Chemoselective hydrogenation of nitriles to primary amines catalyzed by water-soluble transition metal catalysts

Article abstract of DOI:10.1002/aoc.4481

The water-soluble rhodium complex generated in situ from [Rh (COD)Cl]₂ in aqueous ammonia has been revealed as a highly efficient catalyst for the hydrogenation of aromatic nitriles, to primary amines with excellent yields. The catalyst is also highly selective towards primary amines in the case of sterically hindered aliphatic nitriles. The catalytic system can also be recycled and re-used with no significant loss of activity.

Full text of DOI:10.1002/aoc.4481

Received: 20 April 2018
DOI: 10.1002/aoc.4481
Revised: 30 May 2018
Accepted: 1 June 2018
C O M M U N I C A T I O N
Chemoselective hydrogenation of nitriles to primary amines
catalyzed by water‐soluble transition metal catalysts
Abdelaziz Nait Ajjou1
| André Robichaud2
1 Department of Chemistry and
The water‐soluble rhodium complex generated in situ from [Rh (COD)Cl]2 in
aqueous ammonia has been revealed as a highly efficient catalyst for the
hydrogenation of aromatic nitriles, to primary amines with excellent yields.
The catalyst is also highly selective towards primary amines in the case of
sterically hindered aliphatic nitriles. The catalytic system can also be recycled
and re‐used with no significant loss of activity.
Biochemistry, Université de Moncton,
Moncton, New‐Brunswick, Canada, E1A
3E9
2 Health Canada, 1001, Saint‐Laurent Ouest
Blvd, Longueuil, Québec, Canada, J4K 1C7
Correspondence
Abdelaziz Nait Ajjou, Department of
Chemistry and Biochemistry, Université
de Moncton, Moncton, New‐Brunswick,
Canada E1A 3E9.
KEYWORDS
aqueous ammonia, hydrogenation, nitriles, primary amines, water‐soluble catalysts
Email: naitaja@umoncton.ca
1 | INTRODUCTION
depends not only on the nature of the catalyst and its prop-
erties, but also on the reaction conditions employed, and on
Amines are important organic chemicals that are widely
used as solvents, surfactants, disinfectants, and corrosion
inhibitors. There enormous versatility permits there exten-
sive use as precursors for the synthesis of different organic
products, especially biologically active compounds such as
pharmaceuticals[1] and agrochemicals.[2] Amine moieties
and their amide derivatives are frequently found in natural
products and pharmaceutical drugs.[3] The reductive
amination of aldehydes and ketones[4] and the hydrogena-
tion of nitriles[5,6] are among the most commonly used
methods to prepare amines. Although alternative
processes based on hydride reducing agents were devel-
oped to achieve successfully the reduction of nitriles to
amines,[7] catalytic hydrogenations remain the most inter-
esting processes for economical and ecological viewpoints,
especially at the industrial level. One of the most impor-
tant problems of catalytic hydrogenation of nitriles is the
control of the chemoselectivity. Frequently, secondary
and tertiary amines as well as Schiff bases are formed, in
addition to primary amines, and purification of reaction
mixtures are usually difficult. Consequently, chemo-
selective synthesis of primary or secondary amines with
good yields is subject of tremendous investigations.
Numerous literature data indicate that the chemoselectivity
the structure of the substrate itself.[5,6] Thus, for the synthe-
sis of specific amines, proper catalyst and suitable reaction
conditions have to be judiciously chosen.[5,6] As known,
hydrogenation of nitriles leads first to the aldimine and
then to the primary amine.[5,6,8] A highly reactive aldimine
could interact with primary amine and forms the aminal
(gem‐diamine). This intermediate undergoes either
hydrogenolysis to yield secondary amine or elimination of
NH3 to form alkylidenalkylamine (Schiff base). This latter
yields secondary amine after hydrogenation of the C=N
bond.[5,6,8] Tertiary amine could, also, be obtained by con-
densation of secondary amine with the aldimine. With the
presence of water the reaction mixtures may be more com-
plex since aldehydes, primary alcohols, and amides are
expected as additional side‐products.[5] Moreover, water
may enhance the formation of secondary amine after
hydrogenation of secondary imine formed by condensation
of aldehyde and primary amine.[5,9] To improve the
chemoselectivity to primary amines and to circumvent the
formation of over‐alkylated amines, addition of ammonia
in most widely used.[5,6] Strategies were also developed to
trap primary amines in situ before further reaction with
aldimine. Thus suitable trapping agents such as acids,[5,10]
CO2,[11] di‐tert‐butyl dicarbonate,[11,12] and acetic
Appl Organometal Chem. 2018;e4481.
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NAIT AJJOU AND ROBICHAUD
anhydride[11] were successfully used to achieve the prepara-
tion of primary amines with good yields. A plethora of het-
erogeneous hydrogenation processes have been developed
for nitrile‐amine transformation.[5,6] However, the prepara-
tion of the catalysts, their selectivity towards primary
amines, and harsh experimental conditions are among the
limitations of these methods. Catalytic homogeneous
hydrogenations of nitriles were scarce, but recently they
gain considerable importance thanks to the catalysts based
on transition metal Pincer complexes that lead to high
yields and selectivities of primary amines.[5,6,13,14] Unfortu-
nately, the vast majority of these processes are performed in
costly and highly toxic organic solvents including carcino-
genic and mutagenic solvents such as benzene, THF and
1,4‐dioxane. Furthermore, in these homogeneous processes
dry conditions are necessary, with the exception of Leitner
report,[15] and the separation of the catalysts from the reac-
tions products is cumbersome, while their quantitative
recovery in active form have not been performed.
Very few homogeneous hydrogenations of nitriles
have been performed in water although the expected
alcohols and amides as side‐products. Li and co‐workers
reported homogeneous hydrogenation of nitriles cata-
lyzed by water‐soluble RuCl3/TPPTS (P(m‐C6H4SO3Na)3)
complex in organic/aqueous biphasic system.[16] Nitriles
were converted selectively to corresponding alcohols with
good yields and no amines were formed. In another
report, Bianchini and co‐workers described the hydroge-
nation of benzonitrile catalyzed by water‐soluble
(Sulphos)Ru(NCMe)3(OSO2CF3) in aqueous/n‐octane
biphasic system.[17] The conversion was only 25.4% and
benzaldehyde (11.6%) and benzyl alcohol (5.3%) were
ammonia with alcohols, coupling of aryl halides with
ammonia, telomerization of butadiene with ammonia,
and hydroaminomethylation of alkenes.[18] Aqueous
ammonia is cheaper, safer, easy to handle, and more
importantly much less hazardous chemical than many
solvents used with Pincer catalysts for hydrogenation of
nitriles. As part of our program devoted to the synthesis
of organic compounds in water,[19] we are pleased to
report new, simple and convenient procedures for the
homogeneous hydrogenation of nitriles to the corre-
sponding primary amines in aqueous ammonia using
water‐soluble catalysts.
2 | RESULTS AND DISCUSSION
In our preliminary experiment we investigated the hydro-
genation of benzonitrile, chosen as a model substrate, in
pure water using water soluble system [Rh(COD)Cl]2/
BQC (2,2′‐biquinoline‐4,4′‐dicarboxylic acid dipotassium
salt). N‐Benzylidenebenzylamine 3 was obtained as the
major product with 88% yield, along with dibenzylamine
2 (11%) and benzyl alcohol 4 (1%) (Table 1, entry 1). No
traces of benzamide 5 and aromatic ring reduction prod-
ucts 6 (mainly cyclohexanemethylamine) were detected.
When the reaction was performed in aqueous ammonia,
under the same reaction conditions, benzylamine was
obtained as the major product (63%) to the detriment of
N‐Benzylidenebenzylamine (24%), and dibenzylamine
(9%) with only small amounts of benzyl alcohol and
benzamide were formed (Table 1, entry 2). This promis-
ing result, for the formation of benzylamine, led us to test
various catalytic systems based on different catalyst pre-
cursors and the water‐soluble ligands P(m‐C6H4SO3Na)3
(TPPTS) or BQC under 400 psi (27.58 bar) of H2.[20] In
all cases benzylamine was obtained as the major product
except in the case of [Rh(COD)Cl]2/TPPTS that led to
benzamide as the major product (Table 1, entry 4). This
result is not surprising since we reported its catalytic
activity towards the hydration of nitriles.[21] In general,
BQC ligand provided more active catalytic species than
TPPTS. Remarkably, [Rh(COD)Cl]2, very soluble in
aqueous ammonia, led to interesting results with
benzylamine formed in 90% yield (Table 1, entry 5). The
other catalytic precursors are also very soluble in the
aqueous ammonia, but led to much less interesting
results. The durability of the catalytic species generated
from [Rh(COD)Cl]2, ammonia and water was tested by
carrying out three consecutive cycles with the same cata-
lyst aqueous solution separated from the products at the
end of each run (Table 1, entries 5 to 7).[22] Only a slight
decrease in the catalytic chemoselectivity to primary
amine was observed between the second and the third
obtained
as
side
products,
in addition
to
benzylidenebenzylamine (8%) and dibenzylamine (0.5%).
The authors stated, consequently, that aqueous‐biphasic
method is useless for the hydrogenation of organic
nitriles. Recently, Leitner's group performed the hydroge-
nation of nitriles catalyzed by a Pincer ruthenium hydride
complex.[15] The use of water as an additive (water/cata-
lyst ratio = 5) improved selectivities and conversions to
primary amines. In using water as a solvent in the case
of benzonitrile, however, only traces of benzylamine were
obtained beside benzamide as the major product and ben-
zyl alcohol. The group reported also that the reaction of
their Pincer ruthenium hydride complex with ammonia
resulted in an unidentifiable complex mixture. To the
best of our knowledge, we are not aware of any other
example of homogeneous catalysis of nitriles in water,
and no report was published regarding successful homo-
geneous hydrogenation of nitriles in aqueous ammonia.
Water‐soluble catalyst/aqueous ammonia/organic solvent
biphasic systems have been reported successfully for
reductive amination of aldehydes, multialkylation of

NAIT AJJOU AND ROBICHAUD
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TABLE 1 Reduction of benzonitrile catalyzed by MLn/water soluble ligand systems in aqueous ammoniaa
Catalyst
precursor
H2 pressure
(psi)
Conversione
(%)
1
(%)
2
(%)
3
(%)
4
(%)
5
(%)
6
(%)
Run
Ligand
1b
2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pt(COD)Cl2
BQC
200
200
400
400
400
400
400
400
400
400
400
400
400
400
400
400
100
100
100
64
0
63
67
20
90
90
84
67
37
58
74
78
29
60
37
60
11
9
88
24
8
1
2
2
7
2
2
4
4
2
7
0
0
0
1
2
1
0
2
0
0
BQC
3
BQC
4
19
36
2
0
4
TPPTS
1
0
0
5
‐
100
100
100
94
6
0
0
6c
7d
8
‐
4
0
4
0
‐
8
4
~0
14
17
16
9
0
BQC
TPPTS
‐
5
2
2
9
59
3
0
0
10
11
12
13
14
15
16
100
100
100
51
14
9
0
5
BQC
TPPTS
‐
0
8
12
7
0
7
3
0
15
6
0
BQC
TPPTS
‐
100
59
24
2
0
9
Pt(COD)Cl2
0
17
3
1
Pt(COD)Cl2
100
14
0
22
aReaction conditions: Benzonitrile (2.5 mmol), transition metal (0.025 mmol), ligand (0.15 mmol), NH4OH (30%, 10 ml), 100 °C, 24 hours.
bReaction performed in water without the presence of ammonia.
cSecond cycle of entry 5.
dThird cycle of entry 5.
eIdentifications and quantifications (conversions and yields) were determined by 1HNMR and GC–MS analysis using n‐dodecane as an internal standard.
recycling experiments attesting the viability of the cata-
lyst active form. Since atomic absorption tests of the
organic phases showed no traces of rhodium and that
the catalyst remained exclusively in the aqueous‐phase,
this decrease of chemoselectivity is mainly attributable
to the considerable decrease of ammonia concentration
mainly between the second and the third recycling exper-
iments, as shown by pH measurements. The loss of
ammonia gas is due to the manipulations during work‐
up (liquid–liquid extraction of the products and particu-
larly the release of the remaining molecular hydrogen
from the autoclave). Ammonia has a major influence on
the selectivity towards primary amine, and as a ligand it
stabilizes the rhodium organometallic complexes. Thus
its loss is detrimental to the hydrogenation process. While
between the first and second cycles the aqueous‐phase
remained clear solution, it is relevant to point out that
very thin metallic rhodium was observed on the glass
liner between the second and third cycles, indicating very
slight decomposition of the catalyst due probably to the
loss of ammonia.
In the light of these excellent results different nitriles
were hydrogenated under the same conditions (Table 2).[20]
[Rh(COD)Cl]2 showed excellent performance for the reduc-
tion of benzonitrile derivatives despite dehalogenation
observed in the case of 3‐cholorobenzonitrile. The catalyst
exhibited also good selectivities for primary amines in the
case of 3‐cyanopyridine and sterically hindered aliphatic
nitriles namely 2‐phenylbutyronitrile, phenylacetonitrile,
2‐ and 3‐pyridylacetonitrile (Table 2, entries 5 to 9). A
slight drop in selectivity was observed in the case of ali-
phatic nitriles with less steric hindrance (Table 2, entries
10 and 11). Besides the environmental and safety benefits
of this simple method, our results are very interesting in
comparison with those obtained with Pincer complexes
which usually operate under harsh conditions of tempera-
ture and pressure (up to 140 °C and 75 bar of H2). For exam-
ple, our method is more efficient for the transformation of
benzonitrile than the hydrogenation based on the ruthe-
nium hydride complex which gave benzylamine in only
59% yield at 135 °C and 75 bar (H2).[15] The result achieved
also in the case of 3‐cyanopyridine (65%, Table 2, entry 5) is

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NAIT AJJOU AND ROBICHAUD
TABLE 2 Reduction of different nitriles catalyzed by [Rh (COD)Cl]2 in aqueous ammoniaa
Run
Nitrile
Conversioni (%)
1° Amine yield (%)
2° Amine yield (%)
1
Benzonitrile
100
100
100
100
100
55
90
93
96
83
65
50
83
54
67
55
64
4
2b
4‐Methoxybenzonitrile
2‐Methylbenzonitrile
3‐Chlorobenzonitrile
3‐Cyanopyridine
0
3
4
4c
5d
6e
7f
6
4
2‐Phenylbutyronitrile
Phenylacetontrile
2‐Pyridylacetonitrile
3‐Pyridylacetonitrile
3‐Phenylpropionitrile
Hexanenitrile
3
100
66
12
8g
9g
10h
11
Traces
Traces
38
100
100
100
36
aReaction conditions: Nitrile (2.5 mmol), [Rh(COD)Cl]2 (0.0125 mmol), H2 (400 psi), NH4OH (30%, 10 ml), 100 °C, 24 hours.
bThe corresponding imine, alcohol and amide were formed respectively in 4%, 1% and 2% yields.
cThe yield for primary amine includes 16% for dehalogenation products. The corresponding imine, alcohol, amide and ring reduction products were formed
respectively in 6%, 1%, 3% and 1% yields.
dThe corresponding amide and ring reduction products were formed respectively in 14% and 17% yields.
eThe corresponding amide was formed in 2% yield.
fThe corresponding amide was formed in 5% yield.
gUnidentified products were also formed.
hThe corresponding amide was formed in 7% yield.
j
iIdentifications and quantifications (conversions and yields) were determined by 1HNMR and GC–MS analysis analysis using n‐dodecane as an internal
standard.
comparable to the yields reached under more severe condi-
3 | CONCLUSIONS
tions: 71% at 135 °C and 30 bar with cobalt complex,[23] and
69% at 120 °C and 50 bar with manganese catalyst.[24]
In conclusion, the catalyst generated from [Rh(COD)Cl]2
Finally, our results for the aliphatic nitriles are comparable
with those of many homogeneous catalysts, since reduction
of aliphatic nitriles is more difficult than aromatic ones, and
are better than those obtained from some ruthenium Pincer
complexes (35 to 48%).[25] The comparison of our catalytic
system with other homogeneous noble metal catalysts is
also interesting. For the hydrogenation of benzonitrile, our
system is more active than RhH(PiPr3)3 which offered
benzylamine in 45% yield[26] and 61% yield under pressure
of CO2,[11] and the complex Rh2H2(μ‐N2){P(cyclohexyl)3}4
which is completely inactive.[26] Our catalyst is also
more efficient for the production of benzylamine than
and aqueous ammonia was found to be very efficient for
the hydrogenation of nitriles, especially aromatic ones,
to primary amines. The recyclability of the catalytic sys-
tem, its selectivity to primary amines and the mild opera-
tion conditions, prompt further research concerning its
catalytic active form and its scope related to nitriles
structures.
ACKNOWLEDGEMENTS
We are grateful to NSERC of Canada and to FESR of
Université de Moncton for financial support of this
research.
iridium
complexes
[Ir(COD)(PPh3)(PhCN)2]ClO4,
[Ir(COD)(PPh3)2]ClO4, and [Ir(COD)(PhCN)2]ClO4 that
led to the formation of a mixture of primary, secondary
and tertiary amines.[27] Our catalytic system proved more
efficient than several heterogeneous catalysts based on rho-
dium, platinum, palladium and ruthenium for the hydroge-
nation of benzonitrile[28] and phenylacetonitrile.[29]
ORCID
Abdelaziz Nait Ajjou
http://orcid.org/0000-0003-0244-
6324

NAIT AJJOU AND ROBICHAUD
5 of 5
[Rh(COD)Cl]2 (0.0125 mmol) was dissolved in water ammonia
(30%, 10 ml) at room temperature. Then the nitrile (2.5 mmol)
was introduced. The autoclave was flushed three times with 40
psi of N2 then purged with hydrogen. After the autoclave was
pressurized to 400 psi of hydrogen, and then placed in an oil
bath at 100°C for 24 hours. The autoclave was cooled to room
temperature, the remaining hydrogen was vented, then the
mixture was extracted three times with ethyl acetate (3 ml).
The combined organic layers were dried (MgSO4), evaporated
to dryness then the resulting products were analyzed by 1H
NMR,13C NMR and GC‐MS using n‐dodecane as an internal
standard.
REFERENCES
[1] B. Merla, N. Risch, Synthesis 2002, 1365.
[2] D. B. Sharp, in Herbicides: Chemistry, Degradation, and Mode of
Action, (Eds: P. C. Kearney, D. D. Kaufman), Marcel Dekker,
New York 1988 Chapter 7.
[3] T. Henkel, R. M. Brunne, H. Mueller, F. Reichel, Angew. Chem.
Int. Ed. 1999, 38, 643.
[4] A. Robichaud, A. Nait Ajjou, Tetrahedron Lett. 2006, 47, 3633.
[5] C. De Bellefon, P. Fouilloux, Catal. Rev.: Sci. Eng. 1994, 36, 459.
[6] D. B. Bagal, B. M. Bhanage, Adv. Synth. Catal. 2015, 357, 883.
[7] J. Z. Saavedra, A. Resendez, A. Rovira, S. Eagon, D.
[21] M. C. K. B. Djoman, A. Nait Ajjou, Tetrahedron Lett. 2000,
41, 4845.
Haddenham, J. Org. Chem. 2012, 77, 221.
[8] Y. Huang, W. M. H. Sachtler, Appl. Catal. A. 1999, 182, 365.
[22] The aqueous phase obtained after removal of ethyl acetate was
re‐used with a fresh charge of benzonitrile (2.5 mmol).
[9] A. W. Heinen, J. A. Peters, H. van Bekkum, Eur. J. Org. Chem.
2000, 2501.
[23] A. Mukherjee, D. Srimani, S. Chakraborty, Y. Ben‐David, D.
Milstein, J. Am. Chem. Soc. 2015, 137, 8888.
[10] E. Miller, J. M. Sprague, L. W. Kissinger, L. F. McBurney,
J. Am. Chem. Soc. 1940, 62, 2099.
[24] S. Elangovan, C. Topf, S. Fischer, H. Jiao, A. Spannenberg, W.
Baumann, R. Ludwig, K. Junge, M. Beller, J. Am. Chem. Soc.
2016, 138, 8809.
[11] X. Xie, C. L. Liotta, C. A. Eckert, Ind. Eng. Chem. Res. 2004,
43, 7907.
[25] A. Mukherjee, D. Srimani, Y. Ben‐David, D. Milstein,
ChemCatChem 2017, 9, 559.
[12] S. Caddick, A. K. D. K. Haynes, D. B. Judd, M. R. V. Williams,
Tetrahedron Lett. 2000, 41, 3513.
[26] T. Yoshida, T. Okano, S. Otsuka, J. Chem. Soc. Chem. Commun.
1979, 870.
[13] S. Werkmeister, K. Junge, M. Beller, Org. Process Res. Dev. 2014,
18, 289.
[27] C. S. Chin, B. Lee, Catal. Lett. 1992, 14, 135.
[14] H. A. Younus, W. Su, N. Ahmad, S. Chen, Adv. Synth. Catal.
2015, 357, 283.
[28] J. J. W. Bakker, A. G. van der Neut, M. T. Kreutzer, J. A.
Moulijn, F. Kapteijn, J. Catal. 2010, 274, 176.
[15] C. Gunanathan, M. Hölscher, W. Leitner, Eur. J. Inorg. Chem.
2011, 3381.
[29] L. Hegedűs, T. Máthé, T. Kárpáti, Appl. Catal. Gen. 2008,
349, 40.
[16] Y. P. Xie, J. Men, Y. Z. Li, H. Chen, P. M. Cheng, X. J. Li, Cat.
Com. 2004, 5, 237.
[17] C. Bianchini, V. D. Santos, A. Meli, W. Oberhauser, R. Psaro, F.
How to cite this article: Nait Ajjou A,
Robichaud A. Chemoselective hydrogenation of
nitriles to primary amines catalyzed by water‐
soluble transition metal catalysts. Appl
Organometal Chem. 2018;e4481. https://doi.org/
10.1002/aoc.4481
Vizza, Organometallics 2000, 19, 2433.
[18] J. L. Klinkenberg, J. F. Hartwig, Angew. Chem. Int. Ed. 2011,
50, 86.
[19] A. Nait Ajjou, Catal. Today 2015, 247, 177.
[20] Typical procedure for the hydrogenation of nitriles: In a glass
liner of a 45 ml autoclave and under an atmospher of nitrogen,