Synthesis of Secondary Aldimines from the Hydrogenative Cross-Coupling of Nitriles and Amines over Al2O3-Supported Ni Catalysts

Article abstract of DOI:10.1021/acscatal.9b01597

A heterogeneous Ni catalyst was discovered to be active in the synthesis of secondary cross-imines via hydrogenative coupling of nitriles and amines. The mesoporous Al₂O₃-supported Ni nanoparticles (abbreviated as Ni/m-Al₂O₃-600, where 600 represents the reduction temperature) were active in hydrogenative coupling of nitriles and amines reaction at 80 °C and 1 bar H₂, affording corresponding cross-imines with yields in the range 64.1-98.1%. Density functional theory calculations reveal the hydrogenation of benzonitrile (PhCN) to benzylamine (PhCH₂NH₂) has higher activation energy than that for hydrogenative cross-coupling of PhCN and RNH₂ on the Ni/m-Al₂O₃-600 catalyst, suggesting the latter reaction is more favorable. The theoretical calculations are in good agreement with our experimental results.

Full text of DOI:10.1021/acscatal.9b01597

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Article
Synthesis of secondary aldimines from the hydrogenative cross-
coupling of nitriles and amines over Al2O3 supported Ni catalysts
Peng Zhou, Liang Jiang, Shuguo Wang, Xun Hu, Hongming Wang, Ziliang Yuan, and Zehui Zhang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b01597 • Publication Date (Web): 01 Aug 2019
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Synthesis of secondary aldimines from the hydrogenative cross-coupling of
nitriles and amines over Al2O3 supported Ni catalysts
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Peng Zhou,1,2 Liang Jiang,1 Shuguo Wang1, Xun Hu,3* Hongming Wang,4* Ziliang
Yuan,1 Zehui Zhang1*
ABSTRACT: A heterogeneous Ni catalyst was discovered to be active for the synthesis
of secondary cross-imines via the hydrogenative coupling of nitriles and amines. The
mesoporous Al2O3 supported Ni nanoparticles (abbreviated at Ni/m-Al2O3-600, where 600
represents the reduction temperature) was active towards the hydrogenative coupling of
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nitriles and amines reaction at 80 C and 1 bar H2, affording the corresponding cross-
imines with yields in 64.1% to 98.1%. DFT calculations reveal the hydrogenation of
benzonitrile (PhCN) to benzylamine (PhCH2NH2) has a higher activation energy than that
for hydrogenative cross-coupling of PhCN and RNH2 on the Ni/m-Al2O3-600 catalyst,
suggesting the later reaction is more favorable. The theoretical calculations are well in
agreement with our experimental results.
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KEYWORDS: Nickel catalysts; Synthesis of secondary amines; Cross-coupling; DFT
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calculations
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INTRODUCTION
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There has been a growing interest in the synthesis of imines and their derivatives,
because they are widely present in many kinds of products.1 The coupling of amines and
aldehydes in the presence of the acid catalysts has been early reported for the generation
of imines. At present, there are several alternative routes for the production of imines,
which includes the hydroamination of alkynes with amines,2 the dehydrogenation of
secondary amines,3 the self-coupling of two primary amines moleculers,4 the
dehydrogenation of alcohols and the subsequent condensation with amines,5 as well as
the dehydrogenative coupling of alcohols with nitriles.6 However, some of the above
mentioned methods demonstrated distinct drawbacks such as harsh reaction conditions,
poor selectivity, limited substrates, and low atom-efficiency. The hydrogenative coupling
of nitriles with primary amines by the release of one ammonia molecule represents an
attractive route for the generation of imines, particularly unsymmetrical imines, because
both nitriles and primary amines are available with low cost. However, it is a challenge to
develop an effective way for the hydrogenative coupling of nitriles with primary amines
into unsymmetrical imines. Scheme 1 depicts that there are several reaction pathways
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for the hydrogenative coupling of nitriles with primary amines.7 As shown in Scheme 1,
the crucial issue associated with the synthesis of unsymmetrical imines is the control of
its selectivity, because many other kinds of byproducts might be generated. Due to the
high difficulty in the control of the selectivity of unsymmetrical imines, the hydrogenative
coupling of nitriles with primary amines for the synthesis of unsymmetrical imines has
been rarely studied.
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According to Scheme 1, with the aim to realize the high selectivity of unsymmetrical
imines, a catalyst should have an appropriate activity that can only promote the
hydrogenation of the nitrile group into imines (C=N bonds), while it does not catalyze the
subsequent hydrogenation of imines into primary amines. Noble metal catalysts generally
demonstrate high catalytic activity, which can promote either the complete hydrogenation
of nitrile into primary amines or the C=N bonds in imines into secondary amines.8 For
instance, the hydrogenative cross-coupling of aromatic nitriles with pentylamine over Pt
nanowires produced secondary amines as the major products (Scheme 2, Reaction A).8
Therefore, the earth abundant base metal catalysts would be the suitable candidate for
the hydrogenative coupling of nitriles with primary amines into unsymmetrical imines,
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because of the potential adjustable activity towards the selective reduction of nitrile
groups into imines without the further reduction of imines.
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R
R
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N
H
NH2
R
R
-NH3
[H]
N
N
R
R
R
R
R
[H]
CH2NH2
R'
NH2
[H]
R'
R
R'
-NH3
N
CN
R'
NH2
NH2
[H]
N
n
n
NH
n
H
N
H
n
+NH3
R
R
R
R
R
-NH3
N
H
[H]
N
N
H
Al2O3/Ni
+NH3
R
R
R
R
R
R
R'
N
n
H
R'
R'
R
-NH3
[H]
N
N
n
n
NH2
Scheme 1. Possible reaction routes for the reaction of nitriles and amines.
Unfortunately, only one kind of non-noble metal catalysts was applied for the
hydrogenative coupling of nitriles with primary amines to synthesize unsymmetrical
imines.9 The iron complex catalyzed the hydrogenative coupling of nitriles with primary
amines to generate unsymmetrical imines yields in the range from 5~99% (Scheme 2,
Reaction B).9 Besides the difficulty in recycling iron complex, this method required the
use of water sensitive t-BuOK as the additive and high hydrogen pressure up to 20 bar.
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Therefore, the use of supported base metal catalysts is attractive hydrogenative coupling
of nitriles with primary amines to generate unsymmetrical imines. Heterogeneous Ni
catalysts demonstrated high activity in several types of hydrogenation and
dehydrogenation reactions.10 Therefore, we conceived that supported Ni catalysts would
have the potential to realize the success production of unsymmetrical imines via the
hydrogenative coupling of nitriles with amines. Herein, a kind of Ni/Al2O3 catalyst was
studied for the hydrogenative coupling of nitriles with amines.
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Previous work:
Reaction A:
Toluene, H2 ballon
R'
Pt Nanowire
R
CN
+
R' NH2
R
N
H
80 °C
Reaction B:
N
Toluene, 1 equiv. t-BuOK
Br
R'
Fe
P
iPr2
+
R' NH2
R
N
R
CN
P
H
60 °C, 10-20 bar H2
H
iPr2
Homogeneous Fe catalyst
This work:
Hexane, NH3H2O
R'
+
R' NH2
R
N
R
CN
Heterogeneous Ni/Al2O3
H
80 °C, 1 bar H2
Advantages:
1) Non-noble heterogeneous metal catalyst;
3) High selectivity;
2) High activity with low Ni loadings;
4) High stability and facile recycle
Scheme 2. Current methods for the reaction of nitriles and amines8, 9.
RESULTS AND DISCUSSION
Preparation and Characterization of the Catalyst
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Figure 1. Schematic procedure of the Ni/m-Al2O3-T catalysts.
The soft template method was used for the preparation of the Ni/m-Al2O3-T catalysts.
In the first step, a homogenous mixture of aluminium iso-propoxide [Al(O-i-Pr)3],
(EO)20(PO)70(EO)20 triblock copolymer (P123) and Ni(NO3)2 in ethanol was made and
the mixture was stirred for 48 h at 25 oC. During the evaporation of the ethanol process,
the soft template of amphiphilic P123 macromolecules and Al(OiPr)3 spontaneously
assembled, and Ni(NO3)2 was encapsulated in them. After the evaporation of the ethanol,
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the sol-gel was subjected to the calcination in the air at 500 C. During the calcination
process, P123 decomposed completely to generate mesoporous pores while Al(OiPr)3
decomposed into Al2O3 framework with the formation of NiO into its matrix from the
decomposition of Ni(NO3)2 to generate NiO/m-Al2O3 (Figure 1). FT-IR spectra (Figure S1)
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revealed the complete removal of P123, the ligand of Al(OiPr)3 as well as the nitric group
in the sample of NiO/m-Al2O3. Figure S2 provides a photo of the aforementioned samples:
the color of the as-formed sol-gel was green, due to the presence of Ni(NO3)2 in the sol-
gel. After the calcination in air at 500 oC, the color of NiO/m-Al2O3 changed into light gray,
due to the decomposition of Al(OiPr)3 and Ni(NO3)2 into Al2O3 and NiO, respectively. After
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the reduction of NiO/m-Al2O3 with H2 at 600 C, the color of Ni/m-Al2O3-600 was dark
gray, suggesting the formation of metallic nickel nanoparticles. The nickel loadings
determined by ICP-OES analysis were 5.3%, 5.4%, 5.5% and 5.5 wt.% for the Ni/m-Al2O3-
500, Ni/m-Al2O3-550, Ni/m-Al2O3-600 and Ni/m-Al2O3-650 catalysts, respectively (Table
S1).
The reductive behaviors of NiO/m-Al2O3 and Ni/m-Al2O3-T were studied by H2
temperature-programmed reduction (TPR) method (Figure 2). A wide peak with the
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reduction temperature around 609 C was observed for NiO/m-Al2O3. Therefore, four
representative temperatures (500, 550, 600 and 650 oC) were selected for the reduction
of NiO/m-Al2O3 to obtain the Ni/m-Al2O3-T catalysts. As shown in Figure 2, the large peak
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around 609 C disappeared over Ni/m-Al2O3-T, indicating that NiO in NiO/m-Al2O3 was
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almost or completely reduced by H2 to generate metallic nickel nanoparticles at the temperatures
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from 500 to 650oC. However, the other two peaks were observed for the Ni/m-Al2O3-T catalysts.
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The peak at high temperature was attributed to the reduction NiO-like phase in the Al2O3
phase [also called Ni-Al mixed oxides (NiAl2O4)],11 and it gradually shifted to higher values over
Ni/m-Al2O3-T, suggesting that the NiO species in the Ni/m-Al2O3-T catalysts had much stronger
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interaction with Al2O3 with the higher reaction temperature. In addition, the intensity of the peak
at high reduction temperature became weaker for Ni/m-Al2O3-T at higher reduction
temperature, reflecting metallic Ni phase in Ni/m-Al2O3-T increased gradually by the
enhancement of the reduction temperature, and NiO phase was too weak to be visible in
the Ni/m-Al2O3-600 and Ni/m-Al2O3-650 catalysts. On the meanwhile, the other peak with
the lower reduction temperature between 329~344 oC was present in the H2-TPR profiles
of the Ni/m-Al2O3-T samples, which should be due to the reduction of single phase of NiO
by the oxidation of surface metallic Ni nanoparticles in the air.12
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Ni/m-Al O -650
2 3
329
331
830
789
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Ni/m-Al O -600
2 3
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341
344
697
682
Ni/m-Al O -550
2 3
Ni/m-Al O -500
2 3
609
NiO/m-Al O
2 3
0
200
400
600
800
Temperature (C)
Figure 2. Temperature-programmed reduction profiles of NiO/m-Al2O3 and Ni/m-Al2O3-T.
The texture properties of NiO/m-Al2O3 and Ni/m-Al2O3-T were studied by N2
adsorption-desorption isotherms (Figure S3). Table S1 summarized the BET surface
areas and pore volumes of NiO/m-Al2O3 and Ni/m-Al2O3-T. The surface area and the pore
volume of NiO/m-Al2O3 were higher than Ni/m-Al2O3-T, because of the loading of nickel
nanoparticles on m-Al2O3 for Ni/m-Al2O3-T. Generally, Ni/m-Al2O3-T had smaller surface
area by the enhancement of the reduction temperature (Table S1). Similar trend was
also found in the pore volume of Ni/m-Al2O3-T. All catalysts displayed IV isotherms curves
with H2-type hysteresis loops, suggesting Ni/m-Al2O3-T have the typical mesoporous
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structure. In addition, an average size of around 60.5 nm was calculated over Ni/m-Al2O3-
T.
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Ni (111)
Ni/m-Al2O3-650
Ni (200)
Ni (220)
Ni/m-Al2O3-600
Ni/m-Al2O3-550
Ni/m-Al2O3-500
NiO/Al2O3
20
40
60
80
2degree
Figure 3. XRD patterns of NiO/Al2O3 and the Ni/Al2O3-T catalysts.
The crystal structures of NiO/m-Al2O3 and Ni/m-Al2O3-T were characterized by XRD
technology (Figure 3). No distinct peaks were present for NiO/m-Al2O3, suggesting both
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NiO and Al2O3 were amorphous. After the reduction of NiO/Al2O3 at 500~650 C, the
peaks at 2θ = 44.5, 51.8 and 76.5° were clearly observed for the (111) (200), and (220)
reflections of metallic Ni (JCPDS No.65-0380) over Ni/m-Al2O3-T. Although XRD patterns
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could not provide NiO phase for the Ni/m-Al2O3-T catalysts (JCPDS no. 47-1049), we can
observe that the peak intensity of (111) and (200) reflections for the Ni/m-Al2O3-500 and
Ni/m-Al2O3-550 catalysts was smaller than the other two catalysts, and the peak intensity
of the Ni/m-Al2O3-500 catalyst was weaker than that of the Ni/m-Al2O3-550 catalyst. The
reason should be caused by the partial reduction of NiO phase in NiO/m-Al2O3 at low
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reaction temperatures of 500 and 550 C as shown in Figure 2. X-ray Photoelectron
Spectroscopy (XPS) of Ni 2p over Ni/m-Al2O3-600 is shown in Figure S4. The peaks at
851.3 eV (Ni 2p3/2), ∼855.4/873.3 (Ni 2p1/2), and ∼860.8/880.7 eV should be attributed to
metallic Ni, NiO and the satellite peak in the high resolution Ni XPS peak, respectively19.
Although the crystal phase of nickel was metallic state as detected by XRD, the presence
of NiO by XPS was due to the oxidation of surface metallic Ni nanoparticles with O2 in the
air.
TEM images of Ni/Al2O3-T are shown in Figure 4 and Figure S5. Structure with
abundant pores was visible in Figure 4 and Figure S5, suggesting that the soft template
method was effective to prepare Al2O3 with high surface area and abundant pores, which
benefits the mass transfer of the substrates and products. As shown in Figure 4 and
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Figurer S5, nickel nanoparticles with small sizes in the range from 3.97 to 5.61 nm were
homogeneous distributed onto the surface of m-Al2O3 for the Ni/Al2O3-T catalysts without
an apparent aggregation. The slight increase of the Ni nanoparticles in Ni/Al2O3-T at
higher reduction temperature revealing that the rise of the reduction temperature resulted
in a growth of nickel nanoparticles. The representative HAADF-STEM of Ni/m-Al2O3-600
also shows that nickel nanoparticles homogeneously distributed on the surface of m-Al2O3
(Figure 4c). TEM-EDX image reveals that the elements of Al, O and Ni were uniformly
dispersed throughout the sample (Figure 4c). The lattice fringe spacings (Figure 4d) of
0.204 and 0.24 nm were corresponded to the interplanar distances of (111) lattice planes
of metallic Ni and NiO, respectively.
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Figure 4. TEM image of Ni/Al2O3-600 (a) and the size distribution of Ni nanoparticles (b);
High-angle annular dark-field scanning TEM (HAADF-STEM) image and the element-
mapping of Ni/m-Al2O3-600 (c); High resolution TEM image of Ni/Al2O3-600 (d).
Catalyst Screen for the Coupling of Benzonitrile and Butylamine
The hydrogenative cross-coupling of benzonitrile and butylamine was firstly conducted
o
under 1 bar H2 at 80 C with NH3∙H2O as the additive. For comparison, a control
experiment in the presence of NiO/m-Al2O3 afforded no benzonitrile conversion,
suggesting NiO was inert for the activation of hydrogen molecules (Entry 1, Table 1).
Ni/m-Al2O3-T could catalyze the hydrogenative cross-coupling of benzonitrile and
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butylamine (Entries 2~5, Table 1), but the catalytic performance of Ni/m-Al2O3-T was
affected by the reduction temperature. The Ni/m-Al2O3-500 catalyst with the smallest size
of Ni nanoparticles delivered a benzonitrile conversion of 20.6% within 4 h (Entry 2, Table
1), because NiO in NiO/m-Al2O3 was partly reduced to metallic Ni nanoparticles as
discussed above. The enhancement of the reduction temperature to 550 and 600 °C
guaranteed an increase in metallic Ni as determined by H2-TPR and XRD, and thus
benzonitrile conversions rose to 41.9% and 63.4% for the Ni/m-Al2O3-550 and Ni/m-
Al2O3-600 catalysts (Entries 3 & 4, Table 1), respectively. If the catalytic efficiency of Ni/m-
Al2O3-T is solely depended on the amount of metallic nickel, Ni/m-Al2O3-650 and Ni/m-
Al2O3-600 should exhibit similar activity according to the H2-TPR results. However, Ni/m-
Al2O3-650 demonstrated lower catalytic activity than Ni/m-Al2O3-600 (Table 1, Entries 5
vs 4). On the one hand, Ni/m-Al2O3-650 has a larger size of nickel nanoparticles than
Ni/m-Al2O3-600, which provided less active sites at the same loading of Ni. On the other
hand, the surface area of Ni/m-Al2O3-650 was smaller than that of Ni/m-Al2O3-600 (Table
S1), and thus the access to Ni nanoparticles became much more difficult.
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As depicted in Scheme 1, it is a very challenging issue to attain a high selectivity of
unsymmetrical imines from the hydrogenative coupling of nitriles with primary amines.
Interestingly, N-benzylidenebutylamine as the unsymmetrical imine product was obtained
as the main product over the Ni/m-Al2O3-T catalysts. Benzylamine and N-
benzylidenebenzylamine were identified to be the byproducts, which were formed by
complete hydrogenation of benzonitrile via phenylmethanimine (PhCH=NH) as the
intermediate and the self-coupling of two benzonitrile molecules (Scheme 1), respectively.
Unlike the hydrogenation of phenylmethanimine (PhCH=NH) into benzylamine, the
hydrogenation of the N-benzylidenebutylamine did not occur, which was either possibly
caused by N-benzylidenebutylamine in a large steric hindrance or its lower activity under
the reaction conditions of 80 oC and 1 bar H2.
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Table 1. Hydrogenative cross-coupling of benzonitrile with butylamine with various
catalysts.a
CN
1
N
CH2NH2
N
+
NH2
+
+
5
4
2
3
Entry
Catalyst
Conversion (%)
Selectivity (%)
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1
NiO/m-Al2O3
Ni/m-Al2O3-500
Ni/m-Al2O3-550
Ni/m-Al2O3-600
Ni/m-Al2O3-650
Ni/Al2O3
0
-
-
-
2
20.6
41.9
63.4
54.1
41.5
63.6
93.3
96.8
86.1
21.1
33.0
5.3
3.4
1.4
1.2
3.3
0
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3
4
2.0
5
10.6
78.9
6b
a
Conditions: benzonitrile (1 mmol), Ni/m-Al2O3-T catalysts (1.87 mol% Ni based on
benzonitrile), butylamine (2 mmol), hexane (10 mL), 26.5 wt.% NH3·H2O (200 μL, 2.8
o
b
mmol), 80 C, 1 bar H2, 4 h. Commmercial available Al2O3 was used to support Ni (5
wt.%)
The selectivity of N-benzylidenebutylamine was also found to be affected by the Ni/m-
Al2O3-T catalysts with different reduction temperatures (Table 1). The much low selectivity
of the Ni/m-Al2O3-550 catalyst might be caused by the low ratio of metallic Ni in the Ni/m-
Al2O3-550 catalyst, which resulted in a low ability to absorb butylamine, and hence
decreased the selectivity of N-benzylidenebutylamine. Ni/m-Al2O3-600 was the best
catalyst for this transformation, which demonstrated the highest activity and the highest
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selectivity of N-benzylidenebutylamine up to 96.8%. We also compared our catalyst with
commercial Al2O3 supported Ni catalyst with similar Ni loadings (5 %), the result shown
that both activity and selectivity decreased indicating that the mesoporous structure is
important for high activity and selectivity (Table 1, Entry 6).
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The coupling of benzonitrile and butylamine under different conditions
The reaction conditions were then optimized for the coupling of benzonitrile and
butylamine over the Ni/m-Al2O3-600 catalyst. The catalytic activity of Ni/m-Al2O3-600 had
no distinct relationship with the polarity of the solvents, with benzonitrile conversions in
the range from 35.3~78.8% either in polar and non-polar organic solvents as well as water
(Table S2). Besides the target product of N-benzylidenebutylamine, benzylamine and N-
benzylidenebenzylamine as the byproducts were also detected in all the tested solvents.
The reaction in hexane gave the highest selectivity (96.8%) to N-benzylidenebutylamine
(Entry 1, Table S2,), while that was in the range from 53.4 % to 73.6 % in other cases
(Entries 2~6, Table S2). The possible reason should be that much more substrates
especially butylamine would absorb on the surface of the Ni/m-Al2O3-600 catalyst,
resulting in a high selectivity to N-benzylidenebutylamine. The reason should be attributed
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to the non-polar nature of hexane. As shown in Scheme S1, the key step for selectivity of
this reaction is the competition reaction for imine (Compound 2) between the nucleophilic
attack from butylamine and hydrogenation which will further produce benzylamine. Thus,
the concentration of butylamine on the active sites should be of great importance in
selectivity. On one hand, hexane as the non-polar solvent should have limited or no
adsorption on the Ni sites. Therefore, much more butylamine would absorb on the Ni
sites. For the second reason, unlike the possible hydrogen bond formation in solvent like
THF, alcohol, and water which may lead to interaction between butylamine and solvent,
butylamine will have limited interaction with non-polar solvents such as hexane, benefiting
their adsorption on the catalyst surface and enhancing their nucleophilic attack to the
intermediate. Therefore, the hydrogenative cross-coupling of benzonitrile with butylamine
in hexane gave the best results.
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59
60
Table 2. Hydrogenative cross-coupling of benzonitrile and butylamine with different
amount of NH3·H2O.a
Entry
NH3 amount (mmol)
Conversion (%)
Selectivity (%)
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1
2
3
4
5
6
0
5.1
45.2
57.8
68.0
79.0
96.8
97.6
0
54.8
42.2
16.6
6.8
1.2
0.8
0.7
1.4
2.1
2.8
3.5
22.1
55.1
62.8
63.4
61.1
0
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15.4
14.2
2.0
1.6
a Conditions: benzonitrile (1 mmol), Ni/m-Al2O3-600 (1.87 mol% Ni based on benzonitrile),
butylamine (2 mmol), hexane (10 mL), a set amount of 26.5 wt.% NH3·H2O, 80 oC, 1 bar
H2, 4 h.
The hydrogenative cross-coupling of benzonitrile and butylamine was found to be
sensitive to the amount of NH3∙H2O. The reaction proceeded slowly without the addition
of NH3∙H2O, affording a low benzonitrile conversion of 5.1 % (Entry 1, Table 2,), while
benzonitrile conversion greatly increased to 22.1 % in the presence of 0.7 mmol of
NH3∙H2O (Entry 2, Table 2). It indicated NH3∙H2O promoted hydrogenative cross-
coupling of benzonitrile and butylamine. The reaction rate continuously accelerated by
further increasing the amount of NH3∙H2O, and a high benzonitrile conversion of 62.8%
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was attained using 2.1 mmol of NH3∙H2O (Entry 4, Table 2). Benzonitrile conversions
remained stable with 0.15~0.25 mL of 26.5 wt.% NH3∙H2O (2.1~3.5 mmol, Entries 4~6,
Table 2). NH3 itself did not participate the coupling of benzonitrile and butylamine
(Scheme 1), thus NH3 should act as an additive to promote the hydrogenative cross-
coupling of benzonitrile and butylamine. Thus, it is envisaged that NH3 accelerated the
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+
bond cleavage of H2 on the surface of nickel nanoparticles, giving rise to NH4 and Ni-
H-.13 Interestingly, the reaction was completely inhibited when pyridine (2.1 mmol) was
used as the organic base. The possible reason should be that pyridine had a strong
affinity to nickel nanoparticles, thus it blocked the active sites for the substrates. In
contrast, NH3 with a weak affinity to nickel nanoparticles but a strong basicity was an
appropriate additive. In addition, NH3 should also serve as a base to accelerate the
deamination of the geminal diamine intermediate (Compound 3, Scheme S1) to generate
the aim product.
Selectivity of N-benzylidenebutylamine increased with the enhanced loading of
NH3∙H2O, while selectivity of N-benzylidenebenzylamine was greatly inhibited with the
increase of the increase of NH3∙H2O amount. Results in Table 2 verified that deamination
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of the geminal diamine intermediate (Scheme S1) into N-benzylidenebutylamine
(Scheme S1) was accelerated by the base (NH3∙H2O), and the deamination of the
intermediate of Compound 5 into N-benzylidenebenzylamine should be much easier than
that for the formation of N-benzylidenebutylamine, which was the major product without
the addition of NH3∙H2O (Table 2, Entry 1). Benzylamine was not observed without or with
a little amount of NH3∙H2O, due to the low conversions of benzonitrile, and its selectivity
was also inhibited by the increase of the NH4OH loading (Table 2, Entries 1 &2).
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CN
1
N
CH2NH2
+
N
+
NH2
+
5
4
2
3
Conversion
Selectivity of 4
Selectivity of 3
Selectivity of 5
100
80
60
40
20
0
2.5
1
5
Pressure (bar)
Figure 5. The hydrogenative cross-coupling of butylamine with benzonitrile from 1 bar to
5 bar. Conditions: benzonitrile (1 mmol), Ni/m-Al2O3-600 (1.87 mol% Ni based on
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benzonitrile), butylamine (2 mmol), hexane (10 mL), NH3·H2O (26.5 wt.%, 200 μL, 2.8
6
7
8
mmol), 80 oC, 4 h.
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The cross-coupling of benzonitrile with butylamine was also influenced by the hydrogen
pressure. Benzonitrile conversion gradually increased from 63.4% under 1 bar H2 to 100%
under 5 bar H2 after 4 h at 80 oC (Figure 5). The enhancement of H2 pressure resulted in
the enhancement of hydrogen concentration in hexane, thus accelerating reaction rate.
However, selectivity of N-benzylidenebutylamine descended under higher H2 pressure.
According to Figure 5, the enhancement of H2 pressure accelerated the complete
hydrogenation of benzonitrile into benzylamine, and the subsequent coupling of
benzylamine with phenylmethanimine to give N-benzylidenebenzylamine. Interestingly,
the enhancement of H2 did not cause the hydrogenation of N-benzylidenebutylamine and
N-benzylidenebenzylamine, possibly due to the steric hindrance of the C=N bonds in
them, or the low activity of them under mild conditions as described above.
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The cross-coupling of benzonitrile with butylamine was explored at different
temperatures. It should be pointed out that the Ni/m-Al2O3-600 catalyst was even active
at room temperature (Figure 6), albite the conversion of benzonitrile was poor in 7.3%
after 4 h. 98.4% yield of N-benzylidenebutylamine was attained after 96 h at room
temperature. As shown in Figure 6, the hydrogenative cross-coupling of benzonitrile with
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o
butylamine was influenced by the reaction temperature. From 25oC to 120 C, the
conversion of benzonitrile enhanced from 7.3% to 75.1%, which was much more obvious
o
at low temperatures (25~80 C). Unlike the influence of hydrogen pressure and the
amount of NH3•H2O, products selectivity was not greatly depended on the reaction
temperature. The selectivity to N-benzylidenebutylamine slightly decreased from 100% at
25 oC to 91.3% at 120 oC. Therefore, the appropriate reaction temperature should be 80
oC for the cross-coupling of benzonitrile with butylamine.
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CN
N
CH2NH2
+
N
5
+
NH2
+
3
4
7
8
9
Selectivity of 3
Selectivity of 5
Conversion
Selectivity of 4
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100
80
60
40
20
0
120
40
100
25
80
60
Temperature (C)
o
Figure 6. Hydrogenative cross-coupling of benzonitrile with butylamine at 25~120 C.
Conditions: benzonitrile (1 mmol), Ni/m-Al2O3-600 (1.87 mol% Ni based on benzonitrile),
butylamine (2 mmol), hexane (10 mL), NH3·H2O (26.5 wt.%, 200 μL, 2.8 mmol), H2 (1
bar), 4 h.
Molar ratio of butylamine to benzonitrile also influenced benzonitrile conversion and the
products selectivity (Figure S6). Interestingly, benzonitrile conversion gradually reduced
at higher molar ratio of butylamine to benzonitrile, but selectivity of N-
benzylidenebutylamine enhanced. For heterogeneous reactions, substrates (benzonitrile
and butylamine) should first adsorb on Ni nanoparticles. The enhancement of butylamine
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amount would result in an increase of the adsorbed butylamine around nickel
nanoparticles, and thus less benzonitrile molecules adsorbed around nickel nanoparticles.
Therefore, the reaction rate should become slower at a higher molar ratio of butylamine
to benzonitrile, as the partial reduction of benzonitrile into phenylmethanimine was the
starring step (Compound 2, Scheme S1). On the meanwhile, the increase of butylamine
concentration promoted the coupling of butylamine with phenylmethanimine to produce
N-benzylidenebutylamine (Scheme S1), thus improved its selectivity (Figure S5).
Process of the hydrogenative cross-coupling of butylamine with benzonitrile was
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recorded under1 bar H2 pressure at 80 C (Figure S7). During the reaction process,
benzonitrile was gradually consumed with a full conversion after 12 h, and the
concentration of N-benzylidenebutylamine gradually increased. After 12 h, 95.5 % yield
of N-benzylidenebutylamine was achieved. Benzylamine as well as N-
benzylidenebenzylamine were the byproducts with a little amount. The intermediates
such as phenylmethanimine as depicted in Scheme S1 were not detected during the
reaction process because of their instability.
Substrate Scope for the Cross-coupling of Nitriles with Primary amines
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Table 3. Substrate scope of the cross-coupling of nitriles with primary amines.a
6
7
8
9
R'
R CN
+
R' NH2
+
+
R
NH2
R
N
R
N
5
R
3
4
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Substrate
Tim Con
Yield (%)
4
Entry
Product
e
.
Nitrile
Amines
3
5
(h)
(%)
CN
N
1
2
3
4
5
6
7
12
12
12
30
12
12
12
100 93.5 1.4
100 91.7
95.8 86.5 0.7
5.4
8.3
8.6
NH2
NH2
NH2
NH2
NH2
NH2
CN
N
0
MeO
MeO
CN
N
N
CN
91.5 64.1 27.9 3.1
CN
N
97.6 89.1 2.5
6.0
1.0
2.0
CN
N
91.7 90.7
84.6 82.6
100 95.1
100 98.1
0
0
0
0
Cl
F
Cl
F
CN
N
N
NH2
NH2
CN
8
15
4.9
F3C
N
F3C
N
CN
N
9
24
18
36
18
12
12
15
18
1.9
0
NH2
NH2
NH2
CN
N
10
11b
12
13
14
15
16
100 85.1 14.9
100 75.0
93.4 88.3 3.9
100 100
0
25.0
1.2
0
N
CN
CN
N
NH2
CN
CN
CN
CN
CH2NH2
N
0
CH2NH2
N
100 95.1 0.9
95.1 88.1 1.6
4.0
5.4
OMe
Cl
MeO
Cl
CH2NH2
CH2NH2
N
N
98.6 85.7 2.9 10.0
F
F
CN
CN
NH2
N
17
18
20
18
100 93.4
100 91.2
0
0
6.6
9.8
OMe
NH2
N
MeO
Cl
NH2
CN
19
24
100 71.4
0
28.6
N
Cl
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CN
NH2
20b
36
90.2 78.2 10.6 1.4
N
H
6
7
8
9
a Reaction conditions: nitrile (1 mmol), the Ni/m-Al2O3-600 catalyst (1.87 mol% Ni based
on benzonitrile), primary amine (2 mmol), hexane (10 mL), 26.5 wt.% NH3·H2O (200 μL,
2.8 mmol), 80 oC, 1bar H2; b The reaction was performed at 100 oC and 5 bar.
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Scope of the hydrogenative cross-coupling of nitriles with primary amines was studied
(Table 3). Firstly, the coupling of structurally diverse nitriles with butylamine were
o
performed at 80 C and 1 bar H2 pressure. These reactions proceeded smoothly, and
unsymmetrical imines were got in yields from 64.1% to 98.1% under the reaction
conditions. Interestingly, the electron-withdrawing substituted benzonitriles were less
active than the electron-donating substituted benzonitriles, but gave a slightly higher
selectivity to the aim products (Entries 2 & 3 vs Entries 6-8, Table 3). In addition, the
halogen substituted groups remained under the reaction conditions (Entries 6 &7, Table
3), which was observed by supported Co catalyst.14 2-Methylbenzonitrile with a methyl
group in ortho-position bearing a large steric hindrance demonstrated much lower activity
than 4-methylbenzonitrile and 3-methylbenzonitrile (Entries 4 vs 3 & 5, Table 3). In
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addition, the large steric hindrance also inhibited its cross-coupling with butylamine or
itself, resulting in much higher selectivity to 2-methylbenzylamine than those cases with
the 4-methylbenzonitrile and 3-methylbenzonitrile as the substrates (Entries 4 vs 3 & 5,
Table 3). Reaction of 4-pyridinecarbonitrile and naphthalene-2-carbonitrile with
butylamine yielded 98.1% of N-(pyridine-4-ylmethylene)butan-1-amine and 85.1% of N-
(2-naphthalenylmethylene)butane-1-amine after 24 and 18 h, respectively (Entries 9 &
10, Table 3). The long reaction time for the coupling of 4-pyridinecarbonitrile and
butylamine was possibly due to the strong affinity of 4-pyridinecarbonitrile with the metallic
nickel nanoparticles, and the reason for the long reaction time of naphthalene-2-
carbonitrile with butylamine was due to its large steric hindrance of naphthalene-2-
carbonitrile, also accompanying the production of naphthalen-2-ylmethanamine with a
yield of 14.9%. Non-aromatic nitriles demonstrated lower activity in comparison with
aromatic nitriles. For example, the hydrogenative cross-coupling of valeronitrile with
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
butylamine was completed after 36 h at 100 C and 5 bar H2, affording N-
pentylidenehexan-1-amine with a relative low yield of 75% and a 25% yield of self-
coupling byproduct (Entries 1 vs 11, Table 3). It should be pointed out that our method
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