Click. Coordinate. Catalyze. Using CuAAC Click Ligands in Small-Molecule Model Chemistry of Tyrosinase

Article abstract of DOI:10.1002/cctc.201801606

Three triazolylmethylpyridine ligands are synthesized using the copper-catalyzed azide-alkyne cycloaddition (CuAAC). The corresponding copper(I) complexes are investigated as catalysts for the oxygenation of several monophenols, in analogy to the enzyme tyrosinase. Importantly, they show a higher catalytic activity than previously investigated systems. This is ascribed to the lower charge donation of the electron-poor triazole heterocycle, supporting the hydroxylation of phenolic substrates by an electrophilic substitution mechanism.

Full text of DOI:10.1002/cctc.201801606

Accepted Article
Title: Click. Coordinate. Catalyze. Using CuAAC Click Ligands in
Small-Molecule Model Chemistry of Tyrosinase
Authors: Benjamin Herzigkeit, Benedikt Maria Flöser, Nadja Eileen
Meißner, Tobias Adrian Engesser, and Felix Tuczek
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Click. Coordinate. Catalyze. Using CuAAC Click Ligands in Small-
Molecule Model Chemistry of Tyrosinase
Benjamin Herzigkeit,[a] Benedikt M. Flöser,[a] Nadja E. Meißner,[a] Tobias A. Engesser,[a] Felix Tuczek*[a]
Abstract: Three triazolylmethylpyridine ligands are synthesized using
the copper-catalyzed azide-alkyne cycloaddition (CuAAC). The corre-
sponding copper(I) complexes are investigated as catalysts for the
oxygenation of several monophenols, in analogy to the enzyme tyro-
sinase. Importantly, they show a higher catalytic activity than previ-
ously investigated systems. This is ascribed to the lower charge do-
nation of the electron-poor triazole heterocycle, supporting the hy-
droxylation of phenolic substrates by an electrophilic substitution
mechanism.
Type-3 copper proteins are metalloproteins sharing similar active
sites. They contain two copper atoms (CuA and CuB) which are
each coordinated by three histidines and bind dioxygen as perox-
ide in a side-on (-2:2) coordination.[1,2] Even though their active
Scheme 1. Mono- and binucleating ligands used in model complexes for the
sites are almost identical, their reactivities differ greatly.[3] Hemo-
oxygenation of various substrates in a tyrosinase-like fashion.[2,11,15,20]
cyanin (Hc) is involved in oxygen transport in molluscs and arthro-
pods. Tyrosinase (TY) catalyzes the conversion of L-tyrosine to
with a turnover number (TON) of 22. By changing the heterocyclic
and the imine N donor of our parent bidentate ligand we were able
L-DOPAquinone and therefore plays a central role in, e.g., mel-
to create further catalytic model systems achieving TONs of up to
anogenesis of mammals and birds.[4] Catechol oxidase (CO), on
31.[18] Thereby we observed a higher catalytic efficiency in case of
the other hand, is only able to convert L-DOPA to L-DOPAquinone.
benzimidazole/imine, pyrazole/imine or pyrazol/pyrazol contain-
ing systems (Scheme 1) whereas a decrease of catalytic activity
was found for imidazole/oxazoline systems.[18,19] In general, the
use of comparatively electron-poor pyrazole groups in the ligand
framework led to more active catalysts.[20]
Another electron-poor N-donor ligand which to date has not
been utilized in studies regarding the oxygenation of external sub-
The first X-ray crystallographic characterization of a tyrosinase
from the bacterium Streptomyces castaneoglobisporus was pre-
sented by Matoba et al.[5] In the meantime, many more crystal
structures of copper-containing polyphenol oxidases (PPOs) have
appeared, allowing to relate their structural differences to the
functional discrimination between TY and CO activity.[6-8] Never-
theless, details of the molecular mechanism of tyrosinase are still
strates is 1,2,3-triazole. Triazoles are employed in various fields
unclear or under discussion.[6-8]
of chemistry, biochemistry, drug discovery, polymer and material
Important information regarding the reactivity of tyrosinase
science for their unique properties and their easy accessibility.[21]
may be obtained from small-molecule model systems. Many re-
Application of the prominent CuAAC click reaction, which was first
search groups followed this line of research; correspondingly, the
introduced by Sharpless et al., enables the use of a highly efficient,
number of functional models of tyrosinase has steadily increased
stereospecific and easy to purify method to synthesize a wide ar-
over the years (Scheme 1).[1,2,9,10] The first catalytically active sys-
ray of organic products.[21,22] With respect to coordination chemis-
tem was developed by Réglier et al., being able to convert 2,4-di-
try, exploiting the methodology of “clicking” two modular units to-
tert-butylphenol (DTBP-H) to 3,5-di-tert-butylquinone (DTBQ) with
gether allows to effectively tune the properties of ligands.[23,24]
a turnover number (TON) of 16 after 1 h.[11] Further systems were
devised by Casella et al.[12], Stack et al.[13], Lumb et al.[14], Herres-
Pawlis et al.,[15] and others.[1,2,9,16]
Our group´s first catalytic model system was the imino-pyri-
dine Lpy1, derived from Réglier´s Cu2BiPh(impy)2 system
(Scheme 1).[11, 17] It was capable of converting DTBP-H to DTBQ
[a]
B. Herzigkeit, B. M. Flöser, N. E. Meißner, T. A. Engesser,
F. Tuczek
Institut für Anorganische Chemie,
Christian-Albrechts-Universität zu Kiel,
Max-Eyth-Straße 2, 24118 Kiel, Germany
E-mail: ftuczek@ac.uni-kiel.de
Scheme 2. Triazolylmethylpyridine ligands (1a-c) and their heteroleptic Cu(I)
complexes (2a-c) used in this study.
Herein, we report the synthesis of three novel copper(I)
complexes (Scheme 2) supported by triazolylmethylpyridine lig-
ands and their catalytic activity regarding the monooxygenation of
http://www.ac.uni-kiel.de/tuczek
Supporting information for this article is given via a link at the end of
the document.
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Figure 1. Catalytic oxygenation of a 500 μm solution of [Cu(MeCN)TMP1]PF6 (2a) in the presence of DTBP-H (left) , [Cu(MeCN)TMP2]PF6 (2b) in the presence of
TBP-H (middle) and [Cu(MeCN)2TMP3]PF6 (2c) in the presence of MeOP-H (right) under Bulkowski/Réglier conditions (50 equiv. substrate, 100 equiv. triethylamine)
in dichloromethane 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.
the substrates DTBP-H, 3-tert-butylphenol (TBP-H) and 4-meth-
oxyphenol (MeOP-H). The results are compared with those ob-
tained from previously synthesized systems, and the influence of
different substituents (tolyl, anisole and t-butyl) at the triazole moi-
ety on the catalytic activity of the derived copper complex is dis-
cussed.
The two ligands TMP1 (1a) and TMP2 (1b) were synthe-
sized according to a procedure developed by Košmrlj et al.
(Scheme 3).[25] The synthesis of TMP3 (1c) applying the same
protocol, however, resulted in low yields. Using the synthetic path-
way of Bertani et al. gave better results.[26] Employing the ligands
(1a-c) and tetrakis(acetonitrile)copper(I) hexafluorophosphate
(CuP) in a ratio of 1 to 1 the mono-ligated copper(I) complexes
2a-c could be obtained (for details see SI).
Scheme 4. Catalytic reaction of the phenolic substrate DTBP-H to DTBQ and
CCcP.
Upon oxygenation of DTBP-H with 2a-c, the color of the re-
action mixture immediately changed from colorless to yellow, rap-
idly turning brown. For copper complex 2a a TON of 20 was de-
termined after 6 hours (cf. Figure 1, left). Similar results were ob-
served for complex 2b and 2c with TONs of 22 and 24, respec-
tively, after 5 hours (Figure S1, S2). Within the first hour the oxy-
genation of the substrate occurred with a moderate turnover fre-
quency (TOF) for all three complexes (Figure 1, S1, S2, insets).
Formation of DTBQ was further examined by NMR. To this end,
an aliquot was removed from the reaction mixture after one hour,
diluted to a 100 µM solution and quenched with 6 M hydrochloride
acid to remove any copper species. After work-up the residue was
1
investigated by H- and 13C-NMR spectroscopy (Figure S3-S8).
The resulting spectra revealed the formation of DTBQ, the C-C
coupling product CCcP as well as starting material DTBP-H (Tab.
S1).
Scheme 3. Syntheses of the ligands (1a-c) and the heteroleptic copper(I)
complexes (2a, 2b).
As a second substrate we investigated TBP-H (Scheme 5).
In contrast to DTBP-H, there is no tert-butyl group in ortho-posi-
tion to the hydroxyl group, which should decrease the steric inter-
action between the ligand and the substrate and possibly lead to
a higher TON. Due to the lack of the tert-butyl group, however,
the initially formed 4-tert-butylquinone (4-TBQ) undergoes an ox-
idative coupling with TBP-H and reacts to the coupled quinone 4-
(tert-butyl)-5-(3-(tert-butyl)-phenoxy)-cyclohexa-3,5-dien-1,2-di-
one (cpQ, Scheme 5). Oxygenation of the reaction mixture with
complexes 2a, 2b and 2c resulted in TONs of 20 (Figure S9), 19
(Figure 1, middle) and 24 (Figure S10), respectively.
As evident from Figure 1 (middle), the prominent absorption
band at ~395 nm shifts to 425 nm in the course of oxygenation,
reflecting the transformation of the intermediate product 4-TBQ to
the coupled quinone (cpQ). After quenching and work-up of an
aliquot of the reaction mixtures the NMRs showed the product
cpQ and starting material TBP-H (Table S1, Figure S11-S16).
The catalytic tyrosinase activity of the heteroleptic copper(I)
complexes 2a-c was investigated regarding the three monophe-
nolic substrates DTBP-H, TBP-H and MeOP-H which exhibit dif-
ferent structural and electronic properties. Whereas DTBP-H is
converted to the ortho-quinone DTBQ as well as the C-C coupling
product 3,3’,5,5’-tetra-tert-butyl-2,2’-biphenol (CCcP), the less
sterically demanding monophenols TBP-H and MeOP-H form
secondary products after monooxygenation (Scheme 4, 5). All
catalytic reactions were carried out under Bulkowski/Réglier con-
ditions.[27] To this end, oxygen was bubbled into a 500 µM solution
of copper(I) complex in dichloromethane with 50 equivalents of
substrate and 100 equivalents triethylamine under anaerobic con-
ditions at room temperature. Progress of the reactions was moni-
tored by in situ UV/vis spectroscopy based on the absorption
bands of the characteristic products (407 nm,  = 1830 L mol-1
cm-1 for DTBQ[11,18]; 425 nm,  = 898 L mol-1 cm-1 for the coupled
quinone cpQ of TBP-H;[19] and 418 nm,  = 524 L mol-1 cm-1 for
the coupled quinone cpMeOQ, formed from MeOP-H) [19]
.
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Table 1. Overview of the tyrosinase-like activity for the conversion (TON) of several substrates for systems supported by bidentate ligands.
System
DPM
[17]
BPM
[19]
dmBPM
[19]
LIMZ
[19]
BIMZ
[19]
PMP
[20]
dmPMP
[20]
TMP1
this work
20
TMP2
this work
22
TMP3
this work
24
DTBP-H
TBP-H
0
-
21
22
35
11
12
15
16
20
34
9
6
6
14
25
34
11
13
33
20
42
19
45
24
48
MeOP-H
-
Finally, the monooxygenation of MeOP-H with complexes
2a-c was studied (Scheme 5). This reaction initially leads to 4-
methoxyquinone (4-MeOQ), which then reacts to the coupled or-
tho-quinone
4-methoxy-5-(4-methoxyphenoxy)cyclohexa-3,5-
diene-1,2-dione (cpMeOQ). Both of these reactions are rapid due
to the strong mesomeric (+M) effect of the para-methoxy substit-
uent and the lack of a tert-butyl residue in ortho-position to the
hydroxy group. After one hour cpMeOQ is converted to 2-hydroxy-
5-methoxy-[1,4]-benzoquinone (pQ) due to the presence of water
formed in the previous reaction steps (Scheme 5). Notably, all cat-
alysts mediate the conversion of MeOP-H to the coupled quinone
cpMeOQ within the first hour (Figure 1, right, S17, S18, insets).
Oxygenation with complex 2a results in a TON of 42 (Figure S17)
whereas with complex 2b a slightly higher TON (45) is achieved
(Figure S18). Both complexes are topped by 2c exhibiting a TON
of 48 (Figure 1, right). The reaction mixture was quenched after
one and three hours, respectively (Table S1, Figure S19-S30).
Evidently the three new complexes are able to mediate a
tyrosinase-like monooxygenation of all three substrates. Moreo-
ver, TONs for the new catalysts are high compared to the other
model systems (Table 1). Thereby complex 2c is the most active,
achieving a TON of 24 with DTBP-H and TBP-H. Regarding these
two substrates the new systems 2a-c are roughly comparable to
the bispyrazolylmethane systems (BPM),[19] though with respect
to the substrate MeOP-H they exceed the previously achieved
TONs significantly with complex 2c taking the lead (TON = 48).
This demonstrates the overall high versatility of the new catalysts.
A salient difference to the systems investigated earlier is the
fact that a high steric interaction with the substrates, as found in
systems like dmBPM and dmPMP (cf Scheme 1), is absent for
the triazole coordinated catalysts 2a-c. This is evident from the
observation that the substituent at the C4 position of the triazole
moiety exhibits only a small influence on the catalytic activity (Ta-
ble 1). Regarding the reaction mechanism we propose that it pro-
ceeds in the same manner as in our other bidentate model sys-
tems.[2,17] We detected a µ-2:2-peroxo complex for the catalysts
at low temperatures (-90 °C) in acetone, albeit with small intensity
(see Figure S31-33 for experimentally and theoretically obtained
UV/vis-spectra). Generally, a stable peroxo intermediate is more
difficult to detect if the corresponding copper complex has a high
catalytic activity.[17,19]
Scheme 5. Catalytic reaction of the substrate TBP-H to cpQ and MeOP-H to
cpMeOQ and pQ.
electron-poor moieties in this series, leads to the highest turnover
numbers. Supposedly, the negative inductive effect of the addi-
tional nitrogen atom leads to a lower charge donation of the het-
erocycle via coordinating N atom to the metal center, thus render-
ing the reactive copper peroxo species more electrophilic. Based
on the SE mechanism evidenced for the aromatic hydroxylation
reaction in these systems the catalytic activity regarding the
monooxygenation of phenolic substrates is correspondingly en-
hanced.[28]
In summary we have presented three new small molecule
models for a tyrosinase-like oxygenation of three different mono-
phenols. Importantly, the TONs with the substrates DTBP-H (24)
and MeOP-H (48) were found to be higher than in previously in-
vestigated model systems containing exclusively heterocyclic N-
donors whereas the TON with TBP-H (24) was not increased.
Overall, triazole donors generate a higher catalytic conversion
than pyrazole or pyridine donors. On the other hand, a steric in-
fluence at the C4-position of the triazole N-donor plays a less im-
portant role for the conversion of monophenols to ortho-quinones,
as the most reactive system 2c does contain a tert-butyl group
and still shows the highest TON. This indicates that the electronic
properties of the ligands are of utmost importance for the reactivity
of these systems. In the future, expansion of the ligand library with
more clickable triazoles, whose electronic influence can easily be
changed by, e.g., an electron withdrawing carboxylic ester group,
should help to further improve the catalytic activity and the mech-
anistic understanding of functional tyrosinase models.
Keywords: tyrosinase • triazoles • oxygenation • homogeneous
catalysis • ligand design
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Entry for the Table of Contents:
COMMUNICATION
Benjamin Herzigkeit, Benedikt M. Flöser,
Nadja E. Meißner, Tobias A. Engesser,
Felix Tuczek*
Page No. – Page No.
Click. Coordinate. Catalyze. Using
CuAAC Click Ligands in Small-Mole-
cule Model Chemistry of Tyrosinase
Bidentate ligands with triazole groups are readily synthesized via a copper cata-
lyzed azide-alkyne cycloaddition. Their copper complexes turn out to be highly active
catalysts for the oxygenation of various monophenols, in analogy to the enzyme ty-
rosinase.
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Additional Author information for the electronic version of the article.
Author: Felix Tuczek
Author: Tobias A. Engesser
Author: Benjamin Herzigkeit
ORCID identifier: 0000-0001-7290-9553
ORCID identifier: 0000-0002-1287-2661
ORCID identifier: 0000-0002-4322-3285
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