Nanocrystalline CeO2 as a Highly Active and Selective Catalyst for the Dehydration of Aldoximes to Nitriles and One-Pot Synthesis of Amides and Esters

Article abstract of DOI:10.1021/acscatal.6b00272

The dehydration of aldoximes into nitriles has been performed in the presence of various metal oxides with different acid-base properties (Al₂O₃, TiO₂, CeO_2, MgO). The results showed that a nanocrystalline CeO₂ was the most active catalyst. An in situ IR spectroscopy study supports a polar elimination mechanism in the dehydration of aldoxime on metal oxide catalysts, in which Lewis acid sites and basic sites are involved. The Lewis acid sites intervene in the adsorption of the oxime on the catalyst surface while surface base sites are responsible for the C1-H bond cleavage. Thus, the acid-base properties of nanocrystalline CeO₂ are responsible for the high catalytic activity and selectivity. A variety of aldoximes including alkyl and cycloalkyl aldoximes have been dehydrated into the corresponding nitriles in good yields (80-97%) using nanosized ceria which moreover resulted in a stable and reusable catalyst. Additionally, it has been showed that a variety of pharmacologically important products such as picolinamide and picolinic acid alkyl ester derivatives can be obtained in good yields from 2-pyridinaldoxime in a one-pot process using the nanoceria as catalyst.

Full text of DOI:10.1021/acscatal.6b00272

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Article
Nanocrystalline CeO2 As A Highly Active And Selective
Catalyst For The Dehydration Of Aldoximes To
Nitriles And One-Pot Synthesis Of Amides And Esters
Anastasia Rapeyko, Maria Jose Climent, Avelino Corma, Patricia Concepción, and Sara Iborra
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00272 • Publication Date (Web): 01 Jun 2016
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Nanocrystalline CeO2 As A Highly Active And Selective Catalyst For The
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Dehydration Of Aldoximes To Nitriles And One-Pot Synthesis Of Amides
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And Esters
Anastasia Rapeykoa, Maria J. Climenta, Avelino Cormaab,* Patricia Concepcióna, Sara Iborraa*
aInstituto de Tecnología Química (UPV-CSIC)
Universitat Politécnica de València
Avda dels Tarongers s/n, 46022, Valencia (Spain)
Fax: (+34) 963877809
E-mail: acorma@itq.upv.es
siborra@itq.upv.es
bKing Fahd University of Petroleum and Minerals,
P. O. Box 989, Dhahran 31261, Saudi Arabia.
Abstract
The dehydration of aldoximes into nitriles has been performed in the presence of
various metal oxides with different acid-base properties (Al2O3, TiO2, CeO2, MgO). The
results showed that a nanocrystalline CeO2 was the most active catalyst. An in situ IR
spectroscopy study supports a polar elimination mechanism in the dehydration of
aldoxime on metal oxide catalysts, in which Lewis acid sites and basic sites are
involved. The Lewis acid sites intervene in the adsorption of the oxime on the catalyst
surface while surface base sites are responsible for the C1-H bond cleavage. Thus, the
acid-base properties of nanocrystalline CeO2 are responsible for the high catalytic
activity and selectivity. A variety of aldoximes including alkyl and cycloalkyl aldoximes
have been dehydrated into the corresponding nitriles in good yields (80-97%) using
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nanosized ceria which moreover resulted a stable and reusable catalyst. Additionally, it
has been showed that a variety of pharmacologically important products such as
picolinamide and picolinic acid alkyl ester derivatives can be obtained in good yields
from 2-pyridinaldoxime in a one pot process using the nanoceria as catalyst.
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Keywords: nanocrystalline CeO2, acid-base catalyst, aldoxime dehydration, nitriles,
one-pot synthesis, amides, esters.
Introduction
Nitriles are important compounds not only due to its presence in a variety of
natural products, pharmaceuticals and bioactive molecules1-3, but also because they
are useful precursors for a wide variety of organic compounds such as amides,
carboxylic acids, amines and ketones.4
The most efficient and green alternative route for the preparation of aromatic and
aliphatic nitriles, and which has received much recent attention, involves the
dehydration of aldoximes that can be easily obtained from the corresponding
aldehydes. A wide variety of homogeneous catalytic systems have been reported for
the dehydration of aldoximes into nitriles including different metal organic compounds
such as oxorhenium (VII) complexes,5 Pd(OAc)2/PPh3 and Cs2CO3 in CH3CN6, Cu(OAc)2,7
[RuCl2(p-cymene)]2,8 Ga(OTf)3,9 TiCl3(OTf) in [bmim]Br10, pyridinium chlorochromate, 11
diaryl diselenides in the presence of H2O2,12 Pd(en)X2 complexes (X=NO3, BF4, OTf,
ClO4),13 Pd(II) complexes with phosphino-oxime ligands,14 cobalt/nitrophenolate
complex,15 guanidinate-osmium (II) complexes,16 inorganic salts such as InCl3,17
SnCl4,18 NiCl2 2H2O,19, Co(II)Cl2,20 Fe(ClO4)3,21 phosphonium salts,22 Cu, Ni, Co, Zn, Fe
and Mn salts with cupric acetate,23 and organocatalysts such as cyclopropenone24 and
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acetic anhydride and K2CO3 in DMSO.25 Although these methods can be effective for
dehydrating aldoximes, most of them encounter some limitations such as expensive or
not readily available reagents, hazardous organic solvents, long reaction times and
tedious work-up procedure. Therefore, alternative procedures with more general
applicability and environmental friendly conditions are still required.
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The use of heterogeneous catalysts presents important advantages from an
industrial and environmental point of view since they are easily recovered by simple
filtration with the possibility of catalyst regeneration and reuse. However, and in clear
contrast with the extensive variety of homogeneous catalysts used for this
transformation, the use of heterogeneous catalysts for dehydration of aldoximes to
nitriles is really scarce. For example, Montmorillonite K-10 clay, gamma-alumina, acid
zeolites (H-Y, H-MOR, H-Beta, H-ZSM-5),26 and basic zeolites (XCs)27 have been
reported for gas phase dehydration of aldoximes in a fixed bed reactor, giving
moderate to good yields of the corresponding nitriles.
In liquid phase, different heterogeneous catalysts such as Montmorillonite KSF,28
Envirocat-EPZG,29 KF/alumina,30 [RuCl2(p-cymene)]2 complex supported on Carbon,31
H2SO4 supported on SiO2 ,32 and on resin,33 heteropolyacids,34 Cu(II) modified molecular
sieves,35 and more recently, tungsten-tin mixed hydroxide (W-Sn-hydroxide)36 and Cu
(II) immobilized on aminated ferrite nanoparticles,37 have been used in dehydration of
aldoximes with different success. However, most of these catalytic systems suffer from
leaching problems of the active phase while a high catalysts/aldoxime weight ratio (≥
1) is necessary to achieve high performances. Very recently, we have presented that
Fe containing MOFs, particularly a post-synthesis treated MIL-100(Fe), is an efficient
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catalyst to convert aldoximes into nitriles, showing increased catalytic activity when
compared with a wide variety of Brönsted and Lewis acid and base catalysts.38
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CeO2 is a robust metal oxide with acid-base and redox properties that has been
used as an active catalyst for a variety of organic reactions39,40 such as alkylation of
aromatic compounds,41 dimerization of alcohols42 and carboxylic acids into ketones,39
dehydration of alcohols,44-46 reduction of carboxylic acids,47 oxyhalogenation of
activated arenes 48 and CO2 conversion into valuable chemicals.49 Recently, Tamura et
al. have showed that CeO2 is an efficient and recyclable catalyst for the selective one
pot synthesis of esters50 and amides 51 from nitriles in liquid phase (30-160 oC). Thus, if
one could prepare an active and selective CeO2 catalyst for the dehydration of
aldoximes, it could be possible to achieve the direct synthesis of amides and esters
starting from aldoximes. In the present work we presented for the first time that
nanosized CeO2 is a selective, stable and recyclable heterogeneous catalyst for the
dehydration of aldoximes into nitriles in liquid phase at moderate temperature, and
that dehydration of aldoximes can be coupled with hydration and esterification of
nitriles to obtain, amides and esters respectively in one-pot process.
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Experimental Section
Catalysts and reagents
Nanocrystalline ceria (nCeO2, 115 m2/g) was supplied by Rhodia Electronic
Catalysis. Regular CeO2 (surface area, 56 m2/g) was supplied by Aldrich and γ-Al2O3
(150 m2/g) was purchased from Merck. TiO2 (anatase-rutile mixture (3:1)) (56 m2/g)
and MgO sample with a surface area of 670 m2 were supplied by GmbH and NanoScale
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Materials respectively. All reagents were purchased from Sigma Aldrich.
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Synthesis of aldoximes
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2-Chlorobenzaldehyde oxime, 4-nitrobenzaldehyde oxime and syn-2-
pyridinealdoxime were supplied by Aldrich and used as received. The rest of oximes
were synthesized by the following method: hydroxylamine hydrochloride (NH2OH·HCl,
0.065 mol), sodium hydroxide (0.133 mol) and ethanol (45 mL) were successively
placed into a round bottom flask of 100 mL. The reaction mixture was stirred (800
rpm) with a magnetic stir bar under ambient temperature during 15 minutes. After
that the aldehyde (0.043 mol) was introduced into the reaction mixture and the
reaction was continued until the total conversion of aldehyde. The reaction was
monitored by GC analysis. When the reaction was finished, distilled water was added
to the mixture in order to remove the inorganic residues and then the product was
extracted with ethyl acetate. Finally, the solvent was removed by distillation at vacuum
and the oximes with purity of 98-99 % were obtained. All synthesized oximes were
identified by Mass Spectroscopy analysis using HP Agilent 5973 Mass Spectrometer
with a 6980 mass selective detector.
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Reaction procedure for dehydration of aldoximes
Aldoxime (1 mmol), o-xylene (3 mL) and catalyst were added to the two-neck
bottom flask (10 mL) which was connected to a Dean Stark instrument to remove the
water formed during the reaction. The suspension was stirred and heated at 160 °C in
a silicon oil bath with an automatic temperature control system and magnetic stirrer
(1000 rpm) under N2 atmosphere. The reaction was followed by taking samples at
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regular time periods and analyzing them by gas chromatography using a FID detector
and a capillary column (HP5, 30 m - 0.25 mm - 0.25 ꢀm). Undecane was used as the
external standard. All products were identified by Mass Spectroscopy analysis.
When the reaction was finished the catalyst was filtered, thoroughly washed
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with ethyl acetate and acetone and dried at 100 C overnight. Before recycling the
catalyst was calcined at 450 oC under air flow during 5 h.
Reaction procedure for one-pot synthesis of 2-picolinamide from 2-pyridinealdoxime
A mixture of 2-pyridinealdoxime (1 mmol), o-xylene (3mL) and nCeO2 (50 mg)
was placed to the two-neck bottom flask (10 mL) connected to the reflux condenser.
Then, the suspension was heated at 160 °C in a silicon oil bath with an automatic
temperature control system and magnetic stirrer (1000 rpm) under N2 atmosphere.
After 2-pyridinealdoxime was consumed, the temperature of the bath was decreased
from 160 to 110 °C and then, water was added to the reaction mixture. The reaction
was followed by taking samples at regular time periods and analyzing them by gas
chromatography using a FID detector and a capillary column (HP5, 30 m -0.25 mm -
0.25 ꢀm). Undecane was used as the external standard. All products were identified by
Mass Spectroscopy analysis.
Reaction procedure for one-pot synthesis of picolinic acid esters from 2-
pyridinealdoxime
A mixture of 2-pyridinealdoxime (1 mmol), o-xylene (3mL), octanol (10 mmol),
water (2 mmol) and CeO2 (50 mg) were placed to the two-neck bottom flask (10 mL)
connected to the reflux condenser. Then, the suspension was heated at 160 °C in a
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silicon oil bath with an automatic temperature control system and magnetic stirrer
(1000 rpm) under N2 atmosphere. The reaction was followed by taking samples at
regular time periods and analyzing them by gas chromatography using a FID detector
and a capillary column (HP5, 30 m -0.25 mm - 0.25 ꢀm). Undecane was used as the
external standard. All products were identified by Mass Spectroscopy analysis.
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Characterization methods
FTIR spectra have been collected with a Nexus spectrometer from Thermo equipped
with a DTGS detector (4cm–1 resolution, 32 scans). For the CO adsorption experiments,
an IR cell allowing in situ treatments under controlled atmospheres and temperatures
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from -176 C to 500 C has been connected to a vacuum system with gas dosing
facility. Self-supporting pellets (ca. 10 mg cm–2) were prepared from the sample
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powders and treated at 250 C under dynamic vacuum (10-4 mbar). After activation,
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the samples were cooled down to -176 C followed by CO dosing at increasing
pressures (0.1-4 mbar) and the IR spectrum recorded after each dosage. For the CHCl3
adsorption experiments and the in situ IR studies of oxime dehydration a quartz IR cell
allowing in situ treatments under controlled atmospheres and temperatures from 25
o
oC to 600 C has been connected to a vacuum system with gas dosing facility. Self-
supporting pellets (ca. 10 mg cm–2) were prepared from the sample powders and
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treated at 250 C under dynamic vacuum (10-4 mbar). After activation, the samples
were cooled down to 25oC. In the CHCl3 IR studies chloroform was adsorbed at
increasing pressures (1- 30mbar) and the IR spectrum recorded after each dosage. In
the in situ oxime dehydration IR studies, propionaldehyde oxime was adsorbed on the
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pre-activated samples at 25 C and increasing pressure (0.5-7mbar) until spectra
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saturation, followed by evacuation at 10-4 mbar. At that moment, the temperature was
increased to 70, 90, 120 and 160 oC and the sample kept at each temperature 45 min.
IR band areas have been normalized to sample weight and catalyst surface area, for
specific discussion along the text.
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Surface area measurements were obtained with a Micrometrics ASAP 2000
apparatus following the BET procedure by means of nitrogen adsorption at 77 K.
Thermogravimetric analyses (TGA) were performed with a Netzsch STA 409 EP thermal
analyzer with about 20 mg of sample and a heating rate of 10 oC min-1 in air flow.
Results and discussion
Synthesis of nitriles
The dehydration of 4-methoxybenzaldehyde oxime was taken as a model
substrate. The reaction was performed in liquid phase using o-xylene as a solvent at
o
reflux temperature (149 C) and removing the water formed in a Dean-Stark
apparatus. Metal oxides with different acid-base properties such as nanocrystalline
high surface area (115 m2/g) ceria (nCeO2), regular ceria (56 m2g-1) (CeO2), γ-alumina
(Al2O3), titania (TiO2) and magnesia (MgO), were used as catalysts, and the results
obtained are presented in Table 1 and Figure 1. As can be observed there (Table 1,
entries 1-4) the order of activity (initial reaction rate) was nCeO2 > MgO > Al2O3 >CeO2
>TiO2, when the order of activity per unit surface area was calculated the nCeO2 is still
the most active one, while MgO was clearly lower owing to its very high specific
surface area. Total conversion of aldoxime with 93 % selectivity to nitrile (2) has been
achieved with nCeO2 with only 1.5 h reaction time. In all cases, little amounts of 4-
methoxybenzaldehyde (3) (Scheme 1), coming from the hydrolysis of the aldoxime was
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detected. This result indicates that, in spite of using a Dean-Stark apparatus for
removing the water produced during the oxime dehydration, some amount of water
remains adsorbed on the catalyst promoting the hydrolysis of the aldoxime. Moreover,
the formation of benzamide which is formed by further hydration of the nitrile was
only observed in the case of the alumina catalyst at the level of traces (Table 1, entry
4). For comparison purposes the reaction was also performed using a conventional
homogeneous catalysts such as Ce(NO3)3·6H2O and Ce(III)triflate (Table 1, entry 6 and
7). Total conversion of oxime was achieved in both cases after 6 hours of reaction but
both homogeneous catalysts promote in a large extent the hydrolysis of the oxime,
being Ce(III)triflate more selective to the nitrile than Ce(NO3)3·6H2O. Since the Ce salts
showed considerable activity, in order to clarify that the dehydration takes place on
the surface of nCeO2, a leaching test was performed. To do that, in an additional
experiment, the catalyst was removed by filtration in hot when a 40 % conversion was
achieved, and the reaction was then continued in the absence of catalyst. No
conversion was observed after filtration, confirming that Ce species were not leached
from the solid into the reaction medium (see Figure S1 in SI)
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Additionally, when the results obtained with nanosized ceria were compared with
previously reported results using a variety of solid catalysts (see Table 2) it is possible
to see that the nCeO2 catalyst is among the best in terms of nitrile yield, reaction time
and catalyst/oxime ratio.
Nature of the catalytic active sites for dehydration of aldoxime to nitrile
It has been reported that the presence of basic (O2-) and Lewis acid sites (Ce4+) on CeO2
were responsible for the dehydration of 1,4-butanediol in vapor phase,52 as well as for
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the direct conversion of CO2 into dimethyl carbonate,53 cyclic carbonates, cyclic
carbamates and cyclic ureas .49 Then, in order to establish if the different activity found
for the different metal oxides is related with their acid and/or base properties, their
acid and basic properties were measured by adsorption of CO and CHCl3 probe
molecules, respectively, using IR spectroscopy for monitoring.
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When CO is adsorbed on Lewis acid sites, the νC≡O frequency is shiꢀed to higher
frequencies relative to the gas phase value of 2145 cm-1, being the shift directly related
to the acid strength of the adsorption site.54 In our case, two band maxima at 2180 and
2153 cm-1 are observed on Al2O3, and at 2177 and 2150 cm-1 on TiO2, after CO
adsorption (Figure 2). On both samples, the high frequency IR bands (2180 and
2177cm-1) corresponds to CO interacting with surface Lewis acid sites, while the low
frequency IR bands (2153 and 2150 cm-1) are due to CO interacting with surface
hydroxyl groups, according to the simultaneous shift in the OH IR band. On the MgO
sample, two band maxima at 2171 and 2148 cm-1 are evidenced after CO adsorption.
Both bands are associated to Lewis acid sites, since no shift in the hydroxyl groups is
observed. Finally on the CeO2 samples, one peak with maxima at 2153 cm-1 is
observed, associated to Lewis acid sites. From the ν(C≡O) frequency shiꢀ, the acid
strength of the samples can be ranged in the order: Al2O3 > TiO2 > MgO > nCeO2 >
CeO2, in good agreement with previous studies.55 However normalizing the CO IR band
area to catalyst surface area, it doesn’t follow the same order, being CeO2 > TiO2 >
nCeO2 >Al2O3 > MgO (Table 3).
For studying surface basicity on solid catalysts, several probe molecules have been
recommended,56-58 while there is not a clear consensus about which one is the most
adequate probe molecule. Therefore, and on the bases of our previous study in where
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CHCl3 was successfully used to probe surface basicity, we have selected this probe
molecule in the present study. Interaction of chloroform with surface basic sites
through its hydrogen atom shifts the νC-H stretching frequency (3030 cm--1 in the
liquid phase) to lower frequencies, and the band shift can be used as an indicator of
basic strength.60,61
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Thus, chloroform adsorbed on TiO2 and Al2O3 give rise to a well symmetric IR band
located at ~3010cm-1, while in the case of CeO2 samples an asymmetric IR band with a
main component at ~3010 cm-1 and a shoulder at lower frequencies (~2965 cm-1) is
observed (see Figure 3). Chloroform adsorbed on MgO shifts the IR band maxima to
even lower frequencies showing two band maxima at 2980 and 2890 cm-1 (Figure 3)
The IR band at around 3010 cm-1 is related to chloroform interacting with surface
hydroxyl groups, according to the simultaneous shift in the OH stretching vibration,
while the IR bands at lower frequencies (2980-2880 cm-1) are due to chloroform
adsorbed on surface base sites of different strength. Based on the frequency shift of
the νC-H stretching frequencies, the basicity of the samples can be ranked in the
order: Al2O3 < TiO2 < CeO2 < nCeO2 < MgO. On the other hand, normalizing the νC-H IR
band area of adsorbed chloroform to catalyst surface area, (Table 4) a higher value is
obtained on the MgO and nCeO2 sample compared to the other samples, in agreement
with previous studies.62
Therefore, from the IR study of adsorbed probe molecules we can conclude that the
most active and selective catalysts (nCeO2 and MgO) possess strong basic sites while
the Lewis acidity on both samples is rather weak.
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As previously indicated in the introduction, catalysts with either acid or base
properties have been reported in the literature for aldoxime dehydration,26-28,36
however no clear understanding about the role of each site in the reaction mechanism
has been given. Recently, Limtrakul et al.63 based on a DFT study performed on
FeZSM5 zeolite, proposed two reaction mechanisms for the dehydration of
benzaldoxime: a) an oxidative dehydration mechanism and b) a polar elimination
mechanism. While, in both cases the reaction proceeds through a transition state
structure where surface acid and base sites are involved, they mainly differ in the
initial step of interaction of the aldoxime with the metal surface sites. In the oxidative
dehydration mechanism the reaction starts with the interaction of the oxygen of the
oxime with Lewis surface sites, while in the polar elimination mechanism a
coordination complex with the N is initially formed. Taking this into account, an in situ
IR study of propionaldehyde oxime dehydration has been performed on different solid
catalysts to explain the catalytic data reported in Table 1 and contribute to the
understanding the reaction mechanism.
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In situ IR spectroscopy study
Propionaldehyde oxime adsorption on the different metal oxides followed by IR
spectroscopy, shows a shift in the N-OH and C=N vibration to higher frequency versus
the gas phase frequency. While a blue shift would be expected if one assumes
coordination through the oxygen atom of the aldoxime with surface Lewis sites of the
metal oxide support,59,63 a red shift has been reported in the case of an N–bound
interaction of the aldoxime with surface Lewis acid sites.63 More specifically, in the
C=N stretching vibration region (1640 cm-1 in gas phase), an IR band at 1646 cm-1 is
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observed when propionaldehyde oxime was adsorbed on nCeO2, while the band is
shifted to higher frequencies on the more acid supports (1659 cm-1 in MgO, 1662 cm-1
in TiO2 and 1667 cm-1 in Al2O3) (Figure 4a). In a similar way, in the N-OH frequency
region (1028 cm-1 in gas phase) a symmetric IR band at ~1037 cm-1 is observed with the
less acid CeO2 samples, while a high frequency component at ~1051 cm-1 appears on
the more acid supports (Al2O3, TiO2 and MgO) (Figure 4b). It should be considered that
MgO, normally considered as basic support, shows few relatively stronger acid sites
(see Table 3), that can be associated to uncoordinated surface sites like steps or
corners. In conclusion, in both N-OH and C=N vibration modes, a correlation between
Lewis acid strength and IR frequency shift is clearly detected. Moreover, the IR peak
area associated to the N-OH vibration normalized to catalyst surface area (included in
Table S1) is higher on CeO2 and TiO2 samples than on Al2O3 and MgO as it occurs with
the surface area normalized CO IR peak area, associated to Lewis acid sites.
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If one now compares the above spectroscopic results with the catalytic results (Table
1) it should be possible to conclude that, although Lewis acid sites are involved in the
first step of oxime interaction with the catalysts surface, no correlation between Lewis
acid strength and initial reaction rates could be observed. On the contrary, both nCeO2
and MgO samples, with the highest basic strength, appear as the most active samples
at least per gram of catalyst. Thus, surface basicity should play a determinant role in
the reaction mechanism. However, if basicity would be the only parameter that
determines catalytic activity, MgO being more basic than nCeO2, should exhibit a
higher initial reaction rate, which obviously is not the case (Table 1). The difference in
activity would be explained by also taking into account the less presence of Lewis acid
sites on MgO which corresponds to a lower IR band area of adsorbed oxime molecule
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(see Table S1). Thus, we can conclude that both Lewis acid sites (number) and basic
sites (strength) play a role in the reaction mechanism, being the Lewis acid sites
involved in the adsorption of the oxime through the N atom activating the molecule in
such a way that the hydrogen at the C1-H of the oxime becomes slightly more positive
and more reactive toward the attack by the basic site to perform the C1-H cleavage.
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Surface reaction steps
The reaction mechanism of aldoxime dehydration at increasing temperature followed
by in situ IR spectroscopy can be clearly evidenced in the MgO sample (Figure 5). As
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indicated above, oxime adsorption at 25 C on MgO shifts the N-OH and the C=N
stretching frequency to higher frequencies. Specifically, a broad asymmetric IR band
with two components at 1050 and 1037 cm-1 ascribed to the N-OH IR frequency and
an IR band at 1660 cm-1 due to the C=N vibration are observed. No change in the IR
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spectra is observed at 70 C. Increasing the temperature to 90 C the intensity of the
1050-1037 cm-1 IR band and the 1660 cm-1 IR band decrease and a new band at 1184
cm-1 start to appear (Figure 5a). This last band has been associated to the nitrile, being
this the desired reaction product. The C≡ N stretching vibraꢁon is not yet detected,
because of its lower extinction coefficient compared to the 1184 cm-1 IR band
vibration. Moreover an IR band at 3430 cm-1, due to hydroxyl groups, is clearly
detected at 90 oC (Fig.5b). Hydroxyl groups are formed due to C1-H cleavage catalyzed
by oxygen atoms of the support, and N-OH elimination, leading sequentially to C≡N
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bond formation. Increasing the temperature to 120 and 160 C the C≡N IR band at
2244 cm-1 (Fig. 5c) and H2O at 1628 cm-1 (Fig. 5a) and 3475 cm-1 (Fig. 5b) are clearly
detected on the catalyst surface as well as the IR band at 1184 cm-1 which grows in
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intensity due to nitrile. In parallel a strong decrease of the 1050 and 1037 cm-1 IR
bands associated to oxime is observed (Figure 5a). Accordingly the following reaction
steps can be established from all the above in situ IR results: a) oxime activation
through an N-bond complex to Lewis acid sites, b) N-OH bond elimination and C1-H
cleavage with subsequent OH formation and finally water and nitrile formation. Similar
reaction mechanism has been observed on the TiO2 and nCeO2 samples (see Figure S2
for the nCeO2 sample) with the only difference being their different reactivity. Nitrile
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formation has been observed at 90 C on the nCeO2 (C≡N IR band at 2247 cm-1, very
weak) and at 160 oC in the TiO2 (C≡N IR band at 2283 cm-1), which match perfectly their
reactivity performance in the macrokinetic studies. In the case of nCeO2, nitrile
adsorption (being this the reaction product) is much weaker than on the other catalyst
sample, being only detected at 90 oC on the surface as adsorbed specie (weak IR band).
At increasing temperatures it is desorbed to the gas phase. Owing to the base
character and further reactivity of the nitrile their fast desorption from the catalyst
surface is highly desired for maximizing catalyst activity, selectivity and catalyst life.
Therefore the desorption is favored in less acid catalysts.
In conclusion the in situ IR adsorption and reactivity results suggest a reaction
mechanism for the dehydration of aldoxime on metal oxides that would be consistent
63
with a polar elimination mechanism. Both Lewis acid and basic sites are involved,
being the controlling step in the reaction rate, the C1-H bond cleavage in which the
basic sites would be involved. Accordingly, we can assess that the basicity of the
nCeO2, coupled to an appropriate number of Lewis acid sites responsible for the
adsorption of the oxime through the N atom and the activation of the C1-H of the
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oxime, are responsible for the high catalytic performance observed on this sample
compared to the other metal oxide samples.
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Reusability and scope of the reaction on nCeO2
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To study the catalyst reusability after dehydration of 4-methoxybenzaldoxime, the
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nCeO2 sample was washed, calcined at 450 C and reused during four consecutive
cycles. As can be seen in Figure 6 the nCeO2 maintains its activity during four
consecutive cycles.
The scope of nCeO2 for the synthesis of nitriles was studied starting from a variety of
aromatic, heterocyclic, cyclic and aliphatic aldoximes, which were converted
predominantly in the corresponding nitriles (Table 5). In the case of aromatic
aldoximes the presence of electron withdrawing groups in the aromatic ring (entries 2-
4) increases the reactivity with respect to non-substituted aldoximes and aldoximes
with electron donating groups (entries 1 and 6). In the case of heterocyclic aldoximes,
such as thiophen-2-carbaldehyde oxime, pyridine-2-carbaldehyde oxime and furan-2-
carbaldehyde oxime (entries 5, 7 and 8), the corresponding heterocyclic nitriles were
obtained in lower yields due to the formation of the corresponding amides by
subsequent hydration of the nitrile. Similar behavior has been reported for
dehydration of heterocyclic aldoximes in the presence of cupric acetate in
acetonitrile.23These results agree with those reported by Tamura et al.61 who observed
that CeO2 promotes efficiently the hydration of nitriles to amides provided that the
nitrile possess a heteroatom adjacent to the α-carbon of the C≡N group. Finally, good
yields of nitriles (80-95%) were also obtained from cycloalkyl and alkyl aldoximes
(entries 9-12 ) using n-CeO2 as catalyst.
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Taking into account the good results showed by the nanoceria for the dehydration of
aldoximes and considering the previous results reported by Tamura et al.50,51 on the
conversion of nitriles into amides and esters using CeO2 as catalyst, we have
envisioned a one pot synthesis of amides and esters starting from the corresponding
aldoximes.
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One-pot synthesis of 2-picolinamide from 2-pyridinealdoxime
It has been demonstrated that CeO2 is able to promote efficiently the hydration of
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nitriles to amides using water as a solvent, particularly when a heteroatom (N or O)
is adjacent to the α-carbon of the nitrile group, as it is the case of the 2-cyanopyridine.
Mechanistic studies suggested that the catalytic activity of the CeO2 for this
transformation arises from the cooperation of Lewis acid sites (Ce+4) and acid-base (Ce-
O) pair sites which activate an electrophile and a nucleophile, respectively. Thus,
considering the ionic nature of CeO2, a mechanism has been proposed in where the
catalytic cycle starts with the dissociation of H2O on CeO2 to give H+ and OH-. In a
second step the nitrile is adsorbed onto the CeO2 forming a nitrile-CeO2 complex which
in a third step (the rate determining step) will undergo an addition of the OH- to the
carbon atom of the nitrile group to give the amide, followed by desorption of the
amide from CeO2 surface. 64
Owing to the fact that 2-picolinamide derivatives have important pharmacological
activities, for instance in the treating of neurological and psychiatric disorders
associated with glutamate dysfunction,65 we selected 2-pyridine aldoxime as substrate
for the one pot synthesis of 2-picolinamide starting from the aldoxime. Since, water
cannot be used in our case as a solvent since it could promote the aldoxime hydrolysis,
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we have designed a one-pot process which involves two consecutive steps catalyzed by
the nanocrystalline CeO2. Firstly the dehydration of 2-pyridinealdoxime to nitrile (2-
cyanopyridine), which takes place at reflux of o-xylene and then the addition of a
controlled amount of water which promotes the hydration of nitrile to give the
corresponding amide (2-picolinamide) (Scheme 2).
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In this one pot process the presence of water plays an important role, since it was
observed that in the first step the water formed during the dehydration of aldoxime
was already able to promote the hydration of the nitrile to amide yielding picolinamide
(40%), and 2-cyanopyridine (60%). Thus, to complete the hydration of 2-cyanopyridine,
while avoiding the over-hydrolysis into the undesired carboxylic acid, the temperature
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was decreased at 110 C in the second step, while different amounts of water were
added. Results from Table 6 indicate that when working with a molar ratio
water/substrate ≥ 14, a yield of 99% of picolinamide ( 99% selectivity) was obtained.
In Figure 7 the evolution of products versus the reaction time is depicted for the one
pot synthesis of picolinamide from 2-pyridinealdoxime when water (14mmol) was
added. As can be seen from the results presented in Figure 7, the nitrile formed in the
first step was immediately hydrated to picolinamide reaching 99 % of yield after 8h
reaction time. The reaction was extended to other heteroaromatic aldoximes and
good yields of the corresponding amides were obtained, although longer reaction
times were required (Table 7).
One pot synthesis of picolinic acid alkyl esters from 2-pyridinealdoxime
It is known that picolinic acid alkyl esters are important pharmacological compounds
as they possess high activity inducing apoptosis for human leukemia cells.66 Then, the
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possibility to obtain esters from aldoximes through a one pot process was studied here
by selecting the coupling of 2-pyridinealdoxime and n-octanol as reaction model
(Scheme 3). The reaction was performed by reacting 2-pyridinealdoxime with an
excess of octanol in the presence of water in o-xylene at reflux temperature and using
the nanocrystalline nCeO2 as catalyst. Results showed that excellent yield (89 %) and
selectivity to picolinic acid octyl ester (90 %) can be obtained after 26h reaction time.
These results are similar to those reported by Tamura et al.46 starting from 2-
cyanopyridine.
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Figure 8 shows the kinetic curve for ester formation from the pyridinealdoxime. As can
be seen there the picolinamide (2-pyridinecarboxamide) appears as a primary and
unstable product with a maximum yield (62 %) at 2h reaction time, and then
decreases. It is interesting to point out that the hydrolysis of aldoxime was not
detected in the reaction media in spite of the presence of water as reactant. The
corresponding nitrile was neither detected as intermediate compound, indicating that
dehydration of aldoxime is not the controlling step of the reaction. Then, from the
above results and those of the Tamura el al.50 for the esterification of 2-cyanopyridine
with octanol, who found that the rate of hydration of 2-cyanopyridine was calculated
to be 86 times larger than that of esterification of amide, we have to conclude that in
our one pot process, the 2-pyridinealdoxime is rapidly dehydrated to the
corresponding nitrile (2-cyanopyridine) and hydrolyzed into 2-picolinamide which
finally reacts with the alcohol to obtain the corresponding ester. The reaction was
extended to the synthesis of other picolinic acid alkyl esters starting from 2-
pyridinealdoxime and different alcohols (Table 8), achieving good results of the
corresponding esters. It appears then that it is possible in a one pot system using
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nCeO2 as catalyst to carry out a process that involves three consecutive reaction steps
and which yields the corresponding ester directly from 2-pyridinealdoxime.
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Conclusions
The dehydration of aldoximes to nitriles has been studied in the presence of various
metal oxides (Al2O3, TiO2, CeO2, MgO) being the nanocrystalline ceria the most active
catalyst. A polar elimination mechanism has been proposed in the dehydration of
aldoxime on metal oxide catalysts, in which Lewis acid sites and basic sites intervene.
The Lewis acid sites are involved in the adsorption of the oxime on the catalyst surface
and surface base sites are responsible for the C1-H bond cleavage. Thus, the basicity
showed by nCeO2 coupled with the Lewis acid sites is responsible for the high catalytic
activity and selectivity. Good yields of nitriles (80-97%) from aromatic aldoximes
involving electron withdrawing and electron donating groups as well as from alkyl and
cycloalkyl aldoximes were obtained. Nanosized ceria is a stable and reusable catalyst; it
was reused four consecutive cycles without loss of activity. Based on the above
reactions, it is possible to obtain pharmacologically important products such as
picolinamide and picolinic acid alkyl esters from 2-pyridinaldoxime in a one pot process
using the nanoceria as catalyst.
Acknowledgements
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Financial support by Consolider-Ingenio 2010 (project MULTICAT), Generalitat
Valenciana (Prometeo program) and Program Severo Ochoa are gratefully
acknowledged.
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Supporting Information Available: Table of Surface density of adsorbed
propionaldehyde oxime on the different oxides; IR spectra of nCeO2 sample after
oxime adsorption at increasing temperatures; Figure corresponding to the leaching
test of nCeO2. This material is available free of charge via the Internet at
http://pubs.acs.org.
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Scheme 1. Dehydration of 4-methoxybenzaldehyde oxime in presence of metal oxides
as catalyst
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Scheme 2. Reaction pathway of the one pot synthesis of 2-picolinamide from 2-
pyridinealdoxime in the presence of nCeO2 as a catalyst.
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Scheme 3. Reaction pathway of the one pot synthesis of esters of 2-picolinic acid from
2-pyridinealdoxime in the presence of nCeO2 as a catalyst.
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Table 1. Results of dehydration of 4-methoxybenzaldehyde oxime in the presence of different heterogeneous
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and homogeneous catalysts
Time
(h)
7
Conv.(%)
1
Yield (%)
r0
(mmol/h g)a
80
r 0
Entry
Catalyst
2
56
93
38
20
>99
43
82
3
5
4
0
0
0
1
0
0
0
(mmol/h m2)b
1
2
3
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5
6
7
CeO2
nCeO2
63
1.40
4.17
0.28
1.17
0.32
-
1.5
8
100
41
7
480
TiO2
2
16
Al2O3
7
23
2
176
MgO
6
>99
100
100
0
220
Ce(NO3)3.6H2O
Ce(III)triflate
6
56
18
14
6
100
-
Reaction conditions: 4-methoxybenzaldehyde oxime (1 mmol, 151 mg), catalyst 50 mg at reflux of o-xylene (3
mL) under N2 using a Dean Stark apparatus. a Initial rate of formation of nitrile per gram of catalyst. b Initial rate
of formation of nitrile per unit surface area .
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Table 2. Comparative results of dehydration of 4-methoxybenzaldehyde oxime obtained with different
heterogeneous catalyst
Yield
Entry
Catalyst
Time
Solvent
T [oC]
C/S [wt/wt] Ref.
Nitrilea
1
nCeO2
1.5h
o-xylene
149
93
0.33
This
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MIL-100(Fe)-NH4F
W-Sn hydroxide
1h
1h
o-xylene
o-xylene
CH3CN
Toluene
-
149
149
82
91
95
95
78
92
80 c
90
89
0.40
1.52
0.58
3.95
0.13
0.50
47.7
3.30
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Fe3O4@AEPH2-Cu(II)b
Montmorillonite KSF
1h
18h
24h
5h
115
100
119
85
Envirocat EPZG
14-
[NaP5W30O110
]
AcH
KF/alumina
H2SO4/SiO2
8h
DMF
MW,
3min
8h
-
10
11
Cu(II)-MS (4A)d
CH3CN
-
80
96
80b
93
0.65
4.13
3.30
35
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H2SO4/MF resine
MW
5 min
20min
12
[RuCl2(p-cymene)]2/C
CH3CN
80
31
a
c
d
4-methoxybenzonitrile; bCu(II) immobilized on aminated ferrite nanoparticles; benzonitrile; 4A
Molecular sieve modified with Cu(II);eH2SO4 supported on Melamine-Formaldehyde resin; C/S:
Catalyst/oxime (wt/wt) .
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Table 3. Distribution of Lewis acid sites on the different samples monitored by FTIR of CO adsorption.
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Catalyst
Al2O3
TiO2
MgO
nCeO2
IR Lewis Acid sites (cm-1)
OHa
Phyb
2140
2138
2136
2180(1.68) 2177(1.65)
2180(26.9) 2175(8.4)
2171(0.6)
2153(20.86)
2154(21.5)
2163(0.6)
2148 (0.9)
2145(3.5)
2130c (1.2)
2142(13.9)
2128c (5)
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2154(4.4)
2153(98.5)
CeO2
Values in brackets corresponds to the respective CO IR band area normalized to catalyst surface area
(see details in experimental section).a CO interacting with hydroxyl groups, physisorbed CO, CO
b
c
interacting with Ce3+ (55).
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