Solvent free, microwave assisted conversion of aldehydes into nitriles and oximes in the presence of NH2OH · HCl and TiO2

Article abstract of DOI:10.3390/molecules15010094

Aromatic aldehydes bearing electron-donating groups are easily converted into their respective nitriles using NH₂OH · HCl and TiO ₂ under microwave irradiation, while those bearing an electron-withdrawing group give the corresponding oximes.

Full text of DOI:10.3390/molecules15010094

Molecules 2010, 15, 94-99; doi:10.3390/molecules15010094
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Solvent Free, Microwave Assisted Conversion of Aldehydes into
Nitriles and Oximes in the Presence of NH OH·HCl and TiO
2
2
Lucas Villas-Boas Hoelz, Biank Tomaz Gonçalves, José Celestino Barros and Joaquim Fernando
Mendes da Silva *
Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio de Janeiro,
Av. Athos da Silveira Ramos 149, CT Bloco A, Cidade Universitária, Rio de Janeiro, RJ 21941-909,
RJ, Brazil
*
Author to whom correspondence should be addressed; E-Mail: joaquim@iq.ufrj.br.
Received: 27 October 2009; in revised form: 22 December 2009 / Accepted: 23 December 2009 /
Published: 29 December 2009
Abstract: Aromatic aldehydes bearing electron-donating groups are easily converted into
2 2
their respective nitriles using NH OH·HCl and TiO under microwave irradiation, while
those bearing an electron-withdrawing group give the corresponding oximes.
Keywords: titanium dioxide; aldehydes; nitriles; oximes; microwave irradiation
1
. Introduction
Titanium dioxide (TiO
application as a heterogeneous catalyst and as a photocatalyst. In addition, TiO
toxic and safe [1]. TiO may complex with the carbonyl oxygen atoms of aldehydes and ketones, thus
2
) has attracted the attention of synthetic organic chemists due to its
2
is inexpensive, non-
2
activating them for nucleophilic attack [2]. Sharghi and Sarvari converted aldehydes and ketones into
the respective amides in the presence of NH OH·HCl and TiO in a one-pot, solvent free procedure,
2
2
but with long reaction times [3]. Aldehydes may also be converted into their respective nitriles in good
yields and short reaction times using NH OH·HCl under microwave irradiation using, however, the
2
toxic N-methyl-2-pyrrolidinone (NMP) as solvent [4]. In the two cases, the mechanism involves oxime
generation, but while the amides are obtained through Beckmann rearrangement, the nitriles are
generated through dehydration.

Molecules 2010, 15
95
The transformation of aldehydes into nitriles is a highly valued reaction, due to the versatility of the
latter as starting materials in organic synthesis [8]. Although several methods are known for the
transformation of aldehydes to their corresponding nitriles [4,6–13], many drawbacks such as low
yields, harsh reaction conditions and tedious work-up procedures limit the use of some of these
procedures. Furthermore, some of them use corrosive, toxic, expensive or commercially unavailable
reagents [2,4].
Oximes, another important class of aldehyde derivatives, also have useful applications in organic
synthesis and in analytical chemistry. These compounds, besides being intermediates for isoxazoline
[14] and N-hydroxylamino nitrile synthesis [15], also have a potential use in perfumery industry due to
their higher stability when compared to their corresponding aldehydes, while retaining a pleasant
odour [16].
Based on these facts, we decided to evaluate the conversion of aldehydes into oximes and then into
nitriles in the presence of NH OH·HCl and TiO under microwave irradiation, in order to favor
2
2
dehydratation over Beckman rearrangement of the intermediate oxime. Product formation was
followed by GC-MS and the spectroscopic data of products were compared to those available in the
literature.
2
. Results and Discussion
Since we have been interested in the synthetic and medicinal usefulness of vanillonitrile derivatives,
we started our research studying the effects of time and irradiation potency on the conversion of
vanillin to its oxime and nitrile under microwave irradiation. The results obtained are summarized in
Table 1.
Table 1. Time and Potency Effects on the Conversion of Vanillin into Vanillonitrile and
Vanillin Oxime.
Entry
Time (min) Power (W)
% Nitrile
% Oxime
% Others
1
2
3
4
5
6
0,5
1
5
1
1
100
100
100
200
300
300
60
75
83
53
56
62
40
25
4
34
29
20
0
0
13
13
15
18
2
2 2
Conditions: 1 mmol vanillin, 5 mmol TiO , 5 mmol NH OH·HCl.
The results show that the best conversion rate was obtained by irradiating the solid mixture for five
minutes at 100 W (entry 3). Increasing the power (entries 4-6) led to higher yields of undesired
products (such as the amide and degradation products), while reduced reaction times furnished higher
amounts of the oxime (entries 1-2).
It can also be observed that increasing reaction time from one to five minutes (entries 2 and 3)
enhanced vanillonitrile yields, as well as the amounts of undesired products, and thus longer reaction
times were not evaluated. For both reaction times no starting material could be detected.

Molecules 2010, 15
96
We have also explored the effects of the amounts of TiO and NH OH·HCl in the reaction mixture
2
2
on the yield of the nitrile. Reducing the amounts of either of these reagents from 5 mmols to 2.5 mmols
led to incomplete conversion of the aldehyde and, at the same time, to enhanced yields of undesired
products (results not shown). Thus, after determining the best reaction conditions, we applied them to
other aromatic aldehydes, as described in Table 2.
Table 2. Conversion of Aldehydes into Nitriles and Oximes in the Presence of
NH OH·HCl and TiO under Microwave Irradiation.
2
2
Entry
Aldehyde
% Aldehyde % Nitrile % Oxime % Others
1
2
3
4
5
6
7
8
Ethylvanillin
0
0
0
0
0
5
2
0
83
84
81
77
82
15
17
20
5
4
12
12
9
0
11
0
4-Dimethylaminobenzaldehyde
4-Hydroxybenzaldehyde
2-Pyrrolecarboxaldehyde
4-Benzyloxyvanillin
2-Nitrobenzaldehyde
4-Nitrobenzaldehyde
10
22
7
80
81
80
0
0
4-Bromobenzaldehyde
Conditions: 1 mmol aldehyde, 5 mmol TiO
2
2
, 5 mmol NH OH.HCl, 5 min, 100 W.
The aldehydes bearing electron donating groups were readily converted into the corresponding
nitriles (entries 1-5, Table 2) in satisfactory conversion rates (77–84%), whereas substrates bearing
electron withdrawing groups (entries 6-8, Table 2) afforded the respective oximes, along with
significant amounts of the respective nitriles. In fact, it was previously observed that substrates bearing
those groups require longer reaction times for total conversion into nitriles [17]. We further explored
the effects of increasing power and reaction times in the conversion of 4-nitrobenzaldehyde to 4-nitro-
benzonitrile, but no change in product ratios was observed. GC-MS monitoring supports a two step
mechanistic proposal for these reactions (Scheme 1), where the conversion of the aldehyde into the
respective nitrile occurs at the expense of the oxime through acid catalysed dehydration.
Scheme 1. Proposed sequence of transformations during TiO
2
promoted conversion of
aldehydes into nitriles.
n+
Ti
O
NOH
H
-
H O
2
R CN
R
H
R
H NOH
2
In order to test this hypothesis, we performed the reaction between vanillin and hydroxylamine
hydrochloride in the absence of TiO (100 W, 5 min). The HCl liberated during oxime formation
2
promoted dehydration, but with reduced efficiency when compared to titanium oxide (44%
vanillonitrile, 27% oxime, 29% other products). Addition of p-toluenesulfonic acid led to a complex

Molecules 2010, 15
mixture of products, while the addition of NaOH or Na CO , either in the presence or absence of TiO
2
97
2
3
yielded exclusively the oxime with 100% conversion rate. The same occurred with the other
aldehydes, what makes this procedure a useful method for rapid, solvent free, microwave assisted
synthesis of aldoximes. The reaction can be easily scaled-up, and the synthesis of vanillonitrile using a
4
-fold amount of all the reagents led to a 92% conversion to vanillonitrile, which could be purified by
flash column chromatography, yielding pure product in 85% isolated yield (Figure 2).
Figure 2. GC chromatogram of scaled up conversion of vanillin into vanillonitrile and MS
R
of the major compound (t = 6.33 min).
3
. Experimental
.1. General
The HRGC/MS analyses were carried out on a Shidmadzu QP-2010 operating in electron ionization
3
mode at 70 eV. Helium was used as carrier gas and the injection split ratio was 1:100. Separation was
achieved on DB-5 capillary column (30 m × 0.25 mm × 0.25 μm) using the following temperature
program: 1 min at 60 °C, 20 ºC/min until 260ºC, then 10 min at 260 ºC. Ion source and injection
1
temperature were at 260 ºC. H-NMR spectrum of vanillonitrile was recorded on a Bruker HC200
3
spectrometer, using CDCl as solvent. The FTIR spectrum was recorded on a Nicolet 550 spectrometer
(
KBr pellets).
3
.2. Microwave assisted conversion of aldehydes into nitriles and oximes
2
A 25 mL reaction flask was charged with a ground mixture of an aldehyde (1 mmol), TiO (5 mmol,
0
.4 g) and hydroxylamine hydrochloride (5 mmol, 0.35 g). The reaction mixture was placed at a CEM
Discovery microwave reactor (power-time method) and irradiated at the power settings and reaction
times specified in Tables 1 and 2, with air-cooling and magnetic stirring for the duration of the
2 2
reaction. After cooling to room temperature, the reaction mixture was resuspended in CH Cl (10 mL),

Molecules 2010, 15
98
filtered and a sample submitted to CG/MS analysis with the following results: 3-Ethoxy-4-
+
hydroxybenzonitrile: t = 6.92 min. M = 33.7 (71%). 4-Dimethylaminobenzonitrile: t = 7.69 min.
R
R
+
+
M = 146 (67%). 4-Hydroxybenzonitrile: t
R
= 5.94 min. M = 119 (100%). 2-Pyrrolecarbonitrile:
+
+
t = 3.12 min. M = 92 (100%). 4-Benzyloxy-3-methoxybenzonitrile: t = 7.52 min. M = 239 (100%).
R
R
+
+
2
-Nitrobenzonitrile: t
R
= 6.09 min. M = 148 (31%). 4-Nitrobenzonitrile: t
R
= 5.39 min. M = 148
+
(
31%). 4-Bromobenzonitrile: t
.3. Scale-up preparation of vanillonitrile
Vanillin (0.6 g, 4 mmol), TiO (1.6 g, 20 mmol) and NH
R
= 6.23 min. M = 181 (90%), 183 (86%).
3
2
2
OH·HCl (1.4 g, 20 mmol) were ground in
a mortar and the mixture was transferred to a 125 mL reaction flask. The reaction mixture was placed
at a CEM Discovery microwave reactor (power-time method) and irradiated at 100 W for 5 minutes,
with air-cooling and magnetic stirring for the duration of the experiment. After cooling to room
temperature, the reaction mixture was resuspended in ethanol (10 mL), filtered and then purified by
flash column chromatography using silica gel as adsorbent and hexane-ethyl acetate (7:3) as eluant,
1
yielding pure vanillonitrile in 85% yield, m.p. = 84–87 °C (lit. 85–87 °C); H-NMR δ ppm 3,93 (s, 3H,
-1
OCH
3
), 6,20 (bs, 1H, OH), 6,94 (d, 1H, C
5 2 6
-H), 7,02 (s, 1H, C -H), 7,35 (d, 1 H, C -H); FTIR υ cm :
3
373, 3076, 2229
3
.4. Microwave assisted conversion of aldehydes into oximes under basic conditions
A 25 mL reaction flask was charged with a ground mixture of an aldehyde (1 mmol), Na
2 3
CO
(
5 mmol, 0.51 g) and hydroxylamine hydrochloride (5 mmol, 0.35g). The reaction mixture was placed
at a CEM Discovery microwave reactor (power-time method) and irradiated at 100 W for 5 minutes,
with air-cooling and magnetic stirring for the duraction. After cooling to room temperature, the
2 2
reaction mixture was resuspended in CH Cl (10 mL), filtered and a sample submitted to CG/MS
analysis.
4
. Conclusions
Titanium oxide is a useful reagent for the acid promoted conversion of EDG-substituted aldehydes
to nitriles through a solvent free, microwave assisted procedure. On the other hand, neutralization of
the reaction mixture by addition of NaOH or Na CO proved to be an efficient method for obtaining
2
3
the corresponding aldoximes in quantitative conversion rates.
Acknowledgements
The authors wish to thanks CNPq, CAPES and FAPERJ for financial support.
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Sample Availability: Samples of the compounds are available from the authors.
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