Mechanochemical and conformational study of N-heterocyclic carbonyl-oxime transformations

Article abstract of DOI:10.5562/cca2476

New mechanochemical pathways for the transformation of six N-heterocyclic carbonyl compounds into oximes using hydroxylamine hydrochloride were explored. Reactions were performed first without any base since the heterocyclic moieties (imidazole, benzimidazole, pyridine and quinuclidine) have an intrinsic basic nitrogen atom. This green, solvent free method was suitable for all compounds (up to quantitative yields) except for N-benzyl substituted imidazole and benzimidazole-2-carbaldehyde. For the slower reacting aldehydes, reactions with liquid assisted grinding and addition of sodium hydroxide were performed as well. Conformational analysis and quantum-chemical calculations revealed steric and electronic reasons for the lower reactivity of N-benzyl substituted derivatives.

Full text of DOI:10.5562/cca2476

CROATICA CHEMICA ACTA
CCACAA, ISSN 0011-1643, e-ISSN 1334-417X
■ hkd ( T o a t ic a
Croat. Chem. Acta 87 (2) (2014) 153-160.
1926^1 ^ HEMICA
http://dx.doi.org/10.5562/cca2476
Original ScientificArticle
Mechanochemical and Conformational Study of iV-heterocyclic
Carbonyl-Oxime Transformations
Ines Primožič,* Tomica Hrenar,* Krešimir Baumann, Lucija Krišto,
Ivana Križić, and Srđanka Tomić
Department ofChemistry, Faculty ofScience, University ofZagreb, Horvatovac 102a, HR-10000 Zagreb, Croatia
RECEIVED MAY 2, 2014; REVISED MAY 27,2014; ACCEPTED MAY 28,2014
Abstract. New mechanochemical pathways for the transformation of six A-heterocyclic carbonyl com-
pounds into oximes using hydroxylamine hydrochloride were explored. Reactions were performed first
without any base since the heterocyclic moieties (imidazole, benzimidazole, pyridine and quinuclidine)
have an intrinsic basic nitrogen atom. This green, solvent free method was suitable for all compounds (up
to quantitative yields) except for A-benzyl substituted imidazole and benzimidazole-2-carbaldehyde. For
the slower reacting aldehydes, reactions with liquid assisted grinding and addition of sodium hydroxide
were performed as well. Conformational analysis and quantum-chemical calculations revealed steric and
electronic reasons for the lower reactivity ofA-benzyl substituted derivatives.
Keywords: nitrogen heterocycles; oximes; mechanochemical synthesis; conformational analysis; DFT
gen-bond donors.15 As a result of their broad utilisa-
tion, there is a growing interest in finding convenient
synthetic approaches (e.g. solvent free reactions,
higher yields, shorter reaction times, etc.).
INTRODUCTION
Oximes are used as building blocks for the synthesis of
diverse biologically active compounds (e.g. some an-
timicrobial agents,1 insecticides,2 and vasodilators3).
Among the most important oxime drugs are com-
pounds that are used as antidotes of nerve agents.4
Nerve agent inactivates acetylcholinesterase molecules
by phosphorylation of amino acid serine in the active
site. Oximes can reactivate inhibited acetylcholi-
nesterase by a nucleophilic attack of the phosphorus
atom thus forming an oxime-phosphonate and the free
enzyme. The most effective antidotes for nerve-agent
poisoning are A-heterocyclic oximes based on a pyri-
dine skeleton such as pralidoxime (2-PAM), obi-
doxime, HI-6, and TMB-4, Fig. 1. Since oxime func-
tionalities share common electrostatic properties as the
ester linkage, oximes have been used successfully as
bioisosteres for the ester group in the muscarinic
ligands.5 7The oxime moiety is stable and represents a
suitable base for a variety of structural modifications
as well.
The classical method for the preparation of oxi-
mes includes the reaction of a carbonyl compound
with hydroxylamine hydrochloride in the presence of
an equimolar amount of base using solution-based
methods (refluxing alcoholic/aqueous solutions).16
Characteristics for these reactions are usually long
reaction time, elevated temperatures, and abundant use
of organic solvents, which makes them expensive and
environmentally harmful. Some advances have been
made in the greener synthesis of aldoximes from car-
bonyl compounds, for example, by use of calcium
oxide with elevated temperature and solvent free con-
ditions,17 microwave irradiated synthesis in presence
of basic A120 3 and pestle & mortar synthesis with
molecular sives,18 grinding of some aliphatic and aro-
matic ketones and aldehydes with the addition of so-
dium hydroxide without solvent19 and liquid assisted
grinding,20 grinding in conjunction with Bi20 3.21 Up to
now, only one study of solvent free mechanochemical
transformation of A-heterocyclic aldehydes (pyridine-
2-, 3- and 4-carbaldehydes) was conducted20 but no
investigations concerning the use of the A-heterocyclic
carbonyl compound as a substrate and base at the same
time has been reported so far.
Beside their use as intermediates in organic syn-
thesis,8"12 oximes are also of interest for protection,
purification and characterization of carbonyl com-
pounds.13They can be efficient ligands in coordination
chemistry for complexation of various metals,14and in
supramolecular chemistry since they are strong hydro-
* Authors to whom correspondence should be addressed. (E-mails: ines@chem.pmf.hr, hrenar@chem.pmf.hr)

154
I. Primožič et al, Mechanochemical Carbonyl-Oxime Transformations
C)
d)
Figure 1. Some antidotes for nerve-agent poisoning: a) 2-PAM, b) TMB-4, c) HI-6 and d) obidoxime.
In the course of our work in the design and syn-
thesis of new imidazolium, pyridinium and quinuclidin-
ium oximes as antidotes in organophosphorus poison-
ing,2" 26 we decided to explore possible mechanochemi-
cal paths in the search of a more efficient preparation of
desired compounds. In this work, six different
iV-heterocyclic oximes were synthesized from their
corresponding carbonyl derivatives, Fig. 2, in the pres-
ence of hydroxylamine hydrochloride under solvent free
conditions using ball milling. The aim was to find the
synthetic route that is green, thus a solvent-free method
giving products in good yields, at ambient conditions
and without any other additives. Transformations were
monitored by IR spectroscopy in order to obtain the
information about the reaction mixture composition
depending upon time without the interference of added
solvents necessary for other frequently used methods
such as NMR. Molecular modelling was used to ration-
alize the observed differences in reactivity of different
compounds by conformational analysis of reactants and
products.
were recorded on a Broker AV-300 or 600 Spectrometer
at 300 or 600 MHz, respectively. All NMR spectra were
measured in DMSO-d6 using tetramethylsilane as a
reference. IR spectra were recorded as thin films on
NaCl plates or KBr pellets on a Perkin-Elmer Spectrum
Two FT-IR and the signals reported in cm-1. All com-
pounds were identified by comparison of their physical
and spectral data with those reported in the literature.
Mechanochemical Synthesis of Oximes
A Retsch MM200 grinder mill operating at 25 Hz fre-
quency was used for the mechanochemical synthesis.
Ball mill experiments were performed in stainless steel
jar of 10 mL volume using one ball. Reactions were
monitored by TLC (DC-Alufolien Aluminiumoxide 60
F254 plates (Merck) with 9:1 chloroform-methanol as
the eluent) and no side products have been detected. FT-
IR spectra were recorded over the 4000^100 cm-1 range
without baseline corrections up to 30 minutes except for
compound 4a where the reaction was monitored during
90 minutes. In all reactions 100 mg of FTIR-grade KBr
was added. Procedure A: in a jar, 100 mg of the car-
bonyl compound and equimolar amount of hydroxyla-
mine hydrochloride were grounded together in a mill.
Procedure B: (liquid assisted grinding, LAG): 100 mg
of carbonyl compound, equimolar amount of hydroxyl-
amine hydrochloride in the presence of 30 pL of metha-
nol were grounded together in a mill. Procedure C: 100
mg of carbonyl compound, equimolar amount of hy-
droxylamine hydrochloride, equimolar amount of NaOH
in the presence of 30 pL of methanol were grounded
together in a mill.
EXPERIMENTAL
Reagents and solvents used for the synthesis were pur-
chased from Sigma-Aldrich, Co., and used without
further purification. Appropriate imidazole and
benzimidazole 2-carbaldehydes la—4a were prepared
from A-alkyl imidazoles and benzimidazoles in the
reaction with n-butyl lithium (n-BuLi) and DMF.27
Pyridine-3-carbaldehyde (5a) was commercially availa-
ble (Sigma-Aldrich, Co.), while the only ketone used,
quinuclidin-3-one (6a),28 was prepared from the com-
mercially available quinuclidin-3-one hydrochloride
(Fluka). The classical syntheses of A-heterocyclic
oximes lb-5b29’30 and 6b31 were carried out according
to the published procedures. 'H and 13C NMR spectra
Quantum-Chemical Calculation
Conformational search was performed by calculation of
relaxed potential energy surfaces (PES). PES for la and
3a were spanned by two torsional coordinates <p\ and tp2
Croat. Chem. Acta 87 (2014) 153.

I. Primožič et ah, Mechanochemical Carbonyl-Oxime Transformations
155
R i
X
O
NOH
1CH3
2 CH2CMs
3 CHj
a
b
4
CH2C6H5
Scheme 1. Mechanochemical conversion of carbonyl com-
pounds to oximes.
Figure 2. Structures of synthesized A'-heterocyclic carbonyl
compounds (la-6a) and oximes (lb-6b).
amine hydrochloride and sodium hydroxide were done
with a pestle and mortar. Reactions were performed for 9
minutes at room temperature and incomplete reaction was
obtained only for 2-carbaldehyde (65 %). However, no
investigations concerning the use of TV-heterocyclic car-
bonyl compounds as bases that can deprotonate hydro-
xylamine hydrochloride have been reported up to now.
Therefore, we synthesized four TV-heterocyclic aldehydes:
TV-methyl (la) and TV-benzylimidazole-2-carbaldehyde
(2a); TV-methyl (3a) and TV-benzylbenzimidazole-2-
carbaldehyde (4a). Pyridine-3-carbaldehyde (5a) was
commercially available, as well as quinuclidin-3-one
hydrochloride from which quinuclidin-3-one (6a) was
prepared. Those carbonyl compounds were selected be-
cause they all possess a heterocyclic moiety with a basic
nitrogen atom ranging from the most basic quinuclidine40
ring (pA'a= 11.3) to imidazole (pATa=6.95), benzimidazole
(pA"a= 5.53) and pyridine ring (pA'a= 5.25).41 Although
in the relative range of 0-360° from the initial structure
(Fig. 4) whereas PES for 2a and 4a were spanned by
three torsional coordinates <pu tp2 and <p3 (Fig. 5). PES
scans were obtained by varying the torsional coordi-
nates using the automatic conformational generator
implemented in program qcc'52 and optimizing geome-
tries in all geometrical parameters apart from the frozen
torsional angles. Data from relaxed scans were arranged
in a two-way or a three-way array. Parallelized combi-
natorial optimization algorithm for the arbitrary number
of ways (dimensions) implemented in program
moonee33 was used to determine all local minimums on
the investigated PES. All local minimums were
reoptimized at the B3LYP/6-311++G(d,p) level. To
insure that the obtained geometries were local mini-
mums, harmonic frequency calculations were per-
formed. Natural bond orbital analysis (NBO)34 was
carried out on the optimized structures of conformers.
All electronic structure calculations were performed
using the Gaussian 09 program.35 Spectra figures and
PES were plotted using the Gnuplot graphing utility.36
Potential energy on 4-dimensional plots is represented
with the colour gradient ranging from blue to white to
red and simultaneously with the different sizes of
spheres.
Table 1. Mechanochemical synthesis: time required to quanti-
tatively convert carbonyl compounds into oximes. Procedure
A: carbonyl compound and equimolar amount of hydroxyla-
mine hydrochloride; Procedure B: LAG of carbonyl com-
pound with equimolar amount of hydroxylamine hydrochlo-
ride (30 pL of methanol); Procedure C: LAG of carbonyl
compound, equimolar amount of hydroxylamine hydrochlo-
ride and equimolar amount ofNaOH (30 pL of methanol).
Carbonyl
Procedure A
Procedure B Procedure C
compound
t / min
11min
/ / min
RESULTS AND DISCUSSION
la
2a
3a
4a
5a
6a
-
1
1
It is known that mechanochemistry is a useful tool for the
efficient synthesis of a variety of imines: the reactions
can be performed in a single step with quantitative yields
by gas-solid, liquid-solid or solid-solid reactions.37-39
Regarding the oxime synthesis, one study of solvent free
mechanochemical transformations of pyridine-2-, 3- and
4-carbaldehydes into oximes was recently conducted20
were solvent-drop grinding in the presence of hydroxyl-
>30(a)
5
6
5
20
-
>90(b)
>90(b)
5
>90(b)
-
30
>30(a)
10
-
<a)incomplete reaction
(b)no product was detected
Croat. Chem. Acta 87 (2014) 153.

156
I. Primožič et al., Mechanochemical Carbonyl-Oxime Transformations
Figure 3. IR spectra of aldehydes (blue) and reaction mixtures (red) after ball milling according to the Procedure A: a) reaction of
la (after 1minute); b) reaction of 2a (after 30 minutes); c) reaction of 3a (after 5 minutes); d) reaction of 4a (after 90 minutes); e)
reaction of 5a (after 30 minutes); f) reaction of 6a (after 30 minutes).
A'-benzyl and carbonyl substituents at the heterocyclic
moiety are lowering the pKa values (e.g.
A'-benzylimidazole42 has pA'a=6.70, pyridine-3-
The ball milling of carbonyl compounds la-6a
was done at room temperature in the stoichiometric ratio
of 1:1 with hydroxylamine hydrochloride without addi-
tion of any solvent or a base and the reactions were
monitored up to 30 minutes (90 minutes for the reaction
of 4a), Table 1, Procedure A. Oximes lb, 3b and 5b
were obtained in quantitative yields, while in the reac-
tion of ketone 6a, a small amount of protonated reactant
remained, Fig. 3f. The fastest reaction was that of
A'-methy1imidazole aldehyde la (1 minute) and the
slowest was that of A'-benzylimidazole derivative 2a,
while no trace of product was detectable in the reaction
carbaldehyde pATa=3.80 (Ref. 41) and quinuclidin-3-
one40pATa=7.20), a series of carbonyl compounds with a
significant differences in basicity were tested. From
all six carbonyl derivatives respective oximes lb-6b
were synthesized using classical solution-based methods
with hydroxylamine as described in literature in order
to prepare standards for the analysis. Next, mechano-
chemical synthesis using grinder mill was studied,
Scheme 1.
Croat. Chem. Acta 87 (2014) 153.

157
I. Primožič et al., Mechanochemical Carbonyl-Oxime Transformations
a)
EJEh
0.014
0.012
0.010
0.008
0.006
0.004
0.002
0.000
0.014
0.012
0.010
EJE„
0.030
0.008
0.006
0.004
0.002
0.000
0.025
0.020
0.015
0.010
0.005
0.000
0
Figure 4. Conformational space of a) la and b) 3a spanned by two torsional coordinates and calculated using PM6 semiempirical
method. (Potential energy is relative to the global minimum and represented with the color gradient. Ehis atomic unit of energy.)
Figure 5. Conformational space of a) 2a and b) 4a spanned by three torsional coordinates and calculated using PM6
semiempirical method. (Potential energy is relative to the global minimum and represented with the color gradient and different
sizes of spheres. Ehis atomic unit of energy.)
was not the reason for the poor reactivity of that com-
pound as compared to the structurally similar aldehydes
2a (bulky V-benzyl substituent) and 3a (benzimidazole
moiety).
of A'-benzylbenzimidazole 4a. Since a very small
amount (a drop) of liquid can significantly accelerate
mechanochemical reactions (‘liquid assisted grinding’,
LAG)43,44 in a set of new experiments 30 pL of metha-
nol was added in all reaction mixtures, Table 1, Proce-
dure B. As expected, addition of a small quantity of
solvent to the reaction mixture significantly enhanced
the rate of the mechanochemical synthesis and quantita-
tively provided oximes 2b, 5b and 6b in less than 10
minutes. However, the mechanochemical synthesis of
oxime 4b was not successful using LAG method even
when sodium hydroxide was added as a base in equimo-
lar amounts, Table 1, Procedure C. That indicated that
the low basicity of the heterocyclic nitrogen atom of 4a
In order to obtain information about the reaction
mixture composition, reactions were monitored by FT-
IR spectroscopy, Fig. 3. By the use of this method, the
mixture was taken directly from the reaction jar, KBr
pellet made and spectrum recorded without the use of
solvent. Prior to the measurements, the IR spectra of the
reaction components and the product were studied. The
IR spectra were predicted by B3LYP/6-311++G(d,p)
quantum chemical calculations as well. Vibrational
frequencies calculated were scaled and compared with
Croat. Chem. Acta 87 (2014) 153.

158
I. Primožič et al., Mechanochemical Carbonyl-Oxime Transformations
Table 2. Calculated standard Gibbs energies of formation for
conformers of la and 3a (B3LYP/6 311++G(d,p), relative to
conformer 1)
Table 3. Calculated standard Gibbs energies of formation for
conformers of 2a and 4a (B3LYP/6 311++G(d,p), relative to
conformer 1)
Conformer
ArG®(la) / kJ mol-1
ArG6(3a) / kJ mol”1
Conformer
ArGe(2a) / kJ mol”1
ArGe(4a) / kJ mol”1
1
2
0.0
0.0
1
2
3
0.0
23.4
-
0.0
3.1
28.0
26.0
25.5
the experimental values. It was shown that the range of
1800-600 cm"1was the most suitable for monitoring the
oximation because all spectra had wide signals between
2700 and 3500 cm”1. That signals originate from N-H
and O-H stretching vibrations in oximes and deliberated
water molecules suggesting that N -H and O-H groups
are in strong intramolecular and intermolecular hydro-
gen bonding. IR spectra of all six compounds showed
week bands corresponding to the C=N stretching vibra-
tion which were in all cases overlapped with the vibra-
tional frequencies of the carbonyl compounds, thus, the
complete disappearance of the carbonyl O O peak in
spectrum was monitored. The spectra of all compounds
la-6a showed strong wide bands corresponding to the
carboxylic C =0 stretching at 1685, 1688, 1696, 1689,
1706 and 1735 cm”1, respectively, Fig. 3.
w-way space using the combinatorial algorithm. E.g., for
a given point on a 2-way PES (Fig. 4) with indices
( i , j ) , energy value was compared to the surrounding
points defined with indices (i + u , j + v ) with
u,v e {-1,0,1}. Extension to the higher dimensions is
straightforward.
Conformers found at the semiempirical level were
subsequently
optimized
using
DFT
(B3LYP/
6-311++G(d,p)) method. To ensure that optimized struc-
tures were local minimums, harmonic frequency calcu-
lations were performed. Conformational space of la and
3a is consisted of two conformers different in the orien-
tation of the conjugated aldehyde group. Conformers of
la and 3a where the aldehyde oxygen atom is not point-
ing to the TV-methyl group were significantly higher in
energy (Fig. 4 and Table 2). According to the Boltz-
mann distribution, probability of finding these conform-
ers is very low and thus could be excluded from further
analysis. In the conformers that represent global mini-
mums on the PES (carbonyl oxygen pointing toward the
A-methyl group) lower energy is derived from the pres-
ence of the hydrogen bond (=0 -H 2.38 A). Since the
geometry of nucleophilic attack at the carbon atom in
carbonyl sroup should be ideal Biirgi-Dunitz angle
(-107°), it is evident that there is no steric hindrance
of the jV-methyl group. Moreover, NBO analysis
showed that natural atomic orbital occupancies for the
carbon atoms of carbonyl groups in la and 3a are simi-
lar thus giving the similar reaction rates (Table 1).
To explain the differences in reactivity of
IV-methyl and A-benzyl substituted imidazole and
benzimidazole derivatives, conformational and NBO
analysis for aldehydes la 4a were done. Initial geome-
tries for the conformational analysis were obtained by
analysis of PES scans calculated at the semiempirical
level (PM6). PES for A'-methyl la and 3a, as well as for
A'-benzyl derivatives 2a and 4a were spanned in the
space of two and three torsional coordinates, respective-
ly (Figs. 4 and 5). Optimization procedure for finding
local minimums was utilizing brute-force search in
Conformational space of TV-benzyl derivatives is
consisted of two conformers in the case of 2a and three
conformers in the case of 4a (Fig. 5). The second con-
former of 2a and the third conformer of 4a, where the
aldehyde oxygen atom is at the same side as the non-
substituted nitrogen atom of imidazole ring, were again
significantly higher in the energy (Fig. 5 and Table 3).
Furthermore, in this conformer one side of the carbonyl
group is completely blocked with a bulky benzyl group
and the reaction with nucleophile is not possible at all.
In each of the remaining conformers (conformer 1
for 2a and conformers 1 and 2 for 4a) carbonyl oxygen
is pointing toward the A-methylene group ( = 0 - H 2.32
A in 2a; 2.24 and 2.44 A in 4a) and has a contact with
the ortho hydrogen atom of the phenyl ring (Fig. 6).
Although, the flexible iV-benzyl group have less nega-
Figure 6. Overlay of conformers for aldehydes 2a (conformer
1: red) and 4a (conformer 1: blue, conformer 2: yellow). (Dis-
tances are given in angstroms.)
Croat. Chem. Acta 87 (2014) 153.

I. Primožič et al., Mechanochemical Carbonyl-Oxime Transformations
159
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CONCLUSION
Mechanochemistry proved to be an excellent alternative
for the transformations of iV-heterocyclic carbonyl com-
pounds into oximes using hydroxylamine hydrochloride.
There is no need for use of an additional base and only
catalytic amount of solvent is sufficient to enhance the
reaction, which makes this route environmentally
friendly, and a better and greener alternative to the ex-
isting methods for iV-heterocyclic oxime synthesis. It
was not possible to prepare aldoxyme of 7V-benzyl sub-
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tron withdrawing group. With the addition of an exter-
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cyclic nitrogen atom is not responsible for the lowest
reactivity. Conformational analysis pointed at the steric
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