A versatile and green mechanochemical route for aldehyde-oxime conversions

Article abstract of DOI:10.1039/c2cc36315a

A robust, facile and solvent-free mechanochemical path for aldehyde-oxime transformations using hydroxylamine and NaOH is explored; the method is suitable for aromatic and aliphatic aldehydes decorated with a range of substituents. This journal is

Full text of DOI:10.1039/c2cc36315a

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Chemical Communications
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Volume 48 | Number 92 | 28 November 2012 | Pages 11261–11368
ISSN 1359-7345
COMMUNICATION
Christer B. Aakeröy et al.,
A versatile and green mechanochemical route for aldehyde–oxime
conversions
1359-7345(2012)48:92;1-S

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A versatile and green mechanochemical route for aldehyde–oxime
conversionswz
¨
Christer B. Aakeroy,* Abhijeet S. Sinha, Kanishka N. Epa, Christine L. Spartz and
John Desper
Received 30th August 2012, Accepted 21st September 2012
DOI: 10.1039/c2cc36315a
A robust, facile and solvent-free mechanochemical path for aldehyde–
oxime transformations using hydroxylamine and NaOH is explored;
the method is suitable for aromatic and aliphatic aldehydes
decorated with a range of substituents.
Aldoximes form an important class of compounds in funda-
mental organic chemistry, which is employed for protection,
purification1 and characterization of aldehydes.2 They are useful
starting materials for various functional groups such as nitriles,3
nitro compounds,4 amines5 and amides.6,7 Furthermore, they can
offer structure-directing capabilities in supramolecular chemistry
by virtue of being strong hydrogen-bond donors (as well as being
self-complementary synthons).8 Finally, upon deprotonation,
they serve as efficient ligands in the field of coordination
chemistry for complexation with various metals.9 As a result of
their broad-based utility, there is a growing interest in finding
better (high yielding, solvent free) and more convenient (short
reaction times, easy work-up) synthetic routes.
Scheme 1 One-pot mechanochemical conversion of aldehydes to oximes.
formation of oximes in good yields, and oxime-functionalized
cavitands have been prepared using solid-state grinding.17
A
previous study of carbonyl–oxime transformation included
five aldehydes,18 but no systematic investigation into the
versatility of an environmentally friendly, facile, and solvent-
less mechanochemical path to aldehyde–oxime conversions
has been reported.
In this paper we present the synthesis of 20 different oximes
from their corresponding aldehydes using a mechanochemical
route of solvent-drop grinding in the presence of hydroxyl-
amine hydrochloride and sodium hydroxide (Scheme 1). The
grinding is done at room temperature and the reaction time
ranges from 5–10 minutes. This synthetic route is green as it is
essentially solvent-free, and involves short reaction times at
ambient conditions. The workup of each reaction involves a
simple aqueous washing procedure of the ground mixture to
remove inorganic salts resulting in a pure product.
Aldoximes are typically prepared using solution-based methods
involving refluxing alcoholic/aqueous solutions of aldehyde with
hydroxylamine hydrochloride and base.2 The long reaction times,
elevated temperatures, and the extensive use of organic solvents
mean that these procedures are both expensive and environ-
mentally stressful, so there is obviously a need for better options.
Mechanochemistry, which is normally carried out in the absence
of, or with minimal use of, solvents, could potentially offer both
cheaper and greener alternatives.10 A solid-state based mechano-
chemical process conforms to most of the aspects of green
chemistry and thus is appealing for use in the areas of covalent
synthesis and supramolecular chemistry.11 Some advances have
been made in the synthesis of aldoximes from aldehydes; for
The synthetic targets were selected with a view to establishing
versatility and robustness of this mechanochemical approach
(Table 1). Six of the aldehydes contained electron withdrawing
substituents (1–6), one was decorated with electron donating
substituents (7), nine aldehydes contained structurally active
functional groups such as –COOH (8–9), –OH (10–13) and
pyridyl group (14–16), three other aldehydes were multifunc-
tionalized (17–19), and finally, we also included an aliphatic
aldehyde (20). The broad spectrum of aldehydes examined was
meant to provide sufficient data to determine the limits and
limitations (if any) of a solvent-free grinding for the conversion
of aldehydes to oximes.
13
example, the use of catalysts such as BF3ꢀOEt2,12 basic Al2O3
and CaO14 have been developed in conjunction with microwave
15
irradiated synthesis. Also, grinding in presence of Bi2O3 or
ball-milling at elevated temperatures16 has resulted in the
The products were characterized by 1H NMR spectroscopy
in order to establish the complete disappearance of the alde-
hyde proton and the emergence of the two oxime protons. In
none of the 20 reactions was any evidence of an aldehyde
found in the crude solid taken directly from the mortar,
indicating the efficiency of the conversion (Fig. 1), and no
organic side products could be detected. The work-up needed
Department of Chemistry, Kansas State University, Manhattan,
KS 66506, USA. E-mail: aakeroy@ksu.edu
¨
w This article is part of the ChemComm ‘Mechanochemistry’ web
themed issue.
z Electronic supplementary information (ESI) available: Synthesis and
characterization of all compounds, CIF file for the structure of 19.
CCDC 898798. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2cc36315a
c
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Chem. Commun., 2012, 48, 11289–11291 11289

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Table 1 Series of the synthesized oximes
#
Product
M.p.a (1C)
Yield %
#
Product
M.p.a (1C)
Yield %
1
128–132 (133)
100b (78)c 11
110–116 (117)
71c
2
3
138–140 dec (138 dec) 100b (80)c 12
112–114
124–126
100b (83)c
165–169
100b (87)c 13
100b (76)c
4
5
119–121
101–103
100b (85)c 14
130–132 (132)
146–148 (150)
100b (83)c
100b (81)c
61c
59c
15
16
6
7
66–68
110–114 (114)
65c
112–114 (117)
100b (89)c 17
202–204 (201–202) 100b (69)c
8
212–216 (218)
67c
18
180–182 (181–184) 100b (67)c
9
126–128 (128–130)
83–90 (87–88)
100b (73)c 19
239–241
100b (64)c
10
100b (62)c 20
70–72 (72)
100b (77)c
Note: In a mortar, 1.0 mole of aldehyde and 1.2 moles (per aldehyde present) of hydroxylamine hydrochloride is ground together with a pestle. Then,
1.2 moles (per aldehyde present) of crushed sodium hydroxide is added and the mixture is ground further with the addition of 2–4 drops of methanol,
for 2 minutes at room temperature. The reaction mixture is left for 5 minutes, after which it is ground for another 2 minutes with 2–4 drops of
methanol. At this stage the reaction is monitored by TLC. Upon completion of the reaction, a 1H NMR of the crude mixture is taken in d6 DMSO to
confirm the formation of aldoxime. The crude mixture is washed with water to get rid of any inorganic salts and it is air dried, after which the melting
a
point is taken to confirm the formation of pure product. All references for the literature melting points of the products can be found in the ESI.
b
c
% Yield calculated based on the stoichiometric conversion of aldehyde to oxime as demonstrated by the crude 1H NMR spectrum. % Yield
calculated based on the mass of product obtained after washing the crude mixture with water. Lower yield in some cases is due to loss of product during
the washing procedure as some oximes are partially soluble in water. Yields could be improved to 95–100% by carrying out a normal extraction.
for removing inorganic salts involved a simple aqueous washing
procedure. We were also able to grow single crystals of 1,3,5-
benzenetricarboxaldehydetrioxime (Fig. 2). In 15 of the 20 reactions
(1–4, 7, 9–10, 12–15, 17–20), we obtained perfect 1H NMR
data directly from the mortar. No organic side reactions took
place, and the inorganic salts were easily removed through a
c
11290 Chem. Commun., 2012, 48, 11289–11291
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O21–H21ꢀ ꢀ ꢀN23 1.87(4) A), and (O25ꢀ ꢀ ꢀN21 2.851(3) A,
O25–H25ꢀ ꢀ ꢀN21 1.88(4) A), respectively. The third oxime
moiety forms an O–Hꢀ ꢀ ꢀO interaction (O23ꢀ ꢀ ꢀN25 2.799(3) A,
O23–H23ꢀ ꢀ ꢀN25 1.91(4) A) with a neighbouring molecule.
A versatile and facile mechanochemical path to aldehyde–
oxime transformations has been established by examining 20
different aldehydes with different substituents such as electron
withdrawing (1–6), electron donating (7), structurally active
(8–16), multifunctionalized (17–19) and aliphatic (20) groups.
The synthetic path seems to be substituent insensitive (across the
range examined herein), and the ambient reaction conditions,
ease of scalability, and straightforward work-up procedure make
this route environmentally friendly, and a better and greener
alternative to existing methods for aldoxime synthesis.
Fig. 1 1H NMR spectrum of 3 obtained from ground mixture.
We are grateful for financial support from NSF (CHE-0957607)
and from the Johnson Center for Basic Cancer Research.
Notes and references
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The relative efficiency of this mechanochemical approach is
seemingly not influenced by the presence/absence of electron-
withdrawing or electron-donating groups. Furthermore, the
aldehyde–oxime conversion can also be carried out success-
fully using this grinding procedure even in the presence of
functional groups such as –COOH, –OH, and a heterocycle
(pyridine). Furthermore, the process can be carried out on
multiple aldehydes simultaneously (17–19), as well as on aliphatic
aldehydes (20) with no adverse effects. To further characterize the
product of the reaction between hydroxylamine hydrochloride,
NaOH and the 1,3,5-trisaldehyde, we were able to grow crystals
suitable for single-crystal diffraction, which provided supporting
evidence of the successful conversion (Fig. 2).
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the three hydrogen-bond donors (the –OH moieties) are engaged
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 11289–11291 11291