Synthesis, properties and crystal structure of the 2,4-dichlorophenyl- cyanoxime: A powerful carbonyl reductase inhibitor

Article abstract of DOI:10.1007/s10870-013-0401-6

The compound 2,4-dichlorophenylcyanoxime (later H(2,4-diCl-PhCO)) has significance in its possible application in cancer chemotherapy treatments since it acts as an inhibitor of the human carbonic reductase. This enzyme decreases the effectiveness of anthracycline drug treatment of some types of cancer. The compound was synthesized in high yield at ambient conditions from 2,4-dichlorophenylacetonitrile, using gaseous methylnitrite. The compound was characterized by means of UV-visible, IR, ¹H, ¹³C NMR spectroscopy and X-ray analysis. The cyanoxime crystallizes in a monoclinic space group P2₁/c (#14) with unit cell constants: a = 3.7587(9) A, b = 30.087(7) A, c = 7.6874(17) A, β = 96.163(3); V = 864.3(3) A³, Z = 4. The structure was solved, using direct methods, to final R indices [I > 2σ (I)] R1 = 0.0551 (wR2 = 0.1217). The compound adopts a non-planar, trans-anti configuration with the value of the dihedral angle between the cyanoxime and dichlorophenyl planes equal to 50.61.

Full text of DOI:10.1007/s10870-013-0401-6

J Chem Crystallogr (2013) 43:157–164
DOI 10.1007/s10870-013-0401-6
ORIGINAL PAPER
Synthesis, Properties and Crystal Structure of the
2,4-Dichlorophenyl-cyanoxime: A Powerful Carbonyl Reductase
Inhibitor
•
Michael Hilton Nikolay Gerasimchuk
•
•
Svitlana Silchenko Henry A. Charlier
Received: 16 July 2012 / Accepted: 21 January 2013 / Published online: 5 February 2013
Ó Springer Science+Business Media New York 2013
Abstract The compound 2,4-dichlorophenylcyanoxime
(later H(2,4-diCl-PhCO)) has significance in its possible
application in cancer chemotherapy treatments since it acts
as an inhibitor of the human carbonic reductase. This enzyme
decreases the effectiveness of anthracycline drug treatment
of some types of cancer. The compound was synthesized
in high yield at ambient conditions from 2,4-dichlor-
ophenylacetonitrile, using gaseous methylnitrite. The com-
with the value of the dihedral angle between the cyanoxime
and dichlorophenyl planes equal to 50.61°.
Keywords Arylcyanoximes Á Uncompetitive carbonyl
reductase inhibitor Á Crystal structure Á UV–visible Á IR Á
NMR spectroscopy
1
pound was characterized by means of UV–visible, IR, H,
13C NMR spectroscopy and X-ray analysis. The cyanoxime
Introduction
crystallizes in a monoclinic space group P21/c (#14) with
Resistance to established chemotherapy treatments makes
the search for effective compliments and alternatives nec-
essary. Specifically, anthracycline drug treatments are noted
to suffer from eventual resistance [1–3]. The human car-
bonyl reductase is believed to be responsible for the resis-
tance to anthracycline drugs in cancer chemotherapy [4].
Certain cyanoximes have shown a propensity to be an
inhibitor of the human carbonyl reductase [5]. Cyanoximes,
in this regard, could serve as a complement to anthracycline
treatments. The cyanoximes have the twofold benefit of
lowering the resistance to chemotherapy treatments and also
lowering the cardiotoxicity of the anthracycline drugs [5].
Current drugs, such as doxorubicin, can lead to eventual
heart failure from prolonged treatment [6–8]. Of the cyan-
oximes previously studied, (Scheme 1), the 2,4-dichlor-
ophenyl-cyanoxime (further as H(2,4-diClPhCO)) was
found to be the most effective inhibitor, showing activity in
the range around 10 lM. Thus, it was chosen for further
analysis. The Pt and Pd complexes containing 2,4-diC-
lPhCO- anions have previously been examined for their
in vitro cytotoxicity against cancer cells [9], which was
found to be at *15 % of that for the anticancer drug cis-
platin, which was used as a positive control. This paper
describes the synthesis and further characterization of a
biologically active 2,4-dichlorophenyl-cyanoxime.
˚
unit cell constants: a = 3.7587(9) A, b = 30.087(7) A,
˚
3
˚
˚
c = 7.6874(17) A, b = 96.163(3)°; V = 864.3(3) A ,
Z = 4. The structure was solved, using direct methods, to
final R indices [I [ 2r (I)] R1 = 0.0551 (wR2 = 0.1217).
The compound adopts a non-planar, trans-anti configuration
Electronic supplementary material The online version of this
article (doi:10.1007/s10870-013-0401-6) contains supplementary
material, which is available to authorized users.
M. Hilton Á N. Gerasimchuk (&)
Department of Chemistry, Missouri State University, Temple
Hall 456 and 431, 901 South National Avenue, Springfield,
MO 65897, USA
e-mail: NNGerasimchuk@MissouriState.edu
S. Silchenko
Absorption Systems, Inc., 440 Creamery Way, S.300, Exton,
PA 19341, USA
H. A. Charlier
Department of Chemistry and Biochemistry, Boise State
University, 1910 University Drive, Boise, ID 83725-1520, USA
123

158
J Chem Crystallogr (2013) 43:157–164
3
Experimental
General Considerations
doublet; J = 8.4 Hz), 7.60 (5-position, doublet of dou-
blets; 4J = 2.4 Hz, 3J = 8.4 Hz); 7.85 (3-position, doublet;
4J = 2.4 Hz). 13C{1H} NMR spectrum in dmso-d6 (ppm):
110.14 (CN-group), 127.73 (oxime), 128.56 (ipso carbon),
128.67 (6-carbon), 130.38 (5-carbon), 132.96 (3 carbon),
133.24 (4-carbon, to Cl), 136.74 (2-carbon, to Cl).
All solvents and starting compounds, such as the 2,4-
dichlorophenyl-acetonitrile, NaNO2, and K2CO3 were of
reagent grade, obtained from Aldrich and used without
further purification. The identification of the target cya-
noxime—H(2,4-diCl-PhCO)—was carried out using TLC
on silica gel Al-backed plates from Merck, using the
EtOAc:hexanes = 1:4 mobile phase. The melting point
(without correction) of the cyanoxime was determined
using the Mel-Temp digital apparatus in an open Pyrex
glass capillary. An elemental analysis on the C, H, Cl
content was done by the combustion method at the Atlantic
Microlab Inc. (Norcross, GA).
Solutions Studies
pK and pD Determination
Measurements of pKa values for the synthesized 2,4-
dichlorophenyl-cyanoxime were carried out using a Sirius
Analytical Instruments automated titration station (Sussex,
UK) equipped with a temperature-controlled bath. Since
protonated cyanoximes HL are poorly soluble in water, all
measurements were conducted in mixed solvent systems
using dmso as a solubilizing co-solvent. AtenololTM and
LidocaineTM (from Aldrich) were used for calibration of
the instrument. Measurements consisted of the three-step
multi-stage titration in water/dmso mixtures from 20 to
30 wt% with ionic strength adjusted to 0.15 with KCl. The
values were extrapolated to ‘‘zero’’ DMSO content to
obtain an aqueous pKa value using the Yasuda–Shedlovsky
procedure. The pH in titration experiments ranged from 3
to 11. Potentiometric titration experiments were also car-
ried out for measurements of log P and log D (where P is
the partition coefficient between water and n-octanol, and
D is a diffusion coefficient).
Synthesis
Thinly sliced sodium (0.615 g) was placed into a flask
containing 100 mL of n-propyl alcohol. Nitrogen gas was
bubbled through the solution while it was stirred. It took
about 30 min for the sodium to completely dissolve. The
base solution is required to deprotonate the acidic hydrogen
in the methylene group of the 2,4-dichlorophenylacetoni-
trile in the next step. Then 4.998 g (23.2 mM) of 2,4-
dichlorophenylacetonitrile was dissolved in 25 mL of
n-propanol with the help of a sonicator (Branson 1500
Ultrasound Bath) and a heat gun. The dissolved 2,4-
dichlorophenylacetonitrile was added to the flask contain-
ing the C3H7ONa base prepared above; and gaseous
methylnitrite CH3ONO [5, 10] was bubbled through the
reaction mixture, and within *10 min it changed to a
canary yellow color. The reaction mixture was placed in a
refrigerator (overnight). The solvent was removed at first
using the rotovap at ?40 °C, and then under vacuum using
an oil pump. The resulting thick yellow solid was re-dis-
solved in water and HCl:H2O (1:4) was added dropwise to
the solution until the pH was at a value of *3. A pearl-
white fine fibrous compound precipitated out of the clear
solution. The compound was filtered, washed with water
and dried in a dessicator. A representation of the synthesis
can be seen in Scheme 2. The preparation was repeated
three times and resulted in an average yield of 88 %;
m.p. = 151 °C. The Rf value for the cyanoxime was found
to be 0.26, while starting 2,4-dichlorophenylacetonitrile
had a Rf = 0.49. A significant difference in the com-
pounds’ mobility allowed the reaction progress to be reli-
ably monitored by co-spotting the probe from the reaction
mixture and starting compound. The analysis for
C8H4Cl2N2O calculated (found, %): C—44.68 (44.89),
Spectroscopy
UV–Vis data were collected for both the protonated and
deprotonated species of H(2,4-diClPhCO). The compound
was deprotonated with KOH dissolved in alcohol. The
absorbance was measured (EtOH, 0.1 cm cuvette) at room
temperature in the range of 200–1,100 nm using an HP 8453
diode array spectrophotometer. The 1H and 13C{1H} NMR
spectra were collected on a Varian INova spectrometer at
399.85 and 100.54 MHz frequencies respectively. Samples
were dissolved in dmso-d6, and the measurements were
made at room temperature. The IR spectra of the initial
compound 2,4-dichlorophenylacetonitrile and the cya-
noxime were recorded on a Bruker ALPHA-P in ATR mode.
X-ray Crystallography
Crystal Growth
The crystallization process required a small amount
(0.1–0.3 g) of the cyanoxime to be dissolved in a solvent
(ethanol, diethyl ether, and acetonitrile). The dissolved
compound was then added to a long narrow test tube. On
1
H—1.87 (1.80), Cl—32.97 (31.59). H NMR spectrum in
dmso-d6 (ppm): 14.24—OH oxime, 7.67 (6-position,
123

J Chem Crystallogr (2013) 43:157–164
159
software [12, 13]. Numerical absorption corrections were
applied based on crystal face indexing obtained using actual
images recorded by the video-microscope camera (SI 2). The
following data processing was performed using the SAD-
ABS program that was included in the Bruker AXS software
package [14]. The structures were solved by direct methods
and refined by least squares on weighted F2 values for all
reflections using the SHELXTL program [12, 13]. All atoms
received assigned anisotropic displacement parameters and
were refined without positional constraints. Hydrogen atoms
in the structure were all objectively found on a difference
map and refined. Crystal data for the studied compound are
presented in Table 1, while bond lengths and valence angles
are summarized in Table 2. Figures for the crystal structures
of these complexes were drawn using Mercury 4.1.2 and
ORTEP 32 software [15, 16] at a 50 % thermal ellipsoids
probability level. The PLATON checks of crystallographic
data and actual CIF file for reported structure can be found in
the Supplementary Information section. The structure was
deposited onto CSDC.
Table 1 Crystal data and structure refinement for H(2,4-diCl-PhCO)
Empirical formula
Formula weight
Temperature
C8H4Cl2N2O
215.03
120(2) K
˚
0.71073 A
Wavelength
Crystal system
Space group
Monoclinic
P 21/c, #14
˚
Unit cell dimensions
a = 3.7587(9) A, a = 90°
˚
b = 30.087(7) A, b = 96.163(3)°
˚
c = 7.6874(17) A, c = 90°
3
˚
Volume
864.3(3) A
Z
4
Density (calculated)
Absorption coefficient
F(000)
1.652 Mg/m3
0.704 mm-1
432
Crystal size
0.30 mm 9 0.21 mm 9 0.20 mm
1.35–28.28°
-4 B h B 5, -40 B k B 40,
-10 B l B 10
Theta range for data collection
Index ranges
Reflections collected
10,273
Independent reflections
2,110 [R(int) = 0.0834]
Completeness to theta = 28.28° 99.4 %
Results and Discussion
Absorption correction
Numerical from crystal
faces indexing
Acidity and Media Distribution Studies
Max. and min. transmission
Refinement method
0.8719 and 0.8175
Full-matrix least-squares on F2
2,110/0/134
The H(2,4-diCl-PhCO) represents a weak acid with
pKa = 6.44 0.02. The protonated compound itself is not
soluble in water, but, at a pH above 7.5, it dissolves
completely in aqueous solutions with the formation of a
yellow anion. Since this cyanoxime showed the best
inhibitory activity against the human carbonyl reductase
enzyme, it was important to investigate its distribution
between aqueous and non-aqueous solutions. This com-
pound can be further developed as a medical drug
administered during the course of anticancer treatment
involving anthracycline-family antibiotics. Therefore, an
Data/restraints/parameters
Goodness-of-fit on F2
1.093
Final R indices [I [ 2r (I)]
R indices (all data)
R1 = 0.0551, wR2 = 0.1217
R1 = 0.0663, wR2 = 0.1270
-3
˚
Largest diff. peak and hole
0.407 and -0.385 e A
top of this solution, hexane was slowly added. The test
tubes were left to cool in a refrigerator. After several days,
as the hexane slowly dispersed into the solution below,
crystals of the target compound appeared on the wall of the
tube.
˚
Table 2 Selected bond lengths (A) and valence angles (°) for H(2,4-
diCl-PhCO)
Bonds
Angles
Data Collection
C(1)–N(1) = 1.291(3)
C(1)–C(2) = 1.449(4)
C(1)–C(3) = 1.479(4)
C(2)–N(2) = 1.140(4)
C(4)–Cl(1) = 1.733(3)
C(6)–Cl(2) = 1.739(3)
N(1)–O(1) = 1.377(3)
O(1)–H(1O) = 0.84(4)
N(1)–C(1)–C(2) = 121.5(3)
N(1)–C(1)–C(3) = 117.6(2)
C(2)–C(1)–C(3) = 120.7(2)
N(2)–C(2)–C(1) = 177.3(3)
C(4)–C(3)–C(8) = 118.2(2)
C(5)–C(4)–Cl(1) = 117.9(2)
C(3)–C(4)–Cl(1) = 120.6(2)
C(7)–C(6)–Cl(2) = 119.4(2)
C(5)–C(6)–Cl(2) = 118.6(2)
C(1)–N(1)–O(1) = 112.0(2)
N(1)–O(1)–H(1O) = 101(2)
A clear, colourless, block-like specimen of C8H4Cl2N2O,
whose approximate dimensions were 0.20 mm 9 0.21 mm 9
0.30 mm, was used for the X-ray crystallographic analysis
(SI 1). Measurements were carried out at 120 K using Bruker
APEX 2 diffractometers equipped with a SMART CCD area
detector. The intensity data were collected in x-scan mode
˚
using the Mo tube (Ka radiation; k = 0.71073 A) with a
highly oriented graphite monochromator. Intensities were
integrated from four series of 364 exposures, each covering
0.5° in x, and the total data set being a sphere [11]. The space
group determination was done with the aid of XPREP
123

160
J Chem Crystallogr (2013) 43:157–164
no base
+ KOH
2.0
1.5
1.0
0.5
0.0
Cl
CH3 CN (410 nm;
DMF (433 nm;
DMSO (452 nm; ε = 75)
CH3 OH (sh. at ~380 nm)
ε
ε
= 89)
= 75)
1.2
0.9
0.6
0.3
0.0
Cl
Cl
K
Cl
N
CN
N
O-
CN
Cl
OH
299 nm
Cl
260
231
N
O-
CN
600
+
N(C4H9)4
350
400
450
500
550
200
250
300
350
400
450
500
Wavelength, nm
Wavelength, nm
Fig. 2 Spectra of the 2,4-dichlorophenylcyanoxime anion (as tetra-
butylammonium salt) in several solvents in visible region in the area
of n ? p* transitions (Color figure online)
Fig. 1 UV–visible spectra of protonated (blue) deprotonated (red)
with KOH cyanoxime in ethanol showing bathochromic shift of
p ? p* bands. The K? salt was obtained in situ and was not isolated.
An inset shows 9100 magnified region of low-intensity n ? p*
transition in visible region, which is shown in detail in Fig. 2 (Color
figure online)
in basic solutions due to the presence of a weak band of
n ? p* transition (e = 75–90, depending on solvent) in
the nitroso chromophore in the visible region of the spec-
trum (Fig. 2). The cyanoxime anion demonstrates a pro-
nounced negative solvatochromism [17–19]. Thus, the
position of the n ? p* band in visible spectra changes in
an unexpected way with the change of the solvent used for
studies (Fig. 2). That is reflected in the bathochromic shift
of this band in less-polar solvents [17]. Since the K? salt of
the cyanoxime is not soluble in most organic solvents,
tetrabutylammonium hydroxide was used for the cya-
noxime deprotonation in a solvent of interest. Thus, the
formed cyanoxime salt of tetraalkylammonium is soluble
in all studied solvents. Its observed behavior is in line with
investigation of its partitioning between hydrophobic and
hydrophilic media was warranted. A dual-phase titration of
the cyanoxime at ?25 °C over a pH range, during which it
passes from fully protonated to fully deprotonated forms,
was performed. Some specific details of the procedure are
shown in SI 3–5. The compound has a high log P value of
3.65, which testifies that this cyanoxime is highly perme-
able. This fact can explain the high inhibitory activity of
the H(2,4-diCl-PhCO) for the carbonyl reductase enzyme.
Another inhibitor of this enzyme is menadione—2-methyl-
1,4-naphthoquinone—also a highly lipophilic compound.
That explains the similar nature of the enzyme’s active site,
but does not explain why the structurally different mole-
cules have a similar inhibitory effect on the enzyme. The
lipophilicity profile (log D vs pH) shows a drop in the
distribution coefficient at a pH above 5.5 when the
deprotonation of the compound begins to occur (SI 5).
-
the similar performance established for the NO2 anion
[18] and other cyanoximes [20, 21]. A linear correlation
Spectroscopic Properties
The title compound easily undergoes deprotonation at basic
conditions in aqueous and non-aqueous solvents with the
formation of the mono-anion L-. There is a delocalization
of negative charge throughout the anion at which the
nitroso- form is dominant (SI 6). Besides, the 2,4-dichlo-
rophenyl cyanoxime anion, L-, demonstrates a redistribu-
tion of intensities and a considerable bathochromic shift of
p ? p* bands in the UV-spectrum (Fig. 1), as compared to
its protonated precursor HL (SI 7). The protonated cya-
noxime HL is colorless, but it gains a canary yellow color
Fig. 3 Molecular structure and numbering scheme for the H(2,4-
diCl-PhCO); an ORTEP drawing at 50 % thermal ellipsoids proba-
bility level
123

J Chem Crystallogr (2013) 43:157–164
161
Fig. 4 Two orthogonal views
of the structure of H(2,4-diCl-
PhCO) showing H-bonding [(a),
view along a] and p-stacking
[(b), view along c] between
H-bonded sheets
was found between the energy of the n ? p* transition in
the nitroso chromophore in visible spectrum and Kosover’s
solvation energy Z [22, 23], pKa of the alcohol ROH used
(SI 8).
only one geometrical isomer (presumably anti) present in
DMSO solutions. Observed findings are different from the
more common mixture of syn- and anti- isomers typically
present in solutions of other aryl-cyanoximes [9, 24].
1
The H NMR spectrum of the freshly prepared solution
of the cyanoxime in the same solvent showed a rather
narrow singlet of the oxime group at *14.3 ppm which
evidenced the absence of dynamic processes in the solution
and the presence of only one isomer (SI 9, 10). This is
confirmed in the 13C{1H} NMR spectra of the compound
HL which showed one set of signals that correspond to
Crystal Structure
A search of the CCDC database on the presence of a 2,4-
dichlorophenyl fragment resulted in 809 hits that also
includes other 3-,5-, 6-differently-substituted 2,4-dichlo-
rophenyl groups. Out of that large number, 387 structures
123

162
J Chem Crystallogr (2013) 43:157–164
˚
F
Table 3 Hydrogen bonds for H(2,4-diCl-PhCO) (A and °)
F
D–HÁÁÁA
d(D–H)
d(HÁÁÁA)
d(DÁÁÁA) \(DHA)
2.838(3) 165.2(2)
F
F
F
F
O(1)–H(1)ÁÁÁN(2) #1
Symmetry transformations used to generate equivalent atoms
0.84(4)
2.02(4)
NC
N
O
NC
N
O
NC
N
O
H
#1 x ? 1, -y ? 1/2, z ? 1/2
H
H
H(2,6-diF-PhCO)
H(2,4-diF-PhCO)
H(2,5-diF-PhCO)
contained a pure, non-derivatized 2,4-dichlorophenyl frag-
ment. Our title compound was not present in the database,
and the most closely structurally related findings are: 2,4-
dichlorophenylaldoxime (ref code ADELUR, [25]), 2,4-
dichlorobenzo hydroxamic acid (ref code FONHUM, [26]),
and (Z)-1-(2,4-Dichlorophenyl)ethan-1-one semicarbazone
(ref code HUCRED, [27]).
Cl
Cl
Cl
Cl
Cl
H
F
NC
NC
N
O
N
O
NC
N
O
H
H
For the title compound, a total of 1,456 frames repre-
senting a full sphere of data were collected, and the inte-
gration of the data using a monoclinic unit cell yielded a
total of 10,273 reflections to a maximum h angle of 28.28°
H(2F-6Cl-PhCO)
H(2,6-diCl-PhCO)
H(2,4-diCl-PhCO)
Scheme 1 Disubstituted arylcyanoximes with cytotoxic properties
˚
(0.75 A resolution). 2,110 reflections were independent and
compound are arranged into sheets that form the ladder-type
structure, due to a significant dihedral angle (50.61°)
between the aromatic and cyanoxime groups. Slipped p–p
stacking interactions between chloro-phenyl groups at a
the average redundancy was 4.869 with completeness to
2H angle equal 99.4 % (R(int) = 8.34 %, R(r) = 6.32 %)
and 1,820 reflections (86.26 %) had greater than 2r(F2)
intensities. The structure of H(2,4-diCl-PhCO) was solved
using direct methods and refined using the Bruker SHEL-
XTL Software Package [14], using the monoclinic space
group P21/c (#14) with Z = 4 for the formula unit
C8H4Cl2N2O. The final anisotropic full-matrix least-
squares refinement on F2 with 119 variables converged at
R1 = 5.55 (Table 1). All hydrogen atoms in the structure
were found on the electron difference map and refined
objectively.
˚
distance of 3.695 A contribute to the lattice formation and
its overall architecture. The ‘‘slip angle’’ between two p–p
interacting phenyl groups is 21.20°. The distance between
the two closest centroids of the chlorophenyl-rings is
˚
3.759 A. The crystal packing of the H(2,4-diCl-PhCO) can
be described as a staircase (or ladder-type) of H-bonded
2D-sheets of molecules that are joined into columns by
means of p–p stacking interactions to form an elegant 3D
network. Columns are held together via van-der-Waals
forces between dichlorophenyl-groups, with a sheer plane of
the crystal passing through the middle of the b-direction
(Fig. 4; SI 11).
The molecular structure and numbering scheme for
H(2,4-diCl-PhCO) is shown in Fig. 3, while the organiza-
tion of the structure and packing diagrams are presented in
Fig. 4 (SI 11). The values of selected bond lengths and
valence angles are shown in Table 2. The cyanoxime adopts
a non-planar trans-anti configuration in solid state. The
dihedral angle between mean planes of the phenyl ring and
the plane of cyanoxime-group O1–N1–C1–C2–N2 is
50.61°. For comparison it is interesting to note that a similar
compound—2,4-dichlorophenylaldoxime [25]—is almost
planar and the dihedral angle between the aromatic ring and
aldoxime fragment is 17.57°. Bonds in the cyanoxime group
in the structure of H(2,4-diCl-PhCO) are in the range typi-
cally observed for this class of compounds: N(1)–
The crystal structure of the cyanoxime contributes to the
area of structurally characterized chlorinated aromatic
compounds, which possess a variety of properties valuable
for biomedical research. The next steps in this work are: (1)
to synthesize and test on enzymatic inhibitory activity
several other small molecules containing the 2,4-dichlo-
rophenyl fragment known structures of which are deposited
into the CCDC database, and (2) to provide a structure–
activity relationship analysis for a series of studied chlo-
rinated compounds in order to select the best performing
molecule with optimized properties.
˚
O(1) = 1.377(3) and C(1)–N(1) = 1.291(3) A (Table 2).
Geometrical parameters for the dichlorophenyl fragment are
normal for this group. Individual molecules of the cya-
noxime form an elegant system of H-bonds between the
nitrogen atom N2 of the cyano-group and the oxime
OH-group of the neighboring molecule when packed into
the crystal (Fig. 4; Table 3). H-bonded molecules of the
Conclusions
A high-yield preparation of an important non-competitive
inhibitor of the carbonyl reductase enzyme—2,4-dichlor-
ophenylcyanoxime—has been described in detail. The
123

J Chem Crystallogr (2013) 43:157–164
163
Scheme 2 Synthetic route for
target compound H(2,4-diCl-
PhCO)
Acknowledgments NG is grateful to Mr. Leon Goeden for his
pioneering work on the Project and Ms. Alex Corbett for technical
help. A financial support from the ACS PRF award # 39079-B3 and
the Cottrell Research Corporation award # CC6598 is highly
appreciated.
compound was characterized by means of solutions studies
that include pKa, partitioning and pD coefficients mea-
surements, 1H, 13C NMR, IR and UV–visible spectroscopy
and the X-ray analysis. It was found that the cyanoxime
represents a weak organic acid that possesses high per-
meability into non-polar lipophilic media. The crystal
structure revealed that the cyanoxime adopts a non-planar
trans-anti configuration in solid state. The compound is
packed into a crystal by means of the H-bonding between
the molecules that formed 2D-sheets arranged in a staircase
fashion, which then assemble into the 3D framework via
slipped p–p stacking interactions between aromatic
systems.
References
1. Den Boer ML, Pieters R, Kazemier KM, Janka-Schaub GE,
Henze G, Veerman AJ (1999) Relationship between the intra-
cellular daunorubicin concentration, expression of major vault
protein/lung resistance protein and resistance to anthracyclines in
childhood acute lymphoblastic leukemia. Leukemia 13(12):2023
123

164
J Chem Crystallogr (2013) 43:157–164
2. Perego P, Corna E, De Cesare M, Gatti L, Polizzi D, Pratesi G,
14. Software Package for Crystal Structure Solution (2009) APEX 2.
Bruker AXS, Madison
15. Farrugia LJ (1997) Appl Crystallogr 30:565
16. Burnett MN, Johnson CK (1996) ORTEP III: report ORNL-6895.
Oak Ridge National Laboratory, Oak Ridge
Zunino F (2001) Role of apoptosis and apoptosis-related genes in
cellular response and antitumor efficacy of anthracyclines. Curr
Med Chem 8(1):31
3. Baran Y, Gu¨r B, Kaya P, Ural A, Avcu F, Gu¨ndu¨z U (2007)
Upregulation of multi drug resistance genes in doxorubicin
resistant human acute myelogenous leukemia cells and reversal
of the resistance. Hematology 12(6):511–517
4. Ferreira AA, Matsubara LS, Matsubara BB (2008) Anthracy-
cline-induced cardiotoxicity. Cardiovasc Hematol Agents Med
Chem 6(4):278–281
17. Reichardt C (2003) Solvents and solvent effects in organic
chemistry, 3rd edn. Wiley, New York
18. Jolly WL (1970) The synthesis and characterization of inorganic
compounds. Prentice Hall, Englewood Cliffs, pp 320–322
19. Bakshiev NG (ed) (1989) Solvatochromism: problems and
methods, Izd-vo Leningradskogo Universiteta, Leningrad
20. Gerasimchuk N, Esaulenko AN, Dalley KN, Moore C (2010)
2-Cyano-2-isonitroso acetamide and its Ag(I) complexes. Sil-
ver(I) cyanoximate as a non-electric gas sensor. Dalton Trans
39:749–764
21. Ilkun OT, Archibald S, Barnes CL, Gerasimchuk N, Biagioni R,
Silchenko S, Gerasimchuk OA, Nemykin V (2008) Benz(2-het-
eroaryl)cyanoximes and their Tl(I) complexes: new room tem-
perature blue emitters. Dalton Trans 42:5715–5729
22. Gordon AG, Ford RA (1972) The chemist’ companion (hand-
book). Wiley, New York
5. US Patent # 7,727,967 B2; 2010
6. Bogason A, Masquelier M, Lafolie P, Skogastierna C, Paul C,
Gruber A, Vitols S (2010) Daunorubicin metabolism in leukemic
cells isolated from patients with acute myeloid leukemia. Drug
Metab Lett 4(4):228–232
7. Maxwell CB, Jenkins AT (2011) Drug-induced heart failure. Am
J Health Syst Pharm 68(19):1791–1804
8. Minotti G, Licata S, Saponiero A, Menna P, Calafiore AM, Di
Giammarco G, Liberi G, Animati F, Cipollone A, Manzini S,
Maggi CA (2000) Anthracycline metabolism and toxicity in
human myocardium: comparisons between doxorubicin, epiru-
bicin, and a novel disaccharide analogue with a reduced level of
formation and [4Fe-4S] reactivity of its secondary alcohol
metabolite. Chem Res Toxicol 13(12):1336–1341
9. Gerasimchuk N, Goeden L, Durham P, Barnes C, Cannon JF,
Silchenko S, Hidalgo I (2008) Synthesis and characterization of
disubstituted arylcyanoximes and their several metal complexes.
Inorg Chim Acta 361(7):1983–2001
23. Kosower EM, Hoffmann D, Wallenfels K (1962) J Am Chem Soc
84:2755–2760
24. Robertson D, Cannon J, Gerasimchuk N (2005) Double-stranded
metal-organic networks for one-dimensional mixed valence
coordination polymers. Inorg Chem 44(23):8326–8342
25. Cai-Xia Wu, Xiu-Qin Lu (2006) (E)-2,4-Dichloro-benzaldehyde
oxime. Acta Crystallogr E 62:2826
26. Shang X-M, Meng X-G, Wu J-Z, Li Q-S (2005) 2,4-Dichlor-
obenzohydroxamic acid. Acta Crystallogr E61:1961
27. Fun H-K, Balasubramani K, Vijesh AM, Malladii S, Isloor AM
(2009) (1Z)-1-(2,4-Dichloro-phen-yl)ethan-1-one semicarbazone.
Acta Crystallogr E 65:o2072
10. Hartung RC, Crossley F (1936) Isonitrosopropiophenone. Org
Synth 16:44
11. SAINT (2003) Release 7.01; Integration Software for Single
Crystal
12. Blessing RH (1995) Acta Crystallogr A51:33
13. Sheldrick GM (1999) SADABS area-detector absorption correc-
¨ ¨
tion, 2.03. University of Gottingen, Gottingen
123