Synthesis and aminolysis of 2,4-dinitrophenyl and 5-nitropyridine N-hydroxy oxime derivatives

Article abstract of DOI:10.1246/bcsj.20110015

The 2,4-dinitrophenoxy derivatives 12-16 and the 5-nitro-2-pyridyloxy derivatives 18-22 were prepared. The products were identified by elemental analysis, IR, and NMR. The reaction of 12-16 and 18-22 with morpholine as nucleophile in CH₃CN occu

Full text of DOI:10.1246/bcsj.20110015

© 2011 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 84, No. 6, 633–639 (2011)
633
Synthesis and Aminolysis of 2,4-Dinitrophenyl and
5-Nitropyridine N-Hydroxy Oxime Derivatives
Sherine N. Khattab,1 Ezzat Awad Hamed,1 Fernando Albericio,*2,3,4 and Ayman El-Faham*1,2
1Department of Chemistry, Faculty of Science, Alexandria University, Ibrahimia 21321, P. O. Box 426, Alexandria, Egypt
2Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028, Barcelona, Spain
3CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park,
Baldiri Reixac 10, 08028, Barcelona, Spain
4Department of Organic Chemistry, University of Barcelona, Martí i Franqués 1-11, 08028, Barcelona, Spain
Received January 17, 2011; E-mail: Aymanel_faham@hotmail.com
The 2,4-dinitrophenoxy derivatives 12-16 and the 5-nitro-2-pyridyloxy derivatives 18-22 were prepared. The
products were identified by elemental analysis, IR, and NMR. The reaction of 12-16 and 18-22 with morpholine as
nucleophile in CH3CN occurs through nucleophilic aromatic substitutions to give N-(2,4-dinitrophenyl)morpholine (23)
and N-(5-nitro-2-pyridyl)morpholine (24) respectively. Spectrophotometric measurements of the kinetics of these
reactions in CH3CN at a range of temperatures indicated that they are not morpholine-catalyzed. The Brønsted-type plots
for the reactions of 12-16 and 18-22 with morpholine are linear with slopes, ¢12-16 = ¹1.58 « 0.1 and ¢18-22
=
¹1.15 « 0.25 respectively. The relative rate constants compared to the least reactive substrate, as well as the low negative
¢ values, supported that the decomposition of the zwitterionic intermediate is a slow process. The low activation
¹
parameters (¦H# and ¦S#) are in accordance with the proposed transition state (T#). The expulsion of RO anion in the
rate-determining step is assisted by intramolecular hydrogen-bonding with the ammonio-hydrogen present in the
intermediate T#.
Amide bond formation is the main goal in the synthesis of a
huge array of organic compounds of biological interest1-5 such
as peptides, peptoids, oligocarbamates, oligoamides, ¢-lac-
tams, polyenamides, benzodiazepines, diketopiperazines, and
hydantoins. The ester group is another crucial functionality and
can be prepared from a carboxylic acid and a corresponding
alcohol using peptide coupling reagents.
N C N
N C N
DCC, 1
DIC, 2
N
N
N
The coupling technique can be performed in solution or solid
phase by in situ activation of the carboxylic acid. The method
used should be efficient and reliable, especially when long
sequences of amino acids are built up in solid-phase peptide
synthesis.6,7 The maintenance of configuration, especially in
amino acids, is also important. Thus the main challenge in the
development of coupling reagents is to achieve a combination
of high yield and optical purity.
Y
X
OH
Y = H, X = CH; HOBt, 3
Y = H, X = N; HOAt, 4
Y = Cl, X = CH; 6-Cl-HOBt, 5
Figure 1. Coupling additives.
Carbodiimides such as DCC 1 and DIC 2, which have been
used previously as coupling reagents, gained their importance
as useful reagents when used in the presence of several
additives with an X-OH structure.8
As a result of the explosive properties of HOBt derivatives,12
they have been reclassified as class 1 explosives, thus
increasing difficulties for their transportation.
The use of these kinds of additives to fine-tune coupling
reagents is common during peptide bond formation (Figure 1).
Thus, the addition 1-hydroxybenzotriazole (HOBt, 3) mini-
mizes the loss of configuration during coupling.8 Later,
1-hydroxy-7-azabenzotriazole (HOAt, 4) was described as a
more favorable coupling additive for both solution9 and solid-
phase synthesis.10 Recently, 6-Cl-HOBt (5) has been introduced
into solid-phase synthesis. This additive is a good compromise
between HOAt and HOBt in terms of reactivity and price.11
In our search for safe and efficient additives, we came across
a family of acidic oximes reported earlier by Itoh.13 Some of
the N-hydroxyamine derivatives, such as diethyl (hydroxyimi-
no)malonate (6), ethyl cyano(hydroxyimino)acetate (oxyma, 7),
(hydroxyimino)malononitrile (8), (hydroxyimino)-2-pyridyl-
acetonitrile (9), and 1-hydroxypyridin-2(1H)-one (10)
(Figure 2), reported as alcoholic components of active esters
perform well as leaving groups.13 Thus, it was expected that
strongly acidic and nucleophilic oximes, which include
Published on the web June 4, 2011; doi:10.1246/bcsj.20110015

634
Bull. Chem. Soc. Jpn. Vol. 84, No. 6 (2011)
Synthesis and Aminolysis of Oxime Derivatives
Me
N
Me
PF6
CN
COOC2H5
NC
COOC2H5
N
N
N
O
O
O
N
C
C
PF6
N
O
N
O
P
N
O
O
O
3
O
N
OH
N
PyOXm
N
OH
COMU
OH
6
8
7
NC
NC
COOEt
COOEt
O
S
O
S
O N
O N
NC
N
N
OH
O
O
O
N
H3C
OH
10
9
NpsOXY
TsOXY
Figure 2. N-Hydroxyamine derivatives.
Figure 3. Uronium-, phosphonium-, and sulfonate-type
coupling reagents derived from oxyma.
R
X
Cl
O
R-OH / TEA/CH2Cl2
or R-OK / CH3CN
X
NO2
NO2
X = C-NO2, 11
X = N, 17
12-22
O
O
O
NC
N
N
R- =
N
N
N
C
C
O
O
O
O
N
N
N
N
X = C-NO2, 12
X = N, 18
X = C-NO2, 13
X = N, 19
X = C-NO2, 15
X = N, 21
X = C-NO2, 14
X = N, 20
X = C-NO2, 16
X = N, 22
Scheme 1. Synthesis of 2,4-dinitrophenyl and 5-nitropyridine oxime derivatives.
electron-withdrawing groups in the molecule, would be
suitable as additives.
2,4-dinitrophenoxy and 5-nitro-2-pyridyloxy derivatives were
used as reactive spieces to compare their effect on the leaving
ability of different leaving groups (oximino derivatives),
recently used for preparation of different coupling re-
agents.14-16
Ethyl cyano(hydroxyimino)acetate (oxyma, 7), one of the
oximes studied, has been tested by our research group as an
additive for use in the carbodiimide and TFFH approaches
for the formation of peptide bonds. Oxyma 7 displayed a
remarkable capacity to inhibit racemization, together with
impressive coupling efficiency in both automated and manual
synthesis, superior to the performance of HOBt and HOAt.14 In
addition, calorimetry assays (DSC and ARC) indicated a lower
risk of explosion for oxyma 7.14
Results and Discussion
The 2,4-dinitrophenoxy derivatives 12, 14 and the 5-nitro-
2-pyridyloxy derivatives 18, 20 were prepared via the reaction
of 1-chloro-2,4-dinitrobenzene or 2-chloro-5-nitropyridine with
the potassium salt of 6 or 8 in anhydrous ACN (Scheme 1).
The 2,4-dinitrophenoxy derivatives 15, 16 and the 5-nitro-
pyridin-2-yloxy derivatives 21, 22 were prepared via the
reaction of 1-chloro-2,4-dinitrobenzene or 2-chloro-5-nitropyr-
idine with 9 or 10 in the presence of Et3N in anhydrous CH2Cl2
(Scheme 1). In contrast, the 2,4-dinitrophenoxy derivative 13
and the 5-nitropyridin-2-yloxy derivative 19 were prepared via
the reaction of 1-chloro-2,4-dinitrobenzene or 2-chloro-5-
nitropyridine with 7 in the presence of NaOH in anhydrous
ACN (Scheme 1). The structures of compounds 12-16 and 18-
22 were confirmed by IR, 1H NMR, 13C NMR spectroscopy and
elemental analysis.
Thus, a third generation of uronium-14b,14c and phospho-
nium-type15 coupling reagents derived from oxyma
7
(Figure 3) were also studied. In addition, a new family of
sulfonate ester coupling reagents derived from 7 (Figure 3) has
been reported.16
As a continuation of our work in the field of nucleophilic
aryl and acyl reactions,17-19 we addressed kinetic studies of the
leaving group ability of oximes 6-10 (Figure 2). For this
purpose, we used the nucleophilic aromatic substitution of
2,4-dinitrophenoxy and 5-nitro-2-pyridyloxy derivatives by
morpholine in acetonitrile (ACN) involving the departure of
various leaving groups as models. Morpholine was selected as
nucleophile because it posses a comparable pKa value to those
reported for many amino acids. To extend our previous work,19
The reactions of 12-16 and 18-22 with morpholine gave
N-(2,4-dinitrophenyl)morpholine (23) and N-(5-nitro-2-pyri-
dyl)morpholine (24) respectively (Figure 4). The rate of the

S. N. Khattab et al.
Bull. Chem. Soc. Jpn. Vol. 84, No. 6 (2011)
635
reactions of these compounds in ACN were followed spec-
trophotometrically, with maximum absorption of the products
23 and 24 at - = 375 and 370 nm respectively. The UV
absorption of the starting materials and the products did not
overlap.
at four temperatures from 30 to 45 °C and activation parameters
(¦H# and ¦S#) calculated from the Arrhenius equation for the
reactions of 12-16 and 18-22 with morpholine.
To obtain information on the reaction mechanism, we
dissected the apparent second-order rate constants for the
reactions of 12-16 and 18-22 with morpholine on the
assumption that the reactions proceed through initial nucleo-
philic attack to form the zwitterionic intermediate (I), which
undergoes deprotonation to form a Meisenheimer intermediate
(II). The formation of substitution products 23 or 24 is
achieved from the expulsion of the alkoxy group from the
Meisenheimer intermediate (II) (catalyzed pathway, where the
proton transfer is rate limiting and the reaction is second order
in morpholine) or directly from the zwitterionic intermediate (I)
(uncatalyzed pathway, where it is first order in morpholine),
Scheme 2.
The rate of the reactions of 12-16 and 18-22 with
morpholine in ACN may depend on the following: (i) the
electron-withdrawing power of the substituent in the substrate;
(ii) the stabilization of the formed intermediate by intra- or
intermolecular hydrogen bonding; and (iii) the basicity of the
leaving group anion. Also, the rate constants for the morpho-
lino-dealkoxylation can be obtained by applying first-order
conditions. The optical densities of solutions measured after the
completion of the reactions were consistent with the authentic
sample of the corresponding products with the same concen-
tration. Pseudo-first-order rate constants (k /s¹1) were deter-
²
mined from eq 1.
Many aromatic substitutions of activated or moderately
activated aryl ethers or aryl thioethers by amine nucleophiles
are subjected to catalysis.20-23 The base-catalyzed pathway
involves either rate-limiting proton transfer from the zwitter-
ionic intermediate to base for substrates carrying good leaving
groups24-29 (Scheme 2), or general acid catalysis by conjugate
acid for substrates with poor leaving groups.26,27 The uncata-
lyzed pathway either proceeds by initial attack of morpholine
on substrates 12-16 and 18-22 in a slow step followed by rapid
expulsion of the leaving group or by fast attack on these
substrates to form the zwitterionic intermediate I followed by a
slow expulsion of the leaving group (Scheme 2).
In order to predict the reaction mechanism, the first-order
dependence on morpholine concentration is compatible with a
rate limiting nucleophilic attack and also with an intermediate
decomposition without base catalysis. One of the methods to
determine the rate determining step of the reaction is by
changing the nature of the leaving group i.e., “element-effect
like” as well as the significance of coefficient ¢ values of
Brønsted plots.
lnðA1 ꢀ AtÞ ¼ ꢀkꢀt þ C
In general, the correlation coefficients for the linear
ð1Þ
regressions were almost 0.99. The plots of k vs. morpholine
²
concentrations were linear and passed through the origin, thus
indicating that catalysis by morpholine is absent and the
reactions are first order with respect to each reactant. The
apparent second-order rate constants (kA/L mol¹1 s¹1) were
determined from the slope of the linear plots of k vs.
²
morpholine concentrations. The uncertainty in the rate con-
stants was estimated to be less than 3% from replicate runs.
Table 1 provides the apparent rate constant kA values calculated
O
N
O
N
NO2
N
Based on the reactions of 12-16 and 18-22 with morpholine,
similar to several nucleophilic aromatic substitution reac-
tions,24,30,31 which are not morpholine-catalyzed, the kinetic
eq 2 is derived with reference to the uncatalyzed mechanism in
Scheme 2 on the basis of the steady state assumption.
NO2
NO2
23
24
Figure 4. N-(2,4-Dinitrophenyl)morpholine
N-(5-nitro-2-pyridyl)morpholine (24).
(23)
and
kꢀ ¼ k1k2½Moꢁ=ðkꢀ1 þ k2Þ
ð2Þ
Table 1. Specific Rate Constantsa) and Activation Parameters for the Reactions of 12-16 and 18-22 with Morpholine in ACN
¹1
k2 © 103/L mol¹1 s
¦H#
/kcal mol
¹¦S#
/e.u.
Compd
¹1
30 °C
35 °C
40 °C
45 °C
12
13
14
15
16
18
19
20
21
22
11.01 « 0.18
1050.89 « 19.08
2509.33 « 13.77
66.08 « 0.22
129.71 « 0.27
2.02 « 0.01
29.57 « 0.67
138.24 « 0.56
3.72 « 0.01
12.96 « 0.14
1222.96 « 20.46
2976.53 « 30.37
73.07 « 0.42
145.47 « 3.42
2.37 « 0.05
35.46 « 0.79
162.92 « 1.13
4.50 « 0.04
14.35 « 0.07
1378.57 « 20.38
3261.45 « 45.82
83.52 « 0.5
162.33 « 2.98
2.83 « 0.01
40.60 « 0.41
190.74 « 0.84
5.15 « 0.05
16.42 « 0.20
1521.83 « 11.06
3572.51 « 20.22
97.22 « 1.5
188.35 « 1.82
3.32 « 0.02
48.44 « 0.28
223.87 « 1.92
6.15 « 0.05
4.37 « 0.28
4.10 « 0.28
3.80 « 0.48
4.32 « 0.36
4.08 « 0.28
5.76 « 0.11
5.58 « 0.24
5.53 « 0.04
5.674 « 0.26
5.669 « 0.40
53.03 « 3.01
44.87 « 2.60
44.14 « 4.79
49.72 « 3.62
49.14 « 2.93
51.86 « 0.94
47.09 « 1.81
44.20 « 0.19
50.87 « 2.06
48.82 « 3.07
10.60 « 0.20
12.98 « 0.15
14.65 « 0.13
17.59 « 0.24
a) k2 = kobs/[morpholine]. Rate constants were calculated by the least-squares method and the correlation coefficient was 0.99 in
most cases.

636
Bull. Chem. Soc. Jpn. Vol. 84, No. 6 (2011)
Synthesis and Aminolysis of Oxime Derivatives
O
RO
N
X
O
O
OR
RO
N
X
NH
X
NO2
k1
X
HN
O
Meisenheimer
intermediate II
+
k-1
NO2
NO2
NO2
k2
Zwitterionic
intermediate I
12-16, X= C-NO2
18-22, X= N
uncatalyzed
23, X= C-NO2
24, X= N
Scheme 2. Reaction mechanism of oxime derivatives with morpholine.
The kinetic results showed a measurable difference in rates
with changing in the nature of the leaving groups, Table 1. It
shows that kA values are greatly enhanced for the leaving group
containing two cyano groups and the least reactive is that
containing two ethoxycarbonyl groups. The ratios of 14/12,
13/12, 16/12, and 15/12 are 227, 95, 11, and 6 respectively for
the reactions of 12-16 with morpholine while they are 68, 14,
5, and 1.8 for the reactions of 18-22. These ratios indicate that
the order of rate enhancement is 14 > 13 > 16 > 15 > 12 and
20 > 19 > 22 > 21 > 18 for the reactions of 11 and 17 with
morpholine respectively. This order is in harmony with the pKa
values of the free leaving groups.32 These results, in addition to
the observation that our reaction is not catalyzed by morpho-
line, suggest that the departure of the leaving group in reactions
of 12-16 and 18-22 with morpholine in ACN at all temper-
atures is the rate-determining step, unlike most nucleophilic
aromatic substitution reactions.24,30,31
pKa
Figure 5. Brønsted like plot for the reaction of the oxime
derivatives 12-16 with morpholine at 30, 35, 40, and 45 °C.
Therefore
and
k
ꢂ k2
ꢀ1
kꢀ ¼ k1k2½Moꢁ=k ¼ K1k2½Moꢁ
ꢀ1
where
K1 ¼ k1=k
ꢀ1
The formation of kA yields
ð3Þ
pKa
kA ¼ kꢀ=½Moꢁ ¼ K1k2
The eq 3 resembles a bimolecular reaction with a corre-
Figure 6. Brønsted like plot for the reaction of the oxime
derivatives 18-22 with morpholine at 30, 35, 40, and 45 °C.
sponding pseudo-first-order rate constant k /[Mo] where
²
¹ = k2[S][Mo] and ¹ is the rate of the reaction, while [S]
and [Mo] are the concentrations of the substrates and morpho-
line respectively.
bond formation in the transition state, which leads to the
formation of the zwitterionic intermediate in a slow process,18a
while the negative value of ¢ reflects the bond dissociation
in the transition state, i.e., where the decomposition of the
intermediate I is a slow process, as in our reaction. This notion
is consistent with the fact that the absolute value of ¢ indicates
the degree of formation or bond cleavage in the rate-determin-
ing step.
The Brønsted type plots for the reactions of 12-16 and 18-
22 with morpholine are linear with slopes
¢
=
12-16
¹1.58 « 0.1 (Figure 5) and ¢18-22 = ¹1.15 « 0.25 (Figure 6)
respectively. However, the ¢ values obtained from the
nucleophilic aromatic substitution reactions gave positive
values ranged between 1.08-0.45, with different nucleophi-
les.18a,33-36 Accordingly, the lower values of ¢ in our case are
presumably due to the change in position of the rate-
determining step and are consistent with the slow departure
of the leaving groups. These observations lead us to hypothe-
size that the positive value of ¢ is due to the association of the
The low activation enthalpies ¦H# and the highly negative
activation entropies ¦S#, Table 1, are in accordance with the
proposed transition states (T#a-c, Figure 7). They involve a
possible intramolecular hydrogen bonding between the am-
monium hydrogen atom and the etheric linkage (T# ), the aza
a

S. N. Khattab et al.
Bull. Chem. Soc. Jpn. Vol. 84, No. 6 (2011)
Conclusion
637
O
H
O
O
O
H
δ
δ
R
δ
δ
O
N
O
N
The aminolysis of O-(2,4-dinitrophenyl) derivatives 12-16
and O-(5-nitro-2-pyridyl) derivatives 18-22 of the oximes is
not catalyzed by morpholine. Unlike most nucleophilic
aromatic substitution reactions, the departure of the leaving
group in reactions of 12-16 and 18-22 with morpholine in
ACN at all the temperatures tested is the rate-determining step.
The neighboring group effect is not relevant in these systems.
This observation thus gives a clear picture of the reactivity
of the different additives in peptide synthesis in terms of
racemization and leaving ability. The proposed mechanism is
supported by the low negative value of ¢, which reflects the
bond dissociation in the transition state, i.e., when decom-
position of the intermediate I is slow. The low activation
parameters are in accordance with the proposed transition states
N
δ
R
H
O
N
X
δ
N
O
R
δ
δ
NO2
NO2
NO2
X= N or C-NO2
T#
T#
T#
a
b
c
Figure 7.
R
O
R
R
O
O
N
O
NO2
NO2
¹
(T#a-c). The expulsion of RO anion in the rate-determining
O
step is assisted by intramolecular hydrogen-bonding with the
ammonio hydrogen present in the intermediate T#
.
a,b
NO2
NO2
N
O
O
Experimental
12-16
Materials. The solvents used for kinetic runs were of
reagent grade (BDH), and further purifications were performed.
Acetonitrile (ACN) was used after distillation from anhydrous
K2CO3. Morpholine (99%) was used after distillation. Melting
points were determined with a Mel-Temp apparatus and
are uncorrected. Magnetic resonance spectra (1H NMR and
13C NMR spectra) were recorded on a JEOL 500 MHz or on a
Mercury 400 MHz spectrometer with chemical shift values
reported in ¤ units (part per million) relative to an internal
standard. Infrared (IR) data were obtained on a Perkin-Elmer
1600 series Fourier transform instrument as KBr pellets.
Ultraviolet (UV) data were recorded on a SHIMADZU (UV-
160A) UV-visible recording spectrophotometer. Elemental
analyses were performed on Perkin-Elmer 2400 elemental
analyzer, and the values measured were within «0.3% of the
theoretical values. Follow up of the reactions and checking the
purity of the compounds were made by TLC on silica gel-
protected aluminium sheets (Type 60 GF254, Merck) and the
spots were detected by exposure to UV-lamp at - 254 nm for a
few seconds. The compounds were named using Chem. Draw
Ultra version 10, Cambridge soft Corporation.
General Procedure for the Preparation of 15, 16, 21,
and 22. (Hydroxyimino)-2-pyridylacetonitrile (1 mmol) or
1-hydroxypyridin-2(1H)-one (1 mmol) was dissolved in 3 mL
anhydrous methylene chloride, TEA (2 mmol) was added, then
1 mmol of 1-chloro-2,4-dinitrobenzene or 2-chloro-5-nitropyr-
idine was added to the reaction mixture. The reaction mixture
was stirred overnight at room temperature and then filtered and
washed with water. The crude product was recrystallized from
ethanol.
R
R
N
O
O
N
N
NO2
O
O
18-22
Figure 8.
group (T# ) in compounds 18-22 whereas compounds 12-16
exhibit T# (hydrogen bond to the o-nitro group).17c Such
hydrogen bonding facilitates the attack of the morpholine to
form zwitterionic intermediate I rather than its decomposition.
Actually, the energy of formation of the N-H£O bond is
µ2000 cal and that of N-H£N is µ1930 cal.17c The expulsion
b
c
¹
of RO anion in the rate-determining step is assisted by the
intramolecular hydrogen-bonding with the ammonio hydrogen
present in T# , which accordingly will lower the ¦H# value,
a
whereas the structured and rigid T# reflects the observed large
negative ¦S# value.
For compounds 12-16 and 18-22, the bulk of the
2-substituent as well as its activating effect clearly have to be
considered. The effect of changing the nature of the ring
substituents on the rate constants kA is given in Table 1. The
results show that the activating effects of the ortho substituents
is in the order NO2 > ring aza. The effect of ring activation
may be due to the ground state stabilization18a (Figure 8), the
thermodynamic stabilities of the zwitterionic intermediate I or
(2,4-Dinitrophenoxyimino)-2-pyridylacetonitrile
(15):
This compound was obtained as white crystals, 0.26 g
the transition states T#
leading to the products. This is
(83.07%) yield, mp 210-211 °C; IR (KBr): 2367 (CN), 1604
a-c
¹1
because of the negligible steric effect of the 2-NO2 and the aza
ring.18d Since the rate constants depend on the pKa of the
(C=N), 1535 and 1345 (NO2) cm ;
1H NMR (CDCl3, 400
MHz): ¤ 7.56 (dt, 1H, Py-H-5, J = 6.4, 0.8 Hz), 7.91 (dt, 1H,
Py-H-4, J = 7.6, 1.6 Hz), 7.97 (d, 1H, Ar-H, J = 9.2 Hz), 8.06
(d, 1H, Py-H-3, J = 7.6 Hz), 8.54 (dd, 1H, Ar-H, J = 9.2,
2.8 Hz), 8.85 (d, 1H, Py-H-6, J = 4.4 Hz), 8.95 (d, 1H, Ar-H,
leaving group, the transition state T# has greater thermody-
c
namic stability than that of T# . This reflects the higher
b
reactivity of compounds 12-16 than 18-22.

638
Bull. Chem. Soc. Jpn. Vol. 84, No. 6 (2011)
Synthesis and Aminolysis of Oxime Derivatives
J = 2.4 Hz). 13C NMR (CDCl3, 100 MHz): ¤ 118.34, 122.33,
122.43, 127.22, 129.39, 137.61, 146.79, 146.84, 146.88,
151.00. Elemental analysis Calcd for C13H7N5O5: C, 49.85;
H, 2.25; N, 22.36%. Found: C, 50.12; H, 2.43; N, 22.55%.
122.30, 129.62, 142.84, 150.29, 155.42, 158.30, 158.89.
Elemental analysis Calcd for C13H13N3O9: C, 43.95; H, 3.69;
N, 11.83%. Found: C, 44.22; H, 3.91; N, 11.58%.
(2,4-Dinitrophenoxyimino)malononitrile (14):
This
1-(2,4-Dinitrophenoxy)pyridin-2(1H)-one (16):
This
compound was obtained as white crystals, 0.21 g (80.46%)
yield, mp 107-108 °C; IR (KBr): 2367, 2246 (CN), 1542 and
compound was obtained as white crystals, 0.24 g (86.64%)
yield, mp 161-162 °C; IR (KBr): 1671 (C=O), 1538 and 1350
1
1350 (NO2) cm¹1; H NMR (CDCl3, 500 MHz): ¤ 7.89 (d, 1H,
1
(NO2) cm¹1; H NMR (CDCl3, 400 MHz): ¤ 6.35 (dt, 1H, Py-
Ar-H, J = 9.2 Hz), 8.60 (dd, 1H, Ar-H, J = 9.2, 2.3 Hz), 8.99
(d, 1H, Ar-H, J = 3.1 Hz). 13C NMR (CDCl3, 125 MHz): ¤
104.70, 107.58, 115.27, 118.58, 122.60, 129.78, 137.61,
144.83, 153.33. Elemental analysis Calcd for C9H3N5O5: C,
41.39; H, 1.16; N, 26.82%. Found: C, 41.11; H, 1.45; N,
27.10%.
H-5, J = 7.2, 2.0 Hz), 6.81 (dd, 1H, Py-H-3, J = 9.2, 1.6 Hz),
7.04 (d, 1H, Ar-H, J = 9.2 Hz), 7.50 (dt, 1H, Py-H-4, J = 6.8,
2.0 Hz), 7.68 (dd, 1H, Py-H-6, J = 7.2, 2.0 Hz), 8.41 (dd, 1H,
Ar-H, J = 9.2, 2.8 Hz), 8.96 (d, 1H, Ar-H, J = 2.8 Hz).
13C NMR (CDCl3, 100 MHz): ¤ 106.59, 116.00, 116.05,
122.82, 122.87, 124.01, 125.24, 129.58, 129.70, 135.12,
140.41, 155.58, 157.01. Elemental analysis Calcd for
C11H7N3O6: C, 47.66; H, 2.55; N, 15.16%. Found: C, 47.41;
H, 2.68; N, 14.97%.
Diethyl (5-Nitro-2-pyridyloxyimino)malonate (18): This
compound was obtained as a colorless oil and was solidified
in a refrigerator to obtain a white solid, 0.27 g (86.79%) yield;
¹1
IR (KBr): 1754, 1725 (C=O), 1539 and 1349 (NO2) cm
;
(5-Nitro-2-pyridyloxyimino)-2-pyridylacetonitrile (21):
This compound was obtained as white crystals, 0.23 g
(85.43%) yield, mp 199-200 °C; IR (KBr): 2371 (CN), 1525
1H NMR (CDCl3, 500 MHz): ¤ 1.39-1.41 (m, 6H, 2CH3), 4.42,
4.47 (quart, 4H, 2CH2, J = 6.9 Hz), 7.47 (d, 1H, Ar-H,
J = 9.2 Hz), 8.56 (dd, 1H, Ar-H, J = 9.2, 2.3 Hz), 9.17 (d,
1H, Ar-H, J = 3.1 Hz). Elemental analysis Calcd for
C12H13N3O7: C, 46.31; H, 4.21; N, 13.50%. Found: C, 46.06;
H, 3.97; N, 13.78%.
1
and 1360 (NO2) cm¹1; H NMR (CDCl3, 400 MHz): ¤ 7.47 (d,
1H, Ar-H, J = 9.2 Hz), 7.53 (dt, 1H, Ar-H, J = 4.8, 1.2 Hz),
7.90 (t, 1H, Ar-H, J = 7.6 Hz), 8.14 (d, 1H, Ar-H, J = 8.0 Hz),
8.63 (dd, 1H, Ar-H, J = 9.2, 1.2 Hz), 8.83 (d, 1H, Py-H,
J = 4.8 Hz), 9.26 (d, 1H, Ar-H, J = 2.4 Hz). 13C NMR (CDCl3,
100 MHz): ¤ 108.37, 109.75, 122.20, 126.89, 126.97, 135.68,
135.74, 137.50, 145.38, 145.44, 147.40, 150.77. Elemental
analysis Calcd for C12H7N5O3: C, 53.54; H, 2.62; N, 26.01%.
Found: C, 53.81; H, 2.48; N, 25.75%.
(5-Nitro-2-pyridyloxyimino)malononitrile (20):
This
compound was obtained as beige crystals, 0.19 g (87.56%)
yield, mp 83-84 °C; IR (KBr): 2367, 2246 (CN), 1540 and
1
1349 (NO2) cm¹1; H NMR (CDCl3, 500 MHz): ¤ 7.43 (d, 1H,
Ar-H, J = 9.2 Hz), 8.56 (dd, 1H, Ar-H, J = 9.2, 3.1 Hz),
9.16 (d, 1H, Ar-H, J = 3.1 Hz). Elemental analysis Calcd for
C8H3N5O3: C, 44.25; H, 1.39; N, 32.25%. Found: C, 44.01; H,
1.63; N, 31.98%.
1-(5-Nitro-2-pyridyloxy)pyridin-2(1H)-one (22):
This
compound was obtained as white crystals, 0.21 g (90.13%)
yield, mp 144-145 °C; IR (KBr): 1671 (C=O), 1525 and 1360
(NO2) cm
General Procedure for the Preparation of 13 and 19.
1 mmol of ethyl cyano(hydroxyimino)acetate was dissolved in
3 mL of ACN, then 2 mmol of NaOH was added, and the
reaction mixture was heated until the NaOH was dissolved.
1 mmol of 1-chloro-2,4-dinitrobenzene or 2-chloro-5-nitropyr-
idine was then added to the reaction mixture. The mixture was
stirred overnight at room temperature. A white precipitate
(NaCl) was formed, which was then filtered. The solvent was
evaporated under vacuo to yield the crude product, which was
recrystallized from ethanol.
¹1
;
1H NMR (CDCl3, 400 MHz): ¤ 6.28 (dt, 1H,
Ar-H, J = 7.2, 1.6 Hz), 6.78 (dd, 1H, Ar-H, J = 9.2, 1.6 Hz),
7.26 (d, 1H, Ar-H, J = 9.2 Hz), 7.46 (dt, 1H, Ar-H, J = 6.8,
2.0 Hz), 7.55 (dd, 1H, Ar-H, J = 7.2, 2.0 Hz), 8.58 (dd, 1H, Ar-
H, J = 9.2, 2.8 Hz), 9.01 (d, 1H, Ar-H, J = 2.4 Hz). 13C NMR
(CDCl3, 100 MHz): ¤ 105.51, 109.63, 123.58, 135.83, 135.92,
135.99, 139.82, 144.73, 157.50, 165.17. Elemental analysis
Calcd for C10H7N3O4: C, 51.51; H, 3.03; N, 18.02%. Found: C,
51.78; H; 3.29; N, 17.81%.
General Procedure for the Preparation of 12, 14, 18,
and 20. 1 mmol of the potassium salt of diethyl (hydroxy-
imino)malonate or (hydroxyimino)malononitrile was dissolved
in 3 mL anhydrous ACN, and then 1 mmol of 1-chloro-2,4-
dinitrobenzene or 2-chloro-5-nitropyridine was added to the
reaction mixture. The reaction mixture was stirred overnight
at room temperature and then allowed to reflux for 1 h. A white
precipitate (KCl) was formed, which was then filtered. The
solvent was evaporated under vacuo to obtain an oily residue.
The crude product was recrystallized from ethanol.
Ethyl Cyano(2,4-dinitrophenoxyimino)acetate (13): This
compound was obtained as pale yellow crystals, 0.28 g
(90.90%) yield, mp 122-123 °C; IR (KBr): 2367 (CN), 1752
¹1
(CO), 1535 and 1346 (NO2) cm
;
1H NMR (CDCl3, 500
MHz): ¤ 1.45 (t, 3H, CH3, J = 7.7 Hz), 4.51 (quart, 2H, CH2,
J = 7.7 Hz), 7.95 (d, 1H, Ar-H, J = 9.2 Hz), 8.55 (dd, 1H,
Ar-H, J = 9.2, 3.1 Hz), 8.94 (d, 1H, Ar-H, J = 3.1 Hz).
13C NMR (CDCl3, 125 MHz): ¤ 14.09, 64.99, 106.63, 118.66,
122.35, 129.54, 131.73, 137.54, 144.02, 154.23, 156.09.
Elemental analysis Calcd for C11H8N4O7: C, 42.87; H, 2.62;
N, 18.18%. Found: C, 43.12; H, 2.96; N, 17.89%.
Diethyl 2-(2,4-Dinitrophenoxyimino)malonate (12): This
compound was obtained as white crystals, 0.29 g (81.69%)
yield, mp 64-65 °C; IR (KBr): 1755, 1726 (C=O), 1539 and
Ethyl Cyano(5-nitro-2-pyridyloxyimino)acetate (19):
This compound was obtained as a white powder, 0.23 g
1
1350 (NO2) cm¹1; H NMR (CDCl3, 400 MHz): ¤ 1.42, 1.44
(87.06%) yield, mp 105-106 °C; IR (KBr): 2371 (CN), 1753
¹1
(t, 6H, 2CH3, J = 7.2 Hz), 4.45, 4.52 (quart, 4H, 2CH2, J =
7.2 Hz), 8.02 (d, 1H, Ar-H, J = 9.6 Hz), 8.50 (dd, 1H, Ar-H,
J = 9.6, 2.8 Hz), 8.92 (d, 1H, Ar-H, J = 2.4 Hz). 13C NMR
(CDCl3, 100 MHz): ¤ 14.14, 14.20, 63.96, 64.01, 117.82,
(CO), 1525 and 1360 (NO2) cm ;
1H NMR (CDCl3, 500
MHz): ¤ 1.45 (t, 3H, CH3, J = 6.9 Hz), 4.51 (quart, 2H, CH2,
J = 6.9 Hz), 7.49 (d, 1H, Ar-H, J = 9.2 Hz), 8.64 (dd, 1H,
Ar-H, J = 9.2, 3.1 Hz), 9.23 (d, 1H, Ar-H, J = 2.3 Hz).

S. N. Khattab et al.
Bull. Chem. Soc. Jpn. Vol. 84, No. 6 (2011)
639
13C NMR (CDCl3): ¤ 14.11, 64.75, 100.00, 109.85, 135.94,
142.66, 145.23, 158.30. Elemental analysis Calcd for
C10H8N4O5: C, 45.46; H, 3.05; N, 21.21%. Found: C, 45.21;
H, 2.77; N, 21.49%.
16 S. N. Khattab, Chem. Pharm. Bull. 2010, 58, 501.
17 a) N. M. El-Mallah, E. A. Hamed, A. A. El-Bardan, Egypt.
J. Chem. 1995, 38, 319. b) E. A. Hamed, Int. J. Chem. Kinet. 1997,
29, 515. c) E. A. Hamed, Int. J. Chem. Kinet. 1997, 29, 599. d)
E. A. Hamed, A. A. El-Bardan, E. F. Saad, G. A. Gohar, G. M.
Hassan, J. Chem. Soc., Perkin Trans. 2 1997, 2415. e) E. A.
Hamed, A. A. El-Bardan, E. F. Saad, M. F. Fathalla, Egypt. J.
Chem. 2000, 2, 177.
18 a) F. M. El-Hegazy, S. Z. Abdel-Fattah, E. A. Hamed, S. M.
Sharaf, J. Phys. Org. Chem. 2000, 13, 549. b) M. F. Fathalla, M. F.
Ibrahim, E. A. Hamed, J. Chem. Res. 2004, 150. c) H. O. M.
Al-Howsaway, M. F. Fathalla, A. A. El-Bardan, E. A. Hamed,
J. Chem. Res. 2007, 509. d) M. F. Fathalla, T. S. Kassem, E. A.
Hamed, Indian J. Chem., Sect. A 2008, 47A, 1348. e) B. H. M.
Asghar, M. F. Fathalla, E. A. Hamed, Int. J. Chem. Kinet. 2009, 41,
777.
The work carried out in Barcelona was partially supported
by CICYT (CTQ2009-07758) and the Generalitat de Cata-
lunya (2009SGR 1024). The Egyptian Academy of Science is
also thanked for its partial support through the Joint Research
Project in collaboration with the Spanish University of
Barcelona, Park Scientific (A/9846/07).
Supporting Information
Kinetic calculations, 1H and 13C NMR spectra of compounds
1
12-16, H and 13C NMR spectra of compounds 18-22. This
material is available free of charge on the web at http://
www.csj.jp/journals/bcsj/.
19 a) S. N. Khattab, S. Y. Hassan, E. A. Hamed, A. El-Faham,
J. Chem. Res. 2007, 247. b) S. N. Khattab, S. Y. Hassan, E. A.
Hamed, F. Albericio, A. El-Faham, Bull. Korean Chem. Soc. 2010,
31, 75.
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