Reduction of aromatic nitriles into aldehydes using calcium hypophosphite and a nickel precursor

Article abstract of DOI:10.1039/c8ob01751d

Herein we report the reduction of aromatic nitriles into aldehydes with calcium hypophosphite in the presence of base and nickel(ii) complex in a water/ethanol mixture. This catalytic system reduced efficiently a series of aromatic nitriles bearing different functional groups such as -Cl, -CF₃, -Br, -CH₃, -OCH₃, -COOCH₂CH₃, -OH and -CHO. The corresponding aldehydes were isolated in moderate to excellent yields (30-94%).

Full text of DOI:10.1039/c8ob01751d

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Reduction of aromatic nitriles into aldehydes using calcium
hypophosphite and a nickel precursor
Rim Mouselmani,a, b Ali Hachem,b Ali Alaaeddine,b Estelle Métay*a and Marc Lemaire*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Herein we report the reduction of aromatic nitriles into aldehydes with calcium hypophosphite in the presence of base
and nickel (II) complex in a water/ethanol mixture. This catalytic system reduced efficiently a series of aromatic nitriles
bearing different functional groups such as –Cl, –CF3, –Br, –CH3, –OCH3, –COOCH2CH3, –OH and –CHO. The corresponding
www.rsc.org/
aldehydes
were
isolated
in
moderate
to
excellent
yields
(30-94%).
amines or aldehydes including the reductions by photo-
irradiation,9 the association of PtO2/aqueous formic acid,10 Ni-
Raney/formic acid,11 Ni-Raney/hydrazine hydrate,12 nickel-
based bimetallic systems in acidic medium,13 multiphase
system of compressed carbon dioxide over Ni/Al2O3,14 Ru- and
Pt-loaded zeolites.15 Silanes were also used, they have found
applications for the reduction of large number of functional
groups.16 TMDS/V(O)(OiPr)3 reducing system has been
reported by our group with high efficiency. Unfortunately, the
limitation concerns the high price of this reagent.17
Introduction
Aldehydes are often important intermediates in organic
chemistry, their selective synthesis is challenging due to their
high reactivity. One way to obtain aldehydes is the reduction
of nitriles. This transformation has been less investigated
compare to the reduction of C=C, C=O, C=N and NO2 bonds.
Nitriles possess high redox potentials compared to other
carboxylic acid derivatives. In addition, undesired decyanation
can occur during reduction due to the low dissociation energy
of C-CN bond. The high reactivity of the imine intermediate
could explain the side reactions such as the formation of
alcohols or reductive amination.1
In our search for a new reducing system which is selective,
economically accessible and with low environmental impact
we were interested by hypophosphites. These reagents are
available in large scale, and they are identified to be non-
hazardous substances. Hypophosphites have been described
to be efficient reagents for the reduction of different
functional groups in association with transition metals (Pd, Ni,
Ru ...). Notably in our group, nitro and ketones were
transformed with this reductant.18
Nitriles can be transformed into aldehydes by the Stephen
reduction, which involves the use of tin chloride and
hydrochloride acid.2 Aluminium hydrides were also used such
as Li(OEt)3AlH,3 DIBAL-H,4 and other derivates.5,6 In the
literature, borohydride reagents have been also reported for
this type of transformation.7 Aluminium and boron hydrides
are efficient, but they are not environmentally benign due to
the coproduction of stoichiometric amounts of waste salts.8
Moreover the workup is exothermic, reactions require the use
of water-soluble solvents, and the handling should be under
anhydrous conditions because of their violent reactivity upon
contact with water.
For the reduction of nitriles into aldehydes, using sodium
hypophosphite several examples can be found in literature but
always in similar conditions. More precisely, Staskun reported
this transformation using sodium hypophosphite and Ni-Raney
as a catalyst in a water/acetic acid/pyridine solution.19 In these
conditions aliphatic,20 aromatic,21 and heteroaromatic nitriles
were reduced.22 To the best of our knowledge, no
chemoselective reduction of nitriles has been reported using
Other reducing systems have also been reported towards
calcium hypophosphite as
a reducing reagent. Actually,
calcium hypophosphite is not toxic, applications in life sciences
and technology have been reported. For example, it is used on
cows suffering from parturient paresis,23 and has been
suggested as a good candidate for obesity treatment in
humans.24
Herein, we report the reduction of nitriles to the
corresponding aldehydes with calcium hypophosphite using
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Ni(OAc)2.4H2O and Ca(OAc)2.H2O, which are cheap and easy to
handle.
Table 1. Reduction of benzonitrile with Ca(H2PO2)2 catalyzed by
different metal catalysts. [a]
Entry
Catalyst
mol% Conv.[%][b
selectivity [%]
]
1
46
-
2
12
-
3
4
-
5
13
100
<5
-
6
<5
-
7
28
-
1
2
3
4
5
6
NiCl2.6H2O
CuCl2.2H2O
20
20
68
6
-
-
-
5 wt.% Pd/C
2.5
2.5
2.5
2.5
100
100
98
-
-
84
100
-
-
14
-
-
10 wt.% Pd/C
[RuCl2(p-cymene)]2
10 wt.% Pt/C
-
-
-
-
-
5
30
81
65
-
-
-
16
-
19
-
-
-
[a] all reactions were carried out with
1
mmol of benzonitrile. [b] Conversion of benzonitrile and GC selectivity were determined by GC
Moreover other catalyst precursors were tested and no
conversion was observed when using Mg(II), Fe(II) and Co(II)
precursors. On the basis of these results, different nickel
Results and Discussion
In a preliminary work with benzonitrile as a model substrate,
several hypophosphites have been tested, such as
hypophosphorous acid, sodium hypophosphite and ferric
hypophosphite and calcium hypophosphite. Only the later
allowed the formation of benzaldehyde. Different metal
catalysts were then screened with benzonitrile using calcium
hypophosphite (250 mol%) as a reductant and potassium
carbonate (40 mol%) in aqueous medium. In the course of this
catalyst screening, various side-products have been observed.
Over reduction of benzaldehyde and benzonitrile resulted in
the formation of benzyl alcohol and benzylamine respectively.
Hydration of the starting material gave benzoic acid and
benzamide. Reductive amination occurred between
catalysts were tested (Table 2). Though aforementioned side-
products were also formed, only GC selectivity of
benzaldehyde is showed, for more clarity. With NiCl2.6H2O as
shown before, benzaldehyde was obtained in 46% after 24h
with 68% conversion of benzonitrile (Table 2, entry 1). NiBr2
gave a lower conversion (37%) and a 51% selectivity for
benzaldehyde (Table 2, entry 2). Similar conversion was
obtained with NiCp2 which gave 62% selectivity of
benzaldehyde. In contrast, Ni(acac)2 was not efficient, as the
desired product was not observed (Table 2, entry 4). Using
Ni(dppe)Cl2, GC selectivity of the aldehyde decreased to 28%
with low conversion of the starting material (Table 2, entry 5).
Phosphine nickel complexes Ni(PPh3)2Br2 and Ni(PPh3)4 were
also evaluated: the conversions were moderate, reaching 51%
and 68% respectively, GC selectivity of benzaldehyde was low
(Table 2, entries 6 and 7).
benzylamine
3
and benzaldehyde, giving dibenzylamine
6, with
dibenzilimine
7
as an intermediate. Various homogeneous and
heterogeneous catalysts were screened (Table 1). Non-noble
metals, such as Ni and Cu, were used in 20 mol% loading
whereas noble metals, such as Ru, Pd and Pt, were introduced
in 2.5 mol%. The first experiment with nickel (II) chloride
Table 2. Reduction of benzonitrile with Ca(H2PO2)2 catalyzed by nickel complexes.[a]
catalyst (Table 1, entry 1) afforded benzaldehyde
selectivity, 12% of benzylalcohol , 13% of benzamide 5,
dibenzylamine and dibenzylimine in <5% and 28%
respectively. Copper (II) chloride catalyst was then tested, only
5% conversion was observed giving traces of benzamide
1 in 46%
2
6
7
5
Entry
Nickel complex
Conv.
[%][b]
68
GC selectivity of
benzaldehyde[b]
(Table 1, entry 2). In the presence of 5 wt% Pd/C, benzonitrile
was completely converted to give 84% selectivity of
1
2
3
4
5
6
7
8
9
NiCl2.6H2O
NiBr2
46
51
62
-
benzylamine
3
, 2% of
4
and 14% of
6
(Table 1, entry 3). With
was the sole
37
10 wt%Pd/C (Table 1, entry 4), benzylamine
3
NiCp2
34
product (Table 1, entry 4). The conversion with [RuCl2(p-
Ni(acac)2
Ni(dppe)Cl2
Ni(PPh3)2Br2
Ni(PPh3)4
Ni(cod)2
4
cymene)]2 was almost complete leading to the formation of
22
28
10
16
6
benzoic acid
1, entry 5). In the presence of 10wt% Pt/C the conversion was
low giving benzoic acid as the major product (81% selectivity)
and benzyl alcohol (19% selectivity) (Table 1, entry 6).
4
and benzamide
5
as the major products (Table
51
68
4
100
76
2
Ni(OAc)2.4H2O
68
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[a] All reactions were carried out with 1 mmol of benzonitrile. [b] conversions and
GC ratio of benzaldehyde were determined by GC.
[a] All reactions were carried out with 1 mmol of benzonitrile. [b] Conversion of
benzonitrile and GC selectivity were determined by GC. [c] 100 mol% of
Ca(H2PO2)2 was used.
[a]
Table 4. Reduction of benzonitrile in the presence of co-solvents
.
Ni(cod)2 was also tested in the reduction of benzonitrile:
although the conversion was complete, a mixture of products
was observed with only 6% of benzaldehyde (Table 2, entry 8).
The best result was obtained with Ni(OAc)2.4H2O: the
conversion of benzonitrile was 76% affording 68% selectivity
Entry
Co-solvent
1,2,3-TMP
CPME
Time [h] Conv. [%] [b] GC Ratio [%] [b]
.
for benzadehyde (Table 2, entry 9). Ni(OAc)2 4H2O was
1
2
3
4
5
6
7
7
73
64
92
83
therefore selected as the best catalyst for this reaction. The
influence of the nature of the base was then explored, in the
presence of 100 mol% of Ca(H2PO2)2 (1M in H2O), 20 mol% of
Ni(OAc)2.4H2O and 40 mol% of base (Table 3). To verify that a
base is essential for this reaction, an experiment was done
without any base, giving no conversion (Table 3, entry 1). In
this case after 24h, the colour of the reaction mixture stayed
green, indicating that NiII was not reduced to Ni0. For all other
entries with different bases, a modification of the reaction
Butanol
7
42
95
tert-butanol
Methanol
Ethanol
7
93
74
21
7
75
91
>99
>99
[a] experimental conditions : benzonitrile (1 mmol), Ca(H2PO2)2 (100 mol%),
Ni(OAc)2.4H2O (20 mol%), Ca(OAc)2.H2O (40 mol%), H2O ([Ca(H2PO2)2]= 1M),
added-solvent ([Benzonitrile]= 1M). [b] Conversion and GC ratio were determined
by GC. This optimization part reveals the importance of solubilization of
benzonitrile and calcium hypophosphite together in the mixture of solvent
mixture
was
observed.
A
reaction
with
N,N-
Diisopropylethylamine (DIPEA) was performed, the conversion
was complete but only 5% selectivity of benzaldehyde was
detected in GC (Table 3, entry 1). Even after 7h a mixture of
different products was observed with 55% of benzaldehyde. In
the presence of K2CO3 (Table 3, entry 3), the conversion
increased up to 91% after 24h in comparison to entry 8 of
table 2, but with lower GC ratio of aldehyde. Na2CO3 and
CaCO3 showed results similar to K2CO3, with high conversions
and moderate GC selectivity of benzaldehyde, reaching 40 and
42% respectively (Table 3, entries 4 and 5). In the presence of
KOAc, the conversion of benzonitrile was 73% and
benzaldehyde was formed in 89% selectivity (Table 3, entry 6).
Benzaldehyde was the only product when NaOAc and
Benzonitrile is poorly soluble in water. A co-solvent was
therefore used to increase solubility. The reduction of
benzonitrile in mixtures of different organic solvents and water
was performed, with 20 mol% of Ni(OAc)2.4H2O, 40 mol% of
Ca(OAc)2.H2O and in the presence of 100 mol% of Ca(H2PO2)2
(Table 4). In the presence of a water/1,2,3-trimethoxypropane
(1,2,3-TMP), which have been synthesized in our laboratory
and reported as solvent in the reduction of different functions
including nitriles,25 after 7 hours, 73% of benzonitrile were
converted to give 92% of
1 and 8% of benzylalcohol (Table 4,
entry 1). Lower conversion and GC ratio were observed with
hydrophobic cyclopentylmethyl ether CPME (Table 4, entry 2).
The rate of the reaction decreased when using butanol as co-
solvent: after 7 hours the conversion was moderate, reaching
42%, with benzaldehyde as the major product (95%) and traces
of benzylalcohol and benzylamine (Table 4, entry 3). With tert-
butanol as a co-solvent, the conversion was 93% after 7h,
.
Ca(OAc)2 H2O were used but with low conversions (Table 3,
.
entries 7 and 8). Ca(OAc)2 H2O was selected as base for this
reaction in order to avoid the presence of different cations in
the reaction media. The presence of the base is important to
have a good pH in the reaction medium that leads to better
conversion and selectivity.
giving 74% of benzaldehyde with the corresponding alcohols
2,
amines 3, and carboxylic acid, 4 as by-products (Table 4, entry
Table 3. Reduction of benzonitrile with Ca(H2PO2)2 catalysed by Ni(OAc)2.4H2O with
different bases. [a]
4). In methanol/water mixture, after 24h, the conversion of
benzonitrile was 75% with a 91% selectivity of benzaldehyde
(Table 4, entry 5). In this case side reactions occur including
over reduction of
amination leading to the formation of benzylalcohol
benzamide and dibenzylamine as by-products respectively.
1, hydration of benzonitrile and reductive
2,
3
4
We found that ethanol/water mixture was the best solvent
mixture for the reduction of benzonitrile: affording complete
Entry
Base
Conv. [%]
[b]
GC ratio of
benzaldehyde[b]
conversion and complete selectivity towards
entry 6).
1 in 7h (Table 4,
1
2
3
4
5
6
7
8
-
DIPEA
0
>99
91
94
97
73
18
12
-
5
To evaluate the scope of this catalytic reductive system, we
investigated the reduction of a series of nitriles in the presence
of 100 mol% of calcium hypophosphite with 20 mol% of
Ni(OAc)2.4H2O and 40 mol% of Ca(OAc)2.H2O in an
ethanol/water mixture at 100°C for 7-26h. For each substrates,
the reactions were performed several times to determine the
time needed for complete conversion avoiding the over
K2CO3
29
40
42
89
>99
>99
Na2CO3
CaCO3
KOAc
KONa
Ca(OAc)2.H2O
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reduction into alcohol. Generally, good to excellent yields of
aldehydes were obtained including aldehydes bearing
electron-withdrawing or electron-donating groups.
Benzonitrile was well reduced to benzaldehyde as mentioned
before in the optimized conditions. However, the isolated yield
was only 50% due to the high volatility of the product which
was partially lost during the evaporation (Table 5, entry 1).
With nitriles bearing an electron-donating group the
reductions were successful. For 4-hydroxy benzonitrile, traces
of by-products were observed resulting from the over
reduction and the corresponding aldehyde was isolated in 90%
yield (Table 5, entry 2). However with a hydroxyl group at the
ortho position, the reaction required 23h, more by-products
were observed but the isolated yield was good reaching 90%
(Table 5, entry 3). The reduction of 4-methoxy benzonitrile
required also a longer time: after 26h, the conversion was
complete and pure aldehyde was obtained with 97% isolated
yield (Table 5, entry 4). p-Tolunitrile was also reduced in a very
good yield of 98% (Table 5, entry 5). The reduction of
substrates containing electron-withdrawing groups such as –
COOEt, –CF3 and –CHO was also performed in good yields,
affording 94%, 84% and 85% of the desired aldehyde
respectively (Table 5, entries 6-8). In the case of 4-
(trifluoromethyl)benzonitrile the reaction was fast (5h, 84%
yield) and the alcohol was obtained as a by-product. With 4-
formyl benzonitrile, after 8h, the conversion was not complete
giving 85% of terephthaldehyde (Table 5, entry 8). When the
reaction was prolonged the conversion was complete, but the
alcohol was obtained as the major product due to over
reduction. The reduction of 2-cyanonaphthalene and 1-
cyanonaphthalene afforded the corresponding aldehydes in
high yields: 80% and 85% respectively (Table 5, entries 9 and
10). Conversion could not be further increased even when
increasing reaction time.
Table 5. Reduction of nitriles
Entry
Aldehydes
Time [h]
Conv. [%]
Isolated
yield [%]
1
2
7
7
100
100
50
90
3
4[c]
5
23
26
17
7
93
100
96
90
97
98
94
84
85
6
100
93
7
5
8
8
86
9
21
91
80
The substrate versatility of this method was further
demonstrated by the reduction of halogenated aromatic
nitriles. For 2-chlorobenzonitrile, complete conversion was not
attained, giving 30% yield for 2-chlorobenzaldehyde (Table 5,
entry 11). Several by-products were observed in this reaction
resulting from the over reduction and dehalogenation.
Bromine substituents at meta and para positions gave both a
high yield of 90% (Table 5, entries 12 and 13). Some limitations
exist for our method. For example in the case of 2-
cyanopyridine and 2-aminobenzonitrile complexations were
observed with blue and offwhite colours respectively. With
nitro substituted nitriles, NiII was not reduced to Ni0, the
10
11
48
7
91
51
85
30
CHO
12
13
29
23
82
81
90
90
Br
[a] experimental conditions : benzonitrile (1 mmol), Ca(H2PO2)2 (100 mol%),
aldehyde was therefore not formed. It is expected that nitro Ni(OAc)2.4H2O (20 mol%), Ca(OAc)2.H2O (40 mol%), H2O ([Ca(H2PO2)2]= 1M),
ethanol ([Nitrile]= 1M). [b] Conversion and GC ratio of aldehyde were determined
group poisons the catalyst. To confirm this hypothesis, the
by GC. [c] Ethanol ([4-methoxybenzonitrile]= 0.66M).
transformation of benzonitrile into benzaldehyde was
attempted with nitrobenzene in the optimized conditions, and
in this case Ni0 was not formed as well and no reaction
Finally, to control the potential of the investigated method, we
occurred.
tested the reaction conditions on the more challenging alkyl
chain substituted benzonitriles and aliphatic nitriles. Complete
conversions with no selectivity towards the corresponding
aldehydes were obtained. Instead, alcohol, diamine and
triamine were observed for the following starting materials:
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hexanenitrile,
octanenitrile,
phenylacetonitrile
and the presence of base at 100°C in a mixture water/ethanol to
give the corresponding aldehydes in moderate to excellent
yields reaching 94%. The type of base, type of nickel catalyst
and the solvent have a large influence on the conversion and
chemoselectivity. On the other hand, the type of substituent
on the aromatic ring might constitute a limitation of this
reducing system.
phenylbutyronitrile (Scheme 1).
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Scheme 1 Reduction of alkyl chain substituted nitriles and aliphatic
nitriles.
The authors thank the Lebanese government for financial
support through a Ph.D. grant to R.M. The researches were
done both in France and Liban.
We were able to propose a mechanism according to the
experimental observations. A control experiment with NiCl2 in
the absence of calcium hypophosphite and base did not lead
to any conversion. This confirms that hypophosphite is
necessary for the formation of Ni0 species which are in turn
crucial for the reduction of nitrile to aldehyde. The reduction
of nitrile to aldehyde occur when there is modification in the
colour of the reaction mixture from green to grey. This could
be attributed to the reduction of NiII to Ni0 by hypophosphite,
leading to the formation of nickel nanoparticles as described in
literature.26 Moreover, a test was done by heating calcium
hypophosphite, nickel catalyst and the base with water at
100°C in a sealed tube. After 30 minutes the colour changed to
black. When the tube was cooled down and opened to add
benzonitrile, a gas was released. The reaction mixture was
heated again at 100°C for 7h. After this time, no conversion of
benzonitrile was observed. This is maybe due to the loss of
hydrogen gas. From these observations we expect to have the
redox reactions shown in scheme 2. The base deprotonates
water to generate OH- (1), and the interaction between
hypophosphite and OH- leads to the formation of hydride
which reduces NiII to Ni0 generating hydrogen (2). The
generated hydrogen is then adsorbed on the surface of Ni0
particles and could be the real reducing agent that reduces
nitrile into aldehyde.
Notes and references
‡ Footnotes relating to the main text should appear here. These
might include comments relevant to but not central to the
matter under discussion, limited experimental and spectral data,
and crystallographic data.
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Conclusions
We reported for the first time the reduction of aromatic
nitriles to aldehydes using calcium hypophosphite and nickel
(II) acetate tetrahydrate as a catalyst. The reactions proceed in
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Reduction of aromatic nitriles into aldehydes using calcium hypophosphite
and a nickel precursor
Rim Mouselmani,a, b Ali Hachem,b Ali Alaaeddine,b Estelle Métay*a and Marc Lemaire*a
The reduction of aromatic nitriles to aldehydes is performed with good to excellent yields and
selectivities. Calcium hypophosphite is used in the presence of nickel (II) catalyst and base in
a water/Ethanol system.