A bio-inspired imidazole-functionalised copper cage complex

Article abstract of DOI:10.1039/c9cc00437h

An imidazole-functionalised cage is synthesised that can coordinate to Cu(i). X-ray analysis reveals a T-shaped coordination of copper by the imidazole ligands reminiscent of the coordination geometry found in enzymatic active sites. This cage complex can

Full text of DOI:10.1039/c9cc00437h

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A bio-inspired imidazole-functionalised
copper cage complex†
Cite this:DOI: 10.1039/c9cc00437h
Sarah C. Bete, Christian Wurtele and Matthias Otte
*
¨
Received 17th January 2019,
Accepted 22nd March 2019
DOI: 10.1039/c9cc00437h
rsc.li/chemcomm
An imidazole-functionalised cage is synthesised that can coordinate to To date, the mimicking of enzymatic active sites containing
Cu(I). X-ray analysis reveals a T-shaped coordination of copper by the histidine by imidazole-functionalised cavity based ligands is
imidazole ligands reminiscent of the coordination geometry found in mainly dominated by cyclodextrins and calix[6]arenes where
enzymatic active sites. This cage complex can catalyse the oxidation of the metal is actually located outside of the cavity with its
1
1
benzylic alcohols to benzaldehydes utilizing oxygen as the terminal binding site pointing towards it. Notably, it has been demon-
oxidant.
strated very recently that imidazole-functionalised metal
organic frameworks are able to coordinate to copper resulting
1
2
The coordination of imidazole moieties from histidines to copper in active catalysts for the conversion of methane to methanol.
ions plays a key role in many enzymatic active sites. Examples are
While active sites of enzymes containing metalloporphyrins
1
,2
13
particulate methane monooxygenases (pMMO),
lytic poly- have been mimicked by the use of molecular cage compounds,
1
saccharide monooxygenases (LPMO) and tyrosinases (Ty, examples of molecular cages that offer such a well-defined ligand
3
Fig. 1a–c). These offer fascinating reactivities and selectivities sphere to mimic non-heme enzymatic active sites via imidazole
that can often not be achieved by man-made catalysts. Chemists coordination are yet unprecedented. This is surprising as endo-
are inspired to develop (functional) molecular compounds that functionalised organic cages have been shown to bind catalytic
14
mimic these active sites. This mimicking has mostly been devoted active centers. Costas and Ribas and co-worker recently synthe-
towards the first coordination sphere, resulting in coordination sised Zn-, Cu- and Fe-coordination complexes based on pyridine
4–7
15
complexes of rather low molecular weight.
coordination within a self-assembled nanocage. However, these
In comparison, the design of cavity-based metal complexes species have not been reported to be catalytically active for the
8
,9
has received way less attention. This approach may allow to transformation of organic substrates.
mimic also features of the active site pocket. It may also grant
Here we present the synthesis and characterization of
the advantages of chemistry in synthetic cages, such as protec- the aza-cyclophane 1 (Scheme 1) and show that it is able to
tion of the catalytic active centre, stabilization of highly reactive coordinate to copper(I) resulting in a catalyst for the oxidation
1
0
species, control of binding events and unusual selectivities.
of benzylic alcohols. Cage 1 was synthesised from known 2
Scheme 1). Via nucleophilic substitution with an imidazolium
(
salt, 3 was obtained in a yield of 54%. Afterwards, a Suzuki–
Miyaura-coupling gave the imidazole-functionalised building
block 4 in 52% yield. Single crystals suitable for X-ray diffrac-
tion analysis were obtained by layer diffusion of pentane into a
dichloromethane solution of 4. 4 and the known compound 5
were subject to a reductive amination protocol with the aim to
obtain 1. Such an approach is well documented for the syn-
1
6
2 2 3
thesis of organic cages. After stirring a CH Cl /CH OH
Fig. 1 Active sites of (a) pMMO, (b) LPMO and (c) Ty.
solution of 4 and 5 for 2 days at room temperature and
subsequent addition of sodium borohydride and purification,
cage 1 was isolated in 46% yield.
Institut f u¨ r Anorganische Chemie, Universit a¨ t G o¨ ttingen, Tammannstraße 4,
3
7077 G o¨ ttingen, Germany. E-mail: matthias.otte@chemie.uni-goettingen.de
Electronic supplementary information (ESI) available: Experimental details.
1
1
13
1
was characterised via ESI-MS, H, H DOSY, C NMR and
†
IR spectroscopy. The ESI-MS reveals signals with m/z values of
1501.8892, 751.4488 and 501.3016 corresponding to 1 + H ,
CCDC 1868264 and 1876236. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c9cc00437h
+
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4 6
Scheme 2 Synthesis of [1-Cu]BF and [1-Cu]SbF .
[
1-Cu]BF
4
shows remarkable changes compared to the one of 1
(Fig. 2b). All three signals that are assigned to the imidazole
protons (labelled with A–C) shift upon addition of 6. These
shifts indicate that a coordination of the imidazole to copper
was successful and that all imidazoles behave identically on
NMR-timescale. Solutions of [1-Cu]BF turn greenish within
4
minutes upon stirring under air (see ESI† for UV Vis spectra). The
NMR spectrum of [1-Cu]BF changes significantly. No separated
4
Scheme 1 Synthesis of cage 1 and molecular structure of 4 in the solid
state.
signals corresponding to the imidazole protons and the
methylene-bridge could be assigned caused by broadening of
all signals (see ESI†). A less pronounced broadening is observed
for the backbone signals further indicating a coordination of
+
+
1
1
+ 2H and 1 + 3H . In the H NMR spectrum, two singlets are
1
copper to the imidazole moieties. The H DOSY NMR spectrum
found at chemical shifts of 3.90 and 3.88 ppm that indicate
the presence of benzylic amines (Fig. 2a). Three signals with
relative integrals of three hydrogens each corresponding to
the hydrogens of the imidazoles are observed, showing the
(
4
see ESI†) of [1-Cu]BF in chloroform shows a single compound
ꢁ
10
2
ꢁ1
with a diffusion coefficient of 4.1 ꢀ 10
m
s
which
translates to a hydrodynamic radius of 9.9 Å. These values are
1
1
close to the ones obtained from the H DOSY NMR spectrum of
imidazole’s equivalence on NMR-timescale. The H DOSY NMR
1, which indicates that copper-coordination does not lead
spectrum (see ESI†) reveals only one molecule size apart from
solvents and trace amounts of grease. A diffusion coefficient of
to any dimeric or oligomeric species. ESI-MS investigations of
ꢁ
10
2
ꢁ1
[1-Cu]BF shows species with m/z values of 1563.8112, 782.4088
4.1 ꢀ 10
m s is found in chloroform. Using the Stokes–
4
+
+
+
and 1652.8288 corresponding to [1-Cu] , [1-Cu] + H and
Einstein equation for spherically shaped molecules, this diffu-
sion coefficient translates to a hydrodynamic radius of 9.8 Å.
With 1 in hand, we studied its behaviour to act as ligand for
+
[
1-Cu]BF
4
+ H .
X-ray analysis of single crystals of [1-Cu]BF , obtained by
4
slow diffusion of THF into a diethylether solution, lead to a low
data quality (see ESI†). However, the overall connectivity of the
cage and its coordination to copper by all three imidazole units
in the solid state could be confirmed. To obtain data of higher
copper(I) (Scheme 2). Reaction with 0.9 equivalents Cu(MeCN)
4 4
BF
(
6) in dichloromethane at room temperature allows for the isolation
1
4
of [1-Cu]BF as a white solid in 77% yield. The H NMR spectrum of
quality, we synthesised [1-Cu]SbF
6
from 1 and Cu(MeCN)
4
SbF
6
(
(
7). NMR and MS gave analogous data compared to [1-Cu]BF
see ESI†). To our delight, we were able to obtain crystallo-
4
graphic data of higher quality by analysing single crystals of
1-Cu]SbF that form in a saturated ethereal solution at room
[
6
temperature. As anticipated, copper is coordinated by each of
the imidazole moieties (Fig. 3). A T-shaped coordination mode
is found with N–Cu–N angles of 1501, 1061 and 1021. Cu–N
bond lengths of 1.9 Å are found for the imidazole units that are
trans to each other, while the one for the remaining imidazole
ligand is 2.1 Å. These values correspond well with the ones
found in enzymatic active sites also showing a T-shaped coor-
dination of the Cu(I) center. The Cu(I)–N(His) bond lengths in
1
LPMOs are 1.9 Å, while the Cu(I)–NH
2
bond length is 2.1 Å. The
Cu(I)–N(His) bond lengths in the pMMO active site are 1.8 Å,
1
7
1
.9 Å and 2.2 Å. The average distance between copper and the
1
Fig. 2 H NMR spectra of (a) 1 and (b) [1-Cu]BF
4
in CDCl
3
.
terminal carbon of the ethyl groups is 10 Å, which is in good
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a
4
Table 2 Investigation of [1-Cu]BF in competition experiments
Entry
[Cu] ([mol%])
[1-Cu]BF (1)
R1
R2
PR1 : PR2
Yield [%]
1
2
3
4
Me
t-Bu
59 : 41
42 : 58
52 : 48
6
22
21
6ꢂ3(NMI) (1)
10ꢂ(bipy)ꢂ2(NMI) (0.6)
4
5
6
[1-Cu]BF
4
(1)
H
t-Bu
67 : 33
55 : 45
52 : 48
7
4
3
6ꢂ3(NMI) (1)
10ꢂ(bipy)ꢂ2(NMI) (0.6)
6
Fig. 3 Molecular structure of [1-Cu]SbF in the solid state: (a) side view;
a
Substrate concentration = 0.11 M; reactions under air; 7 mol%
O; rt; 5.0 h. All yields were determined by
(
b) top view (solvent molecules and anion undisplayed). Carbon bonded
TEMPO; 11.1 equiv. H
2
hydrogen atoms are omitted for clarity.
1
H NMR spectroscopy of the crude product mixtures in presence of
0
internal standards. NMI = N-methylimidazole. bipy = 2,2 -bipyridine.
4
agreement with the hydrodynamic radius obtained for [1-Cu]BF .
ꢁ
For the SbF -counterion three different locations are found (see traces of 9 (entry 5). Control experiments with copper salt 6,
6
ESI†) with the two most populated being located on the cage face empty cage 1 or without TEMPO showed no or only very little
with the largest N–Cu–N bond angle. The obtained crystallo- formation of 9 (maximum yield = 1%; entries 6 to 8). These
graphic data shows four possible positions for two diethylether results show that [1-Cu]BF4 is capable of oxidising organic
molecules (see ESI†). Three of these are inside the cage cavity. substrates at room temperature in a catalytic fashion via
Hydrogen bonding interactions are observed between the cage employing oxygen as terminal oxidant. For the transformation
ꢁ
N–H moieties and the ether and the SbF
6
anion as acceptors.
of 8 to 9 the catalytic performance of [1-Cu]BF is comparable to
4
We next studied the ability of [1-Cu]BF
4
to catalyse the other copper based systems. Using 6 in the presence of three
oxidation of organic substrates. We chose the oxidation of equivalents of N-methylimidazole (NMI) gave 9 in 37% yield
1
9
0
-methoxybenzyl alcohol (8) to 4-anisaldehyde (9) with catalytic (entry 9), while Cu(MeCN) OTf (10) with 2,2 -bipyridine (bipy)
4
4
1
8
amounts of TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxyl in and N-methylimidazole gave 39% yield (entry 10).
a DCM/water mixture under aerobic conditions as model
reaction (Table 1). Performing the reaction for 1.5 h resulted discriminate between substrates in competition experiments,
We were wondering if [1-Cu]BF4 may have the ability to
1
8
in 7 turnovers (entry 1), while overnight reaction time led to 11 especially compared to 6ꢂ3(NMI) and 10ꢂ(bipy)ꢂ2(NMI). When a
turnovers (entry 2). Increasing [1-Cu]BF loading to 10 mol% 1 : 1 mixture of 3,5-di-methylbenzyl alcohol and 3,5-di-tert-butyl-
4
resulted in 88% yield (entry 3), while increasing the substrate benzyl alcohol was reacted with 1 mol% [1-Cu]BF and 7 mol%
4
concentration to 0.50 M resulted in 28% yield (entry 4). TEMPO the overall yield was 6% with a selectivity of 59 : 41 for
Performing the reaction in absence of [1-Cu]BF
4
gave only the smaller substrate (Table 2, entry 1), whereas 6ꢂ3(NMI)
preferably oxidises the larger 3,5-di-tert-butyl-benzyl alcohol
with a selectivity of 42 : 58 (entry 2). 10ꢂ(bipy)ꢂ2(NMI) shows
with 52 : 48 no preference (entry 3). Changing the smaller
substrate to benzyl alcohol resulted in a comparable yield
and a selectivity of 67 : 33 (entry 4). Again, the other two tested
systems showed with 55 : 45 and 52 : 48 a smaller preference for
the smaller substrate. Additional competition experiments of
a
4
Table 1 [1-Cu]BF -catalysed oxidation of 8 to 9
Entry
Catalyst ([mol%])
Yield [%]
t [h]
substrate pairs where the steric demand is further remote of the
1
2
3
[1-Cu]BF
[1-Cu]BF
[1-Cu]BF
[1-Cu]BF
None
6 (1)
1 (1)
4
4
4
4
(1)
(1)
(10)
(1)
7
1.5 functional group and electronic differences are likely to be the
11
88
28
o1
1
14
cause of selectivity can be found in the ESI.† Although the effect
16
b
is not too pronounced, these preliminary results show that
there is a trend that [1-Cu]BF preferably catalyses the conversion
of the smaller substrate.
4
14
14
14
14
14
14
14
5
6
7
4
0
c
In conclusion, we have synthesised an organic cage whose
endo-functionalised cavity offers three imidazole units. These
can coordinate to copper(I), assembling a motif as it is observed
8
[1-Cu]BF
4
(1)
o1
37
39
b
9
6ꢂ3(NMI) (1)
b
1
0
10ꢂ(bipy)ꢂ2(NMI) (1)
a
Substrate concentration = 0.11 M; all reactions under air; 7 mol% in the active sites of many oxygenases. This complex is the first
1
2
TEMPO; 11.1 equiv. H O rt; all yields were determined by H NMR spectro-
example of an imidazole employing mimic of non-heme enzymatic
active sites offering histidine coordination that is assembled in the
cavity of a molecular cage. We used a protocol based on catalytic
scopy of the crude product mixtures in presence of internal standards.
b
c
Substrate concentration = 0.50 M. Without TEMPO. NMI = N-methyl-
0
imidazole. bipy = 2,2 -bipyridine.
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aldehydes under aerobic conditions. The terminal oxidant in
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M. O. thanks the Deutsche Forschungsgemeinschaft (DFG,
German Research Foundation) – OT 540/2-1 and the Fonds der
Chemischen Industrie for funding. Prof. Dr Sven Schneider is
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Conflicts of interest
There are no conflicts to declare.
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