Supported nano-gold-catalyzed N-formylation of amines with paraformaldehyde in water under ambient conditions

Article abstract of DOI:10.1039/c5gc01992c

A simple and efficient Au/Al₂O₃ catalyst was prepared by the co-precipitation method for the oxidative N-formylation of amines with paraformaldehyde. Under the optimized reaction conditions, excellent amine conversion and N-formamide selectivity can be obtained with up to 97% yield with water as the solvent under ambient conditions. This catalyst tolerated a wide range of primary amines and second amines, and it can be reused for at least five runs without obvious deactivation.

Full text of DOI:10.1039/c5gc01992c

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Z. Ke, Y. Zhang, X.
Cui and F. Shi, Green Chem., 2015, DOI: 10.1039/C5GC01992C.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/greenchem

Please do not adjust margins
Green Chemistry
Page 1 of 10
View Article Online
DOI: 10.1039/C5GC01992C
Green Chemistry
ARTICLE
Supported Nano-Gold-Catalyzed N-Formylation of Amines with
Paraformaldehyde in Water under Ambient Conditions
Zhengang Ke,a,b Yan Zhang,a Xinjiang Cui,a and Feng Shi*a
Received 00th January 20xx,
Accepted 00th January 20xx
A simple and efficient Au/Al2O3 catalyst was prepared by co-precipitation method for the oxidative N-formylation of
amines with paraformaldehyde. Under the optimized reaction conditions, excellent amine conversion and N-formamide
selectivity can be obtained with up to 97% yield with water as the solvent under ambient conditions. This catalyst was
tolerated a wide scope of primary amines and second amines, and it can be resued for at least five runs without abvious
deactivation.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
has been reported with various carbonyl source reagents such
as formic acid or formate14-18, esters19,20, cyanide21-29, and
Supported nano-gold catalysts have been widely used in
various catalytic reactions, e.g. selective hydrogenation,
selective oxidation, hydrochlorination of alkynes, carbon
monoxide elimination and many others1-3. Gold nano particles
can dissociate molecular oxygen to atomic oxygen at low
temperature due to its unique surface structure and
physicochemical properties4. So, supported nano-gold catalyst
exhibits excellent catalytic performance in the selective
oxidation reactions. Therefore, the applying of supported
nano-gold catalyst allows the progress of oxidation reaction at
low reaction temperature thus the side reactions can be
inhibited. As we all know, selective oxidation reaction
constitutes one of the industrial core technologies for
converting bulk chemistry to useful products of a higher
oxidation state5, so nano-gold catalysis presents a good choice
in the development of selective oxidation reactions.
N-Formamide is an important class of compounds6 which
are widely used in organic synthesis and biological
intermediates in fungicide7, isocyanate8, nitrile, and
pharmaceuticals synthesis9,10. Traditionally, the N-formamide
synthesis involves the use of stoichiometric amounts of
coupling reagents, such as a carbodiimide, it makes the
reaction operations complicated, and causes equipment
corrosion and poor atom-economy11-13. The direct catalytic
synthesis of N-formamide from amines and carbonyl
compounds has become a field of emerging importance due to
its high atom efficiency. The catalytic N-formylation of amines
37,38
oxime30-36
,
CO2/H2
and
methanol39-42
.
Notably,
formaldehyde as the carbonyl source for N-formamide
synthesis has been less studied.
Recently, the direct N-formylation of amines with
formaldehyde as the carbonyl source was reported. Originally,
the N-formylation of aliphatic amines can be realized with 3.0
equivalent of aqueous formaldehyde or paraformaldehyde at
115 oC in the presence of homogeneous iridium catalyst43
.
Following several nano-gold catalyst systems were applied in
this transformation. For example, N-formylation of amine with
1.5 equiv., formalin in the presence of 1.0 equiv., NaOH can be
realized using ethanol/water (1:2) as solvent under aerobic
oxidation conditions catalyzed by PVP stabilized gold nano
particles44. The N-formylation reaction of aromatic amines can
also be performed with 2.0 equiv., aqueous formaldehyde
solution and 3.0 equiv., NaOH catalyzed by carbon nanotube
supported nano-gold catalyst45. However, the above reaction
systems have one or more shortcomings such as difficulty in
separation of catalysts with product, the applying of a great
deal of base, excessive amount of formaldehyde, and organic
solvent.
Scheme 1. Oxidative N-formylation of amine with paraformaldehyde catalyzed
by supported nano-gold catalyst under ambient conditions
a.State Key Laboratory for Oxo Synthesis and Selective Oxidation, Centre for Green
Chemistry and Catalysis, Lanzhou Institute of Chemical Physics, Chinese Academy
of Sciences, No. 18, Tianshui Middle Road, Lanzhou, P. R. China. E-mail:
fshi@licp.cas.cn.
In this work, a simple and efficient Au/Al2O3 catalyst was
developed for the N-formylation reaction of amines with
stoichiometric amount of paraformaldehyde applying water as
the sole solvent. The N-formylation of aliphatic and aromatic
amines with different structures can be realized with excellent
b.University of Chinese Academy of Sciences, Beijing, 100049.
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 2 of 10
View Article Online
DOI: 10.1039/C5GC01992C
ARTICLE
Journal Name
yields (Scheme 1), and the catalyst can be reused for five runs Catalytic performance test
without obvious deactivation.
The catalytic activity was tested by N-formylation of
morpholine as the model reaction. 1.0 mmol morpholine, 1.2
mmol paraformaldehyde, 0.2 mmol NaOH and 2 mL deionized
water were added to a 38 mL press tube and exchanged with
O2. The reaction was carried out at 25 oC for 6 h with the
magnetic stirring speed of 900 rpm. Subsequently, the reaction
mixture was diluted with 5 mL methanol for quantitative
analysis by GC-MS (Agilent 7890B-5977A). And then, the crude
reaction mixture was concentrated by rotary evaporator and
purified by column chromatography to give the isolated
compound. N-formyl morpholine was obtained and purified by
column chromatography, with 97% isolated yields, using
dichloromethane/methanol (10 : 1, Rf = 0.77) to give a
colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 3.74 –
3.63 (m, 4H), 3.59 (q, J = 4.8 Hz, 2H), 3.45 – 3.35 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ 160.82, 67.24, 66.45, 45.80, 40.63.
Experimental section
All solvents and chemicals were obtained commercially and
were used as received.
Catalyst preparation and characterization
The Au/Al2O3 was prepared by co-precipitation method. 18
mmol Al(NO3)3•9H2O and 6.9 mL HAuCl4•4H2O (10 mg/mL)
were added into 120 mL deionized water at rt., under vigorous
stirring. Then, 20 mL Na2CO3 aqueous solution (1.35 M) was
added dropwise to the solution, and the pH value of the finial
solution was ~7.0. After further stirring for 4 h, the resulting
precipitate was separated and washed by deionized water,
o
dried at 100 C in air for 6 h, calcined at 400 oC for 4 h, and
then reduced under hydrogen flow at 350 oC for 3 h. The
resulting catalyst samples were denoted as Au/Al2O3. Pd/Al2O3,
Pt/Al2O3, Ru/Al2O3, Au/FeOx, Au/NiOx and Au/CuOx were
prepared with the same procedures.
Results and discussion
Following, the catalysts ware characterized by inductively Catalyst characterization studies
coupled plasma-atomic emission spectroscopy (ICP-AES), BET
BET characterization
surface-area analysis (BET), transmission electron microscopy
Table 1. The physical properties of catalysts
(TEM), X-ray power diffraction (XRD), X-ray photoelectron
spectroscopy (XPS), and the reaction products were
Noble metal
BET surface
area/m2/g[b]
152.8
Pore volume/
cm3/g[b]
0.57
Sample
characterized by nuclear magnetic resonance spectrum (NMR).
XRD measurements were conducted by using a STADIP
automated transmission diffractometer (STOE) equipped with
an incident beam curved germanium monochromator with
CuKa1 radiation and current of 40 kV and 150 mA,
respectively. The XRD patterns were scanned in the 2 Theta
range of 5-100o. XPS were obtained using a VG ES-CALAB 210
instrument equipped with a dual Mg/Al anode X-ray source, a
hemispherical capacitor analyzer, and a 5 keV Ar+ iron gun. The
electron binding energy was referenced to the C1s peak at
284.8 eV. The background pressure in the chamber was less
than 10-7 Pa. The peaks were fitted by Gaussian–Lorentzian
curves after a Shirley background subtraction. For quantitative
analysis, the peak area was divided by the element-specific
Scofield factor and the transmission function of the analyzer.
The BET surface area measurements were performed on a
Micromeritics 2010 instrument at the temperature of 77 K.
The pore size distribution was calculated from the desorption
isotherm by using the Barrett, Joyner, and Halenda (BJH)
method. Prior to measurements, the samples were degassed
at 200 oC for 10 h, at a rate of 10 oC/min. TEM was carried out
by using a Tecnai G2 F30 S-Twin transmission electron
microscope operating at 300 kV. Single-particle EDX analysis
was performed by using a Tecnai G2 F30 S-Twin Field Emission
TEM in STEM mode. For TEM investigations, the catalysts were
dispersed in ethanol by ultrasonication and deposited on
carbon-coated copper grids. NMR spectra were measured by
using a Bruker ARX 400 or ARX 100 spectrometer at 400 MHz
(1H) and 100 MHz (13C). All spectra were recorded in CDCl3 and
chemical shifts (d) are reported in ppm relative to
tetramethylsilane referenced to the residual solvent peaks.
Loading/wt%[a]
Au/Al2O3
Pd/Al2O3
Pt/Al2O3
Ru/Al2O3
Au/FeOx
Au/NiOx
Au/CuOx
2.62
3.56
166.0
0.36
1.53
147.7
0.73
1.19
150.4
0.91
3.34
5.8
0.11
3.42
6.4
0.07
3.21
5.0
0.03
[a] Determined by ICP-AES, [b] Determined by IQ2 automated gas sorption
analyser.
N2 adsorption-desorption analysis was used to determine
the surface area and structure of the prepared supported
catalysts (Table 1, Fig. S1). The catalysts with Al2O3 as support
provide larger surface areas comparing those with FeOx, NiOx
and CuOx as supports. For example, the BET surface areas of
Au/Al2O3, Pd/Al2O3, Pt/Al2O3 and Ru/Al2O3 are in the range of
147.7-166.0 m2/g, while less than 10 m2/g BET surface areas
are observed in catalysts Au/FeOx, Au/NiOx and Au/CuOx. In
the meanwhile, the pore volumes were significantly decreased,
too. It might be due to the reducibility of FeOx, CuOx and NiOx.
Partial reduction of these metal oxides occurred when the
catalysts were treated under hydrogen flow at 350 oC. The XRD
characterization also reveals the existence of metallic Cu and
Ni in the final catalyst samples.
TEM characterization
TEM images of the as-synthesized catalysts samples Au/Al2O3,
Pd/Al2O3, Pt/Al2O3, Ru/Al2O3, Au/FeOx, Au/NiOx and Au/CuOx are
shown in Fig. 1 and Fig. S2. Based on the TEM images of catalyst
Au/Al2O3, it can be seen that the Au nano-particles were well
dispersed on the support (Fig. 1A and H). According to the statistic
results of TEM image, the average diameter of gold particles is ~2.5
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 3 of 10
Journal Name
View Article Online
DOI: 10.1039/C5GC01992C
ARTICLE
nm, and 73% of nano-gold particles dropped in the range of 2-3 nm.
In catalysts Pd/Al2O3 and Pt/Al2O3, the nano-Pd and nano-Pt
particles were also well dispersed on the surface of Al2O3 (Fig. 1B
and C), and the mean diameters are ~2.7 nm and ~2.8 nm (Fig. S2A
and B). Interestingly, no obvious Ru and Au nanoparticles were
observed from the TEM images of Ru/Al2O3 and Au/CuOx.
(111), (200), (220) and (311). However, there are no Pt, Pd and
Ru diffraction peak can be observed when Pd/Al2O3, Pt/Al2O3
and Ru/Al2O3 were characterized by XRD. It suggests that Pd,
Pt and Ru were well dispersed on the supports and amorphous
Pd, Pt and Ru species were formed in the samples. About the
diffraction patterns of Au/FeOx, Au/NiOx and Au/CuOx, it can
be seen clearly that the diffraction peaks can be attributed to
B
A
Fe3O4, metallic nickel and copper, i.e. 35.5
Fe3O4 (440), 30.1 Fe3O4 (220), 57.0
Fe3O4 (400); 44.4 Ni (111), 98.4 Ni (222), 76.4
51.87 Ni (200), 92.9 Ni (311); 50.5 Cu (200), 43.4
(111), 74.0 Cu (220) and 89.9 Cu (311). No characteristic
º
Fe3O4 (311), 62.5
º
º
º Fe3O4 (511), 42.9
º
º
º
º
Ni (220),
Cu
SAED
SAED
º
º
º
º
º
º
50 nm
diffraction peak ascribed to noble metal species was
observable, indicating that these gold particles were well
dispersed and no crystallized gold formed. The metallic copper
and nickel species should be formed during the reduction of
the catalyst samples.
50 nm
C
D
Al2O3
Au
A
SAED
SAED
Ru/Al2O
50 nm
50 nm
3
Pt/Al2O3
E
F
Pd/Al2O3
Au/Al2O3
SAED
SAED
20
40
60
80
100
2 Theta(°)
50 nm
50 nm
Cu
B
Ni
Fe3O4
d
=2.5nm
m
G
H
1
2
3
4
5
6
Au/CuOx
Au diameter (nm)
SAED
Au(111)
Au/NiOx
Au/FeOx
20
2 nm
50 nm
Figure 1. TEM images of supported catalysts samples synthesized with co-
precipitation method. (A) Au/Al2O3, (B) Pd/Al2O3, (C) Pt/Al2O3, (D) Ru/Al2O3, (E)
Au/FeOx, (F) Au/NiOx and (G) Au/CuOx. Insets: SAED patterns of the
corresponding samples.
40
60
2Theta(°)
80
100
Figure 2. XRD diffraction patterns of catalysts Au/Al2O3, Pd/Al2O3, Pt/Al2O3 (A)
and Ru/Al2O3, Au/FeOx, Au/NiOx and Au/CuOx (B).
It suggests that the Ru and Au species might be encapsulated
inside the supports or highly dispersed on the supports. Bigger
XPS characterization
nano-gold particles, with mean diameter of ~8.3 nm and ~9.4
The catalytic activity should be remarkably influenced by the
surface properties of the catalysts, so XPS characterization was
carried out to determine the surface properties of the
supported catalysts, and the Au 4f spectra were shown in Fig.
3. The Au 4f signals of catalysts Au/Al2O3 and Au/FeOx showed
at 83.26-83.75 eV and 79.61-80.10 eV, and the binding energy
nm were formed if the catalyst supports were FeOx and NiOx
(Fig. 1E and F and Fig. S2D and E). If taking the results of
catalytic performance exploration into consideration together,
we can imagine that the coagulation of nano-gold particles in
catalysts Au/FeOx and Au/NiOx might be one of the reasons for
their low activities.
values of Au 4f7/2 are fixed 3.1 eV more than those of Au 4f5/2
,
XRD characterization
which is agreed with the binding energy of metallic gold. The
aluminium species on the surface of the catalysts were
aluminium oxide (Fig. S3D). The Pd 3d peaks were 330.07 eV
and 335.60 eV, and it is in line with the binding energy of
metallic Pd (Fig. S3A). Meanwhile, the 74.35 eV is the metallic
Fig. 2 shows the XRD diffraction patterns of the as-prepared
supported catalysts. Based on the XRD diffraction patterns, the
Au/Al2O3 sample shows diffraction peaks at 38.3
º, 44.3º, 64.7º
and 77.5º, which can be ascribed to the diffraction peaks of Au
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 4 of 10
View Article Online
DOI: 10.1039/C5GC01992C
ARTICLE
Journal Name
different from the bulk phase. This phenomenon also exists in
Au/FeOx. The surface composition of Au/FeOx is Au0 and Fe2O3
(Fig. 3 and Fig. S3E), while it is Fe3O4 in the bulk phase, which
might be due to the oxidation of catalyst surfaces in the air.
Au4f
4f5/2
4f7/2
Au/NiOx
Au/CuOx
Au/FeOx
Au/Al2O3
Catalyst screening and reaction conditions optimization
3.65eV
Table 2 shows the results of catalyst screening and reaction
conditions optimization with the N-formylation of morpholine
as a model reaction at 25 oC in the presence of 1 atm O2.
Clearly, no N-formyl morpholine was formed and the major
product was 1c if Al2O3 was used as catalyst directly (Table 2,
entry 1). Following, the catalytic performance of catalysts with
different noble metals and supports were tested. Clearly,
Au/Al2O3 exhibits the best catalytic performance, and 96%
morpholine conversion with 98% N-formyl morpholine
selectivity were obtained. If other catalysts including Pd/Al2O3,
Ru/Al2O3 and Pt/Al2O3 were employed, lower conversions or
selectivities were obtained (Entries 2-5). Thus supported nano-
gold catalyst might be more suitable for the N-formylation of
morpholine with paraformaldehyde.
94 92 90 88 86 84 82 80
B.E.(eV)
Figure 3. XPS spectra of Au4f of catalysts Au/Al2O3, Au/FeOx, Au/NiOx and
Au/CuOx.
Pt 4f5/2 binding energy, and 284.84 eV is the metallic Ru 3d5/2
binding energy (Fig. S3B and C). Nevertheless, weak peaks of
gold were found from Au/CuOx and Au/NiOx. It suggests that
the gold particles might be coated by CuOx and NiOx. In
addition, the typical binding energy of CuO was found on the
surface of Au/CuOx (Fig. S3G). As metallic copper was observed
by XRD characterization, the surface phase composition is
Table 2. Reaction conditions optimization for N-formylation of morpholine[a]
Entry
Catalyst/mg
Base
Conv. (%)[b]
Sel. (%)[c]
1b
3
1c
1d
trace
-
1e
-
1
2
Al2O3/25
NaOH
NaOH
99
78
96
63
68
84
88
64
97
95
98
86
78
86
74
90
98
99
96
96
98
99
79
97
Pd/Al2O3/20
Au/Al2O3/20
Ru/Al2O3/20
Pt/Al2O3/20
Au/FeOx/20
Au/NiOx/20
Au/CuOx/20
Au/Al2O3/5
Au/Al2O3/10
Au/Al2O3/25
Au/Al2O3/20
Au/Al2O3/20
Au/Al2O3/20
Au/Al2O3/20
Au/Al2O3/20
Au/Al2O3/20
Au/Al2O3/25
Au/Al2O3/25
Au/Al2O3/25
Au/Al2O3/25
Au/Al2O3/25
Au/Al2O3/25
93
98
26
-
-
7
3
NaOH
2
-
4
NaOH
-
6
68
66
50
88
29
-
5
NaOH
-
34
4
6
NaOH
31
-
15
7
NaOH
11
1
8
NaOH
51
25
79
99
79
51
83
100
80
97
9
-
20
trace
trace
1
9
NaOH
75
10
11
12[d]
13[d]
14[d]
15[d]
16[d]
17[d]
18
19
20
21
22
23[e]
NaOH
21
-
NaOH
-
-
Na2CO3
K2CO3
-
5
16
33
6
-
16
11
-
KOH
-
-
NaOH
-
NaOCH3
tert-BuOK
----
-
13
1
7
1
1
trace
trace
trace
1
91
78
67
3
-
NaOH/2 mg
NaOH/4 mg
NaOH/6 mg
NaOH/8 mg
----
22
33
96
99
57
-
-
-
trace
25
-
-
-
18
[a] Reaction conditions: 1a (1.0 mmol), paraformaldehyde (1.2 mmol), catalyst (5-25 mg), NaOH (0.2 mmol), deionized water (2.0 mL), 25 oC, 6 h. [b] Conversion of
morpholine was determined by GC-MC. [c] Selectivity by GC-MS analysis based on the morpholine consumed. [d] 25 oC, 4 h. [e] 38% formaldehyde solution (1.2 mmol).
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 5 of 10
View Article Online
DOI: 10.1039/C5GC01992C
Green Chemistry
ARTICLE
Then, nano-gold catalysts with other supports, i.e., Au/FeOx,
Au/NiOx and Au/CuOx were tested. However, the yields to the
desired product 1b were <40% (Entries 6-8). The main reason
for their low activity might be attributed to their small surface
areas. By applying Au/Al2O3 as the model catalyst, the catalyst
loadings were varied from 5 mg to 25 mg to check its influence
on the catalytic reaction, and finally we found that 97% yield of
N-formyl morpholine can be achieved if 25 mg catalyst was
added (Entries 3 and 9-11). The influence of base on the
catalytic reaction was further tested. Typical bases including
Na2CO3, K2CO3, KOH, NaOH and tert-BuOK were tested under
the same reaction conditions (Entries 12-17). Although similar
conversions of morpholine were observed, it can be seen that
100% selectivity to N-formyl morpholine was obtained if NaOH
was used. Thus NaOH is the best cocatalyst for this
transformation. Finally the base loadings were tested and the
results suggested that 15-20% is the suitable loadings of base
(Entries 18-22). The presence of base might promote the de-
polymerization of paraformaldehyde and nucleophilic addition
of amine to formaldehyde (Entries 18, 22 and 23).
2
3
88
2
a
2
b
90
91
3
a
a
3
b
b
4
4
4
5
6
7
78
89
5
a
5
b
Next, the generality of catalyst Au/Al2O3 in the N-
formylation
paraformaldehyde were studied (Table 3). For the cyclic
secondary amines, including –10 the N-formylation
products, i.e. 1 –10 , can be synthesized with 78–97% yields
of
different
secondary
amines
with
1
a
a,
6
a
b
b
6b
(Entries 1–10 and Scheme 2). The reactions were also
successful for the N-formylation of aliphatic secondary amines,
and 75%-99% yields of the corresponding products were
obtained (Entries 11–16). The applying of secondary amines
with aromatic substituents as starting materials should be
more challenging due to the weak nucleophilicity of the
nitrogen atom. To our delight, excellent results can be
achieved with 75-93% isolated yields (Entries 17-18). If
secondary amines, i.e., N-benzyl aniline and dibenzyl amine,
with melting points above room temperature, the reaction
temperature should be increased to 100 oC, and 75-84%
isolated yields to the corresponding N-formylation products
were obtained, too (Entries 19-20). Therefore, this Au/Al2O3
catalyst exhibit nice generality in N-formylation reactions of
secondary amines.
83
92
95
7
8
a
a
7
b
b
8
9
8
Table 3. Results of N-formylation of secondary amines[a]
Entry
Substrates
Products
Yields[c]
1
9
a
9b
97
1a
1b
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 6 of 10
View Article Online
DOI: 10.1039/C5GC01992C
ARTICLE
Journal Name
diformylpiperazine can be synthesized with 87% isolated yield
when 2 equiv., paraformaldehyde was used. These results
indicate that piperazine is more active than the N-formyl
piperazine as almost no 1, 4-diformylpiperazine is produced
with the addition of 1 equiv., of paraformaldehyde. Therefore,
the Au/Al2O3 should be a potential catalyst for the selective N-
formylation of polyamines.
10
78
10
a
10
b
11
12
13
99[d]
11
a
11
b
12
a
91
12
b
88
75
83
13
a
a
13
14
b
b
14[b]
Scheme 2. N-formylation of piperazine to synthesis various N-formamine
catalyzed by Au/Al2O3.
14
15
Inspired by the results in Table 3, we further investigated
whether N-formamide can be synthesized from primary
amines (Table 4). Clearly, butyl amine was converted into N-
butylformamide successfully with an isolated yield of 80%
(Entry 1). Following, aliphatic primary amines including iso-
butylamine, 1-heptanamine, 1-decanamine, 1-dodecylamine
and 1-cetylamine can be transformed into the corresponding
15a
15
b
16
17
93
93
16
16
a
b
N-formylation products, 23
2–6). For cyclic primary amines including cyclopentylamine and
cyclohexylamine, the corresponding N-formamides, 28 and
29 , can be synthesized with 81% and 72% isolated yields
(Entries 7–8). If benzylamine derivatives with various
functional groups, i.e. 30 and 31 , were used as starting
-27b, with yields of 79–87% (Entries
b
b
17
a
17
b
a
a
18
materials, the corresponding N-formamides can be obtained
selectively with 84% and 85% isolated yields (Entries 9–10).
Aniline and aniline derivatives with various functional groups
also can be transformed into the corresponding N-formamides
with yield of 73%-80% (Entries 11–13).Thus, Au/Al2O3 can be
used in the N-formylation reactions of primary and secondary
amines almost under ambient conditions.
82
18
a
18
b
19[b]
Table 4. Results of N-formylation of primary amines [a]
75
84
Entry
1
Substrates
Products
Yields[c]
80
19
a
a
19
20
b
b
20[b]
2
22b
2a
2
3
4
5
20
NH2
82
72
83
79
23a
23b
[a] Reaction conditions: amine (1.0 mmol), paraformaldehyde (1.2 mmol),
catalyst (25 mg), NaOH (0.2 mmol), deionized water (2.0 mL), 25 oC, 6 h. [b] 100
oC, 24 h. [c] Isolated yield. [d] The yields were obtained by GC-FID using biphenyl
as the external standard material.
24a
24b
It should be interesting to explore the N-formylation
reaction of piperazine because it has two –NH groups so we
can check its reactivity for mono- and di-N-formylation
reactions (Scheme 2). Clearly, the mono-N-formylation
reaction can be realized selectively with 86% yield when 1
equiv., paraformaldehyde was employed, while 1, 4-
25a
26a
25b
26b
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 7 of 10
View Article Online
DOI: 10.1039/C5GC01992C
Journal Name
ARTICLE
6
After each reaction, the catalyst was recovered by simple
centrifugation and reused without further treatment. As it can
be seen from Fig. 4, the catalyst can be recycled for 5 runs
without obvious deactivation. As it is well known, supported
nano-gold catalysts often face deactivation problem during
storage. Thus, it is very interesting to explore the storage
stability of the Au/Al2O3 catalyst. To our delight, 83%
morpholine was converted into N-formyl morpholine with 98%
selectivity by applying an Au/Al2O3 catalyst being stored in air
for 30 days. Thus this catalyst exhibits nice stability during the
catalytic reactions, and storage in air.
27a
87
81
27b
7
8
28a
28b
72
85
29a
29b
9
Catalytic reaction mechanism
Finally, the reaction mechanism of N-formylation of amine
with paraformaldehyde was studied using morpholine as the
model substrate. To gain insight into the mechanism, control
experiments were conducted under different atmospheres
(Table 5). All the reactions were progressed for 6 h and traced
by GC-MS. Clearly, morpholine can react with
paraformaldehyde to give N-formyl morpholine under 1 atm
oxygen in the presence of the Au/Al2O3 catalyst. Nevertheless,
no N-formyl morpholine was observed under Ar or H2
30a
30b
10
84
3
31b
1a
11[b]
12[b]
13[b]
80
73
32a
33a
atmosphere, and the sole product was aminal 1c. It suggests
32b
33b
that the mechanism was oxidative dehydrogenation rather
than catalytic dehydrogenation.
Table 5. N-formylation of morpholine under different atmosphere.[a]
74
34a
Conv (%)[b]
Sel (%)[c]
34b
Entry
atmosphere
1
b
1c
[a] Reaction conditions: amine (1.0 mmol), paraformaldehyde (1.2 mmol),
catalyst (25 mg), NaOH (0.2 mmol), deionized water (2.0 mL), 100 oC, 24 h. [b] 25
oC, 24 h [c] Isolated yield.
1
2
3
O2
H2
Ar
98
65
78
99
-
-
100
100
-
Catalyst Reusability
[a] Reaction conditions: morpholine (1.0 mmol), paraformaldehyde (1.2
mmol), Au/Al2O3 catalyst (25 mg), NaOH (0.2 mmol), deionized water (2.0
mL), 25 oC, 6 h. [b] Conversion of morpholine was determined by GC-MS. [c]
Selectivity by GC–MS analysis based on the morpholine consumed.
One of the major advantages of heterogeneous catalysts is
the facile catalyst separation and recycling. So the reusability
of the Au/Al2O3 catalyst was tested by the reaction of
morpholine with paraformaldehyde (Fig. 4).
Based on the former report46,
a plausible reaction
100
80
60
40
20
0
mechanism is given in Scheme 3. First, paraformaldehyde was
dissociated in aqueous solution under basic conditions and
molecular oxygen was dissociated on the gold-nano particles
to formed Oad. Then morpholine and dissociated formaldehyde
were spread onto the catalyst surface. Morpholine was
deprotonated and adsorbed to form adsorbed C4H8NOad and
generating water. At the same time formaldehyde was
adsorbed to form HCHOad species. Then, nucleophilic C4H8NOad
attacked the aldehydic carbon of formaldehyde, presumably to
form the hemiaminal. Subsequently 2-hydride elimination
yields N-formyl morpholine. However, the other route cannot
be ruled out.
1
2
3
4
5
Catalyst recycle number
Figure 4. Recyclability test of Au/Al2O3 catalyst for the N-formylation of
morpholine. Reaction conditions: morpholine (1.0 mmol), paraformaldehyde (1.2
mmol), catalyst (25 mg), NaOH (0.2 mmol), deionized water (2.0 mL), 25 oC, 6 h
.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 8 of 10
View Article Online
DOI: 10.1039/C5GC01992C
ARTICLE
Journal Name
11 C. L. Allen and J. M. J. Williams, Chem. Soc. Rev., 2011, 40
3405-3415.
,
12 D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J.
J. L. Leazer, R. J. Linderman, K. Lorenz, J. Manley, B. A.
Pearlman, A. Wells, A. Zaks and T. Y. Zhang, Green Chem.,
2007, 9, 411-420.
13 Gerack and L. McElwee-White, Molecules, 2014, 19, 7689-
7713.
14 A. Chandra Shekhar, A. Ravi Kumar, G. Sathaiah, V. Luke Paul,
M. Sridhar and P. Shanthan Rao, Tetrahedron Lett., 2009, 50
7099-7101.
15 M. Hosseini-Sarvari and H. Sharghi, J. Org. Chem., 2006, 71
6652-6654.
16 J.-G. Kim and D. O. Jang, Synlett, 2010, 2010, 1231-1234.
,
,
17 H. Lundberg, F. Tinnis, N. Selander and H. Adolfsson, Chem.
Soc. Rev., 2014, 43, 2714-2742.
18 I. Sorribes, K. Junge and M. Beller, Chem. Eur. J., 2014, 20
7878-7883.
,
19 C. Han, J. P. Lee, E. Lobkovsky and J. A. Porco, J. Am. Chem.
Soc., 2005, 127, 10039-10044.
20 B. C. Ranu and P. Dutta, Synth. Commun., 2003, 33, 297-301.
21 C. L. Allen, A. A. Lapkin and J. M. J. Williams, Tetrahedron
Lett., 2009, 50, 4262-4264.
Scheme 3. Plausible reaction pathway for N-formylation of morpholine with
paraformaldehyde.
22 B. Anxionnat, A. Guérinot, S. Reymond and J. Cossy,
Tetrahedron Lett., 2009, 50, 3470-3473.
Conclusions
23 E. Callens, A. J. Burton and A. G. M. Barrett, Tetrahedron
Lett., 2006, 47, 8699-8701.
24 A. Goto, K. Endo and S. Saito, Angew. Chem., Int. Ed., 2008,
47, 3607-3609.
25 N. Ibrahim, A. S. K. Hashmi and F. Rominger, Adv. Synth.
Catal., 2011, 353, 461-468.
26 S. Ichikawa, S. Miyazoe and O. Matsuoka, Chem. Lett., 2011,
40, 512-514.
In conclusion, the N-formylation reactions of diffident
amines with paraformaldehyde were achieved successfully
catalyzed by a simple Au/Al2O3 catalyst. Under the optimized
reaction conditions, primary and secondary amines can be
efficiently and selectively transformed into the corresponding
N-formylation products with excellent yields in water under
ambient conditions. It offers a clean and economic method for
the synthesis of N-formylation amines.
27 K. V. Katkar, P. S. Chaudhari and K. G. Akamanchi, Green
Chem., 2011, 13, 835-838.
28 S. Murahashi, T. Naota and E. Saito, J. Am. Chem. Soc., 1986,
108, 7846-7847.
29 M. Tamura, H. Wakasugi, K. i. Shimizu and A. Satsuma, Chem.
Eur. J., 2011, 17, 11428-11431.
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (21203219) and Youth Innovation
Promotion Association CAS.
30 M. A. Ali and T. Punniyamurthy, Adv. Synth. Catal., 2010,
352, 288-292.
31 C. L. Allen, C. Burel and J. M. J. Williams, Tetrahedron Lett.,
2010, 51, 2724-2726.
32 C. L. Allen, S. Davulcu and J. M. J. Williams, Org. Lett., 2010,
12, 5096-5099.
33 D. Gnanamgari and R. H. Crabtree, Organometallics, 2009,
28, 922-924.
34 A. Mishra, A. Ali, S. Upreti and R. Gupta, Inorg. Chem., 2008,
47, 154-161.
35 N. A. Owston, A. J. Parker and J. M. J. Williams, Org. Lett.,
2007, 9, 73-75.
36 R. S. Ramón, J. Bosson, S. Díez-González, N. Marion and S. P.
Nolan, J. Org. Chem., 2010, 75, 1197-1202.
37 X. Cui, Y. Zhang, Y. Deng and F. Shi, Chem. Commun., 2014,
50, 189-191.
38 L. Zhang, Z. Han, X. Zhao, Z. Wang and K. Ding, Angew.
Chem., Int. Ed., 2015, 54, 6186-6189.
39 A. J. A. Watson, A. C. Maxwell and J. M. J. Williams, Org.
Lett., 2009, 11, 2667-2670.
40 S. Tanaka, T. Minato, E. Ito, M. Hara, Y. Kim, Y. Yamamoto
and N. Asao, Chem. Eur. J., 2013, 19, 11832-11836.
41 K. i. Shimizu, K. Ohshima and A. Satsuma, Chem. Eur. J., 2009,
15, 9977-9980.
Notes and references
1
2
3
4
5
6
7
8
9
Y. Zhang, X. Cui, F. Shi and Y. Deng, Chem. Rev., 2011, 112,
2467-2505.
A. Corma, A. Leyva-Pérez and M. J. Sabater, Chem. Rev.,
2011, 111, 1657-1712.
A. Stephen, K. Hashmi and F. D. toste, Modern Gold
Catalyzed Synthesis, 2012.
C. D. Pina, E. Falletta and M. Rossi, Chem. Soc. Rev., 2012, 41
350-369.
,
J. S. Carey, D. Laffan, C. Thomson and M. T. Williams, Org.
Biomol. Chem., 2006, , 2337-2347.
4
A. Jackson and O. Meth-Cohn, J. Chem. Soc., Chem.
Commun., 1995, 1319-1319.
V. K. Das, R. R. Devi, P. K. Raul and A. J. Thakur, Green Chem.,
2012, 14, 847-854.
K. Kobayashi, S. Nagato, M. Kawakita, O. Morikawa and H.
Konishi, Chem. Lett., 1995, 24, 575-576.
G. Pettit, M. Kalnins, T. Liu, E. Thomas and K. Parent, J. Org.
Chem., 1961, 26, 2563-2566.
10 P. C. Wang, X. H. Ran, R. Chen, L. C. Li, S. S. Xiong, Y. Q. Liu, H.
42 C. Gunanathan, Y. Ben-David and D. Milstein, Science, 2007,
317, 790-792.
43 O. Saidi, M. J. Bamford, A. J. Blacker, J. Lynch, S. P. Marsden,
P. Plucinski, R. J. Watson and J. M. J. Williams, Tetrahedron
Lett., 2010, 51, 5804-5806.
R. Luo, J. Zhou and Y. X. Zhao, Tetrahedron Lett., 2010, 51
5451-5453.
,
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 9 of 10
Journal Name
View Article Online
DOI: 10.1039/C5GC01992C
ARTICLE
44 P. Preedasuriyachai, H. Kitahara, W. Chavasiri and H. Sakurai,
Chem. Lett., 2010, 39, 1174-1176.
45 N. Shah, E. Gravel, D. V. Jawale, E. Doris and I. N. N.
Namboothiri, ChemCatChem, 2014, 6, 2201-2205.
46 B. K. Min and C. M. Friend, Chem. Rev., 2007, 107, 2709-
2724.
47 B. Xu, L. Zhou, R. J. Madix and C. M. Friend, Angew. Chem.,
Int. Ed., 2010, 49, 394-398.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins

Green Chemistry
Page 10 of 10
View Article Online
DOI: 10.1039/C5GC01992C
Supported Nano-Gold-Catalyzed N-Formylation of Amines with
Paraformaldehyde in Water under Ambient Conditions
Zhengang Ke, Yan Zhang, Xinjiang Cui, and Feng Shi*
A simple and efficient Au/Al2O3 catalyst was prepared for the oxidative N-formylation of amines
and paraformaldehyde under ambient conditions with up to 97% yield.