Tandem catalysis of amines using porous graphene oxide

Article abstract of DOI:10.1021/ja512470t

Porous graphene oxide can be used as a metal-free catalyst in the presence of air for oxidative coupling of primary amines. Herein, we explore a GO-catalyzed carbon-carbon or/and carbon-heteroatom bond formation strategy to functionalize primary amines in tandem to produce a series of valuable products, i.e., α-aminophosphonates, α-aminonitriles, and polycyclic heterocompounds. Furthermore, when decorated with nano-Pd, the Pd-coated porous graphene oxide can be used as a bifunctional catalyst for tandem oxidation and hydrogenation reactions in the N-alkylation of primary amines, achieving good to excellent yields under mild conditions.

Full text of DOI:10.1021/ja512470t

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Article
Tandem Catalysis of Amines Using Porous Graphene Oxide
Chenliang Su, Rika Tandiana, Janardhan Balapanuru, Wei Tang,
Kapil Pareek, Chang Tai Nai, Tamio Hayashi, and Kian Ping Loh
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja512470t • Publication Date (Web): 31 Dec 2014
Downloaded from http://pubs.acs.org on January 8, 2015
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Tandem Catalysis of Amines Using Porous Graphene Oxide
Chenliang Su†, Rika Tandiana†, Janardhan Balapanuru†, Wei Tang†, Kapil Pareek†, Chang Tai Nai†,
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Tamio Hayashi†, || and Kian Ping Loh*,†
† Department of Chemistry, Graphene Research Centre, National University of Singapore, 3 Science Drive 3, 117543, Singa-
pore
|| Institute of Materials Research and Engineering, A*STAR, 3 Research Link, 117602, Singapore
KEYWORDS: Graphene Oxide, Carbocatalysis, Heterogeneous Catalysis, Tandem Reaction.
ABSTRACT: Porous graphene oxide can be used as a metal free catalyst in the presence of air for the oxidative coupling of prima-
ry amines. Herein, we explore GO-catalysed carbon−carbon or/and carbon−heteroatom bond formation strategy to functionalize
primary amines in tandem to produce a series of valuable products, i. e. α-aminophosphonates, α-aminonitriles and polycyclic het-
ero compounds. Furthermore, when decorated with nano-Pd, the Pd-coated porous graphene oxide can be used as a bifunctional
catalyst for tandem oxidation and hydrogenation reactions in the N-alkylation of primary amines, achieving good to excellent yields
under mild conditions.
uses ambient air as the terminal oxidant is highly desirable. It
is also highly promising to allow the chemistry of C-H bond
Introduction
Owing to the natural abundance of carbon, the development of
functionalization to be extended to the α-position of primary
carbon materials as environmentally benign catalysts is cur-
amines under mild conditions,19 which can be achieved via the
rently an active area of research.1 Graphene oxide (GO),2-4
a
tandem modification strategy described here.
water-soluble derivate of graphene, has emerged as a new
class of carbon catalyst for a wide range of synthetic transfor-
mations.5-10 However, because GO only has moderate catalytic
efficiency when used as a substitute for metal catalysts, a high
weight loading of GO relative to the substrate is usually re-
quired.8 Recently, we reported a sequential base and acid
treatment of GO that dramatically improves its catalytic effi-
ciency due to the generation of porosity by the base treatment
and the acidification of its functional groups.9 To broaden the
classes of reactions catalysed by the porous, acidic GO, we
consider the concept of tandem catalysis whereby distinct mul-
ti-step reactions can be catalysed to generate the desired prod-
uct. In addition, the aromatic scaffold in GO provides an an-
choring site for a second catalyst, which allows the rational
design of a tandem catalytic system in which sequential oxida-
tion and hydrogenation reactions can take place.
Scheme 1. The use of p-GO for the tandem functionalisa-
tion of primary amines via carbon−carbon or/and car-
bon−heteroatom bond formation.
Functionalised secondary amines are important for chemi-
cal, biological and pharmaceutical applications because these
valuable amines are widely used as pharmacophores in many
bioactive compounds and agrochemicals.11-13 Although the
common synthetic route for secondary amines is the coupling
of amines with alkyl halides in the presence of stoichiometric
amounts of bases, this approach often suffers from over-
alkylation.12 The toxic nature of the numerous alkyl halides
and the production of large quantities of undesired waste cre-
ate an undesirable environmental footprint. To address these
problems, a wide variety of alternative environmentally benign
approaches have been developed including the N-alkylation of
amines with alcohols/amines via the hydrogen-borrowing pro-
cess,14-16 tandem oxidation/coupling of amines followed by the
hydrogenation/addition process17, 18 and so on. Along this line,
the discovery of a recyclable bifunctional catalytic system that
Herein, we present a systematic study to explore the carbo-
catalysed carbon−carbon or/and carbon−heteroatom bond
formation strategy to functionalize primary amines in tandem
to produce a series of valuable products in good to excellent
yields, i. e. α-aminophosphonates, α-aminonitriles and poten-
tial bioactive polycyclic hetero compounds. The carbocata-
lyzed active imine intermediates formation is the key step and
the concept is illustrated in Scheme 1. Interestingly, this tan-
dem strategy can also be applied for the production of classes
of potential biologically active heterocyclic compounds, i.e.,
the analogue of Trꢀger’s base, and isoindolo-benzodiazepine
derivative, in moderate to good yields. Highly porous GO (p-
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GO) contains a higher density of catalytically active defect
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sites9 and shows a higher catalytic activity compared to as-
made GO. When hybridised with a nano-Pd catalyst, the com-
posite becomes a bifunctional catalyst for tandem oxidation
(open air) and hydrogenation (H2, 1 atm) in the N-alkylation of
primary amines. In terms of turn over number (TON), the cata-
lytic activity of this bifunctional catalyst is almost 10 times
higher than that of other reported bifunctional catalysts (Figure
S1).17, 18 The latter require harsh conditions such as high pres-
sure of oxygen (>5 atms) and hydrogen (>5 atms).
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Experiment Section
Catalysts Preparation. Synthesis of porous graphene oxide
(p-GO). The as-produced GO was dispersed in 1000 ml DI
water at a concentration of 1.5 mg/mL-1. 10 g of NaOH plate
was added into GO solution. The mixture was refluxed in a
round bottom flask under constant magnetic stirring for 1
hour. Subsequently, the NaOH treated GO were separated by
centrifuging at 13000 rpm and dispersing in 1000 ml DI water.
Then, 25 ml HCl (37%) was added into the solution slowly.
The mixture was refluxed for another 1 hour. The base treat-
ment reduced the GO and introduced porosity, while the sub-
sequent acid treatment ensured that the carboxylic functionali-
ties remained acidic.9 The final p-GO obtained were filtered
and washed by DI water and acetone. The synthesized p-GO
was kept in vacuum desiccators.
Synthesis of Pd@porous graphene oxide (p-GO). 300 mg
of p-GO was added to 40 mL ethylene glycol (EG) and 20 mL
dimethyl formamide (DMF) and the mixture was sonicated for
12 h. Subsequently, a mixture of 6 mg Pd(OAc)2 in 10 mL EG
and 5 mL DMF was sonicated for 1 h. At the same time, a
separate mixture containing 40 mg sodium ascorbate in 10 mL
EG and 5 mL DMF was also sonicated for 1 h. While still
under sonication, the Pd(OAc)2 solution was added to the p-
GO solution. Next, the sodium ascorbate solution was intro-
duced dropwise into the resulting mixture under sonication
before leaving it to stir overnight. The mixture was then cen-
trifuged at 13,500 rpm to remove the supernatant and the
Pd@p-GO obtained was washed with acetone and ethanol
before drying in the oven.
Figure 1. (a) Comparing the catalytic reactivity with various car-
bocatalysts. (b) Time conversion plots showing the temporal evo-
lution of substrates, intermediates and products using p-GO as the
catalyst.
Defect sites, especially in the form of pores or vacancies,
are usually catalytically active9, therefore the porosity of p-GO
is carefully examined by AFM, STM and BET analysis. Due
to the limited resolution of our AFM, only large holes (>10
nm) can be imaged on the surface of p-GO. The area of large-
size holes can be quantified as 1.57% (Figure 2a-b). STM was
applied to image nanosized pores on p-GO. As shown in Fig-
ure 2c-d, p-GO has very high density of pores and the total
holes area of p-GO can be quantified as 5.74% by pore area
analysis of STM images. The size of the pores in p-GO as
observed by STM is also consistent with BJH Adsorption (av-
erage diameter: 2.16 nm). BET analysis further support that p-
GO has high micro-pore area (331.28 m2/g, see Table S2).
Results and Discussion
We first consider the use of p-GO in the phosphonation of
primary amines using an oxidative cross coupling strategies20-
22, which are very attractive as they provide efficient access to
valuable α-aminophosphonates and their derivatives.23, 24 The
carbocatalysed oxidative cross coupling reaction of benzyla-
mine with diethyl phosphonate is investigated in detail here by
screening various heterogeneous carbons. Our results show
that p-GO yields the best results (88% of NMR yield) among
all the tested carbocatalysts, including as-made GO, reduced-
GO, carbon black and CNT (Table S1 and Figure 1a). Figure
1b shows that the conversion of the starting material reaches
100% in the first hour, giving 48% imine intermediate along
with 39% α-aminophosphonate 3a; the NMR yield of 3a
reaches 88% along with a few byproducts after 8 h.
Different substrates are screened and the results are summa-
rized in Table 1. Regardless of the nature of the functional
groups in benzylamine derivatives, the corresponding α-
aminophosphonates can be obtained in good isolated yields
(62-84%). Long alkyl chain substituted phosphonate can be
used as a substrate (Table 1, entry 11). In comparison to as-
made GO, p-GO has much less oxygen-functionalities and
exhibits higher thermal stability. These properties afford the
good stability (Figure S2) and recyclability of this carbocata-
lyst in subsequent multi-run experiments (Table 1, entries 1-
3).
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The three component reaction of aniline, benzylamine and
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diethyl phosphate successfully furnishes the corresponding
products 3j in 84% isolated yield and extremely high selectivi-
ty (Scheme 2, eq 1). Cyanide anion can be employed as a nu-
cleophile in such a three component reaction giving rise to the
α-amino nitrile product in good yield (Scheme 2, eq 2). It is
also attractive to apply carbocatalysts in the synthesis of het-
erocyclic compounds via multi-step oxidation and nucleophilic
addition reactions. A simple example is the one-pot synthesis
of benzimidazole, in which the initial imines generated from
the oxidative coupling reaction undergo intramolecular addi-
tion by amine group and subsequent oxidation to the target
compound (Scheme 2, eq 3).
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Scheme 2. p-GO catalysed tandem reactions of benzyla-
mine with different nucleophiles.
O
2a, 8 h
EtO
P
OEt
Ph
p-GO, air
eq 1
Ph
NH2
Ph NH2
+
Ph
Ph
N
H2O, 90 oC, 8 h
Ph
N
Ph
H
1i, 1.5 mmol
1 mmol
3j, 84% yield
CN
Figure 2. STM and AFM topography images of p-GO. a) AFM
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TMSCN
r. t., 2 h
p-GO, air
eq 2
Ph
Ph
NH2
Ph NH2
+
N
Ph
H2O, 90 oC, 8 h
Ph
N
Ph
topography image of p-GO (scale bar, 100 nm). Large holes (10-
20 nm) can be seen on the surface of p-GO. b) Hole analysis of
AFM topography image of p-GO (scale bar, 100 nm). c) STM
topography image of p-GO (scale bar, 20 nm). d) Hole area anal-
ysis of STM topography image of p-GO (scale bar, 20 nm).
H
1 mmol
1i, 1.5 mmol
3k, 80% yield
H2N
Ph
N
N
p-GO, air
[Ox]
eq 3
NH2
Ph
+
CH3CN, 90 oC, 12 h
N
H
H2N
H2N
1 mmol
1j, 1.5 mmol
3l, 77% yield
Table 1. α-position functionalisation of primary amines via
tandem reaction of primary amines with nucleophiles.
Following the lines of the above results, introducing an
amino group into the primary amine should be suitable for the
construction of heterocyclic compounds using the tandem
reaction strategy. Therefore, the carbocatalysed tandem reac-
tion of 2-amino-benzylamine 1k is explored. Surprisingly, an
unexpected trimer product 4 is obtained in 75% yield, proba-
bly via the formation of the dibenzo[b,f][1,5]diazocine inter-
mediate followed by tandem nucleophilic addition by another
equivalent of primary amine. The structure of 4 is established
O
RO
P
OR
O
P
H
p-GO, air
Neat, 90 o
X
N
NH2
+
RO
OR
2
X
X
H
C
H
3
1, 1 mmol
2, 0.8 mmol
Entry X (1)
R (2)
T (h)
8
Yieldb
84 (88c)
74c (Run 4)d
79c (Run 5)
74
1
H (1a)
Et (2a)
Et (2a)
Et (2a)
2a
as
13-(2-amino-benzyl)-5,6,11,12-tetrahydro-6,12-
2
H (1a)
8
epiminodibenzo-[b,f][1,5]diazocine through X-ray analysis of
its single crystal (Scheme 3). As the analogous scaffold of
Trꢀger’s base,25 these epiminodibenzo[b,f]-[1,5]diazocine
derivatives not only possess most of the applications of
Trꢀger’s base but are also potentially useful in molecular
recognition.26, 27 Here, we have identified a novel methodology
for the convenient synthesis of 4 via the tandem reaction of 2-
aminobenzylamine using a carbocatalyst.
3
H (1a)
8
4
4-Cl (1b)
8
5
4-Me (1c)
3-Me (1d)
2-Me (1e)
4-OMe (1f)
4-CF3 (1g)
2a
12
12
12
12
11
12
80
6
2a
82
7
2a
83 (86c)
78 (87c)
62
8
2a
Scheme 3. p-GO catalysed tandem reactions of 2-
aminobenzylamine for the construction of the analogues of
Trꢀger’s base. The ORTEP representation of product 4 is
inserted.
9
2a
64 (72c)
NH2
S
10
2a
(1h)
11
1a
n-Bu (2b) 11
70 (75c)
a
Unless otherwise specified, nucleophiles (0.8 mmol) was added
very slowly (over 3 hours) into the reaction mixture of primary
amines (1.0 mmol) and p-GO (30 mg) at 90 oC under open air and
b
c
neat conditions; Isolated yield. NMR yield; The conversion is
100% and trace amount of aldehyde and few unidentified mix-
tures can be observed. The catalyst was recovered by simple
d
filtration and further washed by CH3CN for 3 times and then dried
in oven at 60 oC before reuse.
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When o-xylylenediamine 1l, a derivative compound of 2- doublets. The peaks around 335.5 and 340.7 eV are attributed
to metallic Pd0, while those around 338.1 and 343.4eV
correspond to Pd2+ species. Remarkably, a loading of Pd as
low as 0.52wt% on Pd@p-GO shows an isolated yield of 92%
with a reasonably high TON value (459). In comparison to
reported bifunctional catalysts (e.g. Au@TiO2) that require
high pressure of oxygen (> 5 atms) and hydrogen (> 5 atms),
our Pd@p-GO bifunctional catalyst exhibits almost 10 times
higher catalytic reactivity under very mild reaction conditions
(Air and 1 atm H2) (Figure S1).17, 18
1
2
3
4
5
6
7
8
aminobenzylamine, is used as the substrate, isoindolo-
benzodiazepine derivative is obtained in 25% yield along with
a few unidentified mixtures (Scheme 4). The structure is fur-
ther confirmed by NOESY spectrum and X-ray crystallo-
graphic analysis. Due to their potential biological properties,
these isoindolo-benzodiazepine derivatives are the targets of
many synthetic efforts.28-30 The carbocatalysed tandem reac-
tion strategy provides unprecedented straightforward access to
these useful heterocyclic compounds.
9
Scheme 4. p-GO catalysed tandem reactions of o-
xylylenediamine for the construction of heterocyclic com-
pounds. The ORTEP representation of isoindolo[2,1-
b][2,4]benzodiazepine product 5 is inserted.
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p-GO alone does not catalyse the N-alkylation of primary
amines to produce secondary amines. However, we can exploit
the aromatic scaffold in p-GO to anchor a second catalyst,
which allows the carbocatalysed oxidative coupling of primary
amines followed by sequential metal-catalysed hydrogenation
to proceed. To develop this bifunctional catalytic system in
which the advantages of the graphene material as a support
and catalyst can be combined, metal-nanoparticles (i. e. Pd,
Au and Pt) are loaded onto p-GO for sequential catalytic acti-
vation of hydrogen. Here, the extensive screening of metals
and carbon materials is used to identify the strongest coopera-
tive effect between the Pd nanoparticles and p-GO, which
gives 100% conversion along with 91% isolated yield (Table
S3, entry 2). Control experiments using either bare p-GO or Pd
nanoparticles loaded on other carbon supports (i.e. carbon
black or as-synthesised GO) show very poor performance in
these reactions, which indicates that the tandem nature of the
catalysed reaction requires two types of catalytic sites to be
present for concerted action.
Figure 3. (a) TEM images of Pd@p-GO (4.4wt%), scale bar 10
nm; (b) Pd particle size distribution; (c) HRTEM image of
Pd@p-GO, scale bar 3 nm; (d) XPS spectrum of Pd@p-GO.
Table 2. Bifunctional catalysed N-alkylation of primary
amines to secondary amines.a
H
1) Open Air, 90 o
C
2) H2 (1atm)
N
N
X
X
X
X
X
NH2
Pd@PGO
H
Pd@PGO
H
H
 
Entry
X (6)
T (h)
5, 5
Yieldb
1
2
3
4
5
6
7
H (6a)
90
The presence of Pd nanoparticles attached to the surface of
p-GO is confirmed by ICP and the initial loading value of Pd
is determined to be 4.4 wt%. TEM is also applied to
investigate the morphology, composition and crystal structure
of the bi-functional catalyst. From the TEM images in Figures
3a and 3b, we can see the presence of Pd nanoparticles on
Pd@p-GO, and the particle size mostly ranges 4 nm to 8 nm.
Figure 3c shows Pd (111) lattice planes with spacing d(111) =
0.222 nm, which corresponds to the literature value for
nanocrystalline Pd.31 The active Pd surface area, dispersion
(the ratio between surface and total metal atoms) as well as
particle size was further evaluated by means of CO chemisorp-
H (6a)
5, 5
84 (Run 4)
4-Me (6b)
3-Me (6c)
2-Me (6d)
5, 4
93
93
92
88
91
5, 5
5, 4
4-OMe (6e)
5, 5.5
5, 5
4-CF3 (6f)
Ph
Ph
N
H
8c
13, 5
70
(6g)
a
tion test. Assuming the adsorption ratio of CO to Pd = 132, 33
,
The reaction was carried out by using 40 mg of catalyst with 2
mmol of substrate in 0.2 mL CH3CN at 90 oC under open air con-
the fraction of available surface Pd atoms can be calculated.
The dispersion of our Pd-loaded p-GO is 0.18 and the calcu-
lated average particle size is 6.5 nm, which agrees well with
the TEM results (See Table S4). The Pd 3d XPS spectra in
Figure 3d consists of two spin-orbit coupled peaks with
chemically shifted components, which can be fitted using two
o
b
ditions followed by introducing hydrogen (balloon) at 90 C.
c
Isolated yield. The reaction was carried out by using 40 mg of
catalyst with 1 mmol of benzylamine and 1.5 mmol of aniline in
0.1 mL H2O at 90 oC under open air conditions followed by intro-
ducing hydrogen (balloon) at 90 oC.
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With these optimised conditions, the effectiveness of Pd@p-
pling products. Our work suggests that appropriately treated
GO and its composites can be a powerful synthetic tool in
tandem reactions.
1
2
3
4
5
6
7
GO for the tandem catalytic system is assessed (Table 2). The
electronic effects of the substituents on the phenyl ring have
little effect on the efficiency of the coupling process under
mild reaction conditions (Table 2, entries 3-7). Catalytic cross
coupling of benzylamine with aniline can be successfully
achieved by Pd@p-GO with 70% yield of the corresponding
product and excellent selectivity (Table 2, entry 8).
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, analytical
data and NMR spectrua. This material is available free of charge
via the Internet at http://pubs.acs.org.
To date, no studies have reported applying one catalytic ma-
terial for catalytic oxidation and hydrogenation without com-
promising the catalytic reactivity of either. It is interesting to
see whether such “incompatible” reactions can be first
achieved by using graphene bifunctional catalyst. Because it is
not safe to perform the reaction under a mixture gas of hydro-
gen and oxygen (air) at high temperature, this reaction is car-
ried out under low temperature and it successfully furnishes
the desired product in 56% yield (scheme 5).34
8
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AUTHOR INFORMATION
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Corresponding Author
chmlohkp@nus.edu.sg
ACKNOWLEDGMENT
We acknowledge the support of the Singapore Economic Devel-
opment Board (SPORE, COY-15-EWI-RCFSA/N197-1).
Scheme 5. Simultaneous activation of molecular oxygen
and hydrogen.
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Maytum, H. C.; Watson, A. J.; Williams, J. M. J. Am. Chem. Soc.
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1780.
A plausible mechanism for the tandem catalysis by Pd@p-
GO is as follows: first, primary amine undergoes an oxidative
coupling reaction on the active defect sites9 to produce imine
intermediates and H2O2. The imine intermediates react with
the nucleophiles to furnish the corresponding α-position func-
tionalised secondary amines. In the presence of the Pd nano-
catalyst, molecular hydrogen is activated and imine intermedi-
ates are then transferred to secondary amine products via tan-
dem hydrogenation, as shown in Figure 4.
Figure 4. Proposed mechanism for the Pd@p-GO bifunctional
catalytic system.
Conclusion
In conclusion, we have identified several classes of multi-step
reactions involving amines that can be catalysed by p-GO with
high yields. p-GO has been successfully applied as a carbocat-
alyst in the tandem reaction of primary amines to produce
polycyclic N-containing heterocyclic compounds via multi-
step oxidative coupling and intramolecular additions. When p-
GO is hybridised with a co-catalyst such as Pd nanoparticles,
the composite works well as a synergistic catalytic system for
the sequential oxidation of amine and the hydrogenation of
imine intermediates to furnish secondary amines as the cou-
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Loh, K. P.; Tan, C. H. Green. Chem. 2011, 13, 3341.
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L.; Kopajtic, T. A. J. Med. Chem. 2002, 45, 4110.
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(34) Caution!!!: The reaction is potentially explosive. Only a small
spark is needed to trigger an explosive reaction of hydrogen with
oxygen. Sufficient precautions must be taken while carrying out this
reaction. Detailed experimental description of the simultaneous
activation of oxygen and hydrogen by Pd@p-GO. The reaction
should be carried out in a fumehood with an anti-explosion shield: the
obtained Pd@p-GO (40 mg), benzylamine (2.0 mmol) and CH3CN
(0.2 mL) was added to a three necked round bottom flask with water-
cooling system. 1 atm air (balloon) and 1 atm hydrogen (balloon) was
introduced into the reaction. The reaction temperature was slowly
increased to 60 oC and stirred for 6 hours (Caution: the temperature
should be precisely controlled; take note of explosion risk using high-
er temperature and pure oxygen gas instead of air balloon; any spark
source and organic solvent should be removed; the reaction should be
carried out under fully open-system to allow pressure release). After
that, the solution was cooled to RT. After filtration, washing by
CH3CN and evaporation afforded 6a in 56% yield.
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