A bis(pyridyl)-: N -alkylamine/Cu(i) catalyst system for aerobic alcohol oxidation

Article abstract of DOI:10.1039/c7ob01383c

Herein a bis(pyridyl)-N-alkylamine/Cu^I/TEMPO/NMI catalyst system is reported for aerobic oxidation of a variety of primary alcohols to the corresponding aldehydes using readily available reagents, at room temperature and ambient air as the oxidant. ESI-MS analysis of the reaction showed the formation of a [(L1)(NMI)Cu^II-OOH]⁺ species, which is a key intermediate in the alcohol oxidation reaction. Evaluation of the effect of reaction parameters on the initial rate of the reaction allowed us to obtain the optimum conditions for catalytic activity. The careful choice of reaction solvent allowed for the oxidation of 4-hydroxybenzyl alcohol, a substrate which proved problematic in previous studies. In the case of 2-pyridinemethanol as substrate, experimental evidence shows that catalytic activity is diminished due to competitive inhibition of the catalyst by the alcohol substrate.

Full text of DOI:10.1039/c7ob01383c

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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A bis(pyridyl)-N-alkylamine/ Cu(I) catalyst system for aerobic alcoholDoOIx: 1i0d.10a3t9i/oC7nOB01383C
Lindie Marais, a Jordi Burés, b Johan H.L. Jordaan, a Selwyn Mapolie c and Andrew J. Swarts a*
a
Catalysis and Synthesis Research Group, Focus Area for Chemical Resource Beneficiation, North-West
University, 11 Hoffman Street, Potchefstroom 2520, South Africa.
b School of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom.
c
Department of Chemistry and Polymer Science, Stellenbosch University, Private Bag X1, Matieland 7602,
Stellenbosch, South Africa.
*Andrew.Swarts@nwu.ac.za
Herein a bis(pyridyl)-N-alkylamine/CuI/TEMPO/NMI catalyst system is reported for aerobic
oxidation of a variety of primary alcohols to the corresponding aldehydes using readily
available reagents, at room temperature and ambient air as the oxidant. ESI-MS analysis of
the reaction showed the formation of a [(L1)(NMI)CuII-OOH]+ species, which is a key
intermediate in the alcohol oxidation reaction. Evaluation of the effect of reaction parameters
on the initial rate of the reaction allowed us to obtain the optimum conditions for catalytic
activity. The careful choice of reaction solvent allowed for the oxidation of
4-hydroxybenzyl alcohol, a substrate which proved problematic in previous studies. In the
case of 2-pyridinemethanol as substrate, experimental evidence show that catalytic activity
is diminished due to competitive inhibition of the catalyst by the alcohol substrate.
Keywords: Alcohol oxidation, copper catalysis, TEMPO, substrate scope, initial rate investigations
Introduction
Aldehydes and ketones are important in the pharmaceutical industry [1, 2] and in the
synthesis of fine chemicals such as fragrances and food additives [3]. One of the most
widely used reactions to synthesise these carbonyl products is via the oxidation of alcohol
substrates. Traditionally, these oxidation methods employ toxic oxidants or hazardous heavy
metal salts or expensive catalysts containing precious metals such as palladium [4, 5] at
high oxygen pressures, which pose environmental and safety concerns. As a result, there
has been a growing demand for new selective and environmentally benign oxidation
systems catalysed by “green” copper-based complexes [5, 6].
Catalytic oxidation systems employing molecular oxygen as a primary oxidant are
particularly attractive because it is inexpensive, readily available [7] and generates water as
the only by-product [1, 4]. Recent studies have demonstrated that copper-based catalyst
systems, particularly in combination with 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO·) as
co-catalyst, at ambient temperatures with molecular oxygen or air as the oxidant are some of
1

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the most effective catalysts for the oxidation of alcohols to DOaI:l1d0e.10h3y9d/Ce7OsB01383C
[2, 3, 8-12].
These catalytic oxidation systems were developed to understand the functionality of natural
enzymes such as galactose oxidase (GOase), by mimicking the active sites of these
enzymes [10]. Different Cu/TEMPO catalyst systems have been developed over time and
the first catalyst system, which could mimic GOase, was reported in 1984 by Semmelhack. A
number of similar catalyst systems followed in more recent years [2, 10, 11, 13]. Seminal
mechanistic studies by the groups of Stahl and Brückner, under controlled conditions, have
established our current understanding of the mechanism of Cu/TEMPO catalysed alcohol
oxidation [12, 13]. However, we were interested in the performance of the catalyst system
under synthetically relevant conditions.
We have recently reported the development of substituted bis(pyridyl)-N-alkylamine ligands
and the application of their nickel and palladium complexes in catalytic ethylene
oligomerization [14]. These six-membered chelate ligands, upon coordination to a metal
centre, are puckered out of the plane of the metal coordination sphere. We envisaged that
this puckering might lead to a more sterically accessible metal centre, thereby facilitating the
oxidation of secondary alcohols. As such we report their evaluation, in combination with
copper and TEMPO, as aerobic alcohol oxidation catalysts. The influence of varying
[TEMPO], [NMI] and [LCu] on the initial rate of the oxidation reaction will be evaluated.
Finally, we sought to establish the substrate scope of our catalyst system by evaluating the
oxidation of different primary and secondary alcohols.
Results and discussion
Optimisation of the alternative (L)CuI/TEMPO/NMI Catalyst System (Scheme 1).
,
mol%
5
L1-L5
5 mol%
OTf,
Cu(MeCN)4
OH
O
6
5 mol% TEMPO, 10 mol% NMI
6
°
±
2
ambient air
MeCN, 30
C,
Scheme 1: A representative catalyst system for aerobic oxidation of 1-octanol to 1-octanal under
synthetically relevant conditions.
As a point of departure we evaluated bis(pyridyl)-N-alkylamine ligands bearing different
substituents on bridgehead N-atom, L1-L5 (Figure 1), in the aerobic oxidation of 1-octanol to
1-octanal as model reaction under previously reported reaction conditions (Scheme 1) [2].
2

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DOI: 10.1039/C7OB01383C
N
N
N
N
N
N
L1
L2
N
N
N
N
N
N
N
N
N
L4
L3
L5
Figure 1: Six-membered chelate bis(pyridyl)-N-alkylamine ligands evaluated in Cu-catalysed alcohol
oxidation.
The following trend in the initial rates was observed: L1 (0.33 mM.min-1) > L3
(0.29 mM.min-1) > L2 (0.27 mM.min-1) > L4 (0.22 mM.min-1) > L5 (0.15 mM.min-1)
(Table 1, Entries 1-5 and Figure S1 in the Supporting Information). For 1-octanol, and all
other alcohol substrates evaluated, no over-oxidation to the corresponding carboxylic acid
was observed.
The observed activity, expressed as initial rate, of the oxidation of 1-octanol to 1-octanal
reinforces the negligible effect that the substituents on the bridgehead nitrogen atom has on
activity since an increase in donor ability (L4 vs L1) does not result in an increase in activity
of the ligand [14]. In contrast, the introduction of substituents in the ortho positions (L5)
results in a clear two-fold decrease in reactivity in comparison with L1.
Table 1: Evaluation of the effect of different bis(pyridyl)-N-alkylamine ligands on the aerobic alcohol
oxidation of 1-octanol. a
Entry
Ligand
Comment
Time (h)
k
initial (mM.min-1)
GC Yield (%) b
1
2
3
4
5
6
L1
L2
[Cu(MeCN)4]OTf
[Cu(MeCN)4]OTf
[Cu(MeCN)4]OTf
[Cu(MeCN)4]OTf
[Cu(MeCN)4]OTf
[Cu(MeCN)4]OTf
9
9
9
9
9
-
0.327
0.266
0.294
0.221
0.153
1.037
87
75
L3
100
87
L4
L5
64
n.d.c
bpy
a alcohol (1.0 mmol, 0.2 M in MeCN), Cu(MeCN)4OTf (5 mol %, 0.01 M in MeCN), L (5 mol %, 0.01 M
in MeCN), TEMPO (5 mol %, 0.01 M in MeCN), NMI (10 mol %, 0.02 M in MeCN), 30 °C ± 2 °C.
b
GC yields for the aldehyde product are determined with the use of a calibration curve (internal
standard: cyclohexanone). c n.d.: Not determined.
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The difference in the reactivity may be attributed to the steric and electronDicOI:i1n0f.1l0u3e9n/Cc7eOB01383C
imposed by the ortho methyl groups, which has the dual effect of hindering the approach of
the alcohol en route to forming the CuII-alkoxide species and decreasing the electrophilicity
of the copper metal centre as a result of the electron-donating ability of the methyl
substituents [12, 14, 15]. The observed difference in GC yield for L1 and L3 may be
attributed differences in the rate of catalyst deactivation. This is supported by the fact that
unreacted starting material and aldehyde product are the only organic materials observed
during the reaction, while no by-product formation is observed by GC-MS analysis. A
comparative study of bpy as ligand in our hands generated faster initial rates than our
bis(pyridyl)-N-alkylamine ligands (Table 1, Entry 6 and Figure S1 in the Supporting
Information). A possible reason for these variations is the smaller structure of bpy and the
freedom of movement in the absence of the bridgehead N-atom, compared to our
six-membered chelate ligands [16]. Despite the lower rate of reaction, ligand L3 in
combination with Cu/TEMPO, displayed quantitative conversion in 9 hours, significantly less
than the reaction time reported by Stahl and co-workers for this susbtrate [2]. Copper(II)
complexes ligated by bpy and related ligands possess a N-Cu-N bite angle in the range
79-82 ° in a distorted tetrahedral geometry [17-19]. In contrast, Cu(II) complexes bearing
alkyl/allyl substituted bis(pyridyl)amine ligands possess a larger N-Cu-N bite angle in the
range 87-95 ° [20-22]. This has also been observed for analogous Ni(II) and Pd(II)
complexes [14]. Our results indicate that the bite angle constraints clearly overrides the
puckering effect of the ligands, resulting in a sterically more crowded metal centre and lower
initial rates. The fact that full conversion occurs in a shorter time than for the benchmark
system may be attributed to a reduction in the rate of catalyst deactivation. The study of our
catalyst system by ESI-MS revealed the formation of an ion at m/z 363, consistent with the
formation of a CuII-hydroperoxo species, [(L1)(NMI)CuII-OOH]+ (Figure 2). The formation of
this species, which is responsible for H2O2-formation following alcohol oxidation, has
previously been postulated by spectroscopic studies [12, 13]. Our study has provided further
evidence for its formation. Analogous species have been observed in Fe-catalysed alkane
hydroxylation reactions [23]. As a result of ligand L3 displaying the highest conversion of
1-octanol, it was employed in further optimisation studies.
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DOI: 10.1039/C7OB01383C
Intens.
2500
363.9724
365.9719
2000
1500
1000
500
0
Actual isotope cluster
N
N
N
CuII
O
N
HO
N
CH3
360
365
370
Proposed structure: C15H18CuN5O2
Figure 2: ESI-MS spectrum for the ion at m/z 363 which have the mass value and isotope pattern
(inset) that is consistent with the [(L1)(NMI)CuII-OOH]+ intermediate.
Next, we investigated various CuI- and CuII-precursors in combination with ligand L3 in the
oxidation of 1-octanol. The use of CuI-precursors containing non-coordinating anions such
as triflate displayed higher activity than the analogues containing coordinating anions such
as CuBr and CuCl (Figure 3 and Table S1, Entries 1-3 in the Supporting Information). This
effect of the nature of the counter-ion had been previously observed by the groups of
Sheldon, Koskinen and Stahl and their co-workers [2, 11, 24]. This was attributed to the
approach of the substrate to the metal centre being facilitated by non-coordinating anions
which can dissociate faster than their coordinating counterparts.
When employing CuII-precursors, (Table S1, Entries 4 and 5 in the Supporting Information)
low catalytic activity was observed. It is clear that the reaction rate of the oxidation reaction
improved significantly when a CuI-precursor was used rather than a CuII-analogue [25] even
though the CuI-precursor is oxidised to CuII during the catalytic cycle. We observe that the
initial oxidation state of the copper pre-catalyst has the most significant impact on the
reaction efficiency.
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DOI: 10.1039/C7OB01383C
0,04
0,035
0,03
0,025
0,02
0,015
0,01
0,005
0
Cu(MeCN)4OTf
Cu(MeCN)4OTf
CCuBuBr r
CuCl
CuCl
0
50
100
Time (min)
150
200
Figure 3: Initial rate data obtained for various CuI-precursors in the aerobic alcohol oxidation of
1-octanol
Brückner and co-workers have recently reported mechanistic studies of benzyl alcohol
oxidation employing simultaneously coupled operando EPR/UV-Vis/ATR-IR spectroscopy
[13]. Their results showed that CuI activates dioxygen in the presence of TEMPO via a
single-electron transfer (SET) process and that this activation is not possible when initiating
the alcohol oxidation reaction from a CuII-precursor.
Next, we evaluated the effect of different N-substituted imidazole bases on the catalytic
activity by varying their electronic properties to probe the effect of base on the reaction rate
in more detail (Figure S2 and Table S1, Entries 6-8 in the Supporting Information).
N-methylimidazole (NMI) was used as the standard base in the alcohol oxidation reaction.
When a base with a more electron-donating ability (thus, a more active base) was used, the
initial rate of the oxidation reaction increased (N-tert-butylimidazole vs NMI). While, when a
base with a more electron-withdrawing ability (thus, less active) was used, the initial rate
decreased and almost no conversion to the aldehyde was observed (1-acetylimidazole vs
NMI). These results indicate that substituents which enhance the basicity of the N-atom of
the imidazole ring leads to faster deprotonation and faster rate of reaction [13].
Lastly, initial rate experiments were used to determine whether an oxoammonium cation
(TEMPO+) is present in our catalyst system as the reactive intermediate (Figure 4).
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0,04
0,035
0,03
0,025
0,02
0,015
0,01
0,005
0
DOI: 10.1039/C7OB01383C
CuI/TEMPO·: 0.2935 mM.min-1
Cu(I)
.
-1
I
+
Cu(I)/oxoammonium cation
Cu /TEMPO : 0.1707 mM min
0
20
40
60
80
100
120
140
Time (min)
Figure 4: Evaluation of the effect of the oxoammonium salt, [TEMPO]+[OTf]- as the co-catalyst.
Standard reaction conditions: 0.2 M 1-octanol, 10 mM [(L3)CuI], 0.2 M TEMPO+ or 10 mM
TEMPO·, 20 mM NMI, 5 ml MeCN, 30 ºC ± 2 ºC, air.
The initial rate for TEMPO+-mediated oxidation of 1-octanol (0.1707 mM.min-1) was found to
be slower than the TEMPO-mediated reaction (0.2935 mM.min-1), despite the higher
concentration of TEMPO+OTf- (relative to TEMPO·) present in the oxidation reaction. This
result corroborates that an oxoammonium species is not implicated in the catalytic reaction.
Previous groups also highlight the absence of TEMPO+ in the oxidation reaction [10-12].
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Kinetic behaviour of the (L3)CuI/TEMPO/NMI catalyst system.
View Article Online
DOI: 10.1039/C7OB01383C
With the optimised system in hand, we evaluated the effect of [TEMPO], [NMI] and [L3Cu]
on the initial rate of our catalyst system under synthetically relevant conditions i.e. under
ambient air.
The rate of oxidation of 1-octanol exhibits a saturation dependence on the alcohol substrate
(Figure S4 and Table S2 in the Supporting Information) and saturation dependence on
[TEMPO] (Figure 5 and Table S3 in the Supporting Information).
The aerobic alcohol oxidation reaction is performed under O2 limiting conditions and the role
of TEMPO· is the fixation and activation of oxygen by forming weakly coordinated
O2-TEMPO adducts during the oxidation reaction [13]. At higher TEMPO· concentrations, the
amount of copper and O2 present in the system becomes limited which then limits the
amount of TEMPO· that can activate the dioxygen and form the (L)(NMI)CuII-O2-TEMPO
adduct [13].
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
0
10
20
30
40
50
60
70
Concentration of TEMPO (mM)
Figure 5: Kinetic data from the oxidation of 1-octanol by (L3)Cu(MeCN)4OTf/TEMPO/NMI assessing
the kinetic dependence on [TEMPO]. Standard reaction conditions: 0.2 M 1-octanol,
10 mM (L3)CuI, varying [TEMPO], 20 mM NMI, 5 mL MeCN, 30 ºC ± 2 ºC, air. The initial
rates and standard deviations are summarised in the Supporting Information (Table S3).
The rate of oxidation of 1-octanol also exhibits a saturation dependence on [NMI]
(Figure 6 and Table S4 in the Supporting Information). Previous studies proposed that NMI
has a bifunctional role as base and ligand during aerobic alcohol oxidation [13]. Firstly, NMI
is coordinated to the Cu-catalyst stabilising the complex and it serves as an oxidation
facilitator which raises the ability of CuI to reduce O2. NMI also serves as a base to
8

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deprotonate the alcohol substrate to the alkoxide that can coordinate with VietwhAerticle Online
DOI: 10.1039/C7OB01383C
(L)(NMI)CuII-O2-TEMPO adduct [3, 13]. This explains the fact that two equivalents of NMI
are often used in the catalytic reaction.
0,5
0,4
0,3
0,2
0,1
0
0
10
20
30
40
50
60
Concentration of NMI (mM)
Figure 6: Kinetic data from the oxidation of 1-octanol by (L3)Cu(MeCN)4OTf/TEMPO/NMI assessing
the kinetic dependence on [NMI]. Standard reaction conditions: 0.2 M 1-octanol, 10 mM
(L3)CuI, 10 mM TEMPO, varying [NMI], 5 mL MeCN, 30 ºC ± 2 ºC, air. The initial rates and
standard deviations are summarised in the Supporting Information (Table S4).
Higher concentrations of NMI increase the concentration of alkoxide formation but the
amount of Cu-catalyst limits the amount of alkoxide ion that can coordinate to the
(L)(NMI)CuII-O2-TEMPO adduct and as a result, the system becomes saturated at higher
NMI concentrations. In addition, high concentrations of NMI may lead to competition
between the alkoxide species for the coordination site at the copper centre, further inhibiting
substrate oxidation.
Lastly, the reaction also exhibits saturation dependence for [(L3)Cu] (Figure 7 and
Table S5 in the Supporting Info). We observe a direct linear relationship between the initial
rate and the concentration of the catalyst at low concentrations (first-order in catalyst) and an
apparent loss of linearity at higher concentrations of catalyst (order in catalyst smaller than
one). This is likely due to [oxygen] becoming rate-limiting at high [(L3)Cu] leading to a
“levelling off” in the initial rate data.
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DOI: 10.1039/C7OB01383C
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
0
10
20
30
40
50
60
Concentration of L3Cu (mM)
Figure 7: Kinetic data from the oxidation of 1-octanol by (L3)Cu(MeCN)4OTf/TEMPO/NMI assessing
the kinetic dependence on [L3Cu]. Standard reaction conditions: 0.2 M 1-octanol, varying
[(L3)CuI], 10 mM TEMPO, 20 mM NMI, 5 mL MeCN, 30 ºC ± 2 ºC, air. The initial rates and
standard deviations are summarised in the Supporting Information (Table S5).
Our results highlight the impact that operating under O2-limiting conditions has on the [L3Cu]
initial rate profile. The results of our initial rate kinetic studies shows that for our experimental
setup, there is no significant benefit in using more than 20 mM TEMPO· as co-catalyst,
20 mM NMI as base and 20 mM L3Cu as catalyst for optimal catalyst performance.
Scope and Functional Group Tolerance of (L1)CuI/TEMPO/NMI-Catalysed Alcohol
Oxidation.
We evaluated the substrate scope and limitations of our catalyst system. For comparative
purposes we evaluated our catalyst system under previously reported concentrations [2, 13],
rather than the optimal concentrations. Table 2 shows our catalyst system was capable of
oxidising a variety of primary alcohols. These substrates include primary un-activated
(1-octanol), allylic (Table 2, Entries 1 and 2), benzylic (Table 2, Entries 3-8) and heterocyclic
alcohols (Table 2, Entry 9). Most of these alcohols underwent efficient oxidation giving
excellent yields of the target aldehyde.
Our catalyst system was used to improve the oxidation of alcohols resulting in higher product
yields and/or shorter reaction times. By comparing our results, as presented in Table 2, with
previous catalyst systems, it is evident that our system is superior when applied to allylic
[26-31] and benzylic alcohols (Entries 3 [11, 27, 30] and 5 [26-29, 31]).
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Table 2: Evaluation of the substrate scope of our (L1)Cu (MeCN)4OTf/TEMPO/NMI caDtaOlIy:s10t.1s0y3s9/tCe7mOB01383C
for the aerobic oxidation of alcohols to aldehydes.
,
mM
OTf, 10
L1
10 mM
Cu(MeCN)4
R
R
OH
O
10 mM TEMPO, 20 mM NMI
±
5mL
2
ambient air
MeCN,30 ºC
ºC,
Yield b
Alcohol
Aldehyde
Time
Comments
Entry
alcohols
Allylic
O
OH
95
98
1
2
%
%
3 h
2 h
O
OH
alcohols
Benzylic
O
OH
3
4
5
6
92%
2 h
7 h
OH
OH
O
95
98
%
%
O
2.5 h
MeO
MeO
OH
O
3 h
3 h
90
97
%
%
NH2
NH2
OH
I
O
I
7
8
OH
O
23 h
3 h
DMF:MeCN
ml
65
%
HO
2 ml:3
HO
Heterocycles
Under O2
33
GC
%
yield)
%
(100
O
9
OH
O
O
Limitations: Over-oxidation
O
OH
-
-
O
-
-
Maximum GC
10
11
19
%
yield:
Maximum GC
10
OH
O
%
and a
mixture of
yield:
complex
H
H
products
Limitations: Inhibited oxidation
-
-
OH
N
Maximum GC
15
O
N
12
13
14
%
yield:
OH
-
-
-
-
-
n.r.
n.r.
-
OH
b Isolated yields, unless noted otherwise.
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In addition, we were able to oxidise benzylic alcohols (Entries 4, 6 and 7) in high isolated
DOI: 10.1039/C7OB01383C
yields with only a small variation in the yields in comparison to previous systems [2].
However, we could not improve on the isolated aldehyde yield obtained for the oxidation of
furfuryl alcohol (Entry 9) [2]. The oxidation of furfuryl alcohol did not reach completion under
ambient air; however, full conversion (100 % GC yield) was achieved in a short period of
time performing the reaction under O2.
Our catalyst system, in combination with a DMF: MeCN (2 ml: 3 ml) solvent system was
capable of oxidising 4-hydroxybenzyl alcohol to the aldehyde in 65 % isolated yield
(Table 2, Entry 8). The catalyst system as proposed by Stahl and co-workers (further
referred to as the benchmark system) was incapable of oxidising this substrate [2], which we
attribute to the fact that the starting alcohol is insoluble in acetonitrile.
The benchmark system also displayed a number of substrate limitations which we
investigated with our catalyst system (Table 2, Entries 10-14). The homobenzylic alcohol,
2-phenylethanol (Table 2, Entry 10), was found to be susceptible to over oxidation at the
benzylic position to afford a low yield of the α-ketoaldehyde for both our catalyst system and
the benchmark system [2]. In addition, both our catalyst system and the benchmark system
[2] generated a complex mixture of products during the oxidation of the terminal alkyne,
4-pentyl-1-ol (Table 2, Entry 11).
Stahl and co-workers also found that 2-pyridinemethanol as substrate is oxidised with low
conversions [2]. They hypothesized that the substrate coordination to copper is competing
with copper-catalysed substrate oxidation [2]. As such, we evaluated the 2-pyridinemethanol
as substrate and observed the same inhibitory effect (Table 2, Entry 12). MS analysis of the
reaction mixture in the presence/absence of TEMPO· and NMI showed the formation of
identical mass fragments. In particular the mass fragment at m/z 563 corresponds to a
Cu2-hydroxo dimer, in which the substrate acts as ligand (Figures 8, S22 and S23 in the
Supporting Information), providing experimental evidence for the inhibitory effect of the
substrate. Analogous dimeric species have been reported previously [8, 32-36].
Our catalyst system, however, was incapable of oxidising secondary alcohols
(Table 2, Entry 13 and 14). This observation, as in the case when evaluating the reactivity
toward 1-octanol, may be attributed to the steric pressure exerted by the larger bite angle of
our ligands, despite the out-of-plane puckering which occurs, as well as the bulky structure
of TEMPO· and the steric pressure exerted during the TEMPO-mediated C-H abstraction
step [2, 10, 11, 37]. Here again, steric factors override the puckering effect present in our
ligands. The oxidation of secondary alcohols, however, is also important, and Stahl and co-
workers
addressed
the
problem
by
replacing
the
TEMPO·
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co-catalyst with the more expensive 9-azabicyclo[3.3.1] nonane N-oxyl (ABNO) [38]. In
DOI: 10.1039/C7OB01383C
contrast, Wang et al. increased the steric pressure on the reaction by introducing a
bifunctional ligand in their CuI/bpy-TEMPO/NMI catalyst system [31]. The bifunctional ligand
consists of a metal-binding site (bpy) and a stable radical (TEMPO·) which allow them to
oxidise both primary and secondary alcohols.
4
x10
563.278
e cluster
6
+
H H
O
2O
Cu
H H
O
2O
Cu
H
O
H
O
OTf
Cu
OTf
Cu
N
N
O
H
O
H
N
N
O
H
O
H
H2O
TfO
H2O
C13 21OCu2F3N2O9S:
H
observed at m/z 563
4
2
0
565.286
523.333
583.413
519.355
520
545.019
510
530
540
550
560
570
580
590
600
m/z
Figure 8: Mass spectrum of the Cu2-hydroxo dimer responsible for the inhibitory effect that
2-pyridinemethanol has as a substrate.
Conclusions
We have successfully optimised a practical (L3)CuI/TEMPO/NMI catalyst system capable of
the oxidation of primary alcohols to aldehydes. This was accomplished by evaluating the
nature of the ligands, base and copper precursors on the oxidation reaction. ESI-MS studies
of the oxidation reaction, provided additional experimental evidence for the formation of a
CuII-hydroperoxo species, a key intermediate in the accepted mechanistic pathway. An
investigation of the effect of key reaction parameters, [TEMPO], [NMI] and [LCu], on the
initial rate of the oxidation reaction allowed us to identify the optimal reaction conditions for
alcohol oxidation under ambient conditions. Lastly, an investigation of the substrate scope
and limitations showed that our catalyst system is capable of oxidising a variety of primary
aliphatic, allylic, benzylic and heterocyclic alcohol substrates with excellent yields under
synthetically relevant conditions. Unfortunately, our catalyst system could not be used for the
oxidation of secondary alcohols. The careful choice of reaction solvent allowed for the
oxidation of 4-hydroxybenzyl alcohol, a substrate which proved problematic in previous
studies. Future work in our group is focused on the development of catalyst systems which
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operate in the absence of TEMPO·, as co-catalyst, which have the potentiaDl OtIo: 10p.1r0o39v/iCd7eOB01383C
orthogonal reactivity.
Experimental section
General considerations.
All commercially available reagents were obtained from Sigma-Aldrich and/or Merck and
used as received. The different bis(byridyl)-N-alkylamine ligands were prepared by
previously reported literature procedures [14] and characterised by FT-IR spectroscopy and
multinuclear NMR spectroscopy. N-tert-butylimidazole was prepared according to a
previously reported procedure [39]. [TEMPO]+[OTf]- was synthesised from TEMPO·
employing a previously reported procedure [40]. GC and GC-MS analyses were used to
monitor the initial rate kinetic studies, with cyclohexanone as internal standard, to determine
the concentration of the aldehyde product. The oxidation reactions were done in duplicate to
determine an average initial rate value as well as the standard deviation for each
concentration. Complete aldehyde conversion was monitored by TLC using different solvent
systems.
Optimisation of our alternative catalyst system.
The
catalyst
system
was
optimised
by
varying
the
CuI/CuII-precursors,
bis(pyridyl)-N-alkylamine ligands and N-substituted imidazole bases in the oxidation
reaction. To a solution of 1-octanol (1 mmol in 1 mL MeCN) in a test tube at 30 °C ±2 °C was
added the following solutions: (1) Cu-precursor (Cu(MeCN)4OTf, CuBr, CuCl, Cu(OTf)2 or
.
CuOAc2 2H2O, 0.05 mmol in 1 mL MeCN) (2) ligand (L1-L5, 0.05 mmol in 1 mL MeCN)
(3) TEMPO· (0.05 mmol in 1 mL MeCN) (4) base (N-methylimidazole, N-tert-butylimidazole
or 1-acetylimidazole, 0.1 mmol in 1 mL MeCN) for a total volume of 5 mL MeCN and a
substrate concentration of 0.2 M.
Investigation of the reactive intermediate in the oxidation reaction.
To a solution of 1-octanol (1 mmol in 1 mL MeCN) in a test tube at 30 °C ±2 °C was added
the following solutions: (1) Cu(MeCN)4OTf (0.05 mmol in 1 mL MeCN) (2) ligand L3
(0.05 mmol in 1 mL MeCN) (3) TEMPO· (0.05 mmol in 1 mL MeCN) or [TEMPO]+[OTf]-
(1 mmol in 1 mL MeCN) (4) N-methylimidazole (0.1 mmol in 1 mL MeCN) for a total volume
of 5 mL MeCN and a substrate concentration of 0.2 M.
Varying the concentration of different reaction parameters.
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The concentration of different reaction parameters was varied to determine the influence on
DOI: 10.1039/C7OB01383C
the initial rate of the oxidation of 1-octanol. To a solution of 1-octanol (1 mmol) in 1 mL
MeCN in a test tube at 30 °C ±2 °C were added the following solutions: (1) Cu(MeCN)4OTf
precursor (0.05 mmol in 1 mL MeCN) (2) ligand L3 (0.05 mmol in 1 mL MeCN) (3) TEMPO·
(0.05 mmol in 1 mL MeCN) (4) NMI base (0.1 mmol in 1 mL MeCN) for a total volume of
5 mL MeCN and a substrate concentration of 0.2 M. The pale-orange reaction mixture was
stirred rapidly and samples withdrawn every 30 minutes for a total reaction time of
120 minutes. The conversion of alcohols to aldehydes was often accompanied by a change
in reaction colour to green.
The representative procedure as described above is the base conditions for the aerobic
alcohol oxidation, after which the concentrations of [TEMPO], [NMI] and [L3Cu] were varied
in separate reactions. The varying concentrations, initial rates and standard deviations for
each reaction parameter are summarised in the Supporting Information, Tables S2-S5.
Procedure for the oxidation of primary and secondary alcohols.
To a solution of alcohol (different primary and secondary alcohol substrates, 1 mmol) in 1 mL
MeCN in a test tube at 30 °C ±2 °C were added the following solutions: (1) Cu(MeCN)4OTf
precursor (0.05 mmol in 1 mL MeCN) (2) ligand L1 (0.05 mmol in 1 mL MeCN) (3) TEMPO·
(0.05 mmol in 1 mL MeCN) (4) N-methylimidazole (NMI, 0.1 mmol in 1 mL MeCN) for a total
volume of 5 mL MeCN and a substrate concentration of 0.2 M. The conversion of the
aldehydes was monitored by TLC which is often accompanied by a change in the colour of
the reaction mixture to green.
Upon complete conversion to the aldehyde, two different purification methods were used:
(A) The solvent was removed in vacuo and purified by silica column chromatography (with
an appropriate eluent) or (B) the oxidation reaction was quenched by the addition of water
(25 mL) and dichloromethane (DCM, 25 mL). The layers were separated and the aqueous
layer was extracted with DCM (2 x 25 mL) and dried over Na2SO4 and then the solvent was
removed in vacuo. Further details for each substrate are provided in the Supporting
Information.
Conflicts of Interest
There are no conflicts of interest to declare.
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Acknowledgment
DOI: 10.1039/C7OB01383C
This work is based on the research supported by the National Research Foundation of South
Africa for the grant, Unique Grant No. 99305 and North-West University. Any opinion, finding
and conclusion or recommendation expressed in this material is that of the author(s) and the
NRF does not accept any liability in this regard. The infrastructure support provided by the
Focus Area for Chemical Resource Beneficiation (CRB) and in particular the Catalysis and
Synthesis group, at the NWU, is gratefully acknowledged.
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