L
imz1]PF
6
2
6
(
In summary, 2a and 2b show a high activity towards the
substrates 3-TBP-H and 4-MeOP-H and a moderate activity
towards 2,4-DTBP-H in comparison to other tyrosinase model
systems supported by bidentate ligands. For monoxygenation of
the last substrate the catalytic activity of Cu(I) complexes
supported by ligands containing N-heterocyclic donor groups
appears to follow the sequence pyrazole > imidazole  pyridine.
Homoleptic copper pyrazolylmethylpyridine complexes
Figure 4. Crystal structure of [Cu(PMP)
2 6 2 6
]PF (3a, top), [Cu(dmPMP) ]PF
In order to gain further information on the coordination behavior
of the pyrazolylmethylpyridine ligands 1a and 1b towards
copper(I) cations, crystal structures of the heteroleptic
bis(acetonitrile) copper complexes 2a and 2b would be needed.
For the analogous complexes with BPM and dmBPM structural
(
3b, bottom). Hydrogen atoms and PF anions are omitted for better clarity.
6
Selected crystal data and details on the structure refinements can be found
in Table 4. In case of 3a, the pyrazolyl and pyridinyl groups are disordered
and 3a and 3b both crystallize as racemate (for details see Figure S22 and
S23). Thermal ellipsoids are drawn with 50 % probability.
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European Journal of Inorganic Chemistry
10.1002/ejic.201800319
FULL PAPER
Equilibria between homo- and heteroleptic copper
complexes
The fact that crystals of 3a were obtained from a solution of 2a
suggests that the heteroleptic and homoleptic species are in
equilibrium (Scheme 10). If this hypothesis was true, the
concentration of the precatalysts 2a/b according to Scheme 8
would be lowered, thus leading to a concomitant decrease of TON
and TOF. This, however, only applies if the homoleptic complexes
Scheme 10. Equilibrium between hetero- (2a/b), homoleptic (3a/b) and
precursor (CuP) Cu(I) complexes.
Table 2. Overview for the catalytic activity (TON) for the conversion of
3a/b (and [Cu(MeCN)
4
]PF
6
CuP) are not catalytically active. In
2,4-DTBP-H to 3,5-DTBQ under Bulkowski/Réglier conditions and UV/vis
monitoring for heteroleptic complexes [Cu(MeCN)
2 6
PMP/dmPMP]PF (2a/b),
order to get more insight into this matter, it is essential to obtain
information about the catalytic activities of every species involved
in Scheme 10. Homoleptic complexes like 3a/b would a priori be
assumed to be catalytically inactive as their coordination
environment does not support formation of a peroxo intermediate,
in addition to the coordination of a substrate, without major
rearrangement or loss of one ligand. Surprisingly, a test of the
tyrosinase activities of the homoleptic systems 3a and 3b with 2,4-
DTBP-H (Scheme 5) gave a different result; i.e., with a turnover
number of 11 a significant catalytic activity was detected for 3a
homoleptic systems [Cu(PMP/dmPMP) ]PF (3a/b) and precursor complex
2
6
[
Cu(MeCN)
4
]PF
6
(CuP).
System
2a
3a
3a+CuP
2b
3b
3b+CuP
(1:1)
CuP
(1:1)
TON
14
11
13
11
6
7
8
complexes 3a/b and the precursor complex [Cu(MeCN)
4 6
]PF
(
CuP; Scheme 8, top). This was also observed by Garcia-Bosch
(
Table 2, cf. Figure S24 and S25). For 3b, on the other hand, a
relatively low TON of 6 was observed, even lower than that of the
copper(I) precursor [Cu(MeCN) ]PF (CuP; TON = 8; cf. Table 2
and co-workers using bidentate imino-pyridine systems with a
similar framework to investigate the mechanism of intramolecular
hydroxylation of C-H-bonds in their complexes.[ However, in
their case the homoleptic complex was not able to induce an
hydroxylation and only the mono-ligated complex was reactive.[
Following the example of Garcia-Bosch et al., we applied a
4
6
43]
and Figure S26).[24] Nevertheless this shows that, in addition to
the heteroleptic complexes, also the homoleptic complexes and
the pure precursor are catalytically active.
In case of an equilibrium between homo- and heteroleptic
complexes (Scheme 10), it should be possible to generate the
heteroleptic complexes 2a/b by combining the homoleptic
43]
mixture of 3a/b and [Cu(MeCN)
4 6
]PF (CuP) in catalytic runs
(
Table 2; Figure S27, Figure S28).[43] For the 1:1 combination of
Figure 5. Theoretically calculated energy profile for the reaction between the hetero- and homoleptic PMP- and dmPMP-type catalysts [Cu(MeCN)
2 6
PMP]PF
(
2a), [Cu(PMP) ]PF (3a) and [Cu(MeCN) dmPMP]PF (2b), [Cu(dmPMP) ]PF (3b). The molecules shown correspond to the PMP containing species. For
2
6
2
6
2
6
better clarity the calculated intermediates Int3 and Int6 are omitted, which are not affecting the thermodynamics of the equilibrium (Scheme 10; for further
details see Figure S29). Ligand exchange processes are shown by arrows.
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European Journal of Inorganic Chemistry
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FULL PAPER
Table 3: Theoretically obtained Gibbs energies G for each individual step of the proposed equilibrium between hetero- and homoleptic PMP-type catalysts. The
first number given always displays the values calculated for L = PMP and second number for L = dmPMP.
Reaction
G / kcal mol-1
-1.2
A
A
A
1
2
3
[Cu(MeCN)
[Cu(MeCN)
[Cu(MeCN)
[Cu(MeCN)
[Cu(MeCN)
4
3
3
4
2
]+ (CuP)
]+ (Int1) + L → [Cu(MeCN)
L*]+ (Int2)
→ [Cu(MeCN)
]+ (CuP) + L → [Cu(MeCN)
L]+ (2a/b) → [Cu(MeCN)L]+ (Int4) + MeCN
→ [Cu(MeCN)
3
]+ (Int1) + MeCN
L*]+ (Int2)
L]+ (2a/b) + MeCN
L]+ (2a/b) + 2 MeCN
2
3
-3.9/-2.6
-8.3/-9.3
-13.4/-13.1
-0.1/-0.9
-3.4/-3.5
-7.5/-7.6
-11.0/-12.0
+2.4/+1.1
2
A (A
1
1
+A
+B
2
+A
+B
3
)
)
B
B
B
1
2
3
[Cu(MeCN)L]+ (Int4) + L → [Cu(MeCN)LL*]+ (Int5)
[Cu(MeCN)LL*]+ (Int5) ]+ (3a/b)
→ [CuL
[Cu(MeCN)
L]+ (2a/b) + L → [CuL ]+ (3a/b)
2 [Cu(MeCN)
L]+ (2a/b) ⇌ [CuL ]+ (3a/b)
2
+ MeCN
B (B
B-A
2
3
2
2
+ 2 MeCN
+ [Cu(MeCN)
4
]+ (CuP)
2
2
3
a/b with CuP TONs of 13 and 7 were observed. In the presence
mation of 3a than for 3b (+1.1 kcal/mol). This would indicate a
slightly stronger preference for the heteroleptic complex 2a than
for its methylated analog 2b. Methylation of the ligand thus should
not influence the thermodynamics of the ligand exchange process.
The fact that a lower TON is found by mixing 3b and CuP in a 1:1
ratio than by applying pure 2b indicates, however, that the picture
may be more complicated. In the case of an attack of substrate
of the equilibrium shown in Scheme 10 the catalytic activities of
the mixtures should be equal to those observed in case of the
heteroleptic complexes 2a and 2b. Indeed, for the PMP-system
(
3a) the value observed for 2a (TON = 14) was almost reached,
but in case of the dmPMP-system (3b), the activity (TON = 7) was
found to be below the TON of 2b (11; cf. Table 2). As the only
difference between the two homoleptic PMP-type systems are the
methyl substituents of the pyrazole, the greater steric bulk may
hinder the formation of the heteroleptic complex.
To obtain further insight into the equilibrium between homo-
and heteroleptic complexes shown in Scheme 10 DFT was
employed. The computed reaction profiles shown in Figure 5
describe the formation of the heteroleptic complexes 2a/b from
the homoleptic complexes 3a/b and precursor complex
and/or NEt
3
added for the catalytic runs on one of the
intermediates shown in Figures 5 and 6, the condition of a “fast”
pre-equilibrium to the catalytic cycle (which is implicitly assumed
in the treatment of this Section; cf Scheme 8) is not fulfilled any
more, and additional reaction channels have to be considered.
Possible decomposition pathway of the catalyst
[
Cu(MeCN)
4
]PF
6
(CuP). The first step of the reaction involves the
An important aspect of optimizing a catalyst is to explore all
possibilities of increasing its efficiency and stability. Although we
were able to improve the catalytic activity of some of our bidentate
systems a complete conversion of the starting material to the
desired ortho-quinone, corresponding to a TON of 100, was never
achieved. We therefore also addressed the question of how the
loss of activity takes place. Initially, we assumed that hydrolysis
of the imine functions by water which forms during the catalytic
cycle destroys the catalyst.[23,24] Even though this might still be
true for the systems bearing an imine function, the symmetric
transfer of one acetonitrile ligand from CuP to the homoleptic
complex 3a/b, coupled to conversion of one bidentate ligand
bound to the latter to a monodentate coordination mode (Int5). In
1
the next step the  -bound ligand (Int5) dissociates and binds to
the copper tris(acetonitrile) complex (Int1) to form Int2. This is
followed by transfer of an acetonitrile molecule to the
mono(acetonitrile) complex (Int4), ultimately forming two
heteroleptic complexes 2a/b.
The ligand exchange processes shown in Figure 5 can be
separated into reaction sequences “A” (CuP to 2a/b) and “B”
systems [Cu(MeCN)
2
BPM]PF
6
2 6
or [Cu(MeCN) dmBPM]PF
(
2a/b to 3a/b) (cf. Table 1). Overall, the exchange reactions
showed a similar performance and the ligands themselves would
not be affected by water.[25] Therefore, hydrolysis cannot play the
decisive role, and other deactivation processes might influence
the catalysis.
In this context it is of interest that, by slow evaporation of a
solution of 2b in acetone after exposure to air, we were able to
obtain blue crystals of the dinuclear Cu(II) complex
leading from CuP and 3a/b to 2a/b are almost isoergonic (line “B-
A” in Table 1), in agreement with the observation of the
equilibrium of Scheme 10. This is also evident from Figure 6
showing the combined energies of the species involved in Figure
5
along the reaction coordinate. As a matter of fact, a slightly more
positive reaction enthalpy (+2.4 kcal/mol) is calculated for the for-
[
Cu
2
4 6 3
(F)(1b) ](PF ) (4) representing a possible decay product
of the catalyst (Figure 7). Compound 4 crystallizes in the
monoclinic spacegroup C2/c with four formula units per unit cell.
Similar to the homoleptic complex 3b every copper(II) cation is
coordinated by two dmPMP (1b) ligands. The two mononuclear
Cu(dmPMP)
complex exhibiting C
2
units are bridged by a fluoride anion to a dinuclear
symmetry. The coordination environment
2
of each copper center can be described as distorted trigonal
bipyramidal. The bridged fluoride anion located on the symmetry
axis of the molecule shares a plane with four equatorial pyrazole
N-donors at angles of F1-Cu1-N2 143.90(15)°, F1-Cu1-N22
1
11.42(15)° and N2-Cu1-N22 104.68(8)°. The axial positions are
Figure 6. Reaction profile for the formation of 2a/b from a mixture of homoleptic
complex (3a/b) and copper precursor (CuP) and vice versa in compliance with
Scheme 10.
occupied with pyridine N-donors at a N3-Cu1-N23 angle of
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European Journal of Inorganic Chemistry
10.1002/ejic.201800319
FULL PAPER
Experimental Section
General procedures
Chemicals and solvents were purchased from Sigma-Aldrich Co. LLC,
Deutero and Fisher Scientific in reagent grade. Dichloromethane and
acetonitrile were further purified by heating to reflux over calcium hydride
and distilled under a nitrogen atmosphere. Synthesis of the copper(I)
complexes and preparation of the oxygenation mixtures were performed
in
chromatography was carried out by using 0.04–0.063 mm mesh silica gel
Macherey-Nagel). -values were determined by thin-layer
a
glovebox (MBraun,
O
2
2
< 1 ppm; H O < 1 ppm). Column
(
R
f
chromatography on Polygram Sil G/UV254 (Macherey-Nagel, 0.2 mm
particle size). NMR spectra were recorded at 300 K using a Bruker DRX
00 [ H NMR (500.1 MHz),13C NMR (125.8 MHz)] and a Bruker AVANCE
1
5
Figure 7. Crystal structure of [Cu
2
(µ-F)(dmPMP)
4
](PF
6
)
3
(4) (orange = Cu, grey
III HD Pulse Fourier Transform spectrometer operating at frequencies of
4
=
carbon, blue = nitrogen, red = oxygen, green-yellow = fluorine). Hydrogen
00.13 MHz ( H), 100.62 MHz (13C) with TMS as internal standard. The
1
6
atoms and PF anions are omitted for better clarity. Selected crystal data and
elemental analyses were performed using a Euro Vector CHNS-element
analyser (Euro EA 3000): The prepared assays in tin vessels were burnt
in a stream of oxygen. Infrared spectra were recorded on a Bruker ALPHA
FT-IR Spectrum with a Platinum ATR setup. UV/vis measurements of the
oxygenation mixtures were recorded in solution on an Agilent 8453
spectrometer by using a quartz cell with length l = 1 mm. Optical absorption
spectra at low temperatures were recorded in solution on an Agilent Cary
5000 spectral photometer using a CryoVAC KONTI cryostat with a quartz
cell length l = 1 cm. High resolution (HR) mass spectra were measured
with an APEX 3 FT-ICR with an AccuTOF by Jeol (EI). Low-resolution
mass spectra were measured with a MAT 8230 by Finnigan (EI), with a
LCQ Classic by Thermo Finnigan (ESI) or an AutoflexSpeed by Bruker
details on the structure refinements can be found in Table 4. Thermal ellipsoids
are drawn with 50 % probability.
173.95(8)°. The angle between Cu1-F-Cu1 is 151.3(3)°. The bond
distances for Cu-Npz are 2.0284(19) Å (Cu1-N2), 2.1270(19) Å
(
(
Cu1-N22), for Cu-Npy 2.0094(19) Å (Cu1-N3) and 2.0167(19) Å
Cu1-N23) and for Cu1-F1 1.9705(13) Å. The distance between
the two copper cations is 3.818 Å.
The bridging fluoride atom in compound 4 has to be
attributed to a decomposition of the PF -
6
anion. Importantly,
formation of a similar dinuclear complex was observed for a
copper(I) complex supported by tris[(2-pyridyl)methyl]amine
ligand by Karlin and co-workers, where the reaction with oxygen
led to the generation of mono- and dinuclear copper(II)fluorido
complexes.[ 44 ] Mono µ-fluorido bridged dimeric copper(II)
complexes were also observed by Reger and co-workers with
ditopic polypyrazolyl ligands.[ 45 ] In these cases the bridging
(MALDI-TOF).
Single-crystal structure determinations
Data collections were performed with an imaging plate diffraction system
α
(IPDS-2) from STOE & CIE using Mo-K -radiation. Structure solution was
fluorido atoms originated from PF -
and BF -
anions,
6
4
performed with SHELXT and structure refinement was performed against
F2 using SHELXL-2014. A numerical absorption correction was applied
using programs X-RED and X-SHAPE as part of the program package X-
Area. All non-hydrogen atoms were refined with anisotropic displacement
parameters. The hydrogen atoms were positioned with idealized geometry
respectively.[44,45] In future studies we will therefore examine the
effect of more inert (and weakly coordinating) [46] counterions on
the stability and catalytic activity of small-molecule tyrosinase
models.
(
methyl H atoms allowed to rotate but not to tip) and were refined isotropic
with Uiso(H) = -1.2 Ueq(C) (1.5 for methyl H atoms) using a riding model. In
b and 4 one hexafluorophosphate anion is disordered and was refined
3
Conclusions
with a split model using partly restraints (SAME and SADI). In 3a the
cationic complex and the anion are disordered in two orientations in ratio
70:30. There are no hints for super structure reflections and if the structure
is refined in space groups of lower symmetry, the disorder remain constant.
Specific experimental details for growing of the crystals are described in
the supporting information. CCDC-1566899 (3a), CCDC-1566901 (3b),
CCDC-1566900 (4) contain the supplementary crystallographic data for
this paper. These data can be obtained free charge from the Cambridge
In summary, we presented two new copper(I) complexes 2a and
2
b capable of performing a tyrosinase-like monooxygenation
reaction with the substrates 2,4-DTBP-H, 3-TBP-H and
-MeOP-H. The TON for the pyridine-pyrazole mixed N-donor
4
complex 2a with the substrate 2,4-DTBP-H was 14, intermediate
between the active BPM (22) and the inactive DPM system (0).
This suggests that the electronic properties of a multidentate
ligand can be designed in a modular fashion. In contrast to the
moderate activity towards 2,4-DTBP-H, 2a and 2b exhibited high
activities towards the substrates 3-TBP-H and 4-MeOP-H in
comparison to other tyrosinase model systems. Moreover, we
demonstrated experimentally and theoretically that the mono-
ligated complexes 2a/b are in an equilibrium with the homoleptic
systems 3a/3b which also exhibit some catalytic activity towards
the substrate 2,4-DTBP-H. The crystal structure of a fluorido-
bridged dicopper(II) complex is presented which may represent
one of the possible decay products for the bidentate PMP-type
Crystallographic
Data
Centre
via
http://www.ccdc.cam.ac.uk/data_request/cif.
Computational Details
DFT calculations were performed with ORCA 4.0.1.[47] The geometries of
the two binuclear peroxo species studied by UV/vis spectroscopy were
optimised by using the TPSSh functional[ and the Ahlrichs def2-TZVP
48]
basis set[ 49 ] in conjunction with the chain of spheres approximation
50]
(
RIJCOSX)[ and the general Ahlrichs Coulomb fitting basis set denoted
def2/J.[
51 ]
To account for dispersion effects Grimme’s semiempirical
dispersion correction scheme with Becke-Johnson damping (D3BJ)[52] was
used. The antiferromagnetic coupling between the copper centers was
included via a broken symmetry wave function with one unpaired electron
on each metal ion.
ligand systems. This implies that use of a more inert anion than
-
PF
6
may lead to more robust catalytic systems.
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European Journal of Inorganic Chemistry
10.1002/ejic.201800319
FULL PAPER
To speed up the calculation density fitting was used for the correlation part
as well for the coulomb and exchange integrals in combination with the
chain of spheres approximation (RIJCOSX) and the appropriate fitting
basis sets (def2-QZVPP/C[59] and def2/Jin ORCA terminology). To include
solvation effects the SMD continuum solvation model (solvent
dichloromethane) was applied to the electronic energies as it is
parameterised to yield solvation free enthalpies.[60]
Table 4. Selected crystal data and details on the structure refinements
for 3a, 3b and 4.
3a
3b
4
Formula
C
18
H
18CuF
6
N
6
P
C
22
H
6
26CuF N
6
P
C
44
H
52Cu
2
19
F N
12
P
3
MW / gmol-1
526.89
583.0
1329.96
General procedure for the oxygenation and quenching of external
substrates for 2a and 2b
Crystal system
monoclinic
monoclinic
monoclinic
Space group
C2/c
P2
1
/n
C2/c
The copper(I) complex (1.25 µmol) was dissolved in 25 mL
dichloromethane under an inert gas atmosphere resulting in a 500 µM
solution. The monophenol (50 eq., 62.5 µmol) and triethylamine (100 eq.,
a / Å
b / Å
c / Å
8.4065(4)
10.6322(3)
21.9480(4)
11.7581(3)
90
30.0652(8)
9.8809(2)
22.8798(6)
90
0.125 mmol) were added. Subsequent injection of dioxygen at ambient
20.5267(8)
12.8749(6)
90
temperature leads to the conversion to ortho-quinones, identified via
UV/vis spectroscopy by absorption bands at the range of 390-425 nm. For
the characterization of the formed products an aliquot (5 mL) was removed



/ °
/ °
/ °
from the reaction mixture and diluted to
dichloromethane. This solution was treated with 6 M hydrochloric acid
20 mL) and the organic phase separated. The aqueous phase was
a 100 µM solution in
96.755(4)
93.847(3)
128.820(2)
(
90
90
90
extracted with dichloromethane (2x20 mL), the organic phases combined,
dried over magnesium sulphate, filtered, and solvents evaporated in
vacuum. The obtained residue was analysed via H and 13C spectroscopy
V / Å3
T / K
Z
2206.24(17)
170(2)
4
115.852(2)
170(2)
4
5295.6(3)
170(2)
4
1
(see SI).
calc / mgm3
General procedure for the oxygenation of mixtures of 3a or 3b and
Cu(MeCN) ]PF
D
1.586
1.568
1.668
[
4
6
µ / mm-1
1.130
1.018
1.008
max / °
27.447
26.803
25.999
The homoleptic copper(I) complex (0.625 µmol) and [Cu(MeCN)
4 6
]PF
(
0.625 µmol) were dissolved in dichloromethane (25 mL) under an inert
Refl. collected
16462
34767
27797
gas atmosphere. 2,4-di-tert-butylphenol (100 eq., 62.5 µmol) and
triethylamine (200 eq., 0.125 mmol) were added. Subsequent injection of
dioxygen at ambient temperature lead to the conversion to ortho-quinones,
identified via UV/vis spectroscopy by absorption bands at the range of
Unique
reflections
2513
5273
5193
4
07 nm.
R
int
0.0587
2513
0.0429
4725
0.0285
4694
Refl.
0
>4(F )]
2-((1H-pyrazol-1-yl)methyl)pyridine (1a, PMP)
[F
0
Parameters
[F >4(F
287
365
427
2-(Chloromethyl)pyridine hydrochloride (1.08 g, 6.58 mmol) and
H-pyrazole (0.448 g, 6.58 mmol) were dissolved in toluene. A 40%
1
R
1
0
0
)]
0.0428
0.0397
0.0376
aqueous sodium hydroxide solution (10 mL) and 40% aqueous
tetrabutylammonium hydroxide (7 drops) were added and the resulting
mixture was stirred and refluxed for 6 h. After cooling to room temperature,
the solution was stirred overnight. The organic layer was separated, dried
over magnesium sulphate, filtered and the solvent evaporated under
reduced pressure. The crude product was purified by column
wR
2
0.1330
1.075
0.1040
1.041
0.0973
1.048
GOF

max/min / eÅ-3
0.373/ -0.311
0.638/ -0.732
0.329/-
0.356
f
chromatography on silica gel (cyclohexane/ethyl acetate, 1:2, R = 0.35) to
obtain the desired product as a yellow oil (0.892 g, 5.59 mmol, 85%).
Analytical data obtained were in accordance with the literature.[29] IR
TD-DFT calculations were conducted with the same method except
an addition of solvent effects with the conductor-like polarizable continuum
model (CPCM)[53] with acetone as solvent. For the UV/vis spectra the first
(ATR): ν̃ = 3110 (w), 3010 (w), 2937 (w), 1593 (m), 1573 (m), 1515 (m),
1475 (m), 1434 (m), 1394 (m), 1281 (w), 1149 (w), 1097 (m), 1049 (m),
30 roots were computed.
993 (m), 965 (m), 747 (vs), 705 (s), 620 (s), 587 (m) cm-1
. H NMR (500
1
All species included in the reaction profile study were optimized at
MHz, CDCl , 300 K):  = 8.56 (ddd,
3
J = 4.8,
4
J = 1.6,
5
J = 0.8 Hz, 1 H, C -
3
py
the BP86/def2-SVP[ 54 ,49] level with dispersion correction (D3BJ) and
resolution of identity (RIJ[55] with the fitting basis set def2/J) in the gas
phase. To account for basis set superposition errors in the geometries a
geometrical counterpoise correction was employed.[56] The identity of each
structure as a minimum was verified via the absence of imaginary
harmonic frequencies. These were obtained from frequency calculations
which also provided thermochemical data. The enthalpy and entropy
corrections to the electronic energy were taken for the computation of free
enthalpies. The electronic energies for these were calculated with the
DSD-BLYP double hybrid DFA[57]. Therefore a large quadruple zeta basis
set was employed (def2-QZVPP)[49] as recommended by GRIMME et al.[58]
3
4
3
H6), 7.62 (td, J = 7.7, J = 1.8 Hz, 1 H, C -H4), 7.57 (d, J = 1.5 Hz, 1 H,
py
3
C -H3), 7.52 (d, J = 2.3 Hz, 1 H, C -H5), 7.20 – 7.15 (m, 1 H, C -H5),
pz
pz
py
3
3
6.96 (d,
J = 7.9 Hz, 1 H, C -H3), 6.31 (t,
py
J = 2.1 Hz, 1 H, C -H4), 5.45
pz
13
(s, 2 H, CH ) ppm. C NMR (126 MHz, CDCl , 300 K):  = 156.9 (C -2),
2
3
py
149.5 (C -6), 140.1 (C -3), 137.2 (C -4), 130.1 (C -5), 122.8 (C -5),
py
pz
py
pz
py
121.8 (C -3), 106.3 (C -4), 57.6 (CH ) ppm. HR-MS (EI): m/z [M]•+ calcd.
py
pz
2
for C H N , 159.0797; found 159.0803. MS (EI, 70 eV): m/z (%) = 159.08
9
9
3
+
, 92.05 [M-pz]•+
[M] .
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European Journal of Inorganic Chemistry
10.1002/ejic.201800319
FULL PAPER
2
-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)pyridine (1b, dmPMP)
[Cu(PMP)
2 6
]PF (3a)
Compound 1b was prepared in a similar manner as described for 1a using
Tetrakis(acetonitrile)copper(I)
hexafluorophosphate
(135 mg,
2
-(chloromethyl)pyridine hydrochloride (2.16 g, 13.2 mmol) and
0.361 mmol) was dissolved in 6 mL dry acetonitrile and slowly added to a
4 mL solution of 1a (135 mg, 0.722 mmol) in dry acetonitrile via a syringe.
The resulting yellow solution was stirred for 30 min at room temperature
and the solvent evaporated. The desired product was obtained as a yellow
solid (160 mg, 0.304 mmol, 84%). IR (ATR): ν̃ = 3137 (w), 1600 (w), 1430
(m), 1403 (w), 1309 (w), 1275 (w), 1162 (w), 1093 (w), 1063 (w), 979 (w),
3,5-dimethyl-1H-pyrazole (1.27 g, 13.2 mmol). The crude product was
purified by column chromatography on silica gel (ethyl acetate, Rf = 0.31)
to obtain the desired product as a yellow oil (1.71 g, 9.13 mmol, 69%).
Analytical data obtained were in accordance with the literature.[29] IR
(
ATR): ν̃ = 3109 (w), 3054 (w), 3014 (w), 2939 (w), 1593 (m), 1572 (m),
-
1 1
1
1
6
=
511 (m), 1476 (m), 1432 (m), 1394 (s), 1355 (m), 1277 (m), 1215 (w),
150 (w), 1088 (m), 1049 (s), 995 (m), 966 (m), 915 (w), 748 (vs), 705 (s),
21 (s) cm . H NMR (500 MHz, CDCl , 300 K):  = 8.53 (ddd, J = 4.9, J
830 (s), 779 (m), 749 (s), 705 (m), 620 (m), 557 (s), 470 (w) cm . H NMR
(400 MHz, [D ]acetone, 300 K):  = 8.59 (s, 2 H, Cpy-H6), 8.10 – 8.06 (m,
4 H, Cpy-H4, Cpz-H3), 7.89 (s, 2 H, Cpy-H3), 7.70 (s, 2 H, Cpz-H5), 7.55 (s,
2 H, Cpy-H5), 6.46 (s, 2 H, Cpz-H4), 5.81 (s, 4 H, CH
) ppm. 13C NMR (101
MHz, [D ]acetone, 300 K):  = 154.7 (Cpy-2), 150.8 (Cpy-6), 141.1 (Cpz-3),
139.6 (Cpy-4), 132.4 (Cpz-5), 126.0 (Cpy-5), 125.9 (Cpy-3), 107.0 (Cpz-4),
6
-
1
1
3
4
3
1.7, 5J = 0.9 Hz, 1 H, Cpy-H6), 7.62 (td, J = 7.7, J = 1.8 Hz, 1 H, Cpy
3
4
-
2
3
H4), 7.18 – 7.11 (m, 1 H, Cpy-H5), 6.77 (d, J = 7.9 Hz, 1 H, Cpy-H3), 5.86
6
(
C
1
1
s, 1 H, Cpz-H4), 5.32 (s, 2 H, CH
pz5-CH
) ppm. 13C NMR (126 MHz, CDCl
49.4 (Cpy-6), 148.2 (Cpz-3), 139.8 (Cpz-5), 137.2 (Cpy-4), 122.5 (Cpy-5),
21.0 (Cpy-3), 105.8 (Cpz-4), 54.5 (CH ), 13.6 (Cpz3-CH ), 11.2 (Cpz5-CH
2 3
), 2.24 (s, 3 H, Cpz3-CH ), 2.16 (s, 3 H,
3
3
, 300 K):  = 157.6 (Cpy-2),
56.4 (CH
PMP] . C18
2
) ppm. MS (ESI+, CHCl
3 6 6
): m/z = 381.2 [M-PF -
]+, 222.2 [M-PF
+
6 6
H18CuF N P (526.9): calcd. C 41.03, H 3.44, N 15.95; found C
2
3
3
)
41.16, H 3.32, N 15.70.
•+
ppm. HR-MS (EI): m/z [M] calcd. for C11
MS (EI, 70 eV): m/z (%) = 187.11 [M] , 109.08 [M-C
pz+H]+.
H N
13 3
, 187.1110; found 187.1160.
+
• •+
5 4
H N ] , 93.05 [M-
2 6
[Cu(dmPMP) ]PF (3b)
Compound 3b was prepared in a similar manner as described for 3a using
Tetrakis(acetonitrile)copper(I) hexafluorophosphate (148 mg,
.396 mmol) and 1b (126 mg, 0.792 mmol). The desired product was
[
Cu(MeCN)
2 6
(PMP)]PF (2a)
0
Tetrakis(acetonitrile)copper(I)
hexafluorophosphate
(259 mg,
obtained as a yellow solid (144 mg, 0.247 mmol, 62%). IR (ATR): ν̃ = 2920
(w), 1599 (w), 1550 (w), 1472 (m), 1417 (m), 1389 (m), 1315 (m), 1285 (w),
1224 (w), 1060 (w), 1043 (w), 1009 (w), 817 (s), 774 (s), 681 (m), 629 (w),
0.694 mmol) was dissolved in 6 mL dry acetonitrile and a 8 mL solution of
1a (110 mg, 0.694 mmol) in dry acetonitrile was slowly added via a syringe.
-
1 1
The resulting yellow solution was stirred for 30 min at room temperature
and the solvent evaporated. The desired product was obtained as a yellow
solid (161 mg, 0.358 mmol, 52%). IR (ATR): ν̃ = 3133 (w), 2941 (w), 2302
598 (m), 554 (s), 477 (m), 415 (m) cm . H NMR (400 MHz, [D
300 K):  = 8.36 (s, 2 H, Cpy-H6), 7.88 (t, J = 7.3 Hz, 2 H, Cpy-H4), 7.51 (d,
3
]acetonitrile,
3
3
J = 7.3 Hz, 2 H, Cpy-H3), 7.37 (m, 2 H, Cpy-H5), 5.95 (s, 2 H, Cpz-H4), 5.26
(
w), 2276 (w), 1600 (w), 1477 (w), 1432 (m), 1403 (m), 1309 (w), 1275 (w),
(s, 4 H, CH
NMR (101 MHz, [D
149.1 (Cpz-3), 141.8 (Cpz-5), 139.3 (Cpy-4), 125.3 (Cpy-5), 125.1 (Cpy-3),
106.6 (Cpz-4), 53.5 (CH ) 13.7 (Cpz3-CH ), 11.4 (Cpz5-CH ) ppm. MS (ESI+,
acetonitrile): m/z 437.2 [M-PF
]+, 250.2 [M-PF -dmPMP]+.
P (583.0): calcd. C 45.32, H 4.50, N 14.42; found C 45.62,
H 4.50, N 14.25.
2
), 2.34 (s, 6 H, Cpz3-CH
3 3
), 2.00 (s, 6 H, Cpz5-CH
) ppm. 13C
1
5
=
165 (w), 1091 (w), 1066 (w), 826 (vs), 778 (s), 751 (s), 705 (m), 620 (m),
3
]acetonitrile, 300 K):  = 155.4 (Cpy-2), 150.6 (Cpy-6),
-
1 1
56 (s), 482 (m), 448 (m) cm . H NMR (500 MHz, [D
6
]acetone, 300 K): 
3
8.68 (d, J = 4.9, 1 H, Cpy-H6), 8.11 – 8.06 (m, 2 H, Cpy-H4, Cpz-H3), 7.83
2
3
3
3
3
(
d, J = 7.7 Hz, 1 H, Cpy-H3), 7.75 (d, J = 1.9 Hz, 1 H, Cpz-H5), 7.61 (ddd,
=
6
6
3
3
4
3
J = 7.6, J = 5.1, J = 0.9 Hz, 1 H, Cpy-H5), 6.46 (t, J = 2.3 Hz, 1 H, Cpz
H4), 5.69 (s, 2 H, CH ), 2.28 (s, 6 H, NCCH
) ppm. 13C NMR (126 MHz,
]acetone, 300 K):  = 154.5 (Cpy-2), 151.1 (Cpy-6), 141.8 (Cpz-3), 140.4
-
22 6 6
C H26CuF N
2
3
[D
6
(
(
(
C
C
py-4), 133.1 (Cpz-5), 126.1 (Cpy-5), 125.9 (Cpy-3), 118.2 (NCCH
pz-4), 55.9 (CH ), 1.71 (NCCH
NCCH PF
3
), 107.1
[
2 4 6 3
Cu (µ-F)(dmPMP) ](PF ) (4)
2
3
) ppm. MS (MALDI-TOF): m/z (%) = 222.1
100) [M
–
2
3
–
6
]+, 262.9 (76) [M
–
NCCH
3
–
PF ] .
6
+
A 3 mM solution of 2b in 3 mL acetone was exposed to air and the solvent
slowly evaporated. After four weeks small blue crystals of (4) suitable for
X-ray structure determination were obtained.
C
13
6
H15CuF N
5
P (449.8): calcd. C 34.71, H 3.36, N 15.57; found C 34.55,
H 3.56, N 15.45.
[
2 6
Cu(MeCN) (dmPMP)]PF (2b)
Acknowledgements
Compound 2b was prepared in a similar manner as described for 2a using
Tetrakis(acetonitrile)copper(I) hexafluorophosphate (219 mg,
.587 mmol) and 1b (110 mg, 0.587 mmol). The desired product was
obtained as a yellow solid (160 mg, 0.335 mmol, 57%). IR (ATR): ν̃ = 2950
w), 2278 (w), 1601 (w), 1553 (m), 1474 (m), 1431 (m), 1393 (m), 1315 (w),
0
The authors thank Deutsche Forschungsgemeinschaft (Tu58/15-
1) and CAU Kiel for financial support of this research.
(
1
280 (w), 1158 (w), 1056 (w), 829 (vs), 768 (s), 679 (m), 606 (m), 556 (s),
Keywords: type 3 copper enzyme • tyrosinase • dioxygen
activation • catalysis • N-donor ligands
-
1 1
479 (m), 415 (m) cm . H NMR (400 MHz, [D ]acetone, 300 K):  = 8.65
6
3
4
5
3
4
(ddd, J = 5.1, J = 1.6, J = 0.8 Hz, 1 H, Cpy-H6), 8.09 (td, J = 7.7, J =
3
3
1
=
2
.7 Hz, 1 H, Cpy-H4), 7.92 – 7.86 (m, 1 H, Cpy-H3), 7.60 (ddd, J = 7.7, J
4
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5.1, J = 1.3 Hz, 1 H, Cpy-H5), 6.06 (s, 1 H, Cpz-H4), 5.44 (s, 2 H, CH
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) ppm.
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This article is protected by copyright. All rights reserved.

European Journal of Inorganic Chemistry
10.1002/ejic.201800319
FULL PAPER
FULL PAPER
Copper Tyrosinase Models
Benjamin Herzigkeit, Benedikt M. Flöser,
Tobias A. Engesser, Christian Näther
and Felix Tuczek
Page No. – Page No.
Tyrosinase model systems supported
by pyrazolylmethylpyridine ligands:
One pyrazole makes the difference. We studied copper(I) complexes supported by
bidentate ligands containing a combination of pyridine and pyrazole units regarding
their tyrosinase activity towards various monophenols. The properties of the hetero-
leptic complexes and their homoleptic counterparts are elucidated by experimental
and theoretical studies.
electronic
and
steric
factors
influencing the catalytic activity and
impact of complex equilibria in
solution
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