Catalytic oxygenation of various monophenols by copper(I) complexes with bis(pyrazolyl)methane ligands: Differences in reactivity

Article abstract of DOI:10.1080/00958972.2015.1074191

Three new mononuclear copper(I) complexes supported by the symmetric ligands 1,1′-methylenebis-1H-pyrazole (BPM), 1,1′-methylenebis(3-methyl-1H-pyrazole) (mBPM), and 1,1′-methylenebis(3,5-di-methyl-1H-pyrazole) (dmBPM) were synthesized as catalytic model systems of tyrosinase. The influence of various functional groups on the catalytic conversion of monophenols is investigated and the formation of the corresponding ortho-quinones is monitored using UV/vis and NMR spectroscopy. Comparison of various monophenols reveals the differences in reactivity which are analyzed and interpreted based on key intermediates of the mechanistic cycle.

Full text of DOI:10.1080/00958972.2015.1074191

Journal of Coordination Chemistry
ISSN: 0095-8972 (Print) 1029-0389 (Online) Journal homepage: http://www.tandfonline.com/loi/gcoo20
Catalytic oxygenation of various monophenols by
copper(I) complexes with bis(pyrazolyl)methane
ligands: differences in reactivity
Jessica Nadine Hamann, Rebecca Schneider & Felix Tuczek
To cite this article: Jessica Nadine Hamann, Rebecca Schneider & Felix Tuczek (2015) Catalytic
oxygenation of various monophenols by copper(I) complexes with bis(pyrazolyl)methane
ligands: differences in reactivity, Journal of Coordination Chemistry, 68:17-18, 3259-3271, DOI:
10.1080/00958972.2015.1074191
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Date: 14 September 2015, At: 01:13

Journal of Coordination Chemistry, 2015
Vol. 68, Nos. 17–18, 3259–3271, http://dx.doi.org/10.1080/00958972.2015.1074191
Catalytic oxygenation of various monophenols by copper(I)
complexes with bis(pyrazolyl)methane ligands: differences in
reactivity
JESSICA NADINE HAMANN, REBECCA SCHNEIDER and FELIX TUCZEK*
Institute of Inorganic Chemistry, Christian-Albrechts-University, Kiel, Germany
(Received 6 May 2015; accepted 14 July 2015)
Three new mononuclear copper(I) complexes supported by the symmetric ligands 1,1′-methylenebis-
1H-pyrazole (BPM), 1,1′-methylenebis(3-methyl-1H-pyrazole) (mBPM), and 1,1′-methylenebis(3,5-
di-methyl-1H-pyrazole) (dmBPM) were synthesized as catalytic model systems of tyrosinase. The
influence of various functional groups on the catalytic conversion of monophenols is investigated
and the formation of the corresponding ortho-quinones is monitored using UV/vis and NMR
spectroscopy. Comparison of various monophenols reveals the differences in reactivity which are
analyzed and interpreted based on key intermediates of the mechanistic cycle.
Keywords: Type 3 copper enzymes; Tyrosinase; Model systems; Ortho-hydroxylation; Pyrazole
1. Introduction
The copper containing enzyme tyrosinase (Ty) catalyzes the monooxygenation of the amino
acid tyrosine which is first hydroxylated to L-DOPA (L-dihydroxyphenylalanine;
monophenolase activity) that subsequently is converted in a two-electron oxidation to dopa-
quinone (diphenolase activity, scheme 1). Dopaquinone acts as precursor for the biosynthe-
sis of melanin, a pigment that is involved in all biological browning processes [1–4].
The first X-ray crystal structure of tyrosinase was obtained from the bacterium
Streptomyces castaneoglobisporus by Matoba and coworkers in 2006. During the last years,
*Corresponding author. Email: ftuczek@ac.uni-kiel.de
© 2015 Taylor & Francis

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J.N. Hamann et al.
Scheme 1. Formation of dopaquinone, starting from tyrosine via DOPA, catalyzed by tyrosinase.
more crystal structures were determined [5–8]. All of them show that the active site of
tyrosinase contains a binuclear type 3 copper center whereby three histidine residues sur-
round each copper ion (figure 1) [9]. The two other proteins having type 3 copper active
sites are hemocyanin (Hc) and catechol oxidase (CO). Hemocyanin mediates the oxygen
transport in arthropods and molluscs, whereas catechol oxidases are responsible for the
two-electron oxidation of catechols to the corresponding ortho-quinones [10]. All type 3
copper proteins in their oxy form bind dioxygen as peroxide in a typical side-on bridging
geometry (µ-η2:η2) whereby both copper ions oxidized from CuI to CuII [9]. The Cu(II)2
side-on peroxo core shows characteristic properties in the optical and vibrational spectra. In
the UV/vis absorption spectrum, an intense band of the peroxide → Cu CT transition is
observable at ~350 nm, and the Raman spectrum shows an O–O stretching vibration at
~750 cm−1 [2].
Figure 1. Active site of tyrosinase isolated from S. castaneoglobisporus [5].

Copper(I) bis(pyrazolyl)methane
3261
During the last 30 years, many copper complexes have been investigated as small-
molecule models of tyrosinase. These systems are able to hydroxylate (i) an aromatic part of
the ligand framework [11–17] or (ii) external phenolic substrates [18–25] whereby the latter
reactivity can be stoichiometric or catalytic. The first catalytic model system of tyrosinase
was described by Réglier and coworkers in 1990 [19]. The copper(I) complex of their BiPh
(impy)2 ligand was able to convert the monophenol 2,4-di-tert-butyl-phenol (2,4-DTBP-H)
to the corresponding 3,5-di-tert-butyl-ortho-quinone (3,5-DTBQ) in 16 turnovers. Another
system has been reported by Casella and coworkers in 1991 which exhibits stoichiometric as
well as catalytic monooxygenation of external phenols [18]. The first model system of
tyrosinase based on a mononucleating ligand has been described by our group in 2010.
The ligand Lpy1 contains a pyridine ring and a tert-butyl-terminated imine function. The
CuLpy1 complex is able to convert the substrate 2,4-DTBP-H to the corresponding
3,5-DTBQ with a turnover number (TON) of 22 [20, 24]. In 2013, Herres-Pawlis and
coworkers established a model system of tyrosinase that is based on the tridentate ligand HC
(3-tBuPz)2(Py) which is composed of two tert-butyl-substituted pyrazoles and a pyridine
moiety. This system was the first one which both forms a room temperature stable peroxo
intermediate and shows catalytic activity regarding the hydroxylation of monophenols [22].
In recent years, further small-molecule models of tyrosinase were developed by our group in
which the pyridine ring of Lpy1 was replaced by a benzimidazole and a pyrazole ring,
leading to the bidentate ligands Lbzm1, Lhpz1, and Lhpz2, respectively. The corresponding
copper complexes were found to convert DTBP-H to DTBQ with TONs of 31, 29, and 23,
respectively [23, 24].
To obtain further insight into the structural and electronic influences of the ligands on the
catalytic activity of the corresponding copper complexes, we now set out to replace the
imine function of the bidentate Lx ligands by a second heterocycle, generating symmetric
ligands. Replacement of the imine function in the Lpy1 ligand by pyridine led to the
dipyridylmethane L3. The CuL3 complex, however, was found to be inactive with respect
to the catalytic oxygenation of DTBP-H [20]. In an effort to replace the imine functions of
the Lhpz1 and Lhpz2 ligands by a second pyrazole group, we now investigate copper com-
plexes supported by 1,1′-methylenebis-1H-pyrazole (BPM), 1,1′-methylenebis(3-methyl-
1H-pyrazole) (mBPM), and 1,1′-methylenebis(3,5-dimethyl-1H-pyrazole) (dmBPM,
scheme 2). Bis(pyrazolyl)methane-based ligands have been employed for model systems of
tyrosinase before [22, 26].
Herein the catalytic activity of Cu(I) complexes of BPM, mBPM, and dmBPM regard-
ing the ortho-hydroxylation of monophenols is investigated. Besides the standard substrate
2,4-DTBP-H, a range of other monophenols is studied as well (scheme 3). The different
reactivities are analyzed and interpreted on the basis of key intermediates of the mechanistic
cycle.
2. Results and discussion
2.1. Syntheses of the ligands and the corresponding copper(I) complexes
The symmetric pyrazole ligands BPM, mBPM, and dmBPM were prepared in one-step
syntheses, starting from the corresponding pyrazoles which were coupled with dibro-
momethane in DMSO [27]. The corresponding copper(I) complexes were prepared from
tetrakis(acetonitrile)copper(I) hexafluorophosphate under anaerobic conditions (scheme 4).

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J.N. Hamann et al.
Scheme 2. Synthesized symmetric N-donor ligands for further copper(I) model systems of tyrosinase.
2.2. Investigation of catalytic activity
The catalytic activity of the symmetric model systems can be monitored by in situ UV/vis
spectroscopy because ortho-quinones show an intense absorption at 390–450 nm, having
ɛ values from 1100 to 1800 M−1 cm−1 [28]. Catalytic oxygenation reactions were performed
at room temperature. To this end, a 500 µM solution of the respective copper(I) complex in
dichloromethane was prepared and 50 eq. of the respective monophenol (scheme 3) and
100 eq. of triethylamine were added. Subsequent oxygenation at ambient temperature
resulted in the formation of ortho-quinones, as indicated by absorption bands at
390–450 nm. The yield of formed ortho-quinone was determined on the basis of known
extinction coefficients [28–31].
2.2.1. Catalytic monooxygenation of 2,4-DTBP-H. [CuIBPM(NCCH3)2]PF6 catalyzes
the formation of 3,5-DTBQ, starting from 2,4-DTBP-H. Figure 2 shows the UV/vis spectra
of the oxygenation of 2,4-DTBP-H with [CuIBPM(NCCH3)2]PF6 in dichloromethane
Figure 2. UV/vis spectra of a 500 µM solution of [CuIBPM(NCCH3)2]PF6 in CH2Cl2 after addition of 50 eq.
2,4-DTBP-H, 100 eq. NEt3 and oxygenation between 15 min and 6 h; l = 1 mm. Inset: TON and TOF vs. reaction
time.

Copper(I) bis(pyrazolyl)methane
3263
Scheme 3. Set of monophenols used as external substrates in the catalytic oxygenation reactions.
during the first 6 h. The formation of this product is indicated by an absorption at 407 nm
[20, 23, 24]. Oxygenation of DTBP-H occurs rapidly during the first 90 min of reaction and
then slows, leading to a final TON of 21 after 8 h of reaction (figure 2, inset).
To further prove the formation of the 3,5-DTBQ during oxygenation, NMR spectroscopy
was used (figure 3). After 1 h of oxygenation, the solution was quenched with hydrochloric
Figure 3. 1H NMR spectrum of the oxygenation solution after quenching with HCl, measured in CDCl3.

3264
J.N. Hamann et al.
Scheme 4. Synthesis overview of the symmetric ligands and their copper(I) complexes.
acid followed by several extractions with dichloromethane to remove the copper ions. In
agreement with previous studies, the resulting NMR spectra revealed signals from the
formed 3,5-DTBQ, the used substrate 2,4-DTBP-H, and the C–C coupling byproduct
3,3′,5,5′-tetra-tert-butyl-2,2′-biphenol (figure 3, inset). The signals of the three compounds
2,4-DTBP-H, 3,5-DTBQ and the biphenol are present in a ratio of 60 : 14 : 26. The yield
of 14% 3,5-DTBQ is in agreement with the calculated TON of 14 after 1 h of oxygenation.
Analogous experiments were performed with the other systems. Compared with
[CuImBPM(NCCH3)2]PF6 and [CuIdmBPM(NCCH3)2]PF6, the unsubstituted BPM com-
plex shows the highest catalytic activity regarding the formation of 3,5-DTBQ (TON = 21)
after 8 h of oxygenation, closely followed by the methyl-substituted mBPM complex
(TON = 19, table 1). Using the dimethyl-substituted counterpart [CuIdmBPM(NCCH3)2]
PF6 as catalyst a TON of 11 was found (figure S1, see online supplemental material at
http://dx.doi.org/10.1080/00958972.2015.1074191). We attribute this decrease in catalytic
activity to an increasing steric demand of the dmBPM moiety, stabilizing the peroxo inter-
mediate. Moreover, coordination of the substrate gets sterically hindered. Both effects lower
the reaction rate with external phenols [23]. In line with these considerations, we anticipated
that the least reactive dmBPM-based system would form the most stable peroxo intermedi-
ate, whereas the stability of the peroxo intermediate would be decreased for the more reac-
tive mBPM and BPM systems. In fact, the peroxo species could be spectroscopically
identified for the [CuIdmBPM(NCCH3)2]PF6 complex (figure S2), whereas for the other
two systems this was not possible. The absorption bands at ~350 and 550 nm increasing in
Table 1. Overview of the investigated model systems and substrates in the catalytic reactions; ɛ values relating to
the formed ortho-quinones. Listed are the final TON after the appropriate time and TOF @ 15 min s−1
.
BPM
mBPM
dmBPM
TON
TOF
0.27
TON
TOF
0.24
TON
TOF
0.22
2,4-DTBP-H
ɛ = 1830 M−1 cm−1
3-TBP-H
21 (8 h)
19 (8 h)
15 (8 h)
10 (1 h)
12 (6 h)
9 (6 h)
11 (8 h)
9 (8 h)
5 (1 h)
10 (6 h)
9 (6 h)
11 (2 h)
17 (8 h)
10 (1 h)
14 (6 h)
9 (6 h)
0.34
0.51
0.11
0.16
0.26
0.27
0.48
0.03
0.13
0.19
0.24
0.26
0.005
0.11
0.12
ɛ = 1150 M−1 cm−1
4-OMeP-H
ɛ = 1700 M−1 cm−1
4-MeP-H
ɛ = 1400 M−1 cm−1
P-H
ɛ = 1417 M−1 cm−1
NATEE
18 (2 h)
15 (2 h)
ɛ = 1180 M−1 cm−1

Copper(I) bis(pyrazolyl)methane
3265
intensity upon oxygenation are assigned to peroxide → copper charge transfer transitions
[32]. TD-DFT calculations show agreement between the theoretical and the measured
spectrum (inset figure S2).
2.2.2. Catalytic monooxygenation of other substrates. Besides 2,4-DTBP-H, five other
monophenols were investigated regarding their catalytic conversion to the respective
ortho-quinones; i.e. 4-methoxyphenol (4-OMeP-H), 3-tert-butyl-phenol (3-TBP-H),
4-methylphenol (4-MeP-H), the native substrate N-acetyl-L-tyrosine ethyl ester (NATEE),
and unsubstituted phenol (P-H). The observed TONs and TOFs are collected in table 1 and
shown pictorially in figure 4. Evidently, all of these monophenols give lower TONs than
the “standard substrate” 2,4-DTBP-H. With the BPM system, the TON achieved for the lat-
ter substrate is more than twice as large as for the least effect substrate, P-H (TON = 9); for
the mBPM and dmBPM systems, the differences are less pronounced. Regarding TOF, on
the other hand, the substrate 2,4-DTBP-H only has an intermediate position. The reason for
this observation is the fact that this substrate, albeit electronically activated by the tert-butyl
groups in ortho and para position, is sterically hindered.
The second highest TON of all substrates is achieved with the substrate 3-TBP-H
(TON = 17 with BPM). The formation of 4-tert-butyl-ortho-quinone was observed by an
increasing absorption band with a maximum at 402 nm in the UV/vis spectra (figure S3). In
comparison with the substrate 2,4-DTBP-H, the lack of electron-donating tert-butyl
substituents in ortho and para positions leads to a smaller activation of 3-TBP-H toward
electrophilic substitution; it is not sterically hindered.
Catalytic conversion of unsubstituted phenol (P-H) to the ortho-benzoquinone occurs
slowly, reaching saturation after 6 h. In agreement with the complete lack of activating sub-
stituents, this is the slowest of all substrates. A characteristic absorption band at 398 nm
indicates the ortho-hydroxylation and two-electron oxidation of phenol with a TON of 9
(figure S4).
Of particular interest with regard to biomimetic activity of our catalytic model systems is
the native substrate NATEE, which was also investigated concerning the formation of the
Figure 4. Comparison of the results using various substrates in the oxygenation with pyrazole model systems, left:
determined TOFs at 15 min s−1; right: determined TONs.

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J.N. Hamann et al.
Scheme 5. Reaction behavior using the native substrate NATEE in the oxygenation.
corresponding dopaquinone derivative [33]. Using NATEE in catalytic runs with [CuIBPM
(NCCH3)2]PF6, rapid formation of the quinone is observed during the first 2 h of oxygena-
tion. As for the other substrates, the BPM system shows the highest activity (TON = 18).
However, after 2 h the formed quinone decomposes which is apparent in the UV/vis spectra
by a shift of the absorption band from 400 to 370 nm, accompanied by an intensity
decrease (figures S5 and S6). Workup of the oxygenated solution followed by NMR analy-
sis allowed identification of the unoxygenated substrate NATEE as main product and small
amounts of a byproduct which could be identified as the hemiacetal derived from reduction
of the ester group (figure S7). Unfortunately, the formed dopaquinone decomposed upon
quenching with aqueous hydrochloric acid, which is necessary to separate and isolate the
organic compounds. A subsequently measured UV/vis spectrum exhibited no absorption at
400 nm or lower wavelength. Instability toward water probably also explains the intensity
decrease in the absorption band of the quinone product in the reaction mixture after 2 h
(see above; scheme 5). Nevertheless, the oxygenated product could be investigated using
Figure 5. UV/vis spectra of the oxygenation of 4-OMeP-H with [CuIBPM(NCCH3)2]PF6 for 4 h; after 1 h the
absorption at 418 nm saturates whereas the second band at 350 nm further increases in intensity. Inset: Absorbance
values vs. time; l = 1 mm.

Copper(I) bis(pyrazolyl)methane
3267
mass spectrometry and a peak with low intensity could be identified at m/z = 268.1 which
was assigned to the corresponding catechol of NATEE (ESI).
The monophenol 4-OMeP-H is the fastest of all substrates. Based on the time evolution
of the absorbance at 418 nm, a TOF of 0.51 s−1 is achieved for the BPM system after the
first 15 min. Saturation starts after 45 min and is complete after 60 min, leading to a TON
of only 10 (figure 5). The high reaction rate is due to the strong electron-donating effect of
the para-methoxy group, facilitating electrophilic attack by the Cu2O2 moiety on the arene
ring in ortho-position to the phenolic OH group [22]. After saturation of the quinone band
at 418 nm, a second band at 350 nm continues to grow in intensity (figure 5, inset). The
oxygenation of 4-OMeP-H catalyzed by tyrosinase has been investigated by Riley et al.
[34]. According to this study, the formed ortho-quinone product 2 is converted to the
trihydroxyanisole 3 (scheme 6) [34]. Subsequently, this intermediate reacts with the ortho-
quinone 2 to the corresponding para-quinone 4 and the catechol derivative 5 (scheme 6).
By comproportionation of 2 and 5 semiquinone 6 is formed. While the latter product may
be associated with the characteristic absorption band at 350 nm (figure 5) [35], an NMR
spectrum measured after workup of the oxygenation solution showed the signals of para-
quinone 4 besides unoxygenated 4-OMeP-H (ESI).
Anomalous behavior was also exhibited by the substrate 4-methylphenol (4-MeP-H)
when subjected to oxygenation reactions (figure S9). Although the methyl group in para
position should activate this monophenol toward hydroxylation, it shows the lowest TOF of
Scheme 6. Postulated mechanism for the reaction of 4-methoxyphenol with tyrosinase and O2 after Riley et al.
[34].

3268
J.N. Hamann et al.
Figure 6. UV/vis spectra of the oxygenation of 4-MeP-H with [CuIBPM(NCCH3)2]PF6 during the first 2 h. Inset:
UV/vis spectra of the oxygenation for further 4 h, the intense band at 655 nm decreases; l = 1 mm.
all investigated substrates with 0.11 s−1 (BPM system). Based on an absorption band at
445 nm, increasing intensity during the first 6 h of oxygenation, catalytic conversion to the
corresponding quinone does occur (TON = 14, figure 6). However, during oxygenation a
second intense absorption emerges at 655 nm, the intensity of which decreases after 2 h
(figure 6, inset) and completely disappears after 24 h (figure S10). This behavior of
4-methylphenol in oxygenation reactions is known in the literature as well and has been
explained by Meyer et al. [36]. In phenol oxygenation reactions mediated by ruthenium
oxo complexes, these authors identified a ruthenium quinone complex as an intermediate
which has an absorption at 655 nm [36]. In the course of the reaction, this species disap-
pears due to hydrolysis. We suppose that in our system a copper semiquinone complex is
formed in a side reaction. Copper(II)-semiquinone derivatives have intense LMCT bands at
580–655 nm [37]. In addition, a characteristic absorption at 350 nm is observed which can
be assigned to a π-system transition of free semiquinone (figure 6) [35, 37]. In the further
course of the oxygenation reaction, water is formed and the copper(II) semiquinone com-
plex is hydrolyzed. The appearance and disappearance of this intermediate is also apparent
from color changes of the reaction mixture. Upon exposure to dioxygen, the color of the
initially pale yellow solution changes rapidly to a light green. During further oxygenation,
the light green solution becomes dark bluish green and after 24 h, the color changes to red
brown.
Within our proposed mechanistic scheme [20, 23–25], formation of the Cu(II) semiqui-
none complex can be attributed to reaction of the primary ortho-quinone product with the
copper(I) complex 2BPM, leading to intermediate 5BPM (scheme 7). This reduces the concen-
tration of the catalyst and explains the low reaction rate observed for this activated substrate.
3. Summary and conclusion
Three new mononuclear copper(I) complexes supported by symmetric pyrazole ligands
have been synthesized and investigated as model systems of the enzyme tyrosinase which

Copper(I) bis(pyrazolyl)methane
3269
Scheme 7. Proposed catalytic cycle for pyrazole-based symmetric systems in analogy to our previous model sys-
tems. For the last step, a competition reaction occurs, forming a Cu(II) semiquinone complex 5BPM. This reduces
the amount of catalyst, lowering the reaction rate.
mediates the ortho-hydroxylation of external substrates. Importantly, the three BPM sys-
tems have catalytic activities toward the substrate DTBP-H that are comparable to those
observed earlier with catalysts supported by ligands with imine groups [20, 23–25]. This is
in stark contrast to the copper dipyridylmethane complex which was found to be catalyti-
cally inactive [20]. Among the copper complexes supported by bis(pyrazolyl)methane
ligands, the unsubstituted BPM system was more reactive than its mBPM and the dmBPM
derivatives. The differences between the BPM and mBPM system induced by the mono-
substitution of the pyrazole are, however, small. On the other hand, the 3,5-dimethyl sub-
stitution in the dmBPM system leads to considerably lower catalytic activity. Presumably,
this is due to the fact that the peroxo intermediate is more stable. Moreover, the increased
steric hindrance induced by the methyl groups hinders coordination of the substrate to the
peroxo intermediate, further lowering the reaction rate [23].
Various monophenols were subjected to catalytic oxygenations, monitored by UV/vis
spectroscopy. Quite expectedly, the electron-rich phenols 2,4-DTBP-H and 3-TBP-H led to
high yields of quinone. Whereas 2,4-DTBP-H turned out to be the best monophenol for our

3270
J.N. Hamann et al.
catalytic investigations regarding the yield of quinone, the highest reaction rate was
obtained with 4-methoxyphenol. However, the TON obtained with this substrate was found
to be lowered due to secondary reactions of the primary reaction product. Catalytic
monooxygenation of the interesting native substrate NATEE was also investigated and
formation of the corresponding dopaquinone could be observed with a TON of 18 during
the first 2 h of oxygenation. Finally, 4-methylphenol was subjected to catalytic oxygenation
reactions whereby a competition reaction was observed, leading to a lower TOF than
expected for this activated substrate.
In summary, we have investigated copper(I) complexes supported by bidentate bis(pyra-
zolyl)methane ligands as catalysts for the monooxygenation of a range of monophenolic
substrates, closely mimicking the reactivity of the enzyme tyrosinase. Importantly, catalytic
conversion to ortho-quinones was observed for all combinations of substrates and catalysts,
thus enlarging the scope of biomimetic oxygenation reactions mediated by tyrosinase model
systems. Of course, the unmatched activity of the enzyme still leaves room for further
improvement of these artificial systems.
Supplementary material
Electronic Supplementary Information (ESI) available: [Materials and methods, ligand syn-
theses, complex syntheses, UV/vis measurements, NMR measurements].
Acknowledgments
The authors would like to thank Deutsche Forschungsgemeinschaft (DFG), CAU Kiel and
COST CM 1003 for support of this research.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by Deutsche Forschungsgemeinschaft [grant number Tu58/13].
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