Homogeneous CuCl2/TMEDA/TEMPO-Catalyzed chemoselective base- and halogen- free aerobic oxidation of primary alcohols in mild conditions

Article abstract of DOI:10.1016/j.apcata.2021.118289

This article describes the developing of a base- and halogen- free homogeneous system aiming to chemoselectively oxidize allyl, furyl, aryl and heteroaryl primary alcohols. The current easy-to-handle aerobic system uses few amounts of CuCl₂/TMEDA/TEMPO system under mild reaction conditions to produce aldehydes in high yields. Moreover, the CuCl₂/TMEDA cyclic voltammetry was measured for the first time, disclosing that TMEDA as ligand substantially affects the redox potential (E1/2) of the couple E1/2Cu²⁺/Cu⁺ to E1/2Cu²⁺/Cu⁺-TMEDA by 454 mV in the redox system.

Full text of DOI:10.1016/j.apcata.2021.118289

Applied Catalysis A, General 623 (2021) 118289
Contents lists available at ScienceDirect
Applied Catalysis A, General
journal homepage: www.elsevier.com/locate/apcata
Homogeneous CuCl /TMEDA/TEMPO-Catalyzed chemoselective base- and
2
halogen- free aerobic oxidation of primary alcohols in mild conditions
a
a
a
b
Emmanuel D. Silva , Ot ´a vio A.L. Alves , Rog ´e rioT. Ribeiro , Rafael C.R. Chagas , Jos ´e A.F.
b
a,b,
P. Villar , Jefferson L. Princival
*
a
Departamento de Química Fundamental, Universidade Federal de Pernambuco, Recife, PE, Brazil
Laborat ´o rio de Cat a´ lise Org aˆ nica, Universidade Federal de S a˜ o Jo a˜ o del-Rei, Campus Centro-Oeste Dona Lindu, Divin ´o polis, MG, Brazil
b
A R T I C L E I N F O
A B S T R A C T
Keywords:
This article describes the developing of a base- and halogen- free homogeneous system aiming to chemo-
selectively oxidize allyl, furyl, aryl and heteroaryl primary alcohols. The current easy-to-handle aerobic system
Aerobic oxidation
Homogeneous catalysis
Chemoselective
uses few amounts of CuCl
2
/TMEDA/TEMPO system under mild reaction conditions to produce aldehydes in high
/TMEDA cyclic voltammetry was measured for the first time, disclosing that TMEDA
yields. Moreover, the CuCl
2
as ligand substantially affects the redox potential (E1/2) of the couple E1/2Cu2 /Cu to E1/2Cu /Cu -TMEDA
+
+
2+
+
by 454 mV in the redox system.
1
. Introduction
Chemoselective oxidation of primary alcohols into aldehydes is un-
formation of insoluble precipitates during the course of reaction due to
the catalytic system deactivation as the failure [13].
Historically, the first study involving catalytic aerobic oxidation of
doubtedly a relevant transformation in organic chemistry [1,2]. More-
over, due to this ordinary transformation usually requires stoichiometric
or even large excess of oxidants, unwanted chemical wastes, such as
harmful by-products are commonly generated. Therefore, due to the
ability in activate molecular oxygen and thus mediate nitroxyl radical
oxidations, the use of transition metal in catalytic aerobic oxidation
systems, where atmospheric-air can be used as end-oxidant, has proved
to be a valuable alternative to promote this pivotal oxidation [3,4].
Among available general methods the use of TEMPO/NaOCl [5] and
TEMPO/Laccase [6,7] have proved to be a valuable alternative for this
proposal. Some attractive features of these processes include high atom
efficiency (E factor) [8], reagent economy and furthermore, the gener-
ation of water as by-product.
alcohols by copper complexes was reported by Mark o´ et al. in 1996 [17].
At that time, CuCl-phenanthroline and concomitant TEMPO were used
◦
as catalyst in the presence of two equivalents of K
2
CO
3
at 90 C. How-
ever, some aqueous systems [18], especially if peroxides are present [2,
19,20], can lead to a noticeable overoxidation of primary alcohols to
carboxylic acids.
Despite the pioneering work involving catalytic aerobic oxidation of
alcohols by copper complexes has been accomplished a quarter of cen-
tury ago today, the vastly literature still using copper-bipyridine based
system as the most usual method for this proposal [10,21,22].
The first example of base-free homogeneous catalyst was only re-
ported by Repo et al., in 2012, where the alcohol oxidation was per-
◦
formed at 80 C in the presence of 2 mol% of N-isopropyl-3,5-di-tert-
According to the literature, and of particular interest, one of the most
applicable approaches to accomplish these catalytic aerobic oxidations
employs 2,2,6,6-tetramethyl-piperidinyloxyl (TEMPO) concomitantly
with Cu(II) complexes [9–11]. In this regard, binding agents such as
Salen [12], diimine [13], pyridyl-imine [14] and triazine [9] are the
most usually complexing agents found. Although Cu/TEMPO system is
able to oxidize alcohols, large excess of a base and/or co-solvent are
needed to efficiently achieve these transformation [12]. Specifically for
homogeneous systems, the usually troublesome issue came from the
butylsalicylaldimine as ligand [23]. More recently, Shuang Gao et al.
2
reported CuI/Me -bipy/NMI as an alternative for the oxidation of al-
cohols even if that process does not present selectivity amongst primary
and secondary alcohols [24]. It is important to highlight that from the
vastly effective methods reported so far, heating as well as the needing
of auxiliary substances such as basic metallic salts, and/or co-solvents
remains required. Hence, due to the permanent demand for catalytic
methods, and the lack of information for homogeneous CuCl
2
/TMEDA,
we decided investigating the CuCl /TMEDA/TEMPO as a homogeneous
2
*
Corresponding author at: Universidade Federal de S ˜a o Jo a˜ o del-Rei, Campus Centro-Oeste Dona Lindu, Divin o´ polis, MG, Brazil.
E-mail address: princivalj@yahoo.com.br (J.L. Princival).
https://doi.org/10.1016/j.apcata.2021.118289
Received 14 May 2021; Received in revised form 7 July 2021; Accepted 12 July 2021
Available online 15 July 2021
0
926-860X/© 2021 Elsevier B.V. All rights reserved.

E.D. Silva et al.
Applied Catalysis A, General 623 (2021) 118289
catalytic system to chemoselectively oxidize allyl, furyl, aryl and het-
eroaryl primary alcohols.
Table 1
Ligand influence in the oxidation of 1a.
2
. Experimental
2
.1. Materials and methods
Entry
Catalyst
Equivalent
Conversion
1
2
3
4
5
6
7
8
9
CuCl
CuCl
2
2
0.1
1.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
None
None
99 (%)
89 (%)
55 (%)
None
None
None
None
Trace
None
Commercially available (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl
′ ′
CuCl2 + TMEDA (1:1)
(
TEMPO), N,N,N ,N -Tetramethylethylenediamine, (TMEDA), CuCl and
2
CuCl
CuCl
CuCl
2
2
2
+ TMEDA (2:1)
+ TMEDA (1:2)
+ Phen (2:1)
alcohol substrates were purchased from Sigma-Aldrich company and
used without any further purification. The reactions were monitored
using aluminum TLC plates 20 × 20 cm on silica gel 60 of Macherey-
Nagel® and the reagent consumption was accomplished in a SHI-
MADZU® 2010 Plus GC/FID system coupled with an auto sampler in the
CuCl2 + Phen (1:1)
CuCl
CuCl
CuCl
CuCl
2
2
2
2
+ Phen (0.5:1)
+ Bipy (2:1)
+ Bipy (1:1)
+ Bipy (0.5:1)
1
1
0
1
2
presence of N as the carrier gas. The voltammograms were obtained
with an AUTOLAB potentiostat PGSTAT128 N (Metrohm) model in a
three-electrode system electrochemical cell, charged with Ag/AgCl
3
.0 M electrode as reference.The UV–vis spectral data were obtained in
the 300–800 nm range on a UV-Genesys 10S spectrophotometer
Thermo Fisher Scientific, USA).The measurements were carried out in
Table 2
CuCl /TMEDA concentration effect for the oxidation of 1a.
2
(
Entry
Substrate
Product
Conv.
Time (min)
CuCl
2
/TMEDA (mol %)
triplicates using a glassy carbon and a platinum wire as working and
auxiliary electrodes, respectively.
1
2
3
4
5
6
7
8
99 %
99 %
99 %
99 %
98 %
98 %
98 %
89%
90
10
5
110
110
120
120
120
120
160
2.5
1
2
2
.2. Preparation of CuCl /TMEDA coordination compound
0.5
0.25
0.1
To a 25 mL-round bottom flask, containing CuCl
34.4 mg) and equipped with a magnetic stir bar were sequentially
L). The resulting
suspension was stirred until the greenish blue solution turned clear
2
(1.0 mmol,
1
0.012
added, MeCN (10 mL) and TMEDA (1.0 mmol, 150
μ
Conditions: Air; 25 oC; 1a (3 mmol); MeCN (5 mL); TEMPO [1 mol% by adding
300 L of a 0.1 M solution in acetonitrile].
(
10 min). The 0.1 M final concentration solution can be stored for
μ
◦
several months at ꢀ 15 C without losing activity. Alternatively, CuCl
2
/
◦
TMEDA can be obtained as an amorphous solid (m.p. 123 C).
measurements. The reagents CuCl2 (1 mmol, 134.4 mg) and TMEDA
1 mmol, 150 L) were dissolved in a freshly prepared solution of LiCO
(
μ
4
2
.3. Typical procedure for the Aerobic oxidation of alcohols using CuCl
2
/
(0.3 M) in acetonitrile (10 mL). The following parameters were used:
scan rate 100 mV/s and potential window -0.4 V to 1.0 V.
TMEDA/TEMPO
Method A: A 20-mm culture tube with capacity to 15 mL and
2
.5. Structure characterization of compounds 2a-m
equipped with a magnetic stirrer was loaded with MeCN (2 mL), CuCl
2
ꢀ
3
ꢀ 3
(
3.0 × 10 mmol, 0.4 mg) and TMEDA (3.0 × 10 mmol, 0.45
μ
L). To
The structural characterization of the compounds was carried out by
this slightly greenish blue solution, alcohol 1b (3 mmol, 320
μ
L) and
1
13
-
2
H NMR at 300 MHz and 400 MHz, and C at 75 MHz and 100 MHz,
respectively, using deuterated chloroform (CDCl ) as solvent and Me Si
TEMPO (3.0 × 10 mmol, 4.7 mg, 1.0 mol%) were added at room
◦
◦
temperature (25 C). The opened flask reaction was stirred at 25 C
under bubbled air (see apparatus on SI) where within 2 h, the total
conversion of 1b was confirmed by GC/FID. Then, the crude was filtered
off in a minimal amount of silica gel (ca. 10 mg) furnishing 353 mg of
the pure p-tolualdehyde (2b) in 98 % of yield.
3
4
as internal standard. The chemical shifts are expressed in ppm and
coupling constants (J) are in Hz. For the compounds already reported in
the literature, the CAS number was provided.
Method B: Into a 20-mm culture tube with capacity to 15 mL and
3. Results and discussion
charged with a solution of the alcohol 1b (3 mmol, 320
2 mL), were sequentially added TEMPO (300 L of a 0.1 M solution in
acetonitrile, 1.0 mol%) and CuCl /TMEDA (15 L of a 0.1 M solution in
μ
L) in MeCN
(
μ
Initially, the investigation was focused for the formation of soluble
2
μ
complexes. Thus, CuCl
under different organic solvents. From this solubility trials, MeCN and
2
DCM were set as the most effective solvents to generate soluble CuCl /
2
was reacted upon different amounts of TMEDA
acetonitrile, 0.1 mol%) via syringe in one portion. The reaction was
◦
stirred at 25 C under bubbled atmospheric air in an opened flask and
monitored by GC/FID, where within 2 h, the total conversion of 1b was
confirmed. Finally, the crude material was filtered off in a minimal
amount of silica gel (ca. 10 mg) furnishing 2b in 98 % of yield. The
reactions using either Method A or Method B were able to produce 2b
with the same yield. A detailed solvent effect study and a scalable pro-
cedure can be found in S.I. Moreover, the values of TON/TOF/E-factor
are given in the Table 2.
TMEDA (see details in S.I.). Curiously, while different proportions of the
reactants were being tested, a noticeable organoleptically odor could be
rated. Whilst no odor was detected reacting equimolar TMEDA and
CuCl
CuCl
2
an intrinsic TMEDA compatible odor could be detected reacting
with TMEDA in ratios other than 1:1, that suggests the generation
2
of non-stable complexes. In addition, and in order to test the potential of
homogeneous CuCl /TMEDA in the oxidation reactions, we also pre-
2
pared known Phenantroline (Phen) and Bipyridine (Bipy) complexes in
order to evaluate their effectiveness and compare their reactivity in a
base free catalytic system. Thus, the compound 1a was used as the model
substrate in MeCN (Table 1).
2
.4. Voltammetry of CuCl
2
//TMEDA at glassy carbon electrode
◦
The experiments were conducted at 25 C in an inert atmosphere by
purging the cell with
N
2
for 15 min immediately before the
According to the Table 1, where the experiments were carried out
2

E.D. Silva et al.
Applied Catalysis A, General 623 (2021) 118289
2
Fig. 1. CuCl /TMEDA/TEMPO-catalyzed oxidation of 1a under different atmosphere.
under fixed concentration of TEMPO (1 mol%) and air (1 atm) as oxi-
Table 3
◦
dants, at 25 C, a remarkable difference in reactivity was observed in
Base effect for the oxidation of 1b.
favor of CuCl
observe the feasible oxidation of the compound 1a, especially when both
CuCl and TMEDA were used. Although, neither Phen nor Bipy were
capable to produce active catalysts, therefore reaching no conversion of
a. This striking feature indicates that the coordinated TMEDA is acting
2
/TMEDA (Table 1, entries 3–5). There, it is possible to
Base
K
2
CO
3
Pyridine
NMI
Equivalent
Yield
0.1/0.5/1
96/63/54
0.1/0.5/1
90/76/69
0.1/0.5/1
95/90/84
2
◦
1
Conditions: Air; 25 C; 1b (3 mmol); MeCN (2 mL); TEMPO [1 mol% by adding
300 L of a 0.1 M solution in acetonitrile]; CuCl /TMEDA (1 mol %). Yield after
as a more efficient basic co-catalyst ligand, if compared to Phenantroline
and Bipyridine, which generate non-reactive intermediates under the
current base free system, therefore showing unproductive results
μ
2
2
h of reaction.
2
(
Table 1, entries 6–11). Among the most feasible result a feasible
(θ = 0.309). Additionally, these parameters can be reinforced by a
recent reported study, where captive radical-dimer association demon-
strates to be very sensitive upon polar solvents [31].
oxidation of the compound 1a is found when both CuCl and TMEDA
2
were used in equimolar amounts (Table 1, entry 3), reaching a conver-
sion of 99 %. However, slight decrease in reactivity was found when two
Finding great reactivity when the soluble complex was prepared in
equivalents of CuCl
while a deeply low conversion occurred when TMEDA doubled the
CuCl amount (Table 1, entry 5). This result shows that, aside from the
2
compared to TMEDA were used (Table 1, entry 4),
2
MeCN by reacting equimolar amounts of CuCl and TMEDA, an adjust-
ment of the catalyst amounts were performed until an acceptable con-
version of 1a was achieved in the presence of a fixed concentration of
mediator (Table 2). From this adjustment, a decent value of conversion
2
presence of additional base being unnecessary, the soluble catalyst
generated by equimolar amount of TMEDA was crucial for the reaction
effectiveness.
2
could be found ranging the concentration of the CuCl /TMEDA from ca.
0.01 mol % (Table 2, entry 8).
In order to demonstrate the breakthrough of the current results, we
Summarizing the results from Table 2, where the limitation of the
reaction is evidenced when catalyst less than 0.01 mol% is used, we
established the usage of 0.1 mol % of Cu(II)/TMEDA in the presence of
1 mol% of TEMPO as the standard conditions. Under this circumstance,
a 98 % conversion of 1a was observed within 2 h (Table 1, entry 7). It is
also important to highlight that while TEMPO amount is increased from
1 to 10 mol%, the reaction provides identical yields, although becoming
five times faster, correspondingly.
2 3
can mention the need of CuCl/Phenantroline/K CO in equimolar
◦
amount to produce 2a in only 50 % of yield at 80 C [25]. The great
difference in reactivity becomes more evident if the obtained results are
compared to other reported methods, from where bipyridine-based
catalyst have been used. As example, we can mention the need of
3 4
external base when CuCl/Phenantroline/K PO system was applied to
oxidize 1a into 2a, in 73 % after 3 h [26]. Similarly, the process using
Cu/NMI/TEMPO needs two equivalents of NMI, beyond the requirement
of 25 h to furnish 2a [27].
In order to fine-tuning the oxidation batches, we also investigated
the efficiency of the system reacting 1a upon two distinct sources of
oxygen (atmospheric air and pure O
experiments depicted in Fig. 1, a very similar behavior was found using
either air or O in the presence of DCM or MeCN (cyano and green
2
) (Fig. 1). From the most effective
2
colors, respectively), accurately those afore mentioned as the most
efficient solvents to solubilize the catalyst (see details in S.I.). In these
2
reactions, while 1a reaches 97 % (air) and 99 % (O ) of the conversion in
MeCN, the use of DCM leads to a 90 % of conversion independently of
oxidant source. However, when the reactions were performed using
solvents such as DMF or DMSO, a more sensitive effectiveness was
2
detected in favor of pure O instead of air. At last, in THF very low
substrate conversion was observed.
The current process suggests its rate-determining step outcome is due
to the ability of oxygen to be solubilized in MeCN [28], and thus pro-
mote catalyst reoxidation. As the radical intermediates stabilization are
also crucial for the progress of the reaction, and thence the literature
reports MeCN as great radical stabilizing solvent due to its relative po-
Fig. 2. Cyclic voltammogram in MeCN. CuCl
2
(Black line) and CuCl2/TMEDA
2
0.3 M, under N ,
2
(Red line). Conditions: 2.5 mM CuCl , 2.5 mM TMEDA, LiCO
2
4
larity square (θ ) [29], the high activity of the system using this solvent
and 100 mV/s scan rate (For interpretation of the references to colour in this
figure legend, the reader is referred to the web version of this article).
is in agreement with the literature. Indeed, MeCN possess great ability in
solubilize oxygen, where the following values of relative polarity square
2
2
are reported [30]: MeCN (θ = 0.460) > DMSO (θ = 0.444) > > DCM
3

E.D. Silva et al.
Applied Catalysis A, General 623 (2021) 118289
Table 4
2
Alcohols (1a-p) oxidations with catalytic system CuCl /TEMPO.
a
ꢀ 1
b
c
Entry
1
Substrate
Product
Yield /Conv.(%)
Time (h)
2h
TON/TOF(h
980/490
)
E-factor (kg/kg)
5.32
98/99
98/99
(
334/167) [37]
980/490
356/178) [38]
964/482
8/0.87) [33]
2
3
2h
2h
4.30
3.95
(
94/98
(
4
5
93/99
94/99
3 h
2h
960/480
20/0.83) [27]
4.50
3.54
(
964/482
20/0.83) [27]
(
6
7
93/96
92/96
2h
960/480
95/47) [39]
3.24
5.30
(
3 h
944/314
20/0.83) [27]
(
8
9
0/trace
97/98
72h
2h
–
–
388/194
5.09
(
80/40) [37]
384/192
16/4) [24]
1
0
96/98
2h
3.33
(
1
1
1
2
96/99
2h
384/192
1.5/0.16) [33]
4.99
(
0/trace
72h
–
–
1
3
2a 98/99
2h
–
–
2
p 0/trace
◦
Conditions: air, 25 C, 1a-k (3 mmol), MeCN (2 mL), 1 mol % of TEMPO [300
μ
L of a 0.1 M solution in acetonitrile; 0.03 mmol], 0.1 mol% of CuCl
2
/TMEDA [30 L of a
μ
a
b
c
0
.1 M solution in acetonitrile, 0.003 mmol]. Isolated Yield. For: TON/TOF and E-factor see details in the supplementary information.
These parameters induce to an easier oxidation of the substrates,
even if reduced TEMPO was used in the presence of diminished amount
of CuCl /TMEDA. Nonetheless, a limitation is evidenced when TEMPO
and TMEDA as shown on the cyclical voltammetry depicted in the Fig. 2.
The cyclical voltammetry clearly shows the effect of the TMEDA
ligand by decreasing the redox potential (E1/2) of the couple by 454 mV.
2
2
+
+
2+
+
less than 1 mol% was used, where a very slow reaction rate and unsat-
isfactory results were observed (results not shown).
E
1/2 Cu /Cu = 0.546 V to E1/2 Cu /Cu + TMEDA = 0.0925 V.
These results can be represented in terms of energy of complexation
given by ΔG = - nFE and shows the increase in stability of the ion Cu2+
promoted by the nitrogen atoms of the ligand with a ΔG = - 44.3 KJ/
Additionally, the presence of a base was also evaluated in order to
find if it could promote whether the formation of compound 2b in higher
yield or lead to the formation of the product in shorter reaction time
mol, accordingly with complexation values from the literature [32],
+
(
Table 3)
As can be seen in Table 3, effective results were obtained when the
base was used in up to 0.1 equivalent, independently of the source,
therefore establishing K CO and NMI possessing similar behavior.
which also indicates the easier oxidation of Cu by O
2
, recycling the
reagents and completing the cycle of the catalytic reaction
Thus, after having finely tuned, the protocol was further extended in
order to examine its capability and substrate selectivity upon a panel of
substrates (Table 4). Without exception, the current approach shown to
be very effective, being able to oxidize allyl, furyl, aryl and heteroaryl
primary alcohols with very high yield, even if water is produced during
the course of the reaction. The system successful outcome becomes more
evident if the results are compared with other classical reported pro-
cedures, especially considering the selectivity and functional group
tolerance. One example of great interest was the smoothly oxidation of
2-picolinic alcohol 1 m (Table 4, Entry 11). While under the conditions
depicted here 2 m could be obtained in 96 % of yield, according to the
literature none or very poorly results are described when picolinic al-
2
3
Comparing ratios of 50 % and 100 %, the use of NMI turned out to be the
most robust system, leading to the formation of 2b in 90 and 84 %
respectively. Although, as the loading of such bases does not represent
remarkable advantages, and implies in atom economy we decided to
further extended the experiments using a smoothness base free system.
2
Rationalizing that CuCl /TMEDA exhibits higher oxidative ability, it
can be associated to the freedom’s movement and steric effects, as
observed by Kerton et al. [14]. Thus, and due to the lack of information
using homogeneous CuCl
tions, a potentiodynamic electro-chemical measurement was carried out
in order to accomplish the formation of a stable complex between CuCl
2
/TMEDA system in catalytic aerobic oxida-
2
3 3
cohols are subjected to undergo oxidation using Eu(NO ) /TEMPO/
4

E.D. Silva et al.
Applied Catalysis A, General 623 (2021) 118289
approach has great potential for designing homogeneously cooper re-
action other than oxidation of alcohols.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
2
Scheme 1. CuCl /TMEDA/TEMPO selectively catalyzed aerobic oxidation of
allyl, furyl, aryl and heteroaryl primary alcohols.
Acknowledgements
3
NaNO system, under similar conditions [33]. In these studies, the main
catalytic failure is due to deactivation caused by nitrogenized substrates.
Summarizing the factual results, it is important to highlight the high
catalytic performances and the usefulness of the catalytic system (e.g.,
mild reaction conditions, base free, and open-air flask), whereas under
the depicted conditions it was possible obtain aldehydes in very high
isolated yields.
The authors thank CNPq, FACEPE, CAPES, FAPEMIG, UFPE and
UFSJ for financial support as well as for the infrastructure. This paper is
dedicated to Professor Jo a˜ o V. Comasseto on the occasion of his 45 years
as a professor since being hired in 1976. Professor Comasseto was who
inspired me to work for developing simpler and more cost-effective
catalytic processes to efficiently synthesize organic compounds.
2
Taking into account that the CuCl /TMEDA/TEMPO system pro-
motes a very fast oxidation of primary alcohols in neutral conditions, it
implies the current oxidations proceed as a reversed chemoselectivity.
Due to this, and since in neutral conditions the oxidation of secondary
alcohols should be faster than are primary alcohols [34], a competitive
experiment was conducted as statement. Thereby, equimolar amounts of
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