Aerobic C?H Hydroxylation by Copper Imine Complexes: The Clip-and-Cleave Concept – Versatility and Limits

Article abstract of DOI:10.1002/ejic.202100185

The intramolecular ligand hydroxylation of a series of copper(I) imine complexes during their reaction with dioxygen had been systematically studied. The so-called clip-and-cleave concept offers a facile way to oxygenate aldehydes or ketones. A copper(I)

Full text of DOI:10.1002/ejic.202100185

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Aerobic CÀ H Hydroxylation by Copper Imine Complexes:
The Clip-and-Cleave Concept – Versatility and Limits
Pascal Specht,[a] Alexander Petrillo,[a] Jonathan Becker,[a] and Siegfried Schindler*[a]
The intramolecular ligand hydroxylation of a series of copper(I)
imine complexes during their reaction with dioxygen had been
systematically studied. The so-called clip-and-cleave concept
offers a facile way to oxygenate aldehydes or ketones. A
copper(I) complex for example, with an imine ligand derived
from an ethylenediamine derivative and cyclohexanone was
oxidized. Decomposing the complex after the reaction with
hydrochloric acid showed a 50% conversion of the cyclo-
hexanone to 2-hydroxycylohexanone. Depending on the ligand
system, three different reaction pathways have been identified
that can cause hydroxylation reactions. While the radical based
mechanisms are more difficult to identify, the reactions that go
through a copper bis(μ-oxido) complex as active species can be
analyzed by low temperature stopped-flow techniques. In an
ideal case the formation and decomposition of this reactive
intermediate can be spectroscopically observed. It was shown
that this depends strongly on the ligand system: steric effects,
chelate ring size and coordination number play an important
role for the mechanism and the outcome of the reaction.
Introduction
Copper monooxygenases such as e.g. tyrosinase or methane
monooxygenase are important enzymes for the oxygenation of
organic substrates (tyrosine to l-DOPA and methane to
methanol).[1] Besides the interest in a better understanding of
the biological function, these enzymes demonstrate that it is
possible to perform selective oxidation reactions under ambient
conditions (aqueous solutions, room temperature) using dioxy-
gen from air as the sole oxidant.[2] Due to the importance of
catalytic selective oxidation reactions in industry,[3] low molec-
ular weight complexes have been “designed” to model the
reactivity of the copper enzymes.[4,5]
In that regard we recently developed a so called “clip-and-
cleave” system that allows stoichiometric CÀ H hydroxylation in
the γ-position of aromatic and aliphatic aldehydes utilizing a
copper imine complex system,[6,7] similar to the initial oxygen-
ation step of tyrosinase, which catalyzes the ortho-hydroxylation
of L-tyrosine to l-DOPA prior to the further oxidation to l-DOPA
quinone in melanin biosynthesis.[8] In contrast to our previous
work, the nomenclature has been adapted to the nomenclature
of Garcia-Bosch and co-workers for the carbon that is
hydroxylated.[9] In Scheme 1 the general reaction mechanism is
presented using benzaldehyde as a substrate. In a first step the
Scheme 1. Intramolecular hydroxylation of [CuI(1)]+ complex (R=Et) with
dioxygen. The hydroxylation proceeds via a copper bis(μ-oxido)
intermediate.[6]
imine ligand is prepared, here from benzaldehyde and N,N-
diethylethylenediamine, leading to N’-benzylidene-N,N-diethyle-
thylenediamine (BDED, 1). BDED was then reacted with a
copper(I) salt e.g. [Cu(CH3CN)4]OTf, to form the copper(I)
complex [Cu(1)]OTf in situ (most likely one or two CH3CN
molecules are coordinated as ligands additionally). Reaction
with dioxygen caused formation of a copper bis(μ-oxido)
complex as an intermediate followed by intramolecular ligand
hydroxylation. Yields of salicylaldehyde were close to the
limiting 50% (theoretical maximum yield in this reaction)[6,7] and
the formation and decomposition of the intermediate, the
copper bis(μ-oxido) complex, could be followed spectroscopi-
cally by low temperature stopped-flow measurements. Copper
bis(μ-oxido) complexes have been investigated in great detail
during the last years with regard to ligand variation, reaction
conditions etc.[5,10]
[a] P. Specht, A. Petrillo, Dr. J. Becker, Prof. Dr. S. Schindler
Institut für Anorganische und Analytische Chemie
Justus-Liebig-Universität Gießen
Heinrich-Buff-Ring 17, 35392 Gießen, Germany
E-mail: siegfried.schindler@anorg.chemie.uni-giessen.de
https://www.uni-giessen.de/fbz/fb08/Inst/iaac/schindler
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejic.202100185
© 2021 The Authors. European Journal of Inorganic Chemistry published by
Wiley-VCH GmbH. This is an open access article under the terms of the
Creative Commons Attribution Non-Commercial License, which permits use,
distribution and reproduction in any medium, provided the original work is
properly cited and is not used for commercial purposes.
More recently an excellent extensive study on intramolecu-
lar ligand hydroxylation was reported by Garcia-Bosch and co-
workers, using camphor derivatives and steroids as
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substrates.[11] This work is based on results obtained earlier by
complex [Cu(1)2]X (X=different anions) is easily formed leading
herewith to complete suppression of the hydroxylation reac-
tion. Often these complexes exhibit a more intensive color and
furthermore decreased solubility. Figure 1 shows the difference
between solutions containing [Cu(1)]OTf and [Cu(1)2]OTf in
acetone.
Schönecker and later by Baran and co-workers.[12–15] In contrast
to the mechanism described above (Scheme 1), they did not
observe formation of a copper bis(μ-oxido) complex at all. Their
detailed kinetic analysis showed that for these reactions
obviously a different mechanism takes place.[9,11] Their proposed
reaction mechanism for the hydroxylation of sp2 CÀ H bonds is
presented in Scheme 2. Here, using imino pyridine ligands, they
assigned a hydroperoxido complex (LCuII(OOH)) as active
species. By optimizing the reaction conditions, they were able
to achieve yields close to 100% of hydroxylated product.
With regard to the importance of selective oxidation
reactions we were interested to learn more about the
occurrence of the two different mechanisms and investigated
these reactions in more detail.
To avoid this problem, it was decided to modify the ligand
system e.g. by introducing sterically more demanding, bulkier
groups into the ethylenediamine unit. Therefore, the ligands L
presented in Scheme 3 were prepared. Furthermore, due to the
fact that the formation of the [Cu(L)2]OTf complex is also
depending on the solvent used, the influence of different
solvents was tested. While being used successfully in the past,
acetonitrile (or propionitrile) and methanol had to be excluded
for our studies because no hydroxylation reaction was observed
using these two solvents. Methanol can be a problem because
it is a protic solvent, thus leading to decomposition of
intermediates prior to a reaction with the ligand and nitrile
solvents might suppress any further reaction because nitriles
coordinate strongly to the copper(I) ion (blocking it against
dioxygen activation).[17] Acetone so far proved to be the best
solvent for the investigations described herein, however it was
also possible to use dichloromethane, despite some problems
described earlier (low yield and ligand decomposition at low
temperatures), that can occur with this solvent.[6]
Ligands 1 to 7 were investigated under the same conditions
that were applied previously for the hydroxylation reaction
using [Cu(1)]OTf. The results obtained according to Scheme 1
are presented in Table 1 together with the original findings for
this complex (entry 1) for which a ligand conversion to the
hydroxylated product, salicylaldehyde, of almost 50% were
achieved. In our new measurements we had some more
problems with the precipitation of a yellow/orange solid
discussed above in combination with some formation of
Results and Discussion
Influence of solvent and ligand backbone
Many of the reactions leading to selective oxygenation
reactions rely on the formation of a mononuclear copper
complex in a 1:1 ratio of copper(I):ligand.[6,7,9,11,16] However,
when ligands are utilized that do not provide necessary
sterically features/hindrance a strong tendency is observed that
a complex in a copper(I) to ligand ratio of 1:2 forms. These
complexes often are nearly unreactive towards dioxygen. This
problem was observed for the copper BDED system described
above as well.[6] Depending on the conditions, the unreactive
Scheme 2. Proposed mechanism for the intramolecular hydroxylation of
sp2CÀ H bond. Redrawn from Trammell et al.[11]
Figure 1. (A) The 1:1 [Cu:L] complex [Cu(1)]OTf in acetone and (B) the 1:2
[Cu:L2] complex [Cu(1)2]OTf in acetone.
Scheme 3. Ligands used in this study: BDED (1), BDiPED (2), BDPD (3), BTED
(4), BTPD (5), BEP, (6) and BMP (7).
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solvents under our conditions. Still, it is possible to achieve a
Table 1. Conversion of the substrate into hydroxylated products using
ligands 1–7 (Scheme 3) with benzaldehyde as substrate.
conversion of up to 50% with both ligands 1 (entry 1 in Table 1)
and 2 but it is obviously more difficult with 1. Furthermore,
despite the slightly higher conversion in acetone, small
amounts of diisopropylamine were again detected, indicating
that dichloromethane is the better solvent to perform these
reactions.
However, quite surprisingly and despite the structural
similarity of 2 with 1, no copper bis(μ-oxido) complex could be
spectroscopically detected as an intermediate during the
reaction of its copper(I) complex with dioxygen (see Supporting
Information). Two possibilities could account for that: a) if the
formation of the copper bis(μ-oxido) complex (or another
“dioxygen adduct” complex) is rate determining then consec-
utive hydroxylation is fast and there is no chance to observe
the intermediate or b) hydroxylation occurs according to the
mechanism proposed by Garcia-Bosch and co-workers
(Scheme 2).[11] From our data we cannot really say which of the
two cases is more likely here.
In contrast to the formation of a quite stable copper bis(μ-
oxido) complex with ligand 1, the sterically more demanding
isopropyl groups in 2 could lead to some shielding and thus
exclude formation of such a binuclear unit. To some extent this
is supported by the molecular structure of the copper(I)
complex [Cu(2)]Cl (Figure 2, crystallographic data are reported
in the Supporting Information and selected bond lengths and
angles are reported in Table 2) in which the two isopropyl
groups definitely require some space. This steric shielding
furthermore allowed us to crystallize this complex in a 1:1
copper to ligand ratio. With ligand 1 it only had been possible
to crystallize the 1:2 complex [Cu(1)2]SbF6.[6] In general, it is not
easy to crystallize and structurally characterize copper(I) com-
Entry
Ligand
Acetone[a]
Conversion [%]
Dichloromethane
1[b]
2[c]
3
4
5
BDED (1)
BDED (1)
BDiPED (2)
BDPD (3)
BTED (4)
BTPD (5)
BEP (6)
Close to 50
–
34
45
0
0
0
33
41
0
0
0
6
7
5
8
8
BMP (7)
5
3
[a] Traces of diisopropylamine after hydroxylation experiment detected. [b]
J. Becker et al.[6] [c] Reproduced results of Entry 1.
diisopropylamine in acetone. Nevertheless, hydroxylation con-
versions of 34% in acetone and 33% in dichloromethane were
observed. The occurrence of diisopropylamine had been
puzzling at first, however it can be explained by a reaction with
the solvent acetone according to the mechanism presented in
Figure S53 (see Supporting Information). In an imine equili-
brium free benzaldehyde can react with acetone followed by a
1,3-H-shift. Cleavage of the imine allows the reaction with a
second acetone molecule and through a hydride transfer,
similar to a Cannizzaro type reaction, diisopropylamine is
formed. The additionally formed side products were most likely
extracted during the aqueous work-up and therefore could not
be detected in GC-MS measurements.
A look at Table 1 immediately shows two important aspects
that are essential for the intramolecular ligand hydroxylation
under these conditions:
1.) Here “wrong” chelate ring sizes seem to completely
suppress ligand hydroxylation. With ligand 3 a six-mem-
bered chelate ring size is achieved in contrast to ligand 1
and 2 that form 5-membered chelate rings. Six-membered
chelate rings are well known to often stabilize copper(I)
complexes better and that might be one of the reasons for
the completely suppressed hydroxylation reaction.[18] How-
ever, this is not generally the case because hydroxylation
reactions also can be observed with copper(I) complexes
with ligands in six-membered chelate rings.[19]
2.) Independent of chelate ring sizes it seems that tridentate
ligands such as e.g. 4 and 5 are not suitable here as well.
For copper(I) complexes with these ligands no hydroxyla-
tion was observed at all. Our intention to avoid formation of
[Cu(L)2]X complexes by using tridentate ligands obviously
was counterproductive. Most likely a bidentate ligand is
necessary (at least in our reactions) to keep the coordina-
tion sites open for their reactivity towards hydroxylation.
Further investigations with these two ligands were not
carried out due to the lack of a hydroxylation reaction as
well as due to the high cost and time-consuming prepara-
tion of the reactants for ligand syntheses.
Figure 2. ORTEP plot of molecular structure of [Cu(2)Cl]. Hydrogen atoms are
omitted for clarity. Anisotropic displacement ellipsoids set to 50% proba-
bility.
°
Table 2. Selected bond length [Å] and angles [ ] for complex [Cu(2)Cl]
(Figure 2).
Cu(1)À N(1)
Cu(1)À Cl(1)
Cu(1)À N(2)
Cu(1)À Coxid
1.9415(9)
2.1577(3)
2.3727(9)
3.263(1)
N(1)À Cu(1)À Cl(1)
N(1)À Cu(1)À N(2)
Cl(1)À Cu(1)À N(2)
Dihedral angle[a]
153.44(3)
84.09(3)
122.17(2)
158.8
Our approach to introduce more bulky groups to suppress
the 1:2 copper:ligand formation was valid because copper(I)
complexes with ligand 2 showed higher hydroxylation con-
versions in comparison to complexes with ligand 1 in both
[a] Coxid.À Cu(1)À N(2) angle.
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plexes of this type. Therefore, chloride or iodide as co-ligands
Cyclohexane is an important basic chemical in industry, e.g.
for the manufacturing of polymers such as 6,6 nylon where it is
oxidized in a first reaction sequence to cyclohexanol and
cyclohexanone. With regard to this, new possibilities for the
derivatization of cyclohexane could become interesting. There-
fore, experiments with cyclohexane derivatives, cyclohexane
carboxaldehyde as well as cyclopentane carboxaldehyde and
cyclohexanone (see further below) were carried out to expand
the range of substrates and to investigate reaction parameters
for possible selective hydroxylation reactions. Ligands 8, 9, 10
and 11 (Scheme 4) were synthesized in good yields and applied
in analogy to the aromatic systems described above. However,
in contrast to these systems investigations with the ligands 8, 9,
10 and 11 turned out to be much more problematic.
While the copper(I) complex with ligand 11 did not seem to
react at all with dioxygen copper(I) complexes with ligands 8, 9
and 10 at least showed some reactivity. However, GC-MS results
of the product mixtures only showed cyclohexane carboxalde-
hyde (the substrate) while the expected product, 2-hydroxycy-
clohexane-1-carboxaldehyde was not detected at all. Instead,
formation of some other products was observed which could
not be identified so far. Most likely this is caused by
decomposition reactions during the oxidation process, either
directly or of the hydroxylated product (if it actually was formed
in the process). Aspects that control CÀ C cleavage versus CÀ H
bond hydroxylation by copper complexes was previously
discussed by Schoenebeck and co-workers.[23]
Efforts to crystallize copper(I) complexes with ligands 8, 9,
10 and 11 only were successful with ligand 9 and chloride as a
co-ligand. However, in contrast to our expectations that [Cu(9)
Cl] would be obtained, the molecular structure revealed that
[Cu(9)2][CuCl2] formed instead (Figure 3, crystallographic data
are reported in the Supporting Information).
Despite the fact that the molecular structure in the solid
state might not represent the actual molecule in solution, it
gives an idea why no hydroxylation reaction was observed. A
chelate complex, necessary at least for the formation of a
copper bis(μ-oxido) complex, obviously is avoided.
have been used.[20]
[Cu(2)]Cl shows a trigonal coordination of copper by the
imine and amine nitrogen atoms and chloride. Whether the
amine-copper bond is a strong coordinative bond is worth
discussing, since the bond length is relatively long. The copper-
amine nitrogen distance is 2.3727(9) Å, whereas the distance
between imine nitrogen and copper is 1.9415(9) Å. In the
copper(I) BDED complex, the largest distance between nitrogen
and copper is 2.239(3) Å. CuÀ N amine distances higher than
2.37 Å are less common, nevertheless, similar bond lengths
were determined with structurally very similar ligands and also
the CuÀ N imine distances fit very well.[21]
Only low reactivity was achieved with ligands 6 and 7
(entry 7 and 8 in Table 1). Here a pyridyl group with an ethylene
respectively a methylene bridge was introduced instead of the
ethylene diamine backbone. The conversion is well below that
of 1 and 2, however, See et al. have shown that higher yields
with copper(I) complexes with this type of imino pyridine
functionalized ligands (steroids) were possible under slightly
different reaction conditions.[15] We also tried to apply these
reaction conditions, using a reducing agent and dioxygen as
oxidant, but instead of a clean hydroxylation reaction with high
yields we observed overoxidation of the aromatic substrate and
the formation of various by-products.
Recently, Trammell et al. reported the molecular structure of
the copper(I) complex with 7 as a ligand ([(7)Cu(CH3CN)]PF6).[9]
The complex shows a trigonal planar coordination geometry
which is comparable to the molecular structure of the copper(I)-
2 complex with chloride (Figure 2). Within estimated standard
°
deviation there is no difference of the NÀ CuÀ N angles (84.09(3)
°
vs. 84.4(4) ). Also, the CuÀ Coxid. distance is very similar
(3.263(1) Å vs. 3.243(13) Å), only the dihedral angle (Coxid.À CuÀ N)
°
°
is slightly more angled (158.8 vs. 178.8 ) in case of the
copper(I)-2 complex.
The hydroxylation of benzaldehyde with this complex was
performed using hydrogen peroxide instead of dioxygen. In
comparison with their other investigated systems the conver-
sion of 39% was quite low but still significantly higher than in
our experiment with dioxygen (entry 8 in Table 1). Stopped-
flow measurements of the reaction of dioxygen with the
copper(I) complexes with the ligands 6 and 7 did not indicate
the formation of a “dioxygen adduct” complex as an intermedi-
ate and only showed a slow oxidation to corresponding
copper(II) complexes.
In addition, it was tried to obtain single crystals of the
corresponding copper(II) complexes with ligands 8, 9, 10 and
11. Again, we only succeeded with ligand 9 by reacting it with
copper(II) chloride dihydrate in either acetone or in acetonitrile.
Aliphatic hydroxylation
A particular challenge is the hydroxylation of aliphatic sub-
strates (non-activated CÀ H bonds), which already has been
described by Réglier et al.[22] In comparison to a selective
aromatic hydroxylation, very few examples for selective
aliphatic hydroxylations are known in the literature. Based on
the BDED ligand, Becker et al. reported the selective hydrox-
ylation of trimethylacetaldehyde, an adamantane carboxalde-
hyde as well as of an diadamantane-1-carboxaldeyde.[7]
Scheme 4. Ligands CyDED (8), CyDiPED (9) and CyMPy (10), substrate:
cyclohexane carboxaldehyde and ligand CypMPy (11), substrate: cyclo-
pentane carboxaldehyde.
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given in the references)[24] and according to these previous
results we propose the mechanism presented in Scheme 5 for
this hydroxylation reaction.
In a first step deprotonation at the β-position of the ligand
leads to formation of an enamine. The CuII enamine complex is
in resonance with a CuI complex coordinated by a radical
ligand. The CuI is oxidized by oxygen from air to CuII. The
resulting complex is again in resonance with a CuI complex that
is coordinated by a positively charged ligand. The last steps are
a nucleophilic attack of a hydroxide anion in the β-position,
subsequent deprotonation of the alcohol and coordination to
the copper center.
Unfortunately, so far, we did not find a way to perform this
reaction efficiently to allow the synthesis of 1-hydroxycyclohex-
ane-1-carboxaldehyde by removing the copper ions similar to
the synthesis of salicylaldehyde in Scheme 1. While this reaction
definitely has to be investigated further it presents a third
possible mechanism for copper-mediated hydroxylation of
organic substrates that is promising with regard to an
alternative facile way for further oxygenation reactions.
Furthermore, this reaction also can give a hint, why the
expected reaction of a β-hydroxylation with a copper(I) complex
and oxygen (see general hydroxylation procedure) does not
result in the expected product. In contrast to all the other
aliphatic substrates, which can be hydroxylated with a BDED
based ligand system, the substrates do not have a hydrogen at
the β-carbon (e.g. adamantane carboxaldehyde or trimeth-
ylacetaldehyde).
Figure 3. ORTEP plot of the molecular structure of [Cu(9)2][CuCl2]. Hydrogen
atoms are omitted for clarity. Anisotropic displacement ellipsoids set to 50%
probability.
Dark green crystals were obtained in both solvents after a few
days with the same orthorhombic unit cell. The molecular
structure of the complex [Cu2(OÀ CyDiPED)2Cl2] that crystallized
in the orthorhombic space group Pba2 in a 2:2 copper to
ligand ratio with two coordinated chloride anions is presented
in Figure 4 (crystallographic data are reported in the Supporting
Information and selected bond lengths and angles are reported
in Table 3).
This result is surprising in so far, that obviously a β-
hydroxylation of the ligand had occurred under ambient
conditions (presence of air and moisture) during the crystal-
lization process. Reactions of copper(II) complexes with dioxy-
gen and water are well known (a few selected examples are
To investigate this further and by avoiding this kind of β-
hydroxylation we switched from cyclohexane carboxaldehyde
to cyclohexanone as a substrate. Therefore, ligands 12, 13, 14
and 15 were synthesized (Scheme 6). It turned out that the
synthesis of these imine ligands starting from a ketone as a
substrate are much more difficult than expected. The imine
condensation could not be performed under the same mild
conditions as described for the ligands above: reaction temper-
ature needed to be elevated, a change of solvent was
necessary, and p-toluene sulfonic acid was added in catalytic
amounts. Furthermore, it turned out that these imine ligands
Figure 4. ORTEP plot of molecular structure of [Cu2(OÀ CyDiPED)2Cl2]. Hydro-
gen atoms are omitted for clarity. Anisotropic displacement ellipsoids set to
50% probability.
°
Table 3. Selected bond length [Å] and angles [ ] for complex [Cu2(O-9)2Cl2]
(Figure 4).
Cu(1)À O(1)#1
Cu(1)À Cl(1)
Cu(1)À N(4)
1.921(3)
1.925(3)
1.977(3)
2.2185(11)
3.0274(9)
O(1)#1À Cu(1)À O(1)
O(1)#1À Cu(1)À Cu(1)#1
O(1)#1À Cu(1)À N(4)
O(1)À Cu(1)À N(4)
76.15(12)
38.13(8)
81.78(12)
157.78(13)
176.98(17)
102.79(8)
Cu(1)À Cl(5)
Cu(1)À Cu(1)#1
O(1)#1À Cu(1)À Cl(5)
O(1)À Cu(1)À Cl(5)
Scheme 5. Proposed mechanism for β-hydroxylation of 9 with copper(II).
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were extremely sensitive towards water which led to a back
reaction to the reactants despite applying a drying agent. Thus,
working under inert conditions together with a drying agent
was essential to prepare these ligands. Furthermore, all ligands
were purified by “Kugelrohr” distillation. Caused by these
problems, only decent yields of all four of these ligands were
obtained.
With ligands 14 and 15 we succeeded in crystallizing the
corresponding copper(I) complexes that turned out to be quite
different with regard to their molecular structures. The
binuclear complex [Cu2(14)2](OTf)2 in which two copper(I) are
bridging two ligands is shown in Figure 5 (Crystallographic data
are reported in the Supporting Information and selected bond
lengths and angles in Table 4).
In contrast, the copper(I) complex with ligand 15 crystallized
as expected. The molecular structure of the cation of [Cu-
(15)(MeCN)]OTf is presented in Figure 6 (Crystallographic data
are reported in the Supporting Information). The molecular
structure shows the same trigonal planar coordination geome-
try of copper(I) which was also observed with similar ligands
(see Figure 2 and Trammel et al. 2019).[9] The NÀ CuÀ N angle is
Scheme 6. Ligands CyonDED (12), CyonDiPED (13), CyonEPy (14), and
CyonMPy (15), bottom: hydroxylated product 2-hydroxycyclohexanone.
°
very similar with 84.01 (average of both angles), the dihedral
°
angle 178.5 and the CuÀ Coxid. distance is 3.267 Å and has a
comparable length towards the other molecular structures.
Despite the problems with the ligand handling described
above, no changes were necessary for the experiments of the
intramolecular ligand hydroxylation and they could be carried
out according to our general procedure in acetone and
dichloromethane. The hydroxylation of the substrate cyclo-
hexanone to 2-hydroxycyclohexanone (Scheme 6) could be
carried out successfully with the copper(I) complexes of all four
ligands and conversions are presented in Table 5.
Figure 5. ORTEP plot of molecular structure of [Cu2(14)2](OTf)2. Hydrogen
atoms and counter ions are omitted for clarity. Anisotropic displacement
ellipsoids set to 50% probability.
It was observed that with imine amine-based ligands 12
and 13 higher conversion to the hydroxylated product (close to
the limiting 50% if a copper bis(μ-oxido) complex is the reactive
intermediate; see below under kinetic measurements) were
achieved in comparison with the imino pyridyl ligands (14 and
15). Furthermore, acetone turned out to be the better solvent
compared to conversions in dichloromethane. Again, as dis-
cussed above, diisopropylamine was detected after the hydrox-
ylation reaction in acetone (as well as some other small
amounts of by-products).
°
Table 4. Selected bond length [Å] and angles [ ] for complex
[Cu2(14)2](OTf)2 (Figure 5).
Cu(1)À N(2)
1.9074(12)
1.9164(13)
3.284
N(2)À Cu(1)À N(1)#1
172.95(5)
Cu(1)À N(1)#1
Cu(1)À Cu(1)#1
So far, we did not manage to obtain 2-hydroxycyclohex-
anone in pure form from the reaction mixtures. Therefore,
trying to increase the conversion/yield, hydroxylation experi-
Table 5. Conversion of the substrate into hydroxylated products using
ligands 12–15 with cyclohexanone as substrate.
Entry
Ligand
Acetone[a]
Conversion/%
Dichloromethane
1
2
3
4
CyonDED (12)
CyonDiPED (13)
CyonEPy (14)
CyonMPy (15)
47
35
21
7
46
22[b]
16
3[b]
Figure 6. ORTEP plot of the molecular structure of the cation of [Cu-
(15)(MeCN)]OTf. Hydrogen atoms are omitted for clarity. Anisotropic
displacement ellipsoids set to 50% probability.
[a] Traces of diisopropylamine detected. [b] Blue precipitate after oxygen
treatment.
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ments were performed with copper(II) complexes with 12 and
reported previously for the hydroxylation of trimeth-
ylacetaldehyde as a substrate.[7] The negative activation entropy
indicates an associative mechanism, the formation of a copper
superoxido complex as the rate-determining step and a fast
consecutive reaction to the copper bis(μ-oxido) complex.[16]
In contrast, during the reaction of dioxygen with the
copper(I) complex with ligand 13 in acetone (measurements in
dichloromethane were excluded due to disproportionation of
the complex), no copper bis(μ-oxido) complex as an intermedi-
ate was spectroscopically observed (see Supporting Informa-
tion). However, while the mechanism is not quite clear for the
reaction of the copper(I) complex with the ligand 2 as described
above, the situation is different here. The lack of reactivity of
the copper(II) complex with ligand 13 towards H2O2 speaks
against the hydroxylation mechanism described in
Scheme 2.[11,15] Instead and most likely here the formation of the
copper bis(μ-oxido) complex is rate determining while the
consecutive hydroxylation is fast and therefore does not allow
to observe the intermediate.
13 as ligands and hydrogen peroxide as the oxidant according
to the reaction conditions reported by Trammell et al.[4,11]
However, in both cases only the non-hydroxylated substrate,
cyclohexanone, could be detected and no conversion to a
hydroxylated product was observed. This is particularly interest-
ing with regard to our observations by UV-vis spectroscopy (see
kinetic investigations below).
Kinetic investigations
The reaction of dioxygen with the copper(I) complexes with
ligands 12 and 13 in acetone and dichloromethane was
investigated with low temperature stopped-flow measure-
ments.
The reaction of dioxygen with the copper(I) complex with
ligand 12 is very fast in both solvents. Time resolved spectra at
°
À 93.0 C in acetone are shown in Figure 7. An absorbance
increase is observed with maxima at 405 nm and at 490 nm.
The spectrum fits perfectly well to a copper bis(μ-oxido)
complex as an intermediate and is in line with our previous
No kinetic studies were performed with the copper(I)
complexes of ligands 14 and 15. Here the formation of a solid
during the reaction with dioxygen precluded the stopped-flow
measurements.
observations for the copper(I) complex with ligand
1
(Scheme 1).[6] The formation of this intermediate is complete in
about 7 s with a rate constant kobs =2·10À 3 sÀ 1 under these
conditions (calculated from the absorbance time trace shown as Conclusions
an inset in Figure 7). Analysis of the same reaction in dichloro-
methane gave the same result, however only half of the height
of the absorbance maxima was observed (see Supporting
Information). Therefore, a kinetic analysis herein is only reported
for the reaction in acetone.
Over time, different new findings have helped a lot to gain
better understanding of stoichiometric or catalytic oxygenation
reactions with copper complexes either in the active site of
enzymes or applied in form of their model complexes in the
lab. For a long time, it was thought that only ligands
preorganized for the formation of binuclear copper complexes
were suitable for these reactions, however, Tolman and co-
workers could demonstrate that this is not required and that
mononuclear copper complexes can self-organize themselves
to form a binuclear copper bis(μ-oxido) complex.[25] While the
ligand system by Tolman was excellent as proof of concept it
was not suitable for synthetic applications. By introducing our
clip-and-cleave concept it became possible to perform hydrox-
ylation reactions of different aldehydes and ketones.[6,7] We
believe that this concept has a great potential for future
applications due to the easy handling and the mild reaction
conditions. However, one of the problems that comes with this
approach is the formation of copper(I) complexes in a copper to
ligand ratio of 1:2 that can completely suppress the hydrox-
ylation reaction. Our systematic study on ligand modification to
avoid this (reported in here) showed how difficult it is to
optimize such a system. Furthermore, the formation of the
binuclear copper bis(μ-oxido) complex limits the maximum
yield of the hydroxylation to 50%. Based on earlier work by
Schönecker[12–14] with the same limitations Baran, Garcia-Bosch
and coworkers could increase the yields in their synthetic
applications on steroids close to 100% by applying an addi-
tional reducing agent (e.g. ascorbate) or working with copper
(II) complexes and hydrogen peroxide.[9,11,15] While it seemed
that this problem was solved we now could show that this only
Stopped-flow measurements in the temperature range
°
°
between À 94 C and À 55 C allowed to obtain activation
parameters of ΔH� = +24.2�0.2 kJmolÀ 1 and ΔS� =À 115�
1 JKÀ 1 molÀ 1, calculated from an Eyring plot (see Supporting
Information). These data are well in line with the results
Figure 7. Time resolved stopped-flow UV-vis spectra of the formation of
copper(I) bis(μ-oxido) complex with ligand 12 in acetone
(ccomplex =0.50·10À 3 molLÀ 1, cO2 =5.7·10À 3 molLÀ 1, after mixing) at À 93.0 C.
°
Inlay (time trace): Absorbance vs. time at 405 nm (black: experimental, red:
exponential fit).
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Semi-empirical absorption correction from equivalents was applied
might work if a radical mechanism takes place (as reported by
Trammell et al.)[11] but not if a copper bis(μ-oxido) complex is
formed. Furthermore, with two different mechanisms at place
for ligand hydroxylation we now would like to add a third
possible reaction pathway starting from simple copper(II)
complexes in the presence of air and moisture. While this type
of reaction is well known since a long time, to the best of our
knowledge it has not been really applied in the context of
selective ligand hydroxylation. Our results show how sensitive
the oxygenation reaction is towards small changes in the whole
system that can lead either (depending on the mechanism) to
β- or γ- hydroxylation of the substrate or completely suppress
the reaction. With the new findings we now hope to design a
system that would allow its application in synthetic chemistry.
Once such a complex system is identified it could be optimized
e.g. by immobilization (and chemical reactivation) or by
reactivating it through electrochemistry or photochemistry. Our
goal still remains to identify simple copper complexes that can
be used to selectively oxidize organic substrates in good yields
with dioxygen from air. That this is possible has been
demonstrated previously by Lumb and co-workers who showed
that they could catalytically oxidize phenols and derivatives
with dioxygen.[26]
using SADABS-2016/2[29] and the structures were solved by direct
methods using SHELXT2014/5.[30] Refinement was performed
against F2 on all data by full-matrix least squares using
SHELXL2018/3.[31] All non-hydrogen atoms were refined anisotropi-
cally and CÀ H hydrogen atoms were positioned at geometrically
calculated positions and refined using a riding model. The isotropic
displacement parameters of all hydrogen atoms were fixed to 1.2×
or 1.5× (CH3) the Ueq value of the atoms they are linked to.
Ligand syntheses
General procedure for the syntheses of ligands 1–15: The
substrate (aldehyde or ketone functionalized) and the ligand
backbone (amine functionalized) were dissolved in diethyl ether
and stirred over sodium sulfate for one hour at room temperature
and were kept for another hour under reflux. After the reaction
mixture was filtered the solvent was removed using a rotary
evaporator. Finally, the product was dried under oil pump vacuum.
The general procedure is based on the ligand synthesis of BDED (1)
published previously.[6] Amounts of reactants, yields, analyses and
notes (in case that ligand synthesis deviates from the general
procedure) are listed for each ligand in the supporting information.
Ligand hydroxylation
General procedure for ligand hydroxylation: Depending on the
ligand 1.00 mmol (1–3 and 6–15) or 0.10 mmol of ligand (4–5) were
dissolved in 5–10 ml solvent (absolute dichloromethane, acetone,
methanol or acetonitrile) and added to a solution of 377 mg
(1.00 mmol, for 1–3 and 6–15) or 37.7 mg (0.10 mmol, for 4–5)
[Cu(MeCN)4]OTf in 5–10 ml solvent in a Schlenk tube. Subsequently
dioxygen was passed through the solution for 15 min. For the
workup 10 ml hydrochloric acid (1 molLÀ 1) were added and stirred
for one hour at room temperature and additionally for one hour
under reflux. After cooling the organic solvent was removed and
the remaining reaction mixture extracted three times with dichloro-
methane. The combined organic phases were dried over sodium
sulfate, filtered and concentrated using a rotary evaporator for GC-
MS analysis. The conversion rate was estimated on the basis of the
integrals of the different fractions of hydroxylated product and
reactant.
Experimental Section
Materials and methods
Solvents and reagents used were of commercially available reagent
1
quality. 13C-NMR and H-NMR spectra were measured on a Bruker
Avance II 400 MHz and Avance III 400 MHz HD spectrometer.
Electrospray-ionization MS (ESI-MS) measurements were performed
on a Bruker micro-TOF mass spectrometer. All measurements under
inert conditions were carried out in argon or nitrogen atmosphere
by standard Schlenk techniques or working in a glove box (MBraun,
Garching, Germany). For these experiments extra dry solvents were
distilled under an argon atmosphere with a drying agent and
transferred into the glove box. For gas chromatography with
coupled mass spectrometry (GC-MS) a HP-GC 5890 Series II with
coupled HP 5972 Series mass detector and Agilent Technologies
5977B MSD with 7820 A GC system was used. For gas chromatog-
raphy (GC) a 5890 Series II GC was used. For low-temperature
stopped-flow measurements HI-TECH Scientific SF-61SX2 instru-
ment (TgK Scientific, Bratford on Avon, UK) was used. Setup and
kinetic measurements procedure were described in detail
previously.[27] Kinetic data were analysed with the integrated
software Kinetic Studio (Version 5.02 Beta, TgK Scientific). For the
reactions of copper(I) complex solutions with dioxygen a gastight
syringe was filled with argon saturated solvent and saturated with
dioxygen by bubbling a dioxygen stream through the solvent for
Low-temperature stopped-flow measurements
[Cu(CyonDED)]OTf with dioxygen in acetone: 96 mg (0.25 mmol)
[Cu(MeCN)4]OTf and 50 mg (0.25 mmol) CyonDED (12) were dis-
solved in 10 ml of absolute acetone. The solution was diluted to a
complex concentration of 0.50 mmolLÀ 1 and filled into a gastight
°
syringe. Measurements were performed between À 94 C and
°
À 55 C
[Cu(CyonDED)]OTf with dioxygen in dichloromethane: 107 mg
(0.283 mmol) [Cu(MeCN)4]OTf and 56 mg (0.28 mmol) CyonDED (12)
were dissolved in 10 ml absolute dichloromethane. The solution
was diluted to a complex concentration of 0.56 mmolLÀ 1 and filled
into a gastight syringe. Measurements were performed between
15 min
(cmax(O2)=11.44 mmolLÀ 1
in
acetone,
cmax(O2)=
11.08 mmolLÀ 1 in dichloromethane).[28] Due to the mixing of the
complex and dioxygen solutions in the stopped-flow instrument,
the maximum concentrations have to be divided by two resulting
in c(O2)=5.72 mmolLÀ 1 in acetone and c(O2)=5.54 mmolLÀ 1 in
dichloromethane. Diffraction data for all samples were collected at
low temperatures (100 K) using ϕ- and ω-scans on a BRUKER D8
Venture system equipped with dual IμS microfocus sources, a
PHOTON100 detector and an OXFORD CRYOSYSTEMS 700 low
°
°
À 93 C and À 39 C.
[Cu(CyonDiPED)]OTf with dioxygen in acetone: 92 mg (0.24 mmol)
[Cu(MeCN)4]OTf and 55 mg (0.24 mmol) CyonDiPED (13) were
dissolved in 10 ml absolute acetone. The solution was diluted to a
complex concentration of 0.96 mmolLÀ 1 and filled in a gastight
°
syringe. Measurements were performed between À 92 C and
temperature system. MoÀ Kα radiation with
a wavelength of
°
À 49 C.
0.71073 Å and a collimating Quazar multilayer mirror were used.
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[Cu(BDiPED)Cl]: 23 mg (0.10 mmol) BDiPED (2) and 9.9 mg
(0.10 mmol) copper(I) chloride were dissolved in acetonitrile each.
The ligand solution was added to the copper(I) salt solution
dropwise and stirred for about 30 min. After a few days at room
temperature crystals were obtained.
[Cu2(OÀ CyDiPED)2Cl2]: 119 mg (0.500 mmol) CyDiPED (9) and
85.2 mg (0.500 mmol) copper(II) chloride dihydrate were dissolved
in 3 ml acetone (or acetonitrile) each. Under stirring the ligand
solution was added to the copper(I) salt solution dropwise.
Subsequently a few drops of diethyl ether were added, and the
solution was stirred for 30 min. After three days at room temper-
ature dark green crystals were obtained. Crystals with the same
orthorhombic unit cell and molecular structure of the complex
were obtained, but the co-crystallized solvent was acetonitrile
instead of acetone.
[Cu(CyDiPED)2][CuCl2]: In a glovebox 119 mg (0.500 mmol) Cy-
DiPED (9) and 49.5 mg (0.500 mmol) copper(I) chloride were
dissolved in 3 ml dry acetonitrile (or dichloromethane) each. The
ligand solution was added to the copper(I) salt solution dropwise
and stirred for 30 min. After a few days at room temperature
crystals were obtained. Crystals with the same triclinic unit cell and
molecular structure of the complex were obtained, just with
dichloromethane instead of acetonitrile.
[Cu2(CyonEPy)2](OTf)2: 20.2 mg (0.100 mmol) CyonEPy (14) and
37.7 mg (0.100 mmol) [Cu(MeCN)4]OTf were dissolved in THF each.
The ligand solution was added to the copper(I) salt solution
dropwise and stirred for about 30 min. After a few days at room
temperature crystals were obtained.
[Cu(CyonMPy)(MeCN)]OTf: 18.8 mg (0.100 mmol) CyonMPy (15)
and 37.7 mg (0.100 mmol) [Cu(MeCN)4]OTf were dissolved in
methanol each. The ligand solution was added to the copper(I) salt
solution dropwise and stirred for about 15 min. After a few days at
room temperature colourless crystals were obtained.
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Deposition Numbers 2050690 (for [Cu(2)Cl]), 2050691 (for [Cu-
(9)2][CuCl2]), 2050692 (for [Cu2(14)2](OTf)2), 2050693 (for [Cu-
(15)(MeCN)]OTf), and 2050694 (for [Cu2(O-9)2Cl2) contain the
supplementary crystallographic data for this paper. These data are
provided free of charge by the joint Cambridge Crystallographic
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Open access funding enabled and organized by Projekt DEAL.
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Conflict of Interest
[23] A. S.-K. Tsang, A. Kapat, F. Schoenebeck, J. Am. Chem. Soc. 2016, 138,
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The authors declare no conflict of interest.
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FULL PAPERS
Copper(I) complexes with various
bidentate imine ligands were reacted
with dioxygen, which caused
selective intramolecular hydroxyla-
tion reactions. In some cases, the
copper bis(μ-oxido) complexes could
be observed as intermediates by UV-
vis spectroscopy and kinetic investi-
gations were carried out.
P. Specht, A. Petrillo, Dr. J. Becker,
Prof. Dr. S. Schindler*
1 – 11
Aerobic CÀ H Hydroxylation by
Copper Imine Complexes: The Clip-
and-Cleave Concept – Versatility
and Limits