Cu(II)-nitroxyl radicals as catalytic galactose oxidase mimics.

Article abstract of DOI:10.1039/b305941c

Results from Hammett correlation studies and primary kinetic isotope effects for the CuCl-TEMPO catalysed aerobic benzyl alcohol oxidations are inconsistent with an oxoammonium based mechanism. We postulate a copper-mediated dehydrogenation mechanism, in which TEMPO regenerates the active Cu(II)-species. This mechanism is analogous to that observed for Galactose Oxidase and mimics thereof.

Full text of DOI:10.1039/b305941c

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Cu(II)-nitroxyl radicals as catalytic galactose oxidase mimics
Arné Dijksman, Isabel W. C. E. Arends and Roger A. Sheldon*
Laboratory for Biocatalysis and Organic Chemistry, Department of Biotechnology,
Delft University of Technology, Julianalaan 136, 2628 BL Delft, The Netherlands
Received 28th May 2003, Accepted 24th July 2003
First published as an Advance Article on the web 8th August 2003
Results from Hammett correlation studies and primary kinetic isotope effects for the CuCl–TEMPO catalysed
aerobic benzyl alcohol oxidations are inconsistent with an oxoammonium based mechanism. We postulate a
copper-mediated dehydrogenation mechanism, in which TEMPO regenerates the active Cu()-species.
This mechanism is analogous to that observed for Galactose Oxidase and mimics thereof.
Fukuzumi.11 For example, Stack’s [Cu()BSP], where BSP is
Introduction
a salen-ligand with a binaphthyl backbone (Fig. 1), is able to
catalyse the aerobic oxidation of activated (benzylic and allylic)
alcohols.7 The rate determining step of this system was sug-
gested to involve inner sphere one-electron transfer from the
alkoxide ligand to Cu() followed by hydrogen-transfer to the
phenoxyl radical yielding Cu(), phenol and carbonyl product.
Similarly, Wieghardt et al. reported a dinuclear Cu()-phenoxyl
complex which proved to be effective for the aerobic oxidation
of non-activated (aliphatic) alcohols as well.9
Another system, which bears a superficial resemblance to the
galactose oxidase, is the CuCl–TEMPO system first reported by
Semmelhack and coworkers.12–14 The combination of CuCl and
the stable nitroxyl radical, TEMPO (2,2,6,6-tetramethylpiper-
idinyloxy) is able to catalyse the aerobic oxidation of alcohols
to the corresponding carbonyl compounds. A mechanism
was proposed12 in which one-electron oxidation of TEMPO by
Cu() afforded the oxoammonium cation (Fig. 2). The latter
oxidizes the alcohol substrate and is itself reduced to the corre-
sponding hydroxylamine, TEMPOH. Re-oxidation of the latter,
presumably via TEMPO, completes the catalytic cycle.
The selective oxidation of alcohols into their corresponding
aldehydes and ketones is a pivotal reaction in organic syn-
thesis.1 Traditionally, alcohol oxidations are performed with
stoichiometric amounts of inorganic oxidants, notably chrom-
ium() reagents.2 These – often hazardous or toxic – oxidising
agents are not only relatively expensive, but they also generate
copious amounts of heavy-metal waste. From both an eco-
nomic and environmental point of view, the development of
effective catalytic oxidation processes that simply use oxygen
(or air) as the ultimate stoichiometric oxidant, i.e. a “green
method” for converting alcohols to carbonyl compounds on an
industrial scale, remains an important challenge.3,4
One approach to developing better catalysts is to mimic the
enzymes that perform such transformations in vivo, notably
alcohol dehydrogenases and oxidases. The advantage of the lat-
ter is that they have no stoichiometric cofactor requirement.
Within the class of alcohol oxidases, galactose oxidase (GO)
occupies a special position.5 This mononuclear copper enzyme
couples the oxidation of alcohols to aldehydes with the reduc-
tion of O2 to H2O2 (eqn. 1) through an unusual Cu()-phenoxyl
radical species in the active site.6
More recently, another copper-dependent oxidase, laccase, in
combination with TEMPO was shown to catalyse the aerobic
oxidation of alcohols.15,16 These reactions were assumed to
involve an ‘oxoammonium’ mechanism,16 analogous to the
Semmelhack mechanism outlined above, rather than a copper-
centred oxidation of the alcohol by analogy with the galactose
oxidase.
We recently showed that a related Ru–TEMPO catalysed
aerobic oxidation of alcohols does not involve an ‘oxo-
ammonium’ mechanism.17 Based on results of stoichiometric
oxidations with TEMPO, kinetic isotope effects and Hammett
correlation studies we proposed a hydridometal mechanism
(1)
Recently several succesful biomimetic models of GO have
been developed by the groups of Stack,7,8 Wieghardt9,10 and
Fig. 1 [Cu()BSP]-catalysed aerobic oxidation of benzyl alcohol (adapted from ref. 7).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 2 3 2 – 3 2 3 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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Fig. 2 Mechanism postulated by Semmelhack et al. in 198412 for the Cu–TEMPO catalysed oxidation of alcohols.
Table 1 CuCl–TEMPO catalysed aerobic oxidation of alcoholsa
resulted in the formation of a suspension of a yellow–orange
compound. Evidence for the oxidation of Cu() to Cu() was
provided by UV measurements (Fig. 4). In this case the experi-
ments were performed with Cu() acetate in acetonitrile to avoid
the precipitation of the putative Cu() complex observed in
DMF. Under an inert atmosphere, addition of one equivalent
of TEMPO resulted in a colour change from colourless (see
spectrum Cu()(OAc) in Fig. 4) to green. The UV spectrum
exhibited a maximum at ca. 670 nm (Fig. 4) consistent with
the formation of Cu(), as verified by reference samples of
Cu(OAc)2 in acetonitrile that exhibit the same absorption
maximum.
Alcoholb
Time/h
TONc
p-Methoxybenzyl alcohol
1
9.6
97
18.8
9.2
24d
4e
Benzyl alcohol
Geraniol
Cinammyl alcohol
1.75
2.75
9.3
a Unless otherwise noted, according to the standard procedure: alcohol
(10 mmol), CuCl (1 mmol), TEMPO (1 mmol), DMF (25 ml), 25 ЊC, O2
atmosphere. Selectivity towards aldehyde >99%. b No reactivity was
achieved for 1- and 2-octanol. c TON = turn over number (mmol
of aldehyde per mmol of catalyst). d CuCl (0.1 mmol), TEMPO
(0.1 mmol). e CuCl (0.5 mmol), TEMPO (0.5 mmol).
involving ruthenium-centred oxidative dehydrogenation of the
alcohol affording a ruthenium hydride species. The function of
the TEMPO is to facilitate the re-oxidation of this ruthenium
hydride species. Based on these results we suspected that the
Cu–TEMPO system may involve a copper-centred oxidation of
the alcohol, as outlined in Fig. 3, rather than an ‘oxoam-
monium’ mechanism. Herein, we report the results of a detailed
mechanistic investigation aimed at clarifying this dichotomy.
Fig. 4 UV spectra of 2 mM solutions of Cu()(OAc)–TEMPO (᭿),
Cu()(OAc)2 (ꢀ), TEMPO (x) and Cu()OAc (᭜) in acetonitrile under an
inert atmosphere.
We suggest that the formation of a piperidinyloxy copper()
complex (I), via one-electron oxidation of Cu() by TEMPO, as
shown in eqn. 2, is consistent with the experimental observ-
ations.
Fig. 3 Copper-centred mechanism for the Cu–TEMPO catalysed
aerobic oxidation of alcohols.
(2)
Results and discussion
We first applied the Semmelhack procedure (CuCl–TEMPO in
dimethylformamide at 25 ЊC) to the aerobic oxidation of a
range of alcohol substrates. Benzylic and allylic alcohols
underwent smooth oxidation under these conditions (Table 1).
In contrast, simple aliphatic alcohols were unreactive. This
is not consistent with an ‘oxoammonium’ mechanism since
oxoammonium cations are known for their broad scope, includ-
ing the facile oxidation of simple aliphatic alcohols.18,19
In the alternative mechanism, depicted in Fig. 3, a key step is
the re-oxidation of Cu() to Cu() by TEMPO. In order to
confirm the feasibility of this step we performed an experiment
in which CuCl was allowed to react with one equivalent of
TEMPO in DMF for 24 h, in an inert atmosphere at 25 ЊC. This
A number of metal compounds are known to undergo one-
electron oxidation by TEMPO, to afford piperidinyloxy com-
plexes,20–22 but this is the first example involving Cu() in this
conversion.
Addition of aqueous HCl (1 M) to the suspension of piper-
idinyloxy copper() in DMF afforded a yellow–green solution
which was shown to contain Cu() and (by GC analysis) a
2 : 1 mixture of TEMPO and the corresponding amine
TEMPH. We previously showed17 that the corresponding
hydroxylamine, TEMPOH, formed by protonation of the
piperidinyloxy anion is unstable and, in an inert atmosphere,
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Fig. 5 CuCl-catalysed oxidation of alcohol under nitrogen using TEMPO as terminal oxidant.
spontaneously disproportionates to a 2 : 1 mixture of TEMPO
and TEMPH (see Fig. 5). Indeed, attempts to prepare TEM-
POH in an inert atmosphere always resulted in the formation of
TEMPH.23 The addition of one equivalent of benzyl alcohol to
the yellow–orange suspension of piperidinyloxy copper() in
DMF afforded a white precipitate of CuCl and a colourless
supernatant, which was shown (by GC analysis) to contain one
equivalent of benzaldehyde and one equivalent of TEMPH.
Having demonstrated the separate steps involved, we per-
formed the copper-catalysed oxidation of benzyl alcohol in
DMF, using TEMPO as the stoichiometric oxidant. After stir-
ring for 24 h at room temperature, benzaldehyde and TEMPH
were formed in a 3 : 2 molar ratio. These results can be rational-
ized on the basis of the reaction scheme shown in Fig. 5. Oxid-
ation of the alcohol by TEMPO, catalysed by copper, affords
the carbonyl compound and TEMPOH in a 1 : 2 molar ratio.
The latter spontaneously disproportionates to a 2 : 1 mixture of
TEMPO and TEMPH, resulting in the overall stoichiometry
shown in Fig. 5.
We previously showed that, in the presence of oxygen, TEM-
POH is rapidly oxidized to TEMPO,14 thus rendering the reac-
tion catalytic in TEMPO. The facile conversion of TEMPOH
into TEMPO in air contrasts with the observations of Neu-
mann et al.24 who studied the aerobic oxidation of alcohols
catalysed by a combination of TEMPO and a heteropoly acid.
They postulated that the oxidation of TEMPOH to TEMPO
was the slower, rate-determining step. A similar hypothesis was
made in a catalytic alcohol oxidation system consisting of a
combination of Mn()–Co() or Mn()–Cu() nitrates with
TEMPO in acetic acid as the medium.25 These apparently con-
tradictory results can be rationalized on the basis of the pH-
dependence of this reaction.26 We confirmed this by generating
TEMPOH in water, by ascorbic acid reduction of TEMPO. On
addition of oxygen the orange colour of TEMPO reappeared
instantaneously under basic conditions. In contrast, at acidic
pH the solution remained colourless for more than an hour.
Hence, we conclude that at basic pH aerobic reoxidation of
TEMPOH to TEMPO is rapid while at acidic pH it is relatively
slow and may be rate-determining, as proposed by Neumann
et al.24 At acidic pH the nitrogen of TEMPOH will be proton-
ated making it less susceptible to oxidation.
(3)
(4)
However, we did not observe any hydrogen peroxide form-
ation in our Cu–TEMPO catalysed oxidations. On the other
hand, we showed, by deliberate addition of hydrogen
peroxide during the reaction, that it is not stable under our
reaction conditions, presumably owing to copper-catalysed
decomposition.
Our results support the mechanism depicted in Fig. 3 in
which a key step is the copper-centred dehydrogenation of the
alcohol, rather than the previously proposed ‘oxoammonium
mechanism’.12 The resulting Cu() is rapidly re-oxidized by
TEMPO to afford Cu() and TEMPOH. The role of oxygen is
to re-oxidize the TEMPOH to TEMPO. In separate experi-
ments we showed that oxidation of Cu() by oxygen (in
acetonitrile) is substantially slower than its oxidation by
TEMPO.
Kinetic isotope effects and Hammett correlation studies
Additional evidence for a copper-centred dehydrogenation
step was obtained from kinetic isotope effects and Hammett
correlation studies. For studies of the kinetic isotope effects
α-deutero-p-methylbenzyl alcohol was used as the substrate. In
this case H/D competition is intramolecular and coordination
of the substrate to the catalyst is not a complicating factor. The
primary kinetic isotope effect (kH/kD) for the Cu/TEMPO
catalysed aerobic oxidation of this alcohol at 25 ЊC was deter-
mined to be 5.42. This value indicates substantial C–H bond
cleavage on progressing to the transition state and compares
exceptionally well with isotope effects observed with other
metal-centred dehydrogenations, including galactose oxidase
and Stack’s biomimetic copper complex (see Table 2). In con-
trast, a much smaller kinetic isotope effect was observed in the
stoichiometric oxidation of the same alcohol with the TEMPO
The oxidation of TEMPOH by oxygen is expected to lead to
the formation of hydrogen peroxide via the following steps:
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Table 2 Kinetic isotope effects and Hammett ρ-values for the oxidation of benzyl alcohols
System
Kinetic isotope effect (kH/kD)b
Hammett ρ-value
Reference
CuCl–TEMPO–O2
Oxoammonium chloride
RuCl2(PPh3)3–TEMPO–O2
CuCl–TEMPO–N2
[Cu()BSP]–O2
5.42
1.7–2.3
5.12
5.77
5.3
Ϫ0.16
Ϫ0.3
Ϫ0.58
—
Ϫ0.14
Ϫ0.09
27
17
a
7
28
Galactose oxidase
5.02
a TEMPO is used as stoichiometric oxidant under an inert nitrogen atmosphere. b In all cases α-deutero, p-methyl benzyl alcohol was used for the
determination of KIE.
oxoammonium cation27 (see Table 2). The close similarity of
kinetic isotope effect observed in the stoichiometric oxidation
with TEMPO in an inert atmosphere versus that observed in the
aerobic oxidation in the presence of Cu/TEMPO (kH/kD = 5.77
and 5.42, respectively) is consistent with the same mechanism
being involved in both cases.
Next a series of substituted benzylic alcohols was oxidized
using 1 mol% CuCl. The relative rates for meta- and para-
substituted benzyl alcohols (see Fig. 6) can be readily fitted to
the σ parameters. A Hammett ρ value of Ϫ0.16 was observed
with Cu–TEMPO, which is different to that observed in
stoichiometric oxidation with the oxoammonium cation
(ρ ∼ Ϫ0.3).27 In both cases the negative value is consistent with
Fig. 7 Intramolecular transfer of β-hydrogen, followed by oxidative
electrons being withdrawn from the reactive centre in the transi-
elimination.
tion state. The rather low ρ value suggests that a mechanism
involving the formation of a cationic species, by oxidation of
TEMPOH. Subsequently, inner sphere one-electron transfer
the α–C–H bond, can be excluded. Electron-donating substi-
from the ketyl group to Cu() affords Cu() and the carbonyl
tuents in the alcohol are however expected to favour hydrogen
product. This bears a close resemblance to the rate determining
abstraction as was reported by Stack for the Cu()BSP com-
step in the [Cu()BSP] catalysed aerobic oxidation of (activ-
plex.7 The ρ value in this case was Ϫ0.14 which is also very
ated) alcohols (Fig. 1) reported by Stack and coworkers.7
small and very similar to the value obtained by us.
The complete mechanism which we postulate for the CuCl–
TEMPO catalysed aerobic oxidation of (activated) alcohols,
and which summarizes all the results presented above is
depicted in Fig. 8. The active Cu()-species is generated via a
one-electron oxidation of Cu() by TEMPO. Alkoxy replace-
ment, followed by coordination of a second molecule of
TEMPO and intramolecular β-hydrogen abstraction affords the
desired carbonyl compound, Cu() and TEMPOH. Finally
TEMPO is regenerated by rapid air oxidation of TEMPOH.
Fig. 6 Hammett plot for the Cu–TEMPO catalysed oxidation of
substituted benzylic alcohols.
The similar primary kinetic isotope effects observed with the
three copper systems is particularly striking and strongly sug-
gests that the same (copper-centred) mechanism is involved in
all three cases. By analogy with a Cu()-hydroxide system,29 we
assume that the first step in the dehydrogenation of benzyl
alcohol is an alkoxy replacement, i.e. the piperidinyloxy ligand
is replaced by a benzyloxy group yielding a copper()-alkoxide
and TEMPOH. This also explains the fact that additional base
is not required to achieve good activity, i.e. the piperidinyloxy
ligand acts as a base and deprotonates the alcohol.
The abstraction of the β-hydrogen of the benzyloxy ligand
yielding Cu() and benzaldehyde then probably involves – by
analogy with the Cu()BSP complex – a reaction between the
Cu()-benzyloxy compound and the copper ligated TEMPO
(Fig. 7). Analogous to copper()-TEMPO complexes previously
reported in the literature,30 it is very likely that this involves
η2 coordination of TEMPO to Cu(). As depicted in Fig. 7,
the β-hydrogen of the alkoxide ligand is intramolecularly
transferred to TEMPO generating a ketyl radical anion and
Fig. 8 Postulated mechanism for the CuCl–TEMPO catalysed aerobic
oxidation of (activated) alcohols.
In conclusion, we have shown that the Cu–TEMPO catalysed
aerobic oxidation of alcohols involves
a copper-centred
oxidation which bears a close resemblance to the accepted
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mechanism for analogous oxidations mediated by galactose
oxidase and mimics thereof. Further investigations are
currently underway that are aimed at improving the activity of
the Cu()–TEMPO system in order to broaden the scope to
unactivated primary and secondary alcohols.
Hammett plot studies
Substituted benzylic alcohol (5 mmol), 0.05 mmol CuCl and
0.05 mmol TEMPO were reacted in 12.5 ml DMF at 25ЊC
under an oxygen atmosphere. The log(kx/kH) values for these
substituted benzylic alcohols were determined from the initial
reaction rate (below 10% conversion) in separate experiments.
Reactions were followed by GC relative to internal standard
(hexadecane); selectivities to aldehyde were >99% in all cases.
Under these conditions (only 1 mol% Cu) conversions obtained
after 24 h range from 54% for p-NO2 to 76% for p-OMe substi-
tuted benzylic alcohols.
Experimental
General
The solvents (p.a.) were used as received. TEMPO free
radical and copper() chloride were purchased from the Aldrich
Chemical Co. and used without further purification. Oxo-
ammonium chloride was prepared analogous to a literature
procedure.8 CuOAc was prepared according to literature:31
Under an inert nitrogen atmosphere, Cu(OAc)2 (4.0 mmol)
was dissolved in degassed acetonitrile (40 ml). An excess of
copper powder (10.0 mmol) was added to the green–blue
Cu()-solution and the resulting suspension was stirred for
48 hours. After filtration a colorless Cu() acetate solution was
obtained.
Stoichiometric reaction of benzyl alcohol with TEMPO
Benzyl alcohol (1.0 mmol; 108 mg), CuCl (0.1 mmol; 10 mg)
and TEMPO (2.0 mmol; 312 mg) were dissolved in DMF (5 ml)
and stirred under an inert nitrogen atmosphere at room
temperature for 24 hours. After this period, substrate (benzyl
alcohol and TEMPO) conversion and product (benzaldehyde
and TEMPH) selectivity were determined using GC-analysis.
GC-analyses were done using a CP-WAX 52 CB column
(50 m × 0.53 mm).
Stoichiometric reaction of CuCl with TEMPO
(followed by addition of HCl)
CuCl (3.0 mmol; 297 mg) was added to a solution of TEMPO
(3.0 mmol; 468 mg) in DMF (30 ml) and stirred under an inert
nitrogen atmosphere for 24 hours. The resulting yellow–orange
suspension was treated with an aqueous hydrogen chloride
solution (4 ml; 1.0 M), yielding a clear yellow–green solution.
The colour-change is due to the formation of CuCl2 which
indeed gives a yellow–green solution upon dissolving it in
DMF. The product-distribution (TEMPO–TEMPH) was
determined using GC-analysis.
CuCl–TEMPO catalysed aerobic oxidation of benzyl alcohol
Benzyl alcohol (10.0 mmol; 1.08 g), hexadecane (internal
standard; 2.0 mmol; 0.46 g), CuCl (1.0 mmol; 99 mg) and
TEMPO (1.0 mmol; 156 mg) were dissolved in DMF (25 ml)
and stirred (1000 rpm) under an oxygen atmosphere for
24 hours. Benzyl alcohol conversion and benzaldehyde selec-
tivity were determined using GC-analysis.
Stoichiometric reaction of octan-2-ol and oxoammonium chloride
Stoichiometric reaction of CuCl with TEMPO
(followed by addition of benzyl alcohol)
Octan-2-ol (5.0 mmol; 0.54 g), hexadecane (internal standard;
1.0 mmol; 0.23 g) and oxoammonium chloride (5.5 mmol;
1.05 g) were dissolved in DMF (12.5 ml) and stirred (1000 rpm)
for 24 hours. Octan-2-ol conversion and octan-2-one selectivity
were determined using GC-analysis.
CuCl (3.0 mmol; 297 mg) was added to a solution of TEMPO
(3.0 mmol; 468 mg) in DMF (30 ml) and stirred under an inert
nitrogen atmosphere for 24 hours. The resulting yellow–orange
suspension was treated with benzyl alcohol (5.0 mmol; 540 mg),
yielding a colourless solution and a white precipitate (CuCl).
The product-distribution (benzaldehyde–TEMPH) was deter-
mined using GC-analysis.
Synthesis of ꢀ-deutero-p-methylbenzyl alcohol
α-Deutero-p-methylbenzyl alcohol was synthesised according
to a literature procedure.32 1H-NMR (400 MHz, CDCl3, TMS)
δ 7.25 (d, 2H, 3JHH = 8.0 Hz, 2Hortho), 7.16 (d, 2H, 3JHH = 7.8 Hz,
2Hmeta), 4.60 (s, 1H, CHDOH), 2.35 (s, 3H, CH3), 1.69 (d, 1H,
3JHH = 5.1 Hz, OH ); 13C-NMR (100 MHz, CDCl3, TMS)
δ 137.8 (Cipso), 137.4 (Cpara), 129.2 (2Cmeta), 127.2 (2Cortho), 64.9 (t,
1JCD = 21.8 Hz, CHDOH), 21.2 (CH3); m/z = 124 (17), 123 (Mϩ,
92), 122 (25), 108 (100), 106 (33), 94 (50), 93 (31), 92 (32), 91
(48), 80 (71), 78 (52), 77 (36), 65 (28).
H2O2 stability studies
Benzyl alcohol (10 mmol), 0.1 mmol CuCl, and 0.1 mmol
TEMPO were mixed in 25 ml DMF. Addition of 4 mmol H2O2
followed after 1.5 h, upon which some gas formation was
observed. Iodometric titration of H2O2 after 24 h revealed that
<5% of hydrogen peroxide was left. Direct mixing of H2O2 and
CuCl resulted in rapid gas formation and therefore a high
catalase activity.
Determination of intramolecular kinetic isotope effect
α-Deutero-p-methylbenzyl alcohol (5.0 mmol; 615 mg), CuCl
(0.5 mmol; 49.5 mg) and TEMPO (0.5 mmol; 78 mg) were dis-
solved in DMF (25 ml) and stirred (1000 rpm) under an oxygen
atmosphere for 24 hours. The resulting reaction-mixture was
analysed by GC and the oxidation products, α-deutero-p-meth-
ylbenzaldehyde and p-methylbenzaldehyde, were isolated using
Kugelrohr distillation. The intramolecular kinetic isotope effect
was determined by 1H NMR.
Acknowledgements
We thank the Dutch Ministry for Economic affairs (IOP-
catalysis) catalysis for financial support. Y.-X. Li is gratefully
acknowledged for performing the H2O2 stability studies.
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 2 3 2 – 3 2 3 7
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