Synthesis of ketoximes via a solvent-assisted and robust mechanochemical pathway

Article abstract of DOI:10.1039/c3ra40585k

A versatile and robust mechanochemical route to ketone-oxime conversions has been established for a broad range of ketones via a simple mortar-pestle grinding method. The relative reactivity of aldehydes vs. ketones under these conditions has also been explored, along with an examination of the possible connection between reactivity and electronic substituent effects.

Full text of DOI:10.1039/c3ra40585k

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Synthesis of ketoximes via a solvent-assisted and robust
mechanochemical pathway3
Cite this: RSC Advances, 2013, 3, 8168
Christer B. Aakeroy* and Abhijeet S. Sinha
¨
Received 1st February 2013,
Accepted 3rd April 2013
DOI: 10.1039/c3ra40585k
www.rsc.org/advances
A versatile and robust mechanochemical route to ketone–oxime
conversions has been established for a broad range of ketones
times and high temperatures, these methods are obviously
not completely environmentally benign and thus there is a
need for a less pollutive synthesis of ketoximes. An inherently
greener mechanochemical path may be a better option.
Ketone–oxime conversions have previously been achieved by
grinding in the presence of catalysts in conjunction with
microwave irradiation,9 by ball-milling at elevated tempera-
tures,10 or with the aid of nanostructured pyrophosphate as a
catalyst under solvent-free conditions at elevated tempera-
tures.11 Finally, the synthesis of several ketoximes has been
via
a simple mortar–pestle grinding method. The relative
reactivity of aldehydes vs. ketones under these conditions has
also been explored, along with an examination of the possible
connection between reactivity and electronic substituent
effects.
Introduction
reported via
a a more
simple grinding method,12 but
Most chemical syntheses are usually environmentally pollutive but
can be made less wasteful and ‘‘greener’’ by minimal to no use of
solvents, as well as by shortening reaction times, using ambient
conditions and more facile means of product separation and
purification. A mechanochemical process may be feasible for
reducing waste, and such strategies have received considerable
attention recently.1 Mechanochemical synthetic processes typically
involve either ball-milling or grinding, and due to their simplicity
they provide an attractive alternative to the traditional solution-
based methods of chemical synthesis.2
Ketoximes comprise an important class of compounds in
synthetic organic chemistry owing to their use as precursors of
functional groups such as amines,3 nitriles4 and nitro com-
pounds.5 Via a Beckmann rearrangement they can be converted to
amides,6 whereas ketoxime tosylates can be converted to a-amino
ketones or a-amino acetals by a Neber rearrangement.6 Ketoximes
are also of use in the pharmaceutical industry (as organic
medicinal agents such as antibiotics for the treatment of
organophosphate poisoning)6 and as anti-skinning agents in
paints and lacquers.7
systematic investigation into the versatility of solvent-assisted
mechanochemical pathways of ketone–oxime conversions,
akin to what has been established for aldehyde–oxime
conversions,13 has not yet been presented.
Herein, we report the synthesis of 20 different ketoximes
decorated with a range of substituents, through solvent-
assisted grinding of the corresponding ketone with hydro-
xylamine hydrochloride and sodium hydroxide under ambi-
ent conditions (Scheme 1). The products were isolated by a
simple aqueous washing procedure. We have also examined
the relative reactivity of aldehyde–oxime versus ketone–oxime
conversions, and the possible electronic effects involved in
such transformations.
Traditionally, ketoximes are synthesized by solution-based
methods involving heating aqueous/alcoholic solutions of the
ketone with hydroxylamine hydrochloride and base under
reflux.3,8 Because of the use of organic solvents, long reaction
Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA.
E-mail: aakeroy@ksu.edu
Electronic supplementary information (ESI) available: Details of synthesis and
3
Scheme 1 Synthesis of ketoximes via a mechanochemical route.
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characterization. See DOI: 10.1039/c3ra40585k
8168 | RSC Adv., 2013, 3, 8168–8171

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The ketoximes were synthesized by grinding the respective
ketone with a mortar and pestle in the presence of hydroxylamine
hydrochloride and sodium hydroxide with a few drops of
methanol. The ground mixture was analysed by infrared spectro-
scopy (IR) to check for the disappearance of the carbonyl stretch
(around 1700 cm21) in the ketone and the appearance of the –OH
stretch (around 3100–3300 cm21) in the oxime. Following analysis
by IR spectroscopy, 1H NMR spectroscopy was used to characterize
the products in the ground mixture by monitoring the –CH3
protons. The –CH3 protons in the ketone shift upfield by 0.3–0.5
ppm upon conversion to the corresponding ketoxime.
Results
The ketones chosen for the study were selected with the aim of
determining how facile and versatile a mechanochemical process
is for ketone–oxime transformations, and for identifying possible
limitations of the process. Five ketones were decorated with an
electron withdrawing substituent (1–5), two of them had an
electron donating substituent (6 and 7), eight ketones contained
structurally active functional groups such as –OH (8 and 9), –NH2
(10 and 11) and a pyridyl group (12–15), two were multi-
functionalized (16 and 17) and finally, three aliphatic ketones
(18–20) were used (Table 1).
Table 1 Series of synthesized ketoximesc
#
Product
M.p. (uC)
Yield (%)
100a (88)b
#
Product
M.p. (uC)
Yield (%)
100a (68)b
1
90–93 (97–99)14
11
134–136 (135–137)15
2
3
126–129 (128–130)14
93–96 (92–93)17
100a (84)b
100a (91)b
12
13
162–165 (160)16
114–116 (118)16
100a (65)b
100a (56)b
4
5
156–160 (156–158)18
150–153
100a (78)b
100a (72)b
14
15
120–122 (119–121)14
235 dec (236–238)19
100a (67)b
100a (89)b
6
7
81–83 (84–86)14
50–53 (51–52)17
100a (71)b
100a (68)b
16
17
247 dec (248–250)20
209–211 (206–208)21
100a (93)b
100a (78)b
8
9
148–152 (148–149)22
206–208 (209–210)22
128–132 (132–133)24
100a (76)b
18
19
20
—
100a (53)b
57b
58–62 (61–62)23
127–129 (128–134)25
59b
10
70a
64b
% Yield calculated based on the crude 1H NMR spectrum. % Yield calculated based on the mass of the product obtained after washing the
crude mixture with water. Lower yield in some cases is due to the partial solubility of the product oxime in water. Yields could be improved to
a
b
c
95–100% by carrying out a normal extraction. Note: In a mortar, 1.0 mmol of ketone and 1.2 mmol (per ketone present) of hydroxylamine
hydrochloride are ground together with a pestle. Then, 1.2 mmol (per ketone present) of crushed sodium hydroxide is added and the mixture
is ground further with the addition of 0.1–0.2 mL of methanol, for 2 min at room temperature. The reaction mixture is left for 5 min, after
which it is ground for another 2 min with 0.1–0.2 mL of methanol. At this stage the reaction is examined by TLC. Upon completion of the
reaction, a 1H NMR spectrum of the crude mixture is recorded in d6 DMSO to confirm the formation of the ketoxime. The crude mixture is
washed with water to remove any inorganic salts and it is air-dried, after which the melting point is determined to establish the purity of the
product.
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16 of the 20 reactions (1–8 and 11–18) gave complete
stoichiometric conversion of the ketone to the corresponding
oxime as illustrated by the 1H NMR spectrum of the ground
mixture, and no organic side products could be detected (Fig. 1).
However, three reactions (9, 19 and 20) displayed an extra set of
peaks in the 1H NMR spectrum which disappeared upon washing
the ground mixture with water (the correct spectrum of the
corresponding pure compounds was obtained subsequently).
Finally, one reaction (10) showed an incomplete conversion of
the ketone to the oxime, and about 30% of the starting material
remained even after doubling the ratio of hydroxylamine and base
to ketone.
water, the oximes become protonated again and a clean spectrum
is obtained.
In order to take a close look at reaction rates and possible
electronic influences, three additional competitive experiments
were carried out. First, we wanted to examine the relative reactivity
of aldehyde–oxime vs. ketone–oxime conversions (Scheme 2).
Upon grinding
a 1 : 1 mmol ratio of benzaldehyde and
acetophenone with 1 mmol of hydroxylamine and base, the
product ratio was 95% : 5% in favour of the aldehyde conversion,
thus illustrating the greater reactivity of the aldehyde when the two
functional groups are located on different molecules. This is
consistent with a previous study10 which showed that competitive
ortho/para nitrobenzaldehyde vs. ortho/para nitroacetophenone
gave a 100% aldehyde–oxime conversion in a ball-milling reaction
at room temperature. Clearly a comparable distribution of
products can be achieved even by simple mortar–pestle grinding
as illustrated here.
However, the situation changed slightly when an aldehyde and
a ketone were located on the same backbone. When carrying out a
grinding reaction of 1 mmol of 4-acetylbenzaldehyde with 1 mmol
of hydroxylamine and base, the outcome was a 65% : 35%
distribution in favour of the aldehyde conversion. This suggests
that an electronic factor comes into play when the two functional
groups are on the same backbone, and the electron withdrawing
effect of the aldehyde may help to increase the reactivity of the
ketone group. To test this hypothesis, we performed a competitive
reaction with 1 mmol each of 4-methylacetophenone (electron
donating substituent) and 4-acetylbenzonitrile (electron withdraw-
ing substituent) in the presence of 1 mmol of hydroxylamine and
base. The result was an 80% conversion of 4-acetylbenzonitrile
and, consequently, a 20% transformation of 4-methylacetophe-
none which underscores that the electron withdrawing effect of
the nitrile group on the former reactant enhances the reactivity of
the ketone, thereby facilitating the ketone–oxime conversions.
Discussion
The versatility and robustness of a mechanochemically-based
synthetic route for ketone–oxime conversions is illustrated herein
by the facile transformation of a series of aliphatic and aromatic
ketones decorated with a range of substituents to their corre-
sponding oximes. The conversion is not adversely affected by the
presence of electron withdrawing, moderately electron donating,
or structurally active functionalities such as –OH and pyridyl
groups. Even multi-functional (16 and 17) and aliphatic reactants
(18–20) can be successfully converted at ambient conditions with
high yields. In a single case, that of 4-aminoacetophenone (10), we
obtained a conversion of 70% to the corresponding oxime even
upon increasing the ratios of hydroxylamine and base. We believe
that this may be due to the strongly electron donating effect of the
–NH2 group at the 4-position. In the case of 11, the –NH2 group is
at the 3-position and does not exert any electron donating effect as
it is seen in 10; thus, 100% conversion is obtained for 11.
IR spectroscopy is a reliable and robust qualitative technique
for the preliminary analysis of the ground mixtures. The
disappearance of the carbonyl stretch of the ketone and the
appearance of the –OH stretch of the oxime (indicative of
successful transformation) is distinctive and unambiguous in all
cases. A second set of peaks in the 1H NMR spectrum of three of
the reactions (9, 19 and 20) is attributed to the deprotonation of
the oxime in the presence of excess base. Upon washing with
Scheme 2 Relative reactivity of aldehyde vs. ketone (a, b) and the effect of the
Fig. 1 1H NMR spectrum of a ground mixture with 7.
8170 | RSC Adv., 2013, 3, 8168–8171
substituents on the reaction (c).
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Conclusions
A facile, solvent-assisted and room-temperature mechanochemical
synthetic pathway for the generation of ketoximes from ketones
has been explored. The robustness and versatility of this simple
process has been illustrated by performing the reaction on 20
different ketones with electron withdrawing (1–5), electron
donating (6 and 7), structurally active groups (8–15), multi-
functionalized (16 and 17) and aliphatic compounds (18–20).
Several competitive experiments have shown that electronic factors
(as induced by substituents on the aromatic backbone) can
influence the relative reactivity. In particular, electron withdrawing
substituents enhance, and electron donating groups reduce the
relative reactivity of a reactant, although more work is needed to
fully map out the role that such functionalities may play. The
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scalability and the use of environmentally benign reaction
conditions make this mechanochemical route for ketone–oxime
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We are grateful for financial support from NSF (CHE-0957607).
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