Solvent-Free Aerobic Oxidation of Alcohols to Nitriles Catalyzed by Copper Iodide in Combination with a Quaternary Ammonium Modified TEMPO

Article abstract of DOI:10.1007/s10562-015-1634-0

A catalytic system consisting of N,N-dimethyl-(4-(2,2,6,6-tetramethyl-1-oxyl-4-piperidoxyl)butyl)dodecyl ammonium bromide (TEMPO-Q), CuI and 2,2′-bipyridine was established. This catalytic system (CuI/bpy/TEMPO-Q) showed high activity and good to excellent selectivity in the oxidative conversion of various alcohols to the corresponding nitriles with molecular oxygen as terminal oxidant and aqueous ammonia as nitrogen source under solvent-free conditions. Besides, the catalytic system also offers the advantages of simplified workup procedure. This protocol thus represents a greener pathway for the synthesis of nitriles from alcohols. Graphical Abstract: TEMPO-Q, a compound with both a TEMPO and a quaternary ammonium moieties, in combination with copper iodide and 2,2′-bipyridine as a catalytic system performed well in the oxidation of alcohols to nitriles with molecular oxygen as terminal oxidant in aqueous ammonia under solvent-free conditions. The catalytic system not only offers the advantages of simplified workup procedure, but also has high activity and selectivity due to the phase transfer catalysis of TEMPO-Q[Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-015-1634-0

Catal Lett
DOI 10.1007/s10562-015-1634-0
Solvent-Free Aerobic Oxidation of Alcohols to Nitriles Catalyzed
by Copper Iodide in Combination with a Quaternary Ammonium
Modified TEMPO
1
1
1
1
Yuecheng Zhang
•
Rong Huang
•
Baosheng Gao
•
Jiquan Zhao
Received: 15 July 2015 / Accepted: 25 September 2015
Ó Springer Science+Business Media New York 2015
Abstract A catalytic system consisting of N,N-dimethyl-
(
Graphical Abstract TEMPO-Q, a compound with both a
4-(2,2,6,6-tetramethyl-1-oxyl-4-piperidoxyl)butyl)dodecyl
TEMPO and a quaternary ammonium moieties, in com-
0
0
ammonium bromide (TEMPO-Q), CuI and 2,2 -bipyridine was
established. This catalytic system (CuI/bpy/TEMPO-Q)
showed high activity and good to excellent selectivity in the
oxidative conversion of various alcohols to the corresponding
nitriles with molecular oxygen as terminal oxidant and aqueous
ammonia as nitrogen source under solvent-free conditions.
Besides, the catalytic system also offers the advantages of
simplified workup procedure. This protocol thus represents a
greener pathway for the synthesis of nitriles from alcohols.
bination with copper iodide and 2,2 -bipyridine as a
catalytic system performed well in the oxidation of
alcohols to nitriles with molecular oxygen as terminal
oxidant in aqueous ammonia under solvent-free condi-
tions. The catalytic system not only offers the advantages
of simplified workup procedure, but also has high
activity and selectivity due to the phase transfer catalysis
of TEMPO-Q
O2
H
O2
Organic phase
Ph
OH
Ph
N
Ph
O
Interface
TEMPO-Q
[bpyCu]
TEMPO-Q + TEMPO-Q
Ph
NH
[bpyCu]
.
H O
NH H O H O
H O
2
2
3
2
2
Aqueous phase
Keywords N,N-Dimethyl-(4-(2,2,6, 6-tetramethyl-1-
oxyl-4-piperidoxyl)butyl) Á Dodecyl ammonium bromide Á
Copper iodide Á Alcohol Á Nitrile Á Solvent-free Á Aerobic
oxidation
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-015-1634-0) contains supplementary
material, which is available to authorized users.
1
Introduction
&
Jiquan Zhao
zhaojq@hebut.edu.cn
Nitriles are a very important class of compounds in chem-
istry because they serve as versatile synthetic precursors and
intermediates in pharmaceuticals, material, and fine chemi-
cals [1–7]. Traditionally, nitriles were synthesized through
1
School of Chemical Engineering and Technology, Hebei
University of Technology, Tianjin 300130,
People’s Republic of China
123

Y. Zhang et al.
the nucleophilic displacement of various leaving groups,
such as halogen compounds, aryl sulfonates, alcohols, esters,
ethers, nitro or amino compounds and diazonium salts with
inorganic cyanide ions [8, 9]. However, the use of toxic
solvents and stoichiometric amounts of reagents along with
the production of large amounts of inorganic waste and
tedious work-up procedures limits their application from a
viewpoint of green chemistry. Therefore, the development
of environmentally friendly procedures for nitrile synthesis
is a very important subject in modern organic synthesis. As a
consequence, many novel methods including use of DMF as
the CN source for C-H functionalization of arenes [10–12],
oxidative dehydrogenation of benzylic alcohols or methy-
larenes in the presence of various nitrogen sources [13–19],
and dehydrogenation or oxidative dehydrogenation of pri-
mary amines [20–23] have been developed. Among all of
them, the ones based on the aerobic oxidation of alcohols to
nitriles in the presence of aqueous ammonia or its surrogate
are the most attractive due to easy availability of molecular
combination with urea and Fe(NO ) Á9H O showed good
3
3
2
performances in the selective oxidation of various alcohols to
the corresponding aldehydes and ketones under mild and
solvent-free conditions with molecular oxygen as terminal
oxidant. Moreover, TEMPO-Q is stable and non-volatile,
thus, could be recovered easily and recycled up to five times
in the oxidation of benzyl alcohol without significant loss of
catalytic activity. When we employed TEMPO-Q in the
oxidative conversion of alcohols to nitriles in aqueous
ammonia under solvent-free conditions, good results were
also received and TEMPO-Q could be easily separated from
the mixture and recycled, too. Herein, we report the catalytic
performances of TEMPO-Q in combination with a copper
iodide (CuI) in the oxidative conversion of alcohols to nitriles
with molecular oxygen as a terminal oxidant.
2 Experimental
oxygen and H O as the only by-product in principle. Several
2
2.1 Materials and Apparatus
strategies for this transformation have been accomplished
either under the promotion of heterogeneous or homoge-
neous catalysts. Ru(OH) /Al O [24], MnO or MnO -sup-
0
Aqueous ammonia (25 %), copper iodide (CuI), 2,2 -
bipyridine and other reagents were obtained from Tianjin
Fuchen Chemical Reagent Factory, China. All reagents
were used as received without further purification. The
secondary alcohols were obtained from Alfa Aesar China
(Tianjin) Co., Ltd. The N,N-dimethyl-(4-(2,2,6,6-tetram-
ethyl-1-opiperidoxylxyl-4-)butyl)dodecyl ammonium bro-
mide (TEMPO-Q) was prepared as described in the
literature [32] reported by us.
x
2
3
2
2
ported on graphite [25, 26] and nitrogen-doped graphene-
layered cobalt or iron oxides [27] as heterogeneous catalysts
have been proved to be effective in the reaction. However,
high temperature and pressure are generally required in
these cases. Amongst homogeneous catalysts, Cu/TEMPO
and Fe/TEMPO which have been demonstrated earlier to
oxidize alcohols to aldehydes under aerobic conditions at
ambient temperature also showed good performances in the
aerobic oxidation of alcohols to nitriles in the presence of
aqueous ammonia. For instances, Tao et al. [28] employed
Cu(NO ) /TEMPO in DMSO whereas Huang et al. [29] used
1
H MNR spectra of nitriles were recorded with TMS as
internal standard on a Bruker AC-P 400 spectrometer.
Oxidation reaction samples were analyzed on a Shandong
Lunan Ruihong Gas Chromatograph (SP-6800A) equipped
with a FID detector and a SE 30 column (30 m 9 0.5 lm).
3
2
CuI/TEMPO/bipyridine in ethanol or acetonitrile in the
presenceofoxygentoprepare nitrilesfromalcohols;Muldoon
et al. [30] and Batra et al. [31] respectively used Cu(OTf)2/
TEMPO/bipyridine and Fe(NO ) /TEMPO in acetonitrile in
2.2 Catalytic Oxidation
3
3
the presence of air instead of pure oxygen to achieve the
conversion of alcohols to nitriles. These homogeneous sys-
tems have been found being effective in the aerobic oxidative
conversion of alcohols to nitriles. However, a solvent is gen-
erally required in the homogeneous catalytic systems men-
tioned above, and the separation of TEMPO from reaction
products remains a problem especially on a large scale pro-
duction due to its volatility at distillation temperature of
products. Therefore, there is a need for developing a catalytic
system which can avoid the disadvantages described above.
Recently, we synthesized a quaternary ammonium with a
TEMPO moiety known as N,N-dimethyl-(4-(2,2,6,6-tetram-
ethyl-1-oxyl-4-piperidoxyl)butyl)dodecyl ammonium bro-
mide (TEMPO-Q). A catalytic system from this compound in
In a typical process, into a 5 ml two-necked, round-bottom
flask equipped with a magnetic stirrer and an oxygen bal-
loon were added TEMPO-Q (0.25 mmol, 130 mg), CuI
0
(0.25 mmol, 47.5 mg), 2,2 -bipyridine (0.25 mmol, 39 mg)
and aqueous ammonia (0.75 mL) successively. After which
the mixture was heated to 55 °C under strrring to reach a
clear solution. Then, oxygen from the balloon was intro-
duced and controlled through a triple valve to replace the
air. Finally, benzyl alcohol or other substrate (5 mmol) was
introduced through syringe. The reaction was run at 55 °C
under strong strrring. The final reaction conversion and
selectivity towards the corresponding nitrile were obtained
by adding the sample into 1.0 mL of ethyl alcohol to get a
homogeneous solution, then analyzing by GC.
1
23

Solvent-Free Aerobic Oxidation of Alcohols to Nitriles Catalyzed by Copper Iodide…
Table 1 Effect of each component in the CuI/bpy/TEMPO-Q catalytic system on the conversion of benzyl alcohol to benzonitrile
CN
OH
CuI/bpy/TEMPO-Q
NH (aq.), O balloon
3
2
o
5
5 C, 7 h
Entry
Bpy (mol%)
TEMPO-Q (mol%)
CuI (mol%)
Conversion (%)
Selectivity (%)
Nitrile
Aldehyde
Acid
1
2
3
4
5
–
5
5
5
5
–
5
5
5
5
–
99.8
97.6
5.9
93.9
80.7
71.2
17.1
2.9
19.2
28.8
82.9
3.1
0.1
0
7.3
0
Reaction conditions 5 mmol of benzyl alcohol, 5 mol% bpy, 5 mol% TEMPO-Q, 5 mol% CuI, 0.75 mL NH
reaction time 7 h, O pressure 0.1 MPa
3
2
ÁH O, reaction temperature 55 °C,
2
The results were determined by GC
Table 2 Effect of the copper salt on the aerobic oxidative conversion of benzyl alcohol to benzonitrile
CN
CuX1or 2/bpy/TEMPO-Q
NH (aq.), O balloon
OH
3
2
o
5
5 C, 7 h
Entry
Cu salt
Conversion (%)
Selectivity (%)
Benzonitrile
Benzaldehyde
Benzoic acid
1
2
3
4
5
6
7
CuBr
2
60.4
70.4
72.6
80.8
78.4
97.6
99.8
16.7
61.9
45.7
32.9
76.4
78.3
93.9
83.1
37.6
51.2
65.2
23.6
21.7
2.9
0.1
0.4
3.1
1.9
0
CuCl
CuCl
2
Cu(OAc)
2
Cu(OTf)
2
Cu(NO
CuI
3
)
2
0
3.1
Reaction conditions 5 mmol of benzyl alcohol, 5 mol% bpy, 5 mol% TEMPO-Q, 5 mol% Cu salt, 0.75 mL NH
reaction temperature 55 °C, O pressure 0.1 MPa
The results were determined by GC
3
ÁH
2
O, reaction time 7 h,
2
After reaction the product was extracted with EtOAc
and the extract was distilled at atmospheric pressure to
remove EtOAc. For the reaction with high conversion and
selectivity the product was obtained by direct distillation
under vacuum from the residue; otherwise, the product was
received by column chromatography of the residue on
silica gel using hexanes/EtOAc (95:5) as eluent.
catalytic system in acetonitrile. Therefore, the catalytic
performance of the TEMPO-Q in combination with CuI
and bpy was evaluated for the aerobic oxidative conversion
of benzyl alcohol to benzonitrile. Initially, the reaction was
carried out in 2.5 equiv of aqueous ammonia under atmo-
spheric O pressure and solvent-free conditions at 55 °C in
2
7 h in the presence of TEMPO-Q (5 mol%), CuI (5 mol%)
and bpy (5 mol%). Encouragingly, the expected product
was obtained in a yield of higher than 90 %. Then, the
necessity of each component of the catalytic system was
screened and the results are shown in Table 1. As observed
in the table, either only use of TEMPO-Q without CuI as a
co-catalyst or CuI in the absence of TEMPO-Q afforded
very poor results, which indicated that both TEMPO-Q and
CuI were essential in the aerobic oxidative conversion of
3
Results and Discussion
3
.1 Catalysis of the Novel Catalytic System
Huang et al. [29] first reported the aerobic oxidative con-
version of alcohols to nitriles using CuI/bpy/TEMPO as
123

Y. Zhang et al.
Table 3 The effect of the reaction temperature on the reaction
5 mol%)CuI/(5 mol%)bpy/(5 mol%)TEMPO-Q
CN
(
OH
o
NH (aq.), O balloon, 35~75 C, 7 h
3
2
Entry
Temperature (°C)
Conversion (%)
Selectivity (%)
Benzonitrile
Benzaldehyde
Benzoic acid
1
2
3
4
5
35
45
55
65
75
64.7
94.1
66.9
78.7
95.8
87.8
75.0
33.1
21.2
1.9
0
0.1
[99.0
[99.0
[99.0
2.2
1.5
10.6
23.8
1.1
Reaction conditions 5 mmol of benzyl alcohol, 5 mol% bpy, 6 mol% TEMPO-Q, 5 mol% CuI, 0.75 mL NH
pressure 0.1 MPa
3
2 2
ÁH O, reaction time 7 h, O
The results were determined by GC
benzyl alcohol to benzonitrile (Table 1, entries 3, 4). The
0
selectivity towards benzonitrile increased in the beginning
and reached its maximum (93.9 %) at 5 % mole of CuI
(Table 4, entry 3), and then decreased with further increase
of the CuI loading due to the deep oxidation of benzyl
alcohol to benzoic acid (Table 4, entries 4 and 5).
presence of 2,2 -bipyridine is also important. Though the
0
conversion of benzyl alcohol in the absence of 2,2 -bipyr-
idine was compared to that in the presence of all the
components, the selectivity towards benzonitrile was
decreased to 80.7 % from 93.9 % (Table 1, entries 1, 2).
Next, several other copper salts including copper (I) and
copper (II) salts were also evaluated as co-catalyst in the
aerobic oxidative conversion of benzyl alcohol to ben-
zonitrile in excessive aqueous ammonia. As shown in
Table 2, only CuI gave excellent yield of benzonitrile
The effect of TEMPO-Q loading on the reaction was
also examined under the same conditions, and the results
are also listed in Table 4. As can be seen from Table 4,
increasing the TEMPO-Q loading from 3 to 7 mol% led to
fast reaction, and the increase of the selectivity towards
benzonitrile (Table 4, entries 3 and 6–9). When the
TEMPO-Q loading was higher than 6 mol%, both the
reaction time required to finish the reaction and the
selectivity towards benzonitrile did not changed obviously
(Table 4, entries 8 and 9).
(
Table 2, entry 7). Though high conversion of benzyl
alcohol was received in the case of Cu(NO ) as co-cata-
2
3
lyst, the selectivity towards benzonitrile was only 78.4 %
Table 2, entry 6). Both CuCl and Cu(OTf) only exhib-
(
2
2
ited moderate conversion of benzyl alcohol and selectivity
towards benzonitrile under the same reaction conditions
After receiving the above results, TEMPO-Q and
TEMPO were compared as catalysts in the oxidative con-
version of benzyl alcohol to benzonitrile in various solvent
to screen the advantage of TEMPO-Q over TEMPO and
the results are given in Table 5. From the table we can
find that the use of TEMPO instead of TEMPO-Q resulted
in sharp decreases of both the conversion of benzyl alcohol
and the selectivity towards benzonitrile in water, toluene
and the absence of solvent under the same reaction con-
ditions (Table 5, entries 1–4 and 7, 8); and though
TEMPO-Q and TEMPO showed almost identical catalytic
activity in acetonitrile, the selectivity towards benzonitrile
is higher in the case of TEMPO-Q as catalyst (Table 5,
entries 5, 6). These results confirmed the favorable role of
the quaternary ammonium moiety to the oxidation reaction.
It is believed that TEMPO-Q acted as both a role of
TEMPO and a phase transfer catalyst in the reaction.
Besides, almost same results were obtained in water
compared to those in the absence of solvent (Table 5,
entries 1–4).
(
Table 2, entries 2, 5). Meantime, the other copper salts led
to unfavorable results due to either low activity or bad
selectivity towards benzonitrile (Table 2, entries 1, 3, 4).
For obtaining the optimal reaction conditions, the reac-
tion temperature was examined and the results are listed in
Table 3. It can be seen that the conversion of benzyl alcohol
increased with the increase of temperature; the selectivity
towards benzonitrile increased in the beginning and reached
its maximum at 55 °C (Table 3, entry 3), and then decreased
with further increase of reaction temperature. We speculated
that the decrease of the selectivity towards benzonitrile was
due to the low solubility of ammonia in solution at higher
temperature, leading to the deep oxidation of benzyl alcohol
to benzoic acid (Table 3, entries 3–5).
The amount of CuI was optimized at 55 °C keeping the
other parameters constant. The results are listed in Table 4,
from which it can be learned that the time to finish the
reaction shortened with the increase of CuI loading, and the
1
23

Solvent-Free Aerobic Oxidation of Alcohols to Nitriles Catalyzed by Copper Iodide…
Table 4 Effect of CuI or TEMPO-Q loading on the oxidative conversion of benzyl alcohol to benzonitrile
CN
OH
(x)CuI/(5 mol%)bpy/(y)TEMPO-Q
o
NH (aq.), O balloon, 55 C, 7 h
3
2
Entry
CuI (mol%)
TEMPO-Q (mol%)
Time (h)
Selectivity (%)
Benzonitrile
Benzaldehyde
Benzoic acid
1
2
3
4
5
6
7
8
9
3
4
5
6
7
5
5
5
5
5
5
5
5
5
3
4
6
7
13.5
9.5
7.0
6.5
5.0
7.5
7.0
7.0
7.0
66.3
86.2
93.9
82.3
73.0
67.8
89.3
95.8
96.1
21.4
7.2
2.9
6.5
7.8
28.4
7.4
1.9
1.9
12.2
6.5
3.1
11.1
19.1
3.7
3.2
2.2
1.9
Reaction conditions 5 mmol of benzyl alcohol, 5 mol% bpy, 0.75 mL NH
3
ÁH
2
O, reaction temperature 55 °C, O
2
pressure 0.1 MPa
The results were determined by GC, conversion of benzyl alcohol always higher than 99 %
Table 5 The oxidative conversion of benzyl alcohol to benzonitrile catalyzed by TEMPO-Q and TEMPO in various solvents
(
5 mol%)CuI/(5 mol%)bpy/(5 mol%)TEMPO-Q
CN
OH
or (5 mol%)CuI/(5 mol%)bpy/(5 mol%)TEMPO
o
NH (aq.), O balloon, solvent,
3
2
55 C, 7 h
Entry
Solvent
–
Time (h)
Catalyst
Conversion (%)
Selectivity (%)
Nitrile
Aldehyde
Acid
1
2
3
4
5
6
7
8
7
7
5
7
TEMPO-Q
TEMPO
99.9
57.3
99.9
65.0
99.9
99.9
99.9
80.2
95.8
75.2
95.8
72.9
95.5
80.4
94.7
51.7
1.9
24.8
2.3
2.2
0
2
H O
TEMPO-Q
TEMPO
1.9
0
27.1
2.7
MeCN
TEMPO-Q
TEMPO
1.8
0
19.6
5.1
Toluene
TEMPO-Q
TEMPO
0.1
0
48.3
Reaction conditions 5 mmol of benzyl alcohol, 5 mol% bpy, 6 mol% Cat, 5 mol% CuI, 0.75 mL NH
5 °C, O pressure 0.1 MPa
The results were determined by GC
3
2
ÁH O, 1.0 mL solvent, reaction temperature
5
2
From above experimental results we concluded the
employing various alcohols including benzylic alcohols,
heterocyclic alcohols, cinnamic alcohol, geraniol, and
representatives of aliphatic alcohols as substrates. The
results are shown in Table 6. It can be seen from Table 6
that various types of primary benzylic alcohols, including
those bearing both electron-withdrawing and electron-do-
nating groups, were converted to their corresponding
nitriles in good to excellent yields under the optimal
reaction conditions. However, the time required to finish
the reaction was different (Table 6, entries 1–5). It seems
optimal reaction conditions which are benzyl alcohol
0
5
6
mmol, 2,2 -bipyridine 5 mol%, CuI 5 mol%, TEMPO-Q
mol%, NH ÁH O 0.75 mL, reaction temperature 55 °C,
3
2
O pressure 0.1 Mpa. Under the optimal reaction conditions
2
the benzyl alcohol was converted to benzonitrile in a yield
near 95.8 % (isolated yield 89.0 %) in 7 h in the absence of
solvent.
Having obtained the optimal conditions for the reaction,
we then evaluated the generality of the methodology
123

Y. Zhang et al.
that the catalytic system is more efficient for the substrate
with an electron-withdrawing substituent (Table 6, entries
contradiction with those in the aerobic oxidation of alco-
hols to the corresponding aldehydes catalyzed by the
TEMPO-based catalytic systems, in which the electron-
donating substituents generally can accelerate the reaction
though not very strongly [33–36]. From the mechanism
2
–5, 6 and 7, 8 and 9), which is different from the catalytic
system reported by Huang et al. [29], but same as the one
reported by Batra et al. [31]. These results are in
Table 6 Oxidative conversion of various alcohols to nitriles
(
5 mol%)CuI/(5 mol%)bpy/(5 mol%)TEMPO-Q
R
N
R
OH
o
NH (aq.), O balloon, 55 C, 7 h
3
2
a
Conversion (%)
a
Selectivity (%)
b
Yield (%)
Entry
Substrate
Time (h)
Nitrile
Aldehyde
1.9
Acid
2.2
1
2
OH
7
99.9
93.8
95.8
91.9
95.7 (89.0)
86.2 (79.5)
OH
OH
OH
6.5
8.0
0.1
0.2
Cl
F
3
6.5
99.7
87.2
12.6
86.9 (80.6)
4
5
8.0
8.5
99.9
85.7
89.7
86.7
6.2
4.1
2.8
89.6 (82.2)
74.3 (67.5)
OH
10.5
O
O
6
7
OH
OH
8.0
7.0
82.9
86.4
72.9
97.1
27.0
2.8
0.1
0.1
60.4 (49.5)
83.9 (78.2)
F
8
9
OH
OH
10.5
9.0
73.2
86.2
99.1
77.5
88.8
99.9
20.4
11.2
0
2.0
0
56.7 (45.4)
76.5 (61.6)
99.0 (90.1)
O
Cl
F
1
0
2.5
0
OH
F
1
1
1
1
2
3
8.0
83.6
99.9
94.0
87.0
85.3
75.5
12.9
14.7
24.0
0
72.7 (66.3)
85.2 (77.9)
71.0 (63.1)
OH
S
N
9.0
0
OH
OH
10.0
0.5
1
1
4
5
O
12.0
10.0
93.1
–
87.2
–
12.8
–
0.1
–
81.2 (73.3)
(72.1)
OH
c, d
OH
1
6
0.0
–
–
–
0.0
HO
1
23

Solvent-Free Aerobic Oxidation of Alcohols to Nitriles Catalyzed by Copper Iodide…
Table 6 continued
a
Conversion (%)
a
Selectivity (%)
b
Yield (%)
Entry
Substrate
Time (h)
Nitrile
Aldehyde
–
Acid
–
1
7
8
OH
0.0
0.0
–
–
0.0
0.0
1
–
–
OH
Reaction conditions 5 mmol substrate, 0.75 mL NH
pressure 0.1 MPa
3
ÁH
2
O, 6 mol% TEMPO-Q, 5 mol% CuI, 5 mol% bpy, reaction temperature 55 °C, O
2
a
1
Conversions and selectivity were determined by GC (area normalization method); all products were determined by H NMR
The data in the parentheses is the isolated yields
b
c
d
Reation carried out in MeCN
Using N,N-dimethyl-(4-(2,2,6,6-tetramethyl-1-oxyl-4-piperidoxyl)butyl)benzyl ammonium bromide (TEMPO-Q’) instead of TEMPO-Q gave
same result
Fig. 1 TEMPO-Q promoted
oxidative conversion of alcohol
to nitrile in two-phase system
H
O2
O2
Organic phase
Ph
OH
Ph
N
Ph
O
Interface
TEMPO-Q
[bpyCu]
TEMPO-Q +TEMPO-Q
Ph
NH
[bpyCu]
.
H O
NH H O H O
H O
2
2
3
2
2
Aqueous phase
1
0
0
0
0
0
0
.0
.9
.8
.7
.6
.5
.4
supported by the fact that 3,5-difluorobenzyl alcohol with
two strong electron-withdrawing fluorines in the structure
was almost quantitatively converted to its corresponding
nitrile in only 2.5 h (Table 6, entry 10). In addition, the
position of the substituent on the benzene ring has strong
effects on the reactivity of benzylic alcohols. The substrate
with an o-substituent showed poor reactivity compared to
the ones with an m- and a p-substituent due to the steric
hindrance (Table 6, entries 2 and 9, 5, 6 and 8) present in
both the alcoholate-copper and imine-copper intermediates
[
29]. It is worth noting that the reaction must be carried out
in acetonitrile in the case of a-naphthalenemethanol as
substrate due to its higher melting point preventing it in a
liquid state under the reaction temperature (Table 6, entry
1
2
3
4
5
Times
Fig. 2 Recycling of TEMPO-Q in the aerobic oxidation of benzyl
alcohol to benzonitrile
15).
This catalytic system also showed good tolerance for
proposed by Huang et al. [29] it can be concluded that
aldehyde-to-nitrile transformation is a rate limiting step in
the conversation of alcohol to nitrile by this protocol,
which is in contrast to that in the presence of solvent. In the
aldehyde-to-nitrile transformation process, the strong
electron-withdrawing groups may enhance the reaction rate
due to the increase in electrophilicity of the carbonyl car-
bon of the aldehydes generated from the alcohols, which is
the heterocyclic substrates, and good to excellent yields of
the corresponding nitriles were received (Table 6, entries
12–14). 2-Thioylmethyl alcohol, which is usually regar-
ded as a difficult substrate in the aerobic oxidation to its
corresponding aldehyde catalyzed by transition metals
[37], was smoothly converted into thiophene-2-carboni-
trile in high yield (Table 6, entry 12); 2-pyridyl methanol
was also converted to 2-pyridinecarbonitrile in
a
123

Y. Zhang et al.
conversation of 94.0 % and a selectivity of 75.5 % under
the same reaction conditions in 10 h (Table 6, entry 13).
Cinnamic alcohol, which is a representative of aromatic
allylic alcohols, was converted to its corresponding nitrile
in a conversation of 83.6 % and a selectivity of 87.0 % in
of the total decrease of the selectivity towards benzonitrile
was observed after five times recycling (Fig. 2). The results
indicated that TEMPO-Q was stable and non-volatile and
easily separated from the product, which could overcome
the disadvantages of TEMPO in the same catalytic
reaction.
8
h (Table 6, entry 11).
Same as the copper/TEMPO-based catalytic systems
[
28, 29, 38], but in contrast to the Iron Nitrate/TEMPO
system [31], this catalytic system failed to afford the cor-
responding nitriles with aliphatic alcohols including
geraniol (Table 6, entry 16–18). This is unambiguously
attributed to the inefficiency of the copper/TEMPO-based
catalytic systems in aerobic oxidation of aliphatic alcohols
to aldehydes being intermediates in the oxidative conver-
sion of alcohols to nitriles [39–41].
4 Conclusions
In summary, we have established an efficient catalytic
system (CuI/bpy/TEMPO-Q) for the aerobic oxidative
conversion of benzylic and allylic alcohols to their corre-
sponding nitriles by using aqueous ammonia as the nitro-
gen source. TEMPO-Q with both a TEMPO and a
quaternary ammonium moiety acted as both a role of
TEMPO and a phase transfer catalyst, which allowed the
reaction proceeding smoothly under the solvent- and
additive-free reaction conditions. The novel catalytic sys-
tem not only offers the advantages of simplified workup
procedure, but also has high activity and selectivity due to
the phase transfer catalysis of TEMPO-Q. This protocol
thus represents a greener pathway for aerobic oxidation of
alcohols into their corresponding nitriles, which manifested
in the aspects of use of aqueous ammonia as nitrogen
source, absence of solvent in reaction.
Control experiments indicated that use of TEMPO
instead of TEMPO-Q resulted in a sharp decrease of
conversion of benzyl alcohol to benzonitrile (Table 5,
entries 1–4). In addition, the alcohol to nitrile conversion
rate in this case is much higher than the ones catalyzed by
the copper/TEMPO-based catalytic systems in the pres-
ence of various solvents [28–30]. On the basis of our
investigation and the reports in literature it can be con-
cluded that the attachment of a quaternary ammonium to
TEMPO plays central roles in the aerobic oxidative con-
version of alcohols to nitriles. Herein, due to the absence
of solvent the reaction system was consisting of aqueous
ammonia and alcohol (or aldehyde) two phases. In prin-
ciple the oxidative conversion of alcohol to nitrile is
consisting of three fundamental steps, which are the aer-
obic oxidation of alcohol to aldehyde, the condensation of
aldehyde with ammonia to intermediate imine, and the
aerobic oxidation of imine to nitrile [19, 29]. From both
Acknowledgments The authors are grateful for financial supports
from the National Natural Science Foundation of China (No.
2
1276061), Natural Science Foundation of Hebei Province, China
No. B2013202158), and Research Fund for the Doctoral Program of
(
Higher Education of China (No. 20121317110010).
?
the structures of the bpy-Cu generated in situ and
TEMPO-Q, it is convincible that they will mainly exist in
the interface between alcohol and aqueous ammonia.
Thus, all the three fundamental steps mainly take place in
the interface. Except for acting as a role of TEMPO,
TEMPO-Q also acting as a phase transfer catalyst helped
to transfer alcohol, aldehyde and ammonia into the
interface in the reaction process, which accelerated the
whole reaction (Fig. 1).
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