Crystal and Molecular Structure, and Cytotoxic Activity of diethyl ether of 2-[(phenyl-(phenyl-o-carboranyl)- methyl]malonic acid

Article abstract of DOI:10.1134/S0022476618010377

The crystal and molecular structure of diethyl ether of 2-[(phenyl-(phenyl-o-carboranyl)-methyl]malonic acid is determined by single crystal X-ray diffraction and NMR spectroscopy for the first time. The cytotoxic activity of the molecule is analyzed.

Full text of DOI:10.1134/S0022476618010377

Journal of Structural Chemistry. Vol. 59, No. 1, pp. 231-234, 2018.
Original Russian Text © 2018 E. M. Suleimen, A. V. Kazantsev, K. Van Hecke, Zh. B. Iskakova, K. Akatan.
CRYSTAL AND MOLECULAR STRUCTURE,
AND CYTOTOXIC ACTIVITY OF DIETHYL ETHER
OF 2-[(PHENYL-(PHENYL-O-CARBORANYL)-
METHYL]MALONIC ACID
1
E. M. Suleimen , A. V. Kazantsev , K. Van Hecke ,
2
3
1
Zh. B. Iskakova , and K. Akatan
4
The crystal and molecular structure of diethyl ether of 2-[(phenyl-(phenyl-o-carboranyl)-methyl]malonic
acid is determined by single crystal X-ray diffraction and NMR spectroscopy for the first time. The
cytotoxic activity of the molecule is analyzed.
DOI: 10.1134/S0022476618010377
Keywords: o-carborane derivatives, malonic acid derivatives, single crystal X-ray diffraction analysis,
NMR spectroscopy, cytotoxic activity.
With the aim to continue the research in the chemistry of о-carboranes, we have determined for the first time the
crystal structure and obtained the NMR spectral data of diethyl ether of 2-[(phenyl-(phenyl-o-carboranyl)-methyl]malonic
acid 2.
Compound 2 was synthesized by the interaction of lithium phenyl-о-carboranyl 1 with benzylidenemalonic ester
according to the following scheme [1]:
Scheme of the synthesis of compound 2 and atomic numbering.
RESULTS AND DISCUSSION
1
The H NMR spectra show two triplets at 0.66 ppm and 1.23 ppm (3H), corresponding to methyl groups, two
quartets at 3.56 ppm and 4.23 ppm (2H), corresponding to methylene groups, and two doublets at 3.92 ppm and 4.12 ppm
1
Institute of Applied Chemistry, Gumilyov Eurasian National University, Astana, Republic of Kazakhstan;
2
suleimen_em@enu.kz. Central Kazakhstan Academy, Karaganda, Republic of Kazakhstan. XStruct, Department of
3
4
Inorganic and Physical Chemistry, Ghent University, Krijgslaan, Ghent, Belgium; kristof.vanhecke@ugent.be. Sarsen
Amanzholov East Kazakhstan State University, Ust-Kamenogorsk, Republic of Kazakhstan; ahnur.hj@mail.ru. Translated
from Zhurnal Strukturnoi Khimii, Vol. 59, No. 1, pp. 233-236, January-February, 2018. Original article submitted February 9,
2017; revised June 19, 2017.
0022-4766/18/5901-0231 © 2018 by Pleiades Publishing, Ltd.
231

(1H), corresponding to hydrogen atoms at С9 and C2 atoms in the trans-position relative to each other (spin-spin coupling
constant of 10 Hz). The signals of hydrogen atoms of the benzene rings (at С3–C8 and С17–C22) produce a complicated
multiplet in the range 6.65-7.80 ppm.
13
The C NMR spectrum displays signals corresponding to the ester moiety of the molecule of 2 (С15, С12, С14,
С11, С13, С10), which are in the following regions: 13.52 ppm, 14.13 ppm, 61.84 ppm, 62.67 ppm, 166.94 ppm, and
165.62 ppm respectively. The signals of the С9 and C2 carbon atoms are observed at 47.33 ppm and 59.02 ppm. The
13
disappearance of signals at 85.46 ppm, 85.75 ppm, 129.49 ppm, and 137.13 ppm in the С NMR Dept. spectrum confirms
their correspondence to the С16, С1, С17, and С3 atoms. The signals at 128.92 ppm, 132.17 ppm, and 129.89 ppm belong to
the carbon atoms of benzene rings.
The structure of compound 2 is determined by a single crystal X-ray diffraction analysis.
Compound 2 crystallizes in an centrosymmetric orthorhombic space group Pbca. The asymmetric unit of the crystal
contains one molecule of diethyl ether of 2-[(phenyl-(phenyl-o-carboranyl)-methyl]malonic acid. The substituents at carbon
atoms of the carborane moiety (С(16) and С(1)) are in the syn-peri-planar (cis) conformation; the torsion angle С(2)–C(1)–
C(16)–C(17) = 3.1(2)°; a synclinal (gauche) conformation is implemented along the С(1)–C(2) bond (the torsion angle
C(16)cage–C(1)cage–C(2)–C(3) = –74.35(15)°), as a result of which the phenyl rings are at a short distance and slightly
inclined to each other.
Both С10–O1 and С13–O3 bond lengths of the ester moiety are 1.204(2) Å, which corresponds to the typical values
of double bonds, while the C10–O2 (1.3305(17) Å) and C13–O4 (1.3370(17) Å) bond lengths indicate an ordinary bond. The
geometric parameters of the carborane core are typical (the B–C distances vary within 1.712(2) Å and 1.739(2) Å, and B–B
distances are within 1.763(2)-1.790(3) Å). The bond length C(1)cage–C(16)cage = 1.709(2) Å, which is comparable with the
Ccage–Ccage bond in bis-(2-benzyl-о-carborane-1-yl)-benzene [2], bis-((2-phenyl-о-carborane-1-yl)methyl)-benzene [3], and
1-phenyl-2-(4-vinylbenzyl)-о-carborane [4].
Fig. 1 shows the geometry of the molecule of 2.
Fig.1. Geometry of the molecule of compound 2 in the crystal
and numbering of non-hydrogen atoms. Thermal ellipsoids are
drawn at the 50% probability level.
232

EXPERIMENTAL
The NMR spectra were recorded on an Avance III Bruker DRX-500 spectrometer (with the operating frequency of
1 13
500.13 MHz for Н, and 125.76 MHz for С, δ-scale) using the following standard programs for the measurement of two-
1 1
dimensional spectra: COSY Н– Н, НМВС, HSQC, Dept.
The IR spectra were recorded on an IR-Fourier Cary 600 Series spectrometer (Agilent Technologies, USA) using
Gladiatr single reflection ATR accessories with a diamond crystal (PIKE, USA). All the measurements were carried out with
–1
the resolution of 4.0 cm ; the number of scanning was 40.
The reaction course was controlled by TLC. Sorbfil plates in the ethyl acetate–hexane system were used for TLC.
Diethyl ether of 2-[(phenyl-(phenyl-o-carboranyl)-methyl]malonic acid 2. Compound 2 is readily soluble in
DMSO, DMFA, chloroform, ethyl acetate, and hexane and poorly soluble in alcohol and water. The melting point is 109.7-
111.9°C (103-104°C [1]).
1
Н NMR (500 MHz, DMSO, δ, ppm, J, Hz): 0.66 (3Н, t, J = 7.0), 1.23 (3H, t, J = 7.0), 3.56 (2Н, quint), 4.23 (2H,
quint), 3.92 (1Н, d, J = 10), 4.12 (1H, d, J = 10), 6.65-7.80 (10H, m).
13
С NMR (125.76 MHz, DMSO): 13.52 (q, C-15), 14.13 (q, C-12), 47.33 (d, C-9), 59.02 (d, C-2), 61.84 (t, C-14),
62.67 (t, C-11), 85.46 (s, C-16), 85.75 (s, C-1), 128.92 (d, C-5, C-7, C-19, C-21), 129.49 (s, C-17), 129.89 (d, C-4, C-8, C-18,
C-22), 132.17 (d, C-6, C-20), 137.13 (s, C-3), 166.94 (s, C-13), 165.62 (s, C-10).
–1
IR spectrum (KBr, ν, cm ): 3064 (C–Haryl), 2984 (C–Halkyl), 2605 (B–H), 1756 (C=O ester group, intens.), 1725
(C = O), 1496, 1455, 1370, 1341, 1302, 1278, 1249, 1205, 1183, 1143, 1093, 1025, 1007, 977, 864, 754, 723, 694, 633, 578,
540.
Single crystal X-ray diffraction analysis. The unit cell parameters and reflection intensities of the crystal of
compound 2 were measured at 100 K on a SuperNova, Dual, Cu at zero, Atlas diffractometer (Agilent, USA), equipped with
a CCD detector, with MoK (λ = 0.71073 Å) radiation and ω-scanning. The images were integrated using the CrysAlisPro
α
program [5]; the intensities (scale-up, absorption correction and LP corrections) were processed using the Olex2 program [6].
2
The structure was solved by the direct method using the ShelXS program and refined by the least-squares technique on F
using the ShelXL program [7, 8]. Non-hydrogen atoms were refined in the anisotropic approximation; all hydrogen atoms
were placed in the calculated positions and refined in a riding model with isotropic temperature factors, with 1.2U(eq) for the
corresponding carbon atoms and 1.52U(eq) for the methyl groups.
Crystallographic data of compound 2 at T = 100 K. C22H32B10O4, M = 468.58, orthorhombic, space group Pbca
3 3
(no. 61), a = 13.3238(3) Å, b = 15.9244(4) Å, c = 24.5816(5) Å, V = 5215.6(2) Å , Z = 8, T = 100 K, ρcalc = 1.194 g/cm ,
–1
μ(Мо) = 0.072 mm , F(000) = 1968, 30999 reflections measured, 6555 independent reflections (Rint = 0.0543), which were
used in all calculations. The final divergence factors were R1 0.0521 (for 4919 observed reflections with I > 2σ(I)) and wR2
0.137 (for all data).
The results of the X-ray diffraction analysis of the crystal of compound 2 have been deposited with the Cambridge
Crystallographic Data Centre (CCDC 1531811), and can be easily obtained by request via the website:
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44-1223-336033; or deposit@ccdc.cam.ac.uk).
Cytotoxic activity. In order to study the cytotoxic activity of compound 2, we have carried out tests by the known
method using brine shrimps Artemia salina [9]. It is found that in all the tested concentrations (1-10 mg/ml) compound 2
exhibits acute lethal toxicity; the larval mortality is 65-70%.
The authors express their gratitude to Dr. M. V. Zdorovets (Laboratory of Engineering Profile, L. N. Gumilyov
Eurasian National University, Republic of Kazakhstan) for his assistance in measuring IR spectra of the sample, to Hercules
Foundation (project Auge/11/029 “3D-SPACE: 3D Structural Platform Aiming for Chemical Excellence”), to Research
Foundation – Flanders (FWO) for the financial support, and to Dr. V. V. Butyaikin for his assistance in the synthesis of the
compound.
233

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