Highly active and selective supported iron oxide nanoparticles in microwave-assisted N-alkylations of amines with alcohols

Article abstract of DOI:10.1039/c003410j

Highly active and stable supported iron oxide nanoparticles show excellent activities and switchable selectivities to target products in the microwave-assisted N-alkylation of amines with alcohols. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c003410j

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Highly active and selective supported iron oxide nanoparticles
in microwave-assisted N-alkylations of amines with alcohols
Camino Gonzalez-Arellano,a Kenta Yoshida,b Rafael Luque*c and Pratibha L. Gaib,d
Received 19th February 2010, Accepted 25th March 2010
First published as an Advance Article on the web 18th May 2010
DOI: 10.1039/c003410j
Highly active and stable supported iron oxide nanoparticles show excellent activities and
switchable selectivities to target products in the microwave-assisted N-alkylation of amines with
alcohols.
N-Alkylation reactions through hydrogen autotransfer pro-
cesses are very attractive strategies in organic synthesis,1,2
granting access to a wide variety of important chemicals that
find applications as dyes, pharmaceuticals, agrochemicals, sur-
factants and biologically active compounds.3 These approaches
have also significant advantages compared to conventional
alkylations and hydroaminations including the simplicity of the
protocol, availability of starting materials and most importantly
the variety of catalysts able to carry out these reactions.
compatible and cheaper alternative catalysts for a wide range of
reactions11,12 that are especially valuable to the pharmaceutical
industry.
Following these preliminary studies in the development of
highly active and reusable supported Fe materials, we report
here, for the first time, the activity of supported Fe oxide
nanoparticles in the microwave assisted selective N-alkylation
between anilines and benzyl alcohols mediated by hydrogen
autotransfer (Scheme 1).
With regards to the catalysts employed in hydrogen auto-
transfer processes, the majority are homogeneous catalysts in
which transition metal complexes and salts including Ru, Ir,
Rh, Pt and Au have been extensively reported.1,2,4 Transition
metal-free protocols have also been reported, although they
normally require harsh reaction conditions (high temperatures
and pressures) to achieve reasonable yields of products.1,5
Compared to homogeneous catalysts, heterogeneously catal-
ysed methodologies based on silicon and aluminium,6 Ni,7 Cu,8
Pt9 and more recently an unmodified commercial magnetite10
have been proposed as alternatives. However, all reported
protocols are generally energy intensive (taking 24 h + to
complete),1,6,10 with catalysts having poor recyclabilities and em-
ploy salts and/or catalysts that cannot be properly reused upon
reaction completion. Furthermore, these approaches are also
limited as the methodologies normally work only with activated
compounds (e.g. aromatics), being completely ineffective for less
activated systems (e.g. alkyl derivatives).
In our recent studies towards more environmentally friendly
catalysts and benign reaction conditions, we have reported the
preparation of highly active, selective and reusable supported
iron and iron oxide nanoparticles on a variety of porous
materials in the oxidation of alcohols.11 Among the reported
catalysts, Fe-MCM-41 was found to be highly active and
reusable in the reaction, preserving its initial activity after
5 uses.11 These catalysts were proved to be environmentally
Scheme 1 N-Alkylation of aniline with benzyl alcohol.
Experimental
Materials preparation
Materials were synthesized following a similar protocol to
that previously reported our group,11 using FeCl2·4H2O as
Fe precursor and ethanol–water as solvent under microwave
irradiation.
A typical preparation of the iron supported catalysts was
performed as follows: 0.2 g support were suspended in 2 mL
EtOH containing 100 mg FeCl2·4H2O and microwaved at 200 W
for 15 min (average temperature 100 ◦C, 120 ◦C maximum
temperature reached). Solids were then filtered off, washed
with an excess of ethanol and acetone and dried overnight
at 100 ◦C. The red-orangish powders (supported Fe oxide
nanoparticles) were characterised by means of several tech-
niques including Nitrogen physisorption, Aberration Corrected
(Scanning)-high angle annular dark field Transmission Electron
Microscopy (AC-HAADF-TEM/STEM), X-Ray Diffraction
(XRD) and X-Ray Photoelectron Spectroscopy (XPS).
Different supports were chosen to investigate the effect of the
stabilisation of the nanoparticles on the properties and activity
of the materials in the alkylation. These include porous (silica,
MCM-41 and a mild acidic montmorillonite clay) and non
porous biomaterials (cellulose and chitosan).
aGreen Chemistry Centre of Excellence, University of York, York, UK
bNanocentre, Chemistry Department, Heslington, YO10 5DD, York, UK
cDpto. Qu´ımica Orga´nica, Universidad de Co´rdoba, Campus de
Rabanales, Edif..Marie Curie, Ctra Nnal IV, Km 396, E14014, Co´rdoba,
(Spain). E-mail: q62alsor@uco.es; Fax: +34 957212066;
Tel: +34957212065
Si-MCM-41 and hexagonal mesoporous silica (HMS) were
prepared according to previously reported protocols from our
dDepartment of Physics, University of York, YO10 5BR, York, UK
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group.13,14 Commercial montmorillonite KSF clay (Fluka), cel-
lulose (Sigma, cellulose fibrous medium) and chitosan (Aldrich,
medium molecular weight, 75-85% deacetylated) were used as
purchased.
Materials characterisation
Nitrogen adsorption measurements were carried out at 77 K
using an ASAP 2010 volumetric adsorption analyzer from
Micromeritics. The samples were outgassed for 2 h at 100 ◦C
under vacuum (p < 10-2 Pa) and subsequently analyzed. The
linear part of the BET equation (relative pressure between
0.05 and 0.22) was used for the determination of the specific
surface area. The pore size distribution was calculated from
the adsorption branch of the N2 physisorption isotherms and
the Barret-Joyner-Halenda (BJH) formula. The cumulative
mesopore volume VBJH was obtained from the PSD curve.
The electron microscopy images were recorded in a JEOL
2200FS with double aberration correction (AC-TEM/STEM
and HAADF-STEM), with integral in-column energy filter,
operating at 200 kV and at the highest atomic scale resolution
(0.1 nm or below) with crystallographic and chemical analysis.
The dual aberration-correctors allow AC-TEM and AC-STEM
imaging from the same regions of the nanocatalyst sample,
providing powerful insights into the catalyst nanostructure.
Aberration corrected high-angle annular dark-field TEM (AC-
HAADF-TEM) were also recorded to directly image the isolated
metal centres. Due to its sensitivity to atomic number, HAADF
can image heavy atoms that appear as bright spots in the exper-
iments (Fig. 1 to 2).15 With aberration correction, a continuous
range of interpretable spatial frequencies can be transferred by
the optics without the contrast inversions, therefore the data are
much more directly interpretable. More directly interpretable
(sub) Angstrom level imaging, complemented by compositional
data, uniquely provides new direct insights into the structure of
Fig. 2 a) AC-HAADF-STEM image; b) to d) AC-TEM images of
Fe-HMS material prepared by microwave deposition.
nanoparticles, critical to understanding the nanostructures and
reactivity properties of nanocatalysts. In high angle annular dark
field STEM (HAADF-STEM) imaging we exploit the fact that
electrons scattered at high angles (>30mrad) obey Rutherford’s
scattering law, with the scattering cross section proportional
to Z2 where Z is the atomic number. A HAADF detector is
used for imaging. Imaging of the highly scattered electrons
using a HAADF STEM detector allows the detection of catalyst
nanoparticles with higher Z, on lighter supports.
For AC-TEM/STEM studies, samples were prepared by
ultrasonically dispersing as-synthesised catalyst powders in
alcohol and placing the solution on holey carbon coated copper
microgrids. Low dose electron beam imaging methods were
employed throughout.
XPS measurements were performed in a ultra high vacuum
(UHV) multipurpose surface analysis system (SpecsTM model,
Germany) operating at pressures <10-10 mbar using a conven-
tional X-Ray source (XR-50, Specs, Mg-Ka, 1253.6 eV) in a
“stop-and-go” mode to reduce potential damage due to sample
irradiation. The survey and detailed metal high-resolution
spectra (pass energy 25 and 10 eV, step size 1 and 0.1 eV,
respectively) were recorded at room temperature with a Phoibos
150-MCD energy analyser. Powdered samples were deposited
on a sample holder using double-sided adhesive tape and
subsequently evacuated under vacuum (<10-6 Torr) overnight.
Eventually, the sample holder containing the degassed sample
was transferred to the analysis chamber for XPS studies. Binding
energies were referenced to the C1s line at 284.6 eV from
adventitious carbon.
Metal content in the materials was determined using Induc-
tively Coupled Plasma (ICP) in a Philips PU 70000 sequen-
tial spectrometer equipped with an Echelle monochromator
(0.0075 nm resolution). Samples were digested in HNO3 and
subsequently analysed by ICP/AES at the University of New-
castle.
Fig. 1 a) AC-HAADF-STEM image; b) to d) AC-TEM images of
Fe-Cellulose prepared by microwave deposition.
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Catalytic tests
3.65 (s, 3H), 4.20 (s, 2H), 6.50-6.55 (m, 2H), 6.70-6.75 (m, 2H),
7.20-7.30 (m, 5H); 13C NMR d 48.95, 55.50, 114.00 (2C), 114.65
(2C), 126.75, 126.95, 127.35 (2C), 128.35 (2C), 142.25, 151.90;
MS (EI) m/z 214 (M+ +1, 13%), 213 (84), 212 (21), 211 (86), 210
(18), 198 (10), 197 (16), 196 (100), 169 (30), 122 (55), 92 (11), 91
(50), 77 (12), 65 (12), 63 (12).
Alkylation reactions under microwave irradiation were carried
out in a Microwave CEM-DISCOVER reactor with PC control
and monitored by sampling aliquots of reaction mixture that
were subsequently analysed by Gas Chromatography-Mass
Spectrometry (GC/GC-MS) using an Agilent 6890 N GC
model equipped with a 7683B series autosampler fitted with
a DB-5 capillary column and an FID detector. Experiments
were conducted in a closed vessel (pressure controlled) under
continuous stirring. The microwave method was generally power
controlled. The samples were microwave-irradiated (150-300 W
power output) and different temperatures ranging from 150 to
170 ◦C were reached depending on the reaction and/or the
catalyst. Reaction products were also identified and confirmed
by 1H NMR using a JEOL 400 spectrometer operating at
400.13 MHz. Chemical shifts were calibrated using the internal
SiMe4 resonance.
A typical catalytic test was performed as follows: 1 mmol
benzyl alcohol, 1.2 mmol aniline, 2 mmol NaOtBu, 4 mL toluene
and 0.04 catalyst were microwaved at 300 W (maximum power
output) for 1 h (160-170 ◦C, maximum temperature reached).
The final reaction mixture was analysed by GC. The response
factors of the main reaction products were determined with
respect to the starting materials from GC analysis using known
compounds in calibration mixtures of specified compositions.
Reagents were used as purchased from Sigma-Aldrich, Fluka
or Avocado. Isolated yields were obtained from the resulting
reaction mixture via filtration through celite (solvent removed
under reduced pressure) and purification of the residue (if
needed) by flash chromatography on silica gel (hexane–ethyl
acetate) to give the corresponding products.
Benzyl(4-pyridyl)amine10. White solid; mp 87-89 ◦C; IR
(KBr, cm-1) n 3465, 3125, 1615, 1523, 1448, 1348, 1229;1H NMR
d 4.30 (d, J = 5.6 Hz, 2H), 5.65 (s, 1H), 6.40 (d, J = 6.3 Hz,
2H), 7.20-7.35 (m, 5H), 8.05 (d, J = 5.4 Hz, 2H); 13C NMR d
46.40, 107.50, 126.95 (2C), 127.20, 128.50 (2C), 137.90, 149.30,
153.40; MS (EI) m/z 185 (M+ +1, 10%), 184 (81), 183 (21), 196
(100), 91 (100), 91 (50), 78 (10), 65 (10).
Results and discussion
Materials were found to have different properties depending
on the investigated support. Fe-HMS was a highly mesoporous
material with high surface area (525 m2 g-1), similar to Fe-MCM-
41 (>1,000 m2 g-1) and the Fe-Clay (180 m2 g-1). Fe-chitosan
and Fe-cellulose, on the contrary, were non porous materials
where Fe nanoparticles were supported on the surface of the
biomaterials. The iron loading in all cases was found to be
around 0.3-0.5 % as measured by ICP/AES (Table 1).
Fig. 1 and 2 show AC-HAADF STEM and AC-TEM images
of Fe-Cellulose and Fe-HMS, respectively. AC-TEM/STEM mi-
crographs demonstrated that iron oxide particles were generally
present in the case of Fe-cellulose with an average diameter
of 29.5 nm (Fig. 1). These iron oxide particles (most of them
consistent with Fe2O3 observed by lattice imaging) consisted
of 5 nm diameter averaged nanocrystals. Additionally, a small
number of tiny nanoparticles (<5 nm, shown in (d) by blue
arrows) were also present. Strong contrast in a) and AC-TEM
lattice imaging indicated the presence of some iron single crystals
in the material. Ultra small nanoclusters of iron or iron oxide
clusters were not generally observed. Similar features were
observed for Fe-chitosan, albeit a higher number of iron single
crystals were found in this material.
Catalysts were reused upon reaction finalisation. With this
purpose, catalysts were filtered off after every cycle, washed with
ethanol and acetone and dried overnight at 120 ◦C prior to
their reuse in the reaction. Similar reaction conditions to those
employed in each typical catalytic test (see experimental above)
were employed for each reuse.
Selected examples of characterisation of isolated products, in
good agreement with literature values, are given as follows:
In the case of Fe-HMS materials, AC-HAADF-STEM and
AC-TEM studies generally indicated the presence of iron
particles and iron oxide (Fig. 2a), with an increased number of
Benzyl(phenyl)aniline10. Colourles oil; IR (film, cm-1) n 3420,
3069, 1606, 1512, 1323, 1240, 917; H NMR d 4.22 (s, 2H),
1
4.53 (s, 1H), 6.49-6.56 (m, 2H), 6.65-6.71 (m, 1H), 7.10-7-15 (m,
2H), 7.21-7.31 (m, 5H); 13C NMR d 48.05, 112.70 (2C), 117.35,
127.05, 127.35 (2C), 128.45 (2C), 129.10 (2C), 139.30, 148.00;
MS (EI) m/z 184 (M+ +1, 15%), 183 (93), 182 (43), 181 (58),
180 (71), 106 (20), 104 (17), 91 (100), 78 (11), 77 (55), 65 (25), 63
(11), 51 (31).
Table 1 Activity of various supported iron oxide nanoparticles [con-
version (mol%) and selectivity to the amine (Samine, mol%) and imine
(Simine, mol%)] in the N-alkylation of aniline with benzyl alcohol under
microwave irradiationa
Fe loading Conversion Samine
Simine
Entry Catalyst
(wt%)
(mol%)
(mol%) (mol%)
4-Chlorobenzyl(phenyl)amine10. Pale
yellow
oil;
IR
1
2
3
4
5
6
7
Blankb
Supports
Fe-HMS
Fe-MCM-41 0.32
Fe-Clay
—
—
0.39
<5
<5
58
34
22
<15
40
—
—
35
15
10
38
50
—
—
65
85
90
62
50
(film, cm-1) n 3425, 3060, 1607, 1514, 1430, 1323, 1100;1H
NMR d 3.80, 7.10-7.15 (m, 2H), 7.20-7.25 (m, 4H); 13C NMR
d 47.35, 112.70 (2C), 117.57, 128.50 (2C), 128.55 (2C), 129.15
(2C), 132.60, 137.90, 147.70; MS (EI) m/z 219 (M+ +2, 20%),
218 (14), 217 (73), 216 (35), 215 (47), 214 (50), 182 (10), 127
(35), 125 (100), 106 (20), 106 (10), 104 (12), 89 (23), 77 (50), 75
(11), 65 (11), 63 (12), 51 (24).
0.44
0.29
0.37
Fe-cellulose
Fe-chitosan
a Reaction conditions: 1 mmol benzyl alcohol, 1.2 mmol aniline, 2 mmol
NaOtBu, 4 mL toluene, 0.04 g catalyst, 300 W (max. power output), 1 h,
160-170 ◦C (max. temperature reached). b Without catalyst after 2 h of
microwave irradiation.
Benzyl(4-methoxyphenyl)amine10. Brownish oil; IR (cm-1) n
3377, 3026, 1507, 1450, 1240, 1045, 906; 1H NMR d 3.30 (s, 1H),
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iron nanocrystals compared to Fe-cellulose. The nanostructure
and pores of the hexagonal mesoporous silica were also well
resolved as shown in c) and d).
XPS experiments demonstrated Fe nanoparticles were essen-
tially composed of iron oxides, mainly present as Fe3+ (Fe2O3,
>60% of total Fe content) with minor quantities of Fe0 (<5%
total Fe, shoulder at ~706 eV,16,17 Fig. 3 and 4) in the materials,
regardless of the support (Fig. 3 and 4). These findings were in
good agreement with results obtained by AC-(S)TEM and XRD,
in which hematite (Fe2O3) was the predominant phase, with
only minor traces of FeO found in the materials (Fig. 5). Very
weak diffraction lines were found for the low loaded materials
(Fig. 5, solid line), thereby needing a higher loading material
(3%Fe-MCM-41) to be utilised as comparison to ascertain
the Fe species in the catalysts (Fig. 5, dotted line). In any
case, the supported nanoparticles possessed interesting features
depending on the investigated support. Supported Fe oxides on
porous materials (Fe-HMS, Fe-MCM-41 and Fe-Clay) exhibited
Fe2p bands at 710-711 eV (Fe2p3/2) and 723-724 eV (Fe2p1/2),
typical of the reported Fe2p binding energies of Fe2O3.16
Fig. 4 XP spectra of survey (top) and Fe2p region (bottom) of Fe-
chitosan.
Fig. 3 XP spectra of survey (top) and Fe2p region (bottom) of Fe-
HMS.
Comparatively, Fe-cellulose and Fe-chitosan materials pre-
sented Fe2p bands at remarkably lower binding energies (~708
and 721 eV, respectively, Figure 4), which may indicate a stronger
interaction of the iron oxides with the support (possibly through
the hydroxyl groups of the polysaccharides). These interesting
observations may indicate a difference in the environment of
Fe in the materials and may confer special properties and
applications to these supported nanoparticles.
Having investigated the properties and nature of the sup-
ported nanoparticles on various supports, a novel microwave-
assisted hydrogen autotransfer mediated N-alkylation process
between benzyl alcohol and aniline (Scheme 1) was selected to
investigate the applications of such nanomaterials in heteroge-
Fig. 5 XRD diffraction patterns of 0.5% and 3% Fe-MCM-41
materials.
neous catalysis. Martinez et al. have recently shown this reaction
could be carried out with high yields and selectivity to the
coupling products using magnetite as catalyst.10 Nevertheless,
high quantities of catalysts and extremely long times of reaction
(over 7 days) at relatively high temperatures (90 ◦C) were needed
in order to achieve good amine yields.10
A preliminary screening of all catalysts in the reaction is
summarised in Table 1. Initially, 1 h microwave irradiation,
300 W (maximum power output) and 0.04 g catalyst were chosen
as reaction conditions. Blank runs (in the absence of catalyst)
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Table 2 Effect of the time and power of microwave irradiation, quantity
of catalyst, solvent and base in the activity of Fe-HMS [conversion
An increase in both the microwave power, time of irradiation
and quantity of catalyst increased, in general, both the activity
and the selectivity to amine in the systems (Table 2). Under the
optimum reaction conditions (2 h microwave irradiation, 300 W
and 0.04 g catalyst) a 93% conversion with an 85% selectivity
to the amine was obtained (Table 2). A further increase in time
of irradiation and/or quantity of catalyst did not appreciably
change the activity of the catalyst in the process. Comparatively,
the reaction was performed under similar optimised conditions
under conventional heating (under toluene reflux) to provide
quantitative conversion of starting material in 24 h reaction.
Interestingly, only traces of the amine were found, with the
imine (Scheme 1, B) as the main reaction product under
these conditions. Further runs under conventional heating
showed there was no significant formation of amine under the
investigated reaction conditions (including different solvents,
catalysts and bases) which imply the reduction step (from imine
to amine) and thus the selectivity to the amine is only favoured
under microwave irradiation at short times of reaction (typically
1-2 h), in good agreement with reports proving that activities and
selectivities in organic reactions can be significantly improved
under microwave irradiation.18–20
(mol%) and selectivity to the amine (Samine, mol%) and imine (Simine
,
mol%)] in the N-alkylation of aniline with benzyl alcohola
Conversion Samine
Simine
(mol%)
Investigated effect
(mol%)
(mol%)
Effect of microwave
power
150 W
<25
15
85
200 W
250 W
300 W
0.5 h
38
50
58
27
18
40
35
25
82
60
65
75
Effect of time of
irradiation
1 h
1.5 h
2 h
58
78
93
30
35
60
85
40
65
40
15
60
Effect of the quantity
of catalyst
0.02 g
0.04 g
0.06 g
0.08 g
58
65
81
35
46
67
65
54
33
a Reaction conditions (unless otherwise stated): 1 mmol benzyl alcohol,
1.2 mmol aniline, 2 mmol NaOtBu, 4 mL toluene, 0.04 g catalyst,
300 W (max. power output), 1 h reaction, 150-170 ◦C (max. temperature
reached).
A range of solvents were also investigated in the reaction
(dioxane, THF, ethanol, acetonitrile) in order to check the effect
of the solvent polarity (loss factors) in the microwave-assisted
protocol. Interestingly, the best results were obtained in the
least polar solvent (toluene, Fig. 6), which implies there are
no relevant solvent polarity effects under microwave irradiation,
probably due to the inherent polarity of the reagents (benzyl
alcohol and aniline)18 and that solubility/miscibility effects of
reactants, base and catalyst in the chosen solvent are more
relevant.
The base employed in the reaction also seemed to be impor-
tant, especially to support the reaction mechanism. A screening
of bases in the microwave-assisted protocol demonstrated Na
and KOtBu were very good bases for the process, with K2CO3
and KOH giving very low activities in the reaction. However,
the most relevant finding was obtained when DABCO was
employed as a base in the reaction. We have recently reported the
involvement of this nucleophilic base in metal-free Sonogashira
couplings, via hydrogen abstraction from the alkyne.21 Results
included in Table 3 show a remarkable improvement of converted
starting material (at almost equal selectivities as those found
after 2 h of microwave irradiation gave virtually no conversion
of starting material (Table 1, entry 1).
Results showed all investigated nanomaterials had moderate
to low activities in the reaction with inherent low selectivities
to the amine after 1 h of microwave irradiation. Of note
were the activity of Fe-HMS and the interesting selectivities
to the amine of Fe-cellulose and Fe-chitosan materials. We
believe this peculiar selectivity for these biomaterials-supported
nanoparticles might be related to the reductive properties of the
supports (via hydroxyl groups) in Fe-cellulose and Fe-chitosan,
which may facilitate the last step of hydrogen transfer to the
imine (coupling intermediate) for the formation of the amine.10
In any case, several parameters including the time and power
of microwave irradiation, the quantity of catalyst, solvent and
base employed were further investigated. Results have been
included in Table 2 and Fig. 6.
Table 3 Activity of various supported iron oxide nanoparticles [conver-
sion (mol%) and selectivity to the amine (Samine, mol%) and imine (Simine
,
mol%)] in the microwave-assisted selective N-alkylation of aniline with
benzyl alcohol using DABCO as a basea
Conversion
(mol%)
Entry Catalyst
Samine (mol%) Simine (mol%)
1
2
3
4
5
6
Blank (no cat.) 15
>90
50
30
20
45
<10
50
70
80
55
Fe-HMS
85
75
55
40
70
Fe-MCM-41
Fe-clay
Fe-cellulose
Fe-chitosan
65
35
Fig. 6 Effect of the solvent in the activity of Fe-HMS in the coupling
between benzyl alcohol and aniline. Reaction conditions: 1 mmol benzyl
alcohol, 1.2 mmol aniline, 2 mmol NaOtBu, 4 mL solvent, 0.04 g Fe-
silica, 300 W, 2 h, 160–170 ◦C.
a Reaction conditions: 1 mmol benzyl alcohol, 1.2 mmol aniline, 2 equiv.
DABCO, 4 mL toluene, 0.04 g catalyst, 300 W (max. power output), 1 h,
160-170 ◦C (max. temperature reached).
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Table 4 Selective N-alkyation of a range of amines with benzyl alcohol
Table 5 Selective N-alkylation of a range of substituted benzyl alcohols
using Fe-HMS as catalyst under microwave irradiationa
using Fe-HMS as catalyst under microwave irradiationa
Conversion
Time/h (mol%)
Conversion
Time/h (mol%)
Entry Amine
1
Samine (mol%) Simine (mol%)
Entry Amine
1
Samine (mol%) Simine (mol%)
1.5
>99 (92)
90
10
1.5
1
>99 (92)
>99 (94)
90
10
2
>90
<10
2
3
1
1
>99 (89)
>99 (93)
90
85
10
15
3
4
1
1
>99 (95)
>99 (96)
90
10
>95
<5
4
5
1
2
>95 (90)
85
15
5
6
1.5
1.5
>99 (95)
88
75
12
25
85 (77)
>90
<10
85 (77)
6
2
75
75
25
7
8
2
2
75
70
80
20
7
8
2
70
80
85
20
15
60b
20b
1.5
>99 (91)
a Reaction conditions (unless otherwise stated): 1 mmol benzyl alcohol,
1.2 mmol aniline, 2 equiv. DABCO, 4 mL toluene, 0.04 g Fe-HMS, 300 W
(max. power output), 150-170 ◦C (max. temperature reached). Isolated
yields (where appropriate) are given in brackets; b The remaining 20%
selectivity corresponds to the formation of other products.
9
1.5
1.5
>99 (93)
85
62
15
38
10
85 (78)
Catalysts were also found to be highly reusable under the
reaction conditions, preserving >90% of their initial activity
and selectivity after 3 reuses. No Fe leaching was detected in the
final reaction mixture upon recycling of the catalyst (measured
by ICP/AES).
11
12
2
2
80
30
60
70
40
88 (86)
a Reaction conditions (unless otherwise stated): 1 mmol benzyl alcohol,
1.2 mmol amine, 2 equiv. DABCO, 4 mL toluene, 0.04 g Fe-HMS, 300 W
(max. power output), 150-170 ◦C (max. temperature reached). Isolated
yields (where appropriate) are given in brackets.
The reaction mechanism of these so-called hydrogen au-
totransfer processes has been well established for C–C bond
forming processes.1,2,4 It involves a domino reaction which starts
with an initial hydride abstraction from one of the reagents,
followed by different types of reactions between the two reagents,
and completed with a reductive hydrogen addition to give the
final product, a redox 2-step sequence in which the supported
Fe oxides seem to play a key role (Scheme 2).1,4,10
using NaOtBu) for Fe-silica and Fe-chitosan, respectively, when
DABCO was employed as a base in the reaction.
In order to extend the scope of the protocol, a range of
substituted anilines were then tested in the process under
optimised conditions. Results have been summarised in Table 4.
In general, the protocol was found to be amenable to a wide
range of substrates and substituents and excellent conversions
and selectivities to the corresponding amines were obtained
in most cases (Table 4), even for the particular case of cyclic
and aliphatic amines (Table 4, entries 10 to 12). Of note were
the higher yields obtained for electrowithdrawing (entries 2-
4) compared to electrodonating substituents (entries 5-7), in
good agreement with previous findings.10 Likewise, a range of
substituted benzyl alcohols were also investigated in the process.
Results included in Table 5 show that excellent conversions
and selectivities to the N-monoalkylated product were obtained
in all cases (regardless of the substituent employed), confirming
again the versatility as heterogeneous catalyst of the Fe materials.
Scheme 2 General mechanism for the N-akylation of substituted
anilines with benzyl alcohols as electrophiles via hydrogen autotransfer
processes.
Firstly, the reactions do not work in the absence of base
(sodium tert-butoxide or DABCO), which implies the catalytic
cycle may start with the deprotonation/dehydrogenation of the
alcohol promoted by the base and subsequently catalysed by the
supported iron oxide nanoparticles. The evidences for this claim
1286 | Green Chem., 2010, 12, 1281–1287
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are supported by the fact that only traces of products (up to
15 % conversion with DABCO, Table 3, entry 1) were obtained
in the absence of catalyst after 2 h (Table 1) but the addition
of catalyst drives the reaction to the production of the selective
N-alkylated products. In this step, we believe iron oxides might
be partially reduced to form Fe hydride species, in agreement
with previous reports.1,2,4,10
also thank the University of York, Yorkshire Forward/EU and
JEOL, for sponsoring the York JEOL Nanocentre and KY
thanks the Japan Society for Promotion of Science/Japan Fine
Ceramic Center (JSPS/JFCC) for a fellowship.
Notes and references
1 G. Guillena, D. J. Ramon and M. Yus, Chem. Rev., 2010, 110, 1611.
2 (a) A. Baiker and J. Kijenski, Catal. Rev. Sci. Eng., 1985, 27, 653–697;
(b) D. M. Roundhill, Chem. Rev., 1992, 92, 1–27.
3 (a) R. R. Egan, J. Am. Oil Chem. Soc., 1968, 45, 481–486; (b) S.
Arif, Surfactant Science Series: Detergency of special surfactants, Ed.
F. Friedli, Marcel Dekker, New York, 2001, 98, 71-115; (c) K. S.
Hayes, Appl. Catal., A, 2001, 221, 187–195; (d) H. A. Wittcoff,
B. G. Reuben and J. S. Plotkin, Industrial Organic Chemicals, Wiley-
Interscience, Hoboken, New Jersey, 2004.
Furthermore, the base was also found to play a critical role
in terms of reaction rates (selectivity was almost unaffected by
the addition of different bases). In this way, the addition of
DABCO, a nucleophilic base highly effective in metal-free catal-
ysed couplings,21 provided improved yields at shorter times of
reaction, confirming the involvement of alcohol deprotonation
as a first reaction step (alcohol as electrophile, Scheme 2).
In the second step, an SN2 displacement reaction takes place
and leads to the formation of the imine compounds that are
subsequently reduced by the Fe hydride species to give the
observed N-alkylated products. This reduction step has been
proved to be a transfer hydrogenation reaction that was actually
promoted only under microwave irradiation when a base (e.g.
sodium tert-butoxide) as well as a proper hydrogen donor (2-
propanol, 1 mL added to the mixture) were present in solution,
in good agreement with previous reports on hydrogen transfer
metal catalysed reactions.22 Interestingly, the high selectivities
observed for the Fe-chitosan catalyst might well be related to the
reductive capacity of the hydroxyl groups in the polysaccharide
backbone, sufficient to reduce metal cations in solution to
supported nanoparticles,11,23 a fact that will also correlate well
with the strong interaction Fe-support observed in the XPS of
these materials (Fig. 4).
4 G. Guillena, D. J. Ramon and M. Yus, Angew. Chem., Int. Ed., 2007,
46, 2358–2364.
5 (a) Y. Horikawa, Y. Uchino and T. Sato, Chem. Lett., 2003, 32, 232–
233; (b) Y. Sprinzak, J. Am. Chem. Soc., 1956, 78, 3207–3208.
6 (a) S. Narayanan and B. P. Prasad, J. Chem. Soc., Chem. Commun.,
1992, 1204–1205; (b) F. Valot, F. Fache, R. Jacquot, M. Spagnol and
M. Lemaire, Tetrahedron Lett., 1999, 40, 3689–3692.
7 (a) F. Alonso, P. Riente and M. Yus, Eur. J. Org. Chem., 2008, 4908–
4914; (b) J. L. Garcia-Ruano, A. Parra, J. Aleman, F. Yuste and V. M.
Mastranzo, Chem. Commun., 2009, 404–406.
8 (a) A. Baiker and W. Richarz, Synth. Commun., 1978, 8, 27–32;
(b) T. Yamakawa, I. Tsuchiya, D. Mitsuzuka and T. Ogawa, Catal.
Commun., 2004, 5, 291–295; (c) H. Kimura and H. Taniguchi, Appl.
Catal., A, 2005, 287, 191–196.
9 B. Ohtani, H. Osaki, S. I. Nishimoto and T. Kagiya, J. Am. Chem.
Soc., 1986, 108, 308–310.
10 R. Martinez, D. J. Ramon and M. Yus, Org. Biomol. Chem., 2009, 7,
2176–2181.
11 C. Gonzalez-Arellano, J. M. Campelo, D. J. Macquarrie, J. M.
Marinas, A. A. Romero and R. Luque, ChemSusChem, 2008, 1,
746–750.
12 C. Gonzalez-Arellano, R. Luque and D. J. Macquarrie, Chem.
Commun., 2009, 1410–1412.
13 R. Luque, J. M. Campelo, D. Luna, J. M. Marinas and A. A. Romero,
Microporous Mesoporous Mater., 2005, 84, 11–20.
Conclusions
We have reported the preparation of versatile Fe oxide nanopar-
ticles supported on a variety of (bio)materials that are catalyti-
cally active in the selective N-alkyation of (substituted) amines
with benzyl alcohols. Fe-HMS was found to be the most active
catalyst in the reaction with Fe-chitosan showing the best amine
selectivities. We envisage these materials to be applicable in other
couplings as well as many different redox catalysed processes
that are currently under investigation in our laboratories.
14 D. J. Macquarrie, B. C. Gilbert, L. J. Gilbey, A. Caragheorgheopol,
F. Savonea, D. B. Jackson, B. Onida, E. Garrone and R. Luque,
J. Mater. Chem., 2005, 15, 3946–3951.
15 S. J. Pennycook and L. A. Boatner, Nature, 1988, 336, 565–567.
16 C. D. Wagner, W. N. Riggs, L. E. Davis, G. F. Moulder and
G. E. Muilenberg, (ed.), (Handbook of X-Ray Photoelectron Spec-
troscopy, Perkin Elmer, Eden Praine, 1979.
17 C. Carja, Y. Kameshima and K. Okada, Microporous Mesoporous
Mater., 2008, 115, 541–547and referencestherein .
18 C. O. Kappe, Angew. Chem., Int. Ed., 2004, 43, 6250–6284.
19 V. Polshettiwar and R. S. Varma, Chem. Soc. Rev., 2008, 37, 1546–
1557.
20 V. Polshettiwar and R. S. Varma, Acc. Chem. Res., 2008, 41, 629–639.
21 R. Luque and D. J. Macquarrie, Org. Biomol. Chem., 2009, 7, 1627–
1632.
22 M. J. Gracia, J. M. Campelo, E. Losada, R. Luque, J. M. Marinas
and A. A. Romero, Org. Biomol. Chem., 2009, 7, 4821–4824.
23 P. Mukherjee, C. R. Patra, A. Ghosh, R. Kumar and M. Sastry,
Chem. Mater., 2002, 14, 1678–1684.
Acknowledgements
CG-A is grateful to Ministerio de Educacio´n y Ciencia and
Fundacio´n Espan˜ola para la Ciencia y Tecnolog´ıa for a funded
fellowship and RL to Ministerio de Ciencia e Innovacio´n for
a Ramon y Cajal contract (RYC-2009-04199). The authors
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