Synthesis and crystal structures of 7-bromo-5-(2′-chloro)phenyl-3- hydroxy-1-methyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one and 7-bromo-5-(2′- chloro)phenyl-1-hexyl-1,2,4,5-tetrahydro-3H-1,4-benzodiazepin-2,3-dione

Article abstract of DOI:10.1016/j.molstruc.2012.02.071

Treatment of 7-bromo-5-(2′-chloro)phenyl-3-hydroxy-1,2-dihydro-3H-1, 4-benzodiazepin-2-one (1) with methyl or hexyl tosylate resulted in 7-bromo-5-(2′-chloro)phenyl-3-hydroxy-1-methyl-1,2-dihydro-3H-1, 4-benzodiazepin-2-one (2) and 7-bromo-5-(2′-chloro)phenyl-1-hexyl-1,2,4,5- tetrahydro-3H-1,4-benzodiazepin-2,3-dione (3). As confirmed by X-ray crystallography, the two products differ not only in the identity of the alkyl substituent in position 1 of the benzodiazepine fragment but also crystallize in different molecular forms resulting from proton migration. This alteration of the molecular structure leads to a significant change in the conformation of the central molecular fragment and influences the assembly mode in the crystal. In 3, centrosymmetric dimers formed via a pair of NH?O hydrogen bonds are further linked into chains via CBr?OC halogen bond interaction. In turn in 2 there are two symmetry independent molecules, each giving a different set of intermolecular interactions. One of the molecules forms a dimer via OH?O interactions whereas the second one generates chain via CBr?OC halogen bond that is also assisted by a weak OH?Br hydrogen bond.

Full text of DOI:10.1016/j.molstruc.2012.02.071

Journal of Molecular Structure 1017 (2012) 32–37
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis and crystal structures of 7-bromo-5-(20-chloro)phenyl-3-hydroxy-
1-methyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one and 7-bromo-5-(20-chloro)
phenyl-1-hexyl-1,2,4,5-tetrahydro-3H-1,4-benzodiazepin-2,3-dione
a
b
c
c
Victor Ch. Kravtsov a, , Marina S. Fonari , Maria Gdaniec , Victor I. Pavlovsky , Sergei A. Andronati ,
⇑
Ekaterina A. Semenishyna c
a
˘
Institute of Applied Physics, Academy of Sciences of Moldova, Chißsinau, Republic of Moldova
b Faculty of Chemistry, Adam Mickiewicz University, 60-780 Poznan´, Poland
c A.V. Bogatsky Physico-Chemical Institute of the National Academy of Sciences of Ukraine, Odessa, Ukraine
a r t i c l e i n f o
a b s t r a c t
Treatment of 7-bromo-5-(20-chloro)phenyl-3-hydroxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one (1) with
methyl or hexyl tosylate resulted in 7-bromo-5-(20-chloro)phenyl-3-hydroxy-1-methyl-1,2-dihydro-3H-
1,4-benzodiazepin-2-one (2) and 7-bromo-5-(20-chloro)phenyl-1-hexyl-1,2,4,5-tetrahydro-3H-1,4-ben-
zodiazepin-2,3-dione (3). As confirmed by X-ray crystallography, the two products differ not only in the
identity of the alkyl substituent in position 1 of the benzodiazepine fragment but also crystallize in differ-
ent molecular forms resulting from proton migration. This alteration of the molecular structure leads to a
significant change in the conformation of the central molecular fragment and influences the assembly
mode in the crystal. In 3, centrosymmetric dimers formed via a pair of NAHꢀ ꢀ ꢀO hydrogen bonds are further
linked into chains via CABrꢀ ꢀ ꢀO@C halogen bond interaction. In turn in 2 there are two symmetry indepen-
dent molecules, each giving a different set of intermolecular interactions. One of the molecules forms a
dimer via OAHꢀ ꢀ ꢀO interactions whereas the second one generates chain via CABrꢀ ꢀ ꢀO@C halogen bond
that is also assisted by a weak OAHꢀ ꢀ ꢀBr hydrogen bond.
Article history:
Received 30 December 2011
Received in revised form 29 February 2012
Accepted 29 February 2012
Available online 10 March 2012
Dedicated to the memory of Yurii Simonov
Keywords:
1,4-Benzodiazepine
Synthesis
Crystal structure
Conformation
Intermolecular interaction
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
prototropic migration with conversion into the corresponding
1,2,4,5-tetrahydro-1,4-benzodiazepin-2,3-diones [9–11] as it was
3-Hydroxy-1,2-dihydro-3H-1,4-benzodiazepine and its deriva-
tives have attracted much attention as they exhibit pronounced
anxiolytic, sedative, hypnotic, anticonvulsant activity and low tox-
icity [1–4]. Moreover, 3-hydroxy-1,2-dihydro-3H-1,4-benzodiaze-
pin-2-one is an active metabolite of the most drugs of the
benzodiazepine group [5,6] and therefore 3-hydroxy-1,2-dihydro-
3H-1,4-benzodiazepin-2-ones are of particular interest as they
may act as active pharmaceutical ingredients (APIs).
The effect of substituents in position 1 of the benzodiazepine
fragment on the molecular geometry and anticonvulsant properties
of 1,2-dihydro-3H-1,4-benzodiazepin-2-ones was shown by us pre-
viously [7]. Recently, a series of alkyl derivatives was synthesized
using different alkylating agents [8]. As reported earlier, 3-hydroxy
derivatives of 1,4-benzodiazepin-2-one undergo a pH-dependent
well illustrated by the synthesis of two structural isomers,
7-bromo-5-(20-chloro)phenyl-1-dodecyl-3-hydroxy-1,2-dihydro-
3H-1,4-benzodiazepin-2-one (2c) and 7-bromo-5-(20-chloro)phe-
nyl-1-dodecyl-1,2,4,5-tetrahydro-3H-1,4-benzodiazepin-2,3-dione
(3c), whose crystal structures were confirmed by X-ray crystallogra-
phy [8].
Herein we report synthesis, spectroscopic and crystallographic
studies of two new alkyl derivatives, pure phases of 7-bromo-5-
(20-chloro)phenyl-3-hydroxy-1-methyl-1,2-dihydro-3H-1,4-ben-
zodiazepin-2-one (2) and 7-bromo-5-(20-chloro)phenyl-1-hexyl-1,
2,4,5-tetrahydro-3H-1,4-benzodiazepin-2,3-dione (3) obtained by
alkylation of 7-bromo-5-(20-chloro)phenyl-3-hydroxy-1,2-dihy-
dro-3H-1,4-benzodiazepin-2-one (1) with methyl or hexyl tosyl-
ate, respectively (Scheme 1). It should be emphasized that in the
same reaction conditions different compounds, 3-hydroxy deriva-
tive (2) or 2,3-dione (3) were obtained subject to the size of alkyl
residue of alkylation agent (methyl or hexyl). By the in vitro radio-
ligand method, it has been determined that compound 2 possesses
affinity for central benzodiazepine receptors (Ki 7.4 0.6 nM) and
neurothropic activity.
⇑
Corresponding author. Fax: +373 22 72 58 87.
E-mail addresses: kravtsov@phys.asm.md (V.Ch. Kravtsov), magdan@amu.edu.pl
(M. Gdaniec), medchem_department@ukr.net (V.I. Pavlovsky).
0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2012.02.071

V.Ch. Kravtsov et al. / Journal of Molecular Structure 1017 (2012) 32–37
33
Scheme 1.
and acetonitrile, respectively. The crystal structures confirmed that
the 1-methyl derivative 2 represents 3-hydroxy-substituted com-
pound, viz. the form that has been earlier observed in its solvate
(2 ꢀ 0.5(benzene)) [12], while 1-hexyl derivative 3 represents the
dione form. Both compounds crystallize in monoclinic centrosym-
metric space groups P21/n and P21/c with two (hereinafter labeled
as a and b) and one symmetry-independent molecules in the asym-
metric unit (Fig. 2) in 2 and 3, respectively. Conformations of the
molecules 2a and 2b are similar as shown by the superposition dia-
gram in Fig. 3. In turn, a nonplanar conformation adopted by the se-
ven-membered heterocyclic ring fused with a bromophenyl group
differs in the two compounds.
The seven-membered heterocyclic ring in 2a and 2b has a boat-
like conformation (Fig. 4a). The deviation of atoms N(1), C(2), N(4)
and C(5), which constitute bottom of the boat, from their mean
plane is less than 0.0183(2) Å in both molecules, while atoms
C(3), C(10) and C(11) are displaced from this plane in the same
direction by 0.793(5), 0.745(6) and 0.689(6) Å in 2a and 0.782(5),
0.771(5) and 0.678(6) Å in 2b.
2. Results and discussion
2.1. Spectroscopic analysis
The details of alkylation of 3-hydroxy-1,2-dihydro-3H-1,4-ben-
zodiazepin-2-one were described previously [8]. The resulting
compounds were identified by IR, mass and 1H NMR spectroscopic
methods. The IR spectrum of compound 2 has a broadened band at
3280 cmꢁ1 corresponding to the vibrations of OH bond, and a band
at 1700 cmꢁ1 corresponding to vibrations of C@O bond. The IR
spectrum of compound 3 contains band at 3217 cmꢁ1 correspond-
ing to NAH vibrations of amino groups, and bands corresponding
to C@O vibrations of amide and carbonyl groups at 1660 and
1687 cmꢁ1, respectively.
In the 1H NMR spectrum of 3-hydroxy-1-methyl derivative 2,
measured in deuterated chloroform solution, the characteristic fea-
tures are a doublet for C(3)H proton at 5.00–5.03 ppm, and a dou-
blet for OH proton at 4.76–4.79 ppm. In the case of 1-hexyl-2,
3-dione derivative 3 the characteristic signals are a singlet C(5)H
proton at 5.95 ppm and a singlet for N(4)H proton at 9.47 ppm.
Mass spectra for 2 and 3 obtained by the electron impact differ
significantly (Fig. 1). A small number of peaks in the spectrum of 2,
which is not typical for this class of compounds, might be ex-
plained by insufficient energy of the resulting fragment with m/
z = 351 that is not amenable to further fragmentation.
The skeleton of the molecule 2 is similar to that found in the
solvated crystalline form of 2 ꢀ 0.5(benzene) [12] and 1-dodecyl
(2c) [8] and 1-methoxycarbonylmethyl (2d) derivatives [13], as
well as in
a- and b-polymorphs of phenazepam [14,15]. Arrange-
ment of the 5-phenyl substituent in the molecules and conforma-
tion of the seven-membered ring can be described by three
dihedral angles: h1 – angle between the aromatic rings, h2 – angle
between N(1)C(2)N(4)C(5) and N(1)C(10)C(11)C(5), h3 – angle be-
2.2. X-ray structural study
tween N(1)C(2)N(4)C(5) and C(2)C(3)N(4). Table
1 reveals a
remarkable similarity of these conformational parameters in a
series of relative compounds.
Single crystals of 2 and 3 suitable for single crystal X-ray struc-
ture determination were obtained by recrystallization from ethanol
Fig. 1. Mass-spectra for 2 (a) and 3 (b).

34
V.Ch. Kravtsov et al. / Journal of Molecular Structure 1017 (2012) 32–37
Fig. 2. Molecular structure of 2 (a) and 3 (b) with atom labeling scheme. Displacement ellipsoids are drawn at the 50% probability level.
N(4), C(10) and (C11) are coplanar within 0.045(2) Å and the atoms
N(1), C(20) and C(5) deviate from their plane by 0.893(5), 0.957(5)
and 0.728(5) Å, respectively. The dihedral angles h2 (angle between
C(3)N(4)C(11)C(10) and C(3)C(2)N(1)C(10)), h3 (angle between
C(3)N(4)C(11)C(10) and N(4)C(5)C(11)) indicate some difference
of boat conformation in 2 and 3, while h1 angles are rather similar.
Very similar conformation of the seven-membered ring was ob-
served in the structure of 3c [8] (Tables 1 and 2).
A quantitative measure of distortion of seven-membered het-
erocyclic ring from an ideal cycloheptatriene ‘‘boat’’ with mirror
symmetry Cs may be evaluated by Duax asymmetry parameter
[2,3] given by
D ,
Cs = {1/5[T12 + T42 + T62+(T2 + T3)2+(T5 + T7)2]}1/2
where T1–T7 denote torsion angles along seven-membered hetero-
cyclic ring starting from torsion angle about N(1)AC(2) bond (Table
3). The values
within the range found in 1,4-benzodiazepin-2-ones [3]. The corre-
sponding formal calculation of Cs for compound 3 reveals a huge
magnitude 35.9°, which does not describe the ‘‘boat’’ conformation.
However, the Cs asymmetry parameter equals 12.8° and corre-
sponds to ‘‘boat’’, if T1–T7 sequence starts from torsion angle about
C(3)AN(4) bond (Fig. 4(b)). Table 3 demonstrates that 3 possesses
more distorted seven-membered ring than 2a and 2b as well as rel-
DCs 4.3° and 6.9° for 2a and 2b, respectively are well
D
Fig. 3. Superposition of the molecules 2a and 2b, carbon atoms are shown by
yellow color for 2a and gray for 2b. All non-hydrogen atoms were included in fitting
(RMSD = 0.1395 Å). (For interpretation of the references to colour in this figure
legend, the reader is referred to the web version of this article.)
D
Table 1
ative 3c (DCs = 10.9°).
Selected geometric characteristics of 2 and 3 and relative compounds.
Bond lengths and angles in 2a and 2b are in a good agreement
(Table 3), and a small difference in C(2)@O(2) bond length is most
probably due to the involvement of the atoms O(2a) and O(2b) in
intermolecular interactions of different strength. The N(1) atom
is sp2 hybridized in both compounds and deviation from 360° of
the total angle at N(1) is not exceeding 0.2°. The bond angles at
atoms C(3) and C(5) correspond to their sp3- and sp2-hybridization
in 2 and vice versa in 3 (Table 2). In compound 2 the torsion angles
at the CAC bonds in the aliphatic chain are close to 180° (trans con-
formation) similar to 7-bromo-5-(20-chloro)phenyl-1-dodecyl-
1,2,4,5-tetrahydro-3H-1,4-benzodiazepin-2,3-dione [8].
Compound
h (°)
Reference/ref. code
h1
h2
h3
2a
2b
76.4(1)
80.9(1)
77.9
85.3
84.3
35.6(2)
36.0(2)
39.4
36.6
33.8
62.7(3)
61.3(2)
59.8
61.6
61.7
Present study
Present study
[12], QEMGIY01
[8], CCDC 630347
[13], JIPHAR
2 ꢀ 0.5(benzene)
2ca
2da
Phenazepam,
75.4
33.8
59.8
[14], BCHBZP
a
-Polymorph
Phenazepam
86.2
31.1
53.1
[15], BCHBZP01
b-Polymorph
Crystal packing in 2 and 3 is illustrated in Fig. 5. In general, lack
of a substituent at position 1 (for example both polymorphs of phe-
nazepam [14,15] and nitrazepam [16]) leads to the formation of
dimers via amideꢀ ꢀ ꢀamide interactions that generate R22(8) hydro-
gen-bond pattern [17]. In turn, the presence of a substituent at
position 1 as well as redistribution of hydrogen atoms like in 2
and 3 give rise to different hydrogen-bonding patterns including
dimers via R22(10) synthon, R44(8) tetramers, homomeric R22(8) syn-
thons either via a pair of C(3)AOHꢀ ꢀ ꢀN(4) hydrogen bonds or
involving another amide group [8,12]. In the crystal structure of
2 each of the symmetry independent molecules forms a different
3
80.0(1)
86.1
47.0(1)
45.5
54.6(3)
55.7
Present study
[8], CCDC 630346
3ca
a
The geometrical parameters were calculated using CSD data or deposited in
CCDC CIFs.
Redistribution of hydrogen atoms in the core of molecule 3,
when compared with that in 2, results in significant conforma-
tional changes (Fig. 4b). Although, like in 2, the seven membered
heterocycle in 3 has a boat-like conformation, here the other set
of atoms constitutes the bottom of the boat. The atoms C(3),

V.Ch. Kravtsov et al. / Journal of Molecular Structure 1017 (2012) 32–37
35
Table 2
Selected torsion angles (°) in 2 and 3 and relative compounds 2 ꢀ 0.5(benzene), 2c and 3c.
2a
2b
2 ꢀ 0.5(benzene)
2c
3
3c
T1@C(10)AN(1)AC(2)AC(3)
T2@N(1)AC(2)AC(3)AN(4)
T3@C(2)AC(3)AN(4)AC(5)
T4@C(3)AN(4)AC(5)AC(11)
T5@N(4)AC(5)AC(11)AC(10)
T6@C(5)AC(11)AC(10)AN(1)
T7@C(11)AC(10)AN(1)AC(2)
ꢁ0.3(5)
76.3(4)
ꢁ73.7(4)
ꢁ0.5(5)
40.3(5)
6.9(5)
1.7(5)
11.9(5)
67.5(4)
ꢁ75.5(4)
1.2(6)
44.7(6)
1.5(6)
0.9(4)
ꢁ6.1(5)
63.5(4)
ꢁ19.3(4)
ꢁ61.7(4)
70.8(4)
3.7(4)
ꢁ8.1(3)
61.1(3)
ꢁ14.4(3)
ꢁ65.3(3)
70.4(3)
4.5(3)
74.7(4)
ꢁ72.2(4)
ꢁ0.9(5)
38.5(5)
10.2(5)
ꢁ49.5(5)
6.9
75.5(3)
ꢁ72.5(3)
ꢁ1.7(5)
41.2(5)
7.4(5)
ꢁ46.3(5)
ꢁ51.7(6)
ꢁ47.5(4)
ꢁ45.7(4)
ꢁ44.4(3)
D
D
Cs(T1)
Cs(T3)
4.3
7.2
4.6
35.9
38.0
12.8
10.9
Table 3
Selected bond distances (Å) and angles (°) in 2 and 3.
2
3
2
a
3
a
b
b
Br(1)AC(7)
Cl(1)AC(52)
N(1)AC(2)
N(1)AC(10)
N(1)AC(12)
C(2)AO(2)
C(2)AC(3)
C(2)AN(1)AC(10)
O(2)AC(2)AN(1)
N(1)AC(2)AC(3)
C(2)AC(3)AN(4)
C(5)AN(4)AC(3)
1.890(4)
1.743(4)
1.358(5)
1.425(4)
1.474(4)
1.221(4)
1.521(5)
122.9(3)
123.6(3)
115.4(3)
106.5(3)
116.9(3)
1.894(3)
1.741(4)
1.355(5)
1.429(4)
1.472(5)
1.230(4)
1.528(5)
122.8(3)
122.1(3)
115.6(3)
106.9(3)
117.4(3)
1.896(3)
C(3)AO(3)
C(3)AN(4)
N(4)AC(5)
C(5)AC(11)
C(5)AC(51)
C(6)AC(11)
C(10)AC(11)
N(4)AC(5)AC(11)
1.399(4)
1.397(4)
1.462(4)
1.280(4)
1.485(5)
1.497(5)
1.402(5)
1.396(5)
124.9(3)
1.229(4)
1.337(4)
1.478(4)
1.525(4)
1.492(4)
1.390(4)
1.402(4)
107.1(3)
1.751(4)
1.363(4)
1.435(4)
1.487(4)
1.221(4)
1.540(4)
124.0(3)
124.0(3)
118.8(3)
116.9(3)
119.5(3)
1.462(5)
1.284(5)
1.490(5)
1.504(5)
1.405(5)
1.397(5)
124.6(3)
C(11)AC(10)AN(1)
C(10)AC(11)AC(5)
122.2(3)
122.3(3)
121.0(3)
123.0(3)
119.7(3)
118.3(3)
Fig. 4. Boat-like conformations of the heterocyclic ring in 2a (a) and 3 (b).
set of intermolecular interactions. The centrosymmetric H-bonded
dimers via R22(10) synthon are generated by the molecule 2b
[O(3b)AHꢀ ꢀ ꢀO(2b) (2 ꢁ x, 1 ꢁ y, 2 ꢁ z) = 2.832(3), O(3b)AH =
0.76(5), Hꢀ ꢀ ꢀO(2b) = 2.12(5) Å, angle O(3b)AHꢀ ꢀ ꢀO(2b) = 157(5)°],
while molecules 2a form short CABrꢀ ꢀ ꢀO@C halogen bond
assembling them into chains parallel to the a axis [Br(1a)ꢀ ꢀ ꢀO(2a) =
2.885(3) Å; angle C(7a)ABr(1a)ꢀ ꢀ ꢀO(2a) = 157.0(1)°] [18]. The
hydroxy group of 2a is involved in a multicenter hydrogen bond
acting as H-donor in intramolecular hydrogen bond to the carbonyl
oxygen atom and as a donor in a weak hydrogen bond to the bro-
mine atom, assisting thus the halogen bond interaction. The
dimeric associates of molecules 2b are stacked along the a axis
via anti-parallel 2-chlorophenyl groups with interplanar spacing
of 3.489 Å. The centroidꢀ ꢀ ꢀcentroid distance between the phenyl
rings of 4.583 Å and Cl(1b)ꢀ ꢀ ꢀcentroid separation of 3.537 Å indi-
cate halogenꢀ ꢀ ꢀ
p
rather than
p p interactions [19,20]. These
ꢀ ꢀ ꢀ
interactions organize the dimeric associates of molecules 2b into
chains which alternate in the structure of 2 with the chains of mol-
ecules 2a. It should be mentioned the absence of Brꢀ ꢀ ꢀO short con-
tacts and another way of H-bond interactions in the inclusion
complex of 2 ꢀ 0.5(benzene) [12]. The intermolecular interactions
differ in 2a, 2b and in inclusion complex 2 ꢀ 0.5(benzene) and influ-
ence on the conformation of seven-membered ring and asymmetry
parameter
DCs° which varies from 4.3° to 7.2° (Tables 1 and 2). A

36
V.Ch. Kravtsov et al. / Journal of Molecular Structure 1017 (2012) 32–37
Fig. 5. Fragments of crystal packing in 2 (a) and 3 (b).
weaker CABrꢀ ꢀ ꢀO@C interaction [Br(1)ꢀ ꢀ ꢀO(2) = 3.030(2) Å; angle
C(7)ABr(1)ꢀ ꢀ ꢀO(2) = 174.9(1)°] in 3 connects the hydrogen-bonded
centrosymmetric dimers [R22(8) synthon, N(4)AHꢀ ꢀ ꢀO(3)(2 ꢁ x, 1 ꢁ
y, 1 ꢁ z) = 2.923(4), N(4)AH = 0.86(3), Hꢀ ꢀ ꢀO(3) = 2.09(3) Å, angle
N(4)AHꢀ ꢀ ꢀO(3) = 163(3)°] into the layers parallel to the (bc) crystal-
lographic plane.
1H NMR : d, ppm (CDCl3), (J, Hz): 7.21–7.45 (7H m, H-6, H-8, H-
9, H-30, H-40, H-50, H-60); 5.02 (1H d, J = 9.34, H-3); 4.77 (1H d,
J = 9.33, OH); 3.52 (3H s, ACH3).
3.1.2. 7-Bromo-5-(20-chloro)phenyl-1-hexyl-1,2,4,5-tetrahydro-3H-
1,4-benzodiazepin-2,3-dione (3)
7-Bromo-5-(20-chloro)phenyl-1-hexyl-1,2,4,5-tetrahydro-3H-1,
4-benzodiazepin-2,3-dione (3) was obtained analogously to com-
pound 2 from compound 1 (1.00 g, 2.7 mol) as colorless crystals.
Yield: 38%, m.p. = 196–199 °C, Rf = 0.3.
3. Experimental
3.1. Synthesis
Mass-spectrum:
[MANHAC@O]+(28), 377 [MAC5H11]+ (8), 364 [MAC6H12]+ (52).
IR:
, cmꢁ1: 3217 (NAH), 1660 (C@O amide), 1687 broaden
band (C@O carbonyl).
m/z
(I,%):
448
[M+]
(34),
405
The IR spectra were recorded on a Specord IR-75 in chloro-
form solution, and the 1H NMR spectra on a Varian WXP 300
instrument (300 MHz) in CDCl3, at 25 °C, internal standard was
TMS. Mass spectra were recorded by electron impact on a MX
1321 mass spectrometer (ionizing voltage 70 eV, temperature of
ionization chamber 200 °C). The purity of compounds was
checked by HPLC, Shimadzu chromatograph LC 8A, analytical col-
umn Zorbax C 18, mobile phase, methanol + 2% TFA: water + 2%
TFA, 9:1. TLC checked the progress of reactions. Thin layer chro-
matography was carried out on Silufol UV 254 plates in acetoni-
trile:chloroform:hexane, 1:1:3, visualization was with UV light at
k 254 nm.
m
Table 4
Crystal data and details on the structure refinement.
Compound
Empirical formula
Formula weight
Temperature (K)
Crystal system
Space group
Unit cell dimensions
a (Å)
2
C
3
16H12BrClN2O2
C21H22BrClN2O2
449.77
130(2)
Monoclinic
P21/c
379.64
100(2)
Monoclinic
P21/n
3.1.1. 7-Bromo-5-(20-chloro)phenyl-3-hydroxy-1-methyl-1,2-dihydro-
3H-1,4-benzodiaze-pin-2-one (2)
10.9410(4)
7.4490(2)
37.518(1)
98.021(1)
3027.8(2)
8
9.3956(4)
20.8169(6)
10.8163(4)
107.799(5)
2014.3(1)
4
b (Å)
c (Å)
Potassium carbonate (1.00 g, 7.2 mmol) was added to a suspen-
sion of compound 1 (1.00 g, 2.7 mmol) and methyl tosylate (0.66 g,
4.0 mmol) in anhydrous dioxane (20 mL), and the mixture was stir-
red at 40–50 °C for 10 h. Chloroform (40 mL) was added to the
reaction mixture, which was washed with water (4 ꢂ 20 mL). The
solvent was evaporated on a rotary evaporator at reduced pressure.
The residue obtained in amount of 0.53 g was recrystallized from
benzene as colorless crystals of compound 2. Yield: 51%,
m.p. = 120–127 °C, Rf = 0.4.
b°
V (Å3)
Z
D (calc) (Mg/m3)
1.666
2.899
1.483
2.192
l
(mmꢁ1
)
F(000)
1520
920
Reflections collected
13372
14,004
Independent reflections
5464
3955
[R(int) = 0.0372]
5464/0/405
1.000
[R(int) = 0.0327]
3955/0/248
1.004
Data/restraints/parameters
Goodness-of-fit on F2
R indices [I > 2
R indices (all data) R1, wR2
r
(I)] R1, wR2
0.0395, 0.1028
0.0492, 0.1084
0.985 and ꢁ0.461
0.0391, 0.0979
0.0617, 0.1080
1.775 and ꢁ0.896
Mass-spectrum: m/z (Iony, %): 378 [M+] (10), 349 [MACHO]+
(100), 334 [MACO2]+(7).
Largest diff. peak and hole
(e Åꢁ3
)
IR: m
, cmꢁ1: 3280 (OAHasoc), 1700 broaden band (C@O).

V.Ch. Kravtsov et al. / Journal of Molecular Structure 1017 (2012) 32–37
37
1H NMR: d, ppm, (DMSO-d6), (J, Hz): 7.32-7.68 (7H m, H-6, H-8,
H-9, H-30, H-40, H-50, H-60); 5.95 (1H s, H-4); 6.45 (1H s, H-5);
4.37–4.47 (1H, m, ACH2A(CH2)4ACH3); 4.69–4.75 (1H, m,
ACH2A(CH2)4ACH3); 1.23–1.50 (8H, m, ACH2A(CH2)4ACH3);
0.83 (3H t, J = 7.0, ACH3).
substitutient in position 1 of benzodiazepine fragment may allow
the fine tuning of such interaction. Moreover, the intermolecular
interaction may influence on conformation of seven-membered
ring in 1,4-benzodiazepines and this variation of conformation
parameters should be taken in account in attempts to establish
correlation between geometrical parameters and biological
activity.
3.2. X-ray crystallography
X-ray data for 2 and 3 were collected at 100 and 130 K with an
Acknowledgements
Xcalibur Oxford Diffraction diffractometer, equipped with a CCD
area detector and a graphite monochromator utilizing Mo K
a
This research was supported by joint award of State Agency on
Science, Innovation and Informatization of Ukraine (No. M/268-
2011) and Academy of Sciences of Moldova (10.820.09.13/UF).
radiation. Final unit cell dimensions were obtained and refined
on an entire data set. All calculations to solve the structures and
to refine the model were carried out with the programs SHELXS97
and SHELXL97 [21]. The C–bound H atoms were placed in calcu-
lated positions and were treated in a riding model approximation
with Uiso(H) = 1.2Ueq(C), while the OA and N-bound H–atoms of
hydroxyl and amino groups were found from difference Fourier
maps and were refined with isotropic displacement parameters
Uiso(H) = 1.5Ueq(O), Uiso(H) = 1.2Ueq(N). The Figures were produced
using Mercury [22]. Crystal data and details of the structure refine-
ment are given in Table 4. Selected geometric parameters for 2 and
3 are given in Tables 2 and 3. CCDC 858024, 858025 contain the
crystallographic data for 2–3. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk/data_request/cif.
References
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4. Conclusion
7-Bromo-5-(20-chloro)phenyl-3-hydroxy-1-methyl-1,2-dihydro
-3H-1,4-benzodiazepin-2-one and 7-bromo-5-(20-chloro)phenyl-
1-hexyl-1,2,4,5-tetrahydro-3H-1,4-benzodiazepin-2,3-dione were
obtained by alkylation of 7-bromo-5-(20-chloro)phenyl-3-hydroxy
-1,2-dihydro-3H-1,4-benzodiazepin-2-one, and their crystal struc-
tures were determined by single crystal X-ray diffraction. Redistri-
bution of hydrogen atoms in the core of the molecules resulted in
different self-association hydrogen-bonded patterns in two com-
pounds. The availability of two crystallographically independent
molecules and co-existence of two different associating chains
either only via Oꢀ ꢀ ꢀBr interactions or combination of H-bonds
and halogen–
p
interactions in 7-bromo-5-(20-chloro)phenyl-3-
hydroxy-1-methyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one might
be considered as a prerequisite for the possible polymorphism in
this system as well as indicates the diverse modes of interaction
of 1,4-benzodiazepines with various receptors. The selection of
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Towler, J. van de Streek, J. Appl. Crystallogr. 39 (2006) 453.