Adamantane derivatives of sulfonamide molecular crystals: Structure, sublimation thermodynamic characteristics, molecular packing, and hydrogen bond networks

Article abstract of DOI:10.1039/c4ce02076f

The crystal structures of six adamantane derivatives of sulfonamides have been determined by X-ray diffraction. The molecular conformational states, packing architecture, and hydrogen bond networks were analyzed. The conformational flexibility of the bridge connecting the phenyl ring and the adamantane fragment was studied. The molecular packing architectures of the selected crystals can be for convenience divided into three different groups. The thermodynamic aspects of the sublimation processes of the compounds were studied by determining the temperature dependence of vapor pressure using the transpiration method. The thermophysical characteristics of the fusion processes of the molecular crystals were measured and analyzed. Correlations between the sublimation thermodynamic functions and physico-chemical descriptors were revealed. A regression equation correlating the sublimation Gibbs energies with the van der Waals molecular volumes was derived. The influence of various molecular fragments on the crystal lattice energy was analyzed. The relationship between the melting points of the studied substances and the free volume per molecule in the crystal lattices was evaluated.

Full text of DOI:10.1039/c4ce02076f

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ARTICLE TYPE
fiAdamantane Derivatives of Sulfonamide Molecular Crystals:
Structure, Sublimation Thermodynamic Characteristics, Molecular
Packing, Hydrogen Bonds Networks
German L. Perlovich*a,b, Alex M. Ryzhakova,b, Valery V. Tkachevb,c and Alexey N. Proshinb
5
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
The crystal structures of six adamantane derivatives of sulfonamides have been determined by Xꢀray diffraction. The molecular
conformational states, packing architecture, and hydrogen bond networks were analyzed. Conformational flexibility of the bridge
connecting the phenyl ring and the adamantine fragment was studied. The molecular packing architectures of the selected crystals can be
10 for convenience divided into three different groups. The thermodynamic aspects of sublimation processes of the compounds were studied
by determining the temperature dependence of vapor pressure using the transpiration method. The thermophysical characteristics of
fusion processes of the molecular crystals were obtained and analyzed. Correlations between the sublimation thermodynamic functions
and physicoꢀchemical descriptors were revealed. A regression equation connecting the sublimation Gibbs energies and van der Waals’s
molecular volumes was derived. The influence of various molecular fragments on crystal lattice energy was analyzed. A relationship
15 between the melting points of the studied substances and the free volumes per molecule in the crystal lattices was evaluated.
understanding of the molecular mechanisms underlying, for
example, the replication of Influenza A viruses. Adamantane
Introduction
derivatives have been used as antimalarials.18,19 Frequently, the
Sulfonamides (SA) are an important class of therapeutic agents in
addition of adamantane moieties increases the permeability of the
modern medical science.1 Sulfonamides are capable of many
50 modified compound through the blood−brain barrier.20 Therefore,
20 types of biological activity such as antibacterial,2 hypoglycemic,3
targets of the central nervous system (CNS) today are probably
diuretic,4 and antiglaucoma5,6 action. Recently, many structurally
most promising both academically and commercially. With the
novel aryl sulfonamides have been reported to have significant
fortuitous finding that amantadine gives symptomatic benefits in
antitumor activity.7ꢀ9,11 Atrial fibrillation (AF) is the most
Parkinson disease21 and the approval of memantine by EMA and
common cardiac arrhythmia, and patients suffering from AF
55 FDA for the treatment of moderate to severe stages of Alzheimer
25 generally have a reduced quality of life with a lower cardiac
disease,22 two neurodegenerative diseases of increasing
output and impaired ability to work and exercise. AF patients also
importance in aging societies are being addressed with
have an increased risk of stroke and other cardiovascular
(structurally again remarkably simple) adamantane derivatives.
diseases. Olsson et al.10 described and evaluated a novel class of
Since many sulfonamides are poorly soluble in aqueous
lactam sulfonamides in order to find a potent selective inhibitor
60 solutions, structural modification of the molecule by adding an
30 for regulation of the potassium ion channel responsible for AF.
adamantane fragment can lead to both membrane permeability
No other singular hydrocarbon moiety (apart from the methyl
increase and aqueous solubility improvement. This effect may be
group) is as successful as adamantane in improving or providing
caused by a decrease in the crystal lattice Gibbs energy of the
pharmacological activity in and of bestselling pharmaceuticals.
compounds owing to “friable” (with a free volume excess)
Having the “lipophilic bullet” (adamantane is often viewed as
65 molecular packing in the crystals.
35 providing only the critical lipophilicity) readily available as an
Sulfonamides with different adamantane fragments were
“addꢀon” for known pharmacophors, adamantane was used in the
selected as the objects of the investigations (Fig. 1). This class of
modification of, for example, hypoglycemic sulfonylureas12,
substances is quite promising due to their application as
anabolic steroids13, and nucleosides.14 The adamantane
neuroprotectors in Alzheimer disease correction. The paper opens
modifications were chosen to enhance lipophilicity and stability
70 a cycle of works devoted to the comprehensive study of the
40 of the drugs, thereby improving their pharmacokinetics.
outlined compounds in solid state (crystal structure, sublimation
Aminoadamantanes, such as amantadine15, rimantadine16 and
and fusion processes) and in solutions (solubility, solvation,
tromantadine17 were among the first “hits” that successfully made
distribution and transfer processes in different biological
it to the pharmaceutical market, and most of them are still in use.
mediums).
These remarkable bottomꢀofꢀtheꢀline structures are not only
45 efficiently used as pharmaceuticals but have also improved the
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ARTICLE TYPE
F
F
CH3
Cl
CH3
SO2
NH
SO2
NH
SO2
NH
SO2
NH
SO2
NH
SO2
NH
SO2
NH
H3C
H3C
H3C
CH3
CH3
CH3
1
2
3
4
5
6
7
Fig. 1 Structural formulas of the compounds studied
NMR Experiments
1H NMR spectra were recorded on Bruker CXPꢀ200 instrument
(Germany). As a solvent it was applied CDCl3.
Experimental
5
Synthesis
35
NꢀAdamantanꢀ1ꢀylꢀbenzenesulfonamide (1)
General procedure of the synthesis of the compounds studied
Synthesis of the novel sulfonamide derivatives was carried out
according to Scheme 1.
1H NMR (200 MHz, CDCl3), δ, ppm: 1.28 ꢀ 1.62 (m, 6H, AdH),
1.679 (d, J = 2.79 Hz, 6H, AdH), 1.91 (br. s., 3H, AdH), 4.58 (s,
1H, NH), 7.37 ꢀ 7.60 (m, 3H, ArH), 7.89 (dd, J = 7.58, 1.20 Hz,
40 2H, ArH). Mp 124.3 ± 0.2 °C. Anal. (C16H21NO2S) C, H, N, S.
NꢀAdamantanꢀ1ꢀylꢀ4ꢀfluoroꢀbenzenesulfonamide (2)
R1
R1
O
O
R3
+
1H NMR (200 MHz, CDCl3), δ, ppm: 1.47 ꢀ 1.77 (m, 6H, AdH),
1.77 ꢀ 1.93 (m, 6H, AdH), 2.05 (br. s., 3H, AdH), 4.64 (br. s., 1H,
NH), 7.20 (t, J = 8.84 Hz, 2H, ArH), 7.83 ꢀ 8.09 (m, 2H, ArH).
45 Mp 146.2 ± 0.2 °C. Anal. (C16H20FNO2S) C, H, N, S.
NꢀAdamantanꢀ1ꢀylꢀ4ꢀmethylꢀbenzenesulfonamide (3)
R3
S
Cl
H2N
N
S
R2
R2
H
O
O
III
II
I
10
Scheme 1
1H NMR (200 MHz, CDCl3), δ, ppm: 1.30 ꢀ 1.62 (m, 6H, AdH),
1.70 (d, J = 2.79 Hz, 6H, AdH), 1.95 (br. s., 3H, AdH), 2.44 (s,
3H, CH3), 4.62 (s, 1H, NH), 7.16 ꢀ 7.35 (d, J = 7.83 Hz, 2H,
50 ArH), 7.78 (d, J = 7.83 Hz, 2H, ArH). Mp 164.7 ± 0.2 °C. Anal.
(C17H23NO2S) C, H, N, S.
Triethylamine (0.04 mol) was added to a stirred suspension of 1ꢀ
aminoadamantane I (or Memantine, R1, R2 = CH3) (0.01 mol) in
isopropanol (30 ml) at 0°C, followed by solid sulfonyl chloride II
(R3 = H, CH3, Cl, F) (0.01 mol) over a period of 30 minutes. The
15 reaction mixture was heated at 60°C for 2 hours, after which
HPLC showed that there was no starting material left. The
resulting suspension was cooled to room temperature and the
precipitate of triethylamine hydrochloride was removed by
filtration. The filtrate was evaporated to dryness to afford a
20 colourless oil which was dissolved in ethyl acetate (50 ml),
washed with 0.5N HC1 (50 ml), water (50 m1) and dried over
MgSO4. The solvent was evaporated by a rotary evaporator to
afford sulfonamide as a white crystalline solid. Yields: 80ꢀ90%.
The compounds were carefully purified by reꢀcrystallizing
25 from waterꢀethanol solution. The precipitate was filtered and
dried at room temperature under vacuum until the mass of
compounds remained constant. The outlined procedure was
repeated several times and the product checked by NMR after
each reꢀcrystallization step until the proton NMR signal
30 correspondence to the purity of the compound was over 99 %.
NꢀAdamantanꢀ1ꢀylꢀ4ꢀchloroꢀbenzenesulfonamide (4)
1H NMR (200 MHz, CDCl3), δ, ppm: 1.30 ꢀ 1.62 (m, 6H, AdH),
1.69 (d, J = 2.79 Hz, 6H, AdH), 1.93 (br. s., 3H, AdH), 4.60 (s,
55 1H, NH), 7.28 ꢀ 7.49 (m, 2H, ArH), 7.67 ꢀ 7.86 (m, 2H, ArH). Mp
186.8 ± 0.2 °C. Anal. (C16H20ClNO2S) C, H, N, S.
Nꢀ(3,5ꢀDimethylꢀadamantanꢀ1ꢀyl)ꢀbenzenesulfonamide (5)
1H NMR (200 MHz, CDCl3), δ, ppm: 0.77 (s, 6H, 2CH3), 1.06 (s,
2H, AdH), 1.10 ꢀ 1.31 (m, 4H, AdH), 1.31 ꢀ 1.55 (m, 4H, AdH),
60 1.55 ꢀ 1.71 (m, 2H, AdH), 1.92 ꢀ 2.15 (m, 1H, AdH), 4.86 (br. s.,
1H, NH), 7.37 ꢀ 7.60 (m, 3H, ArH), 7.91 (dd, J = 7.58, 1.22 Hz,
2H, ArH). Mp 143.2 ± 0.2 °C. Anal. (C18H25NO2S) C, H, N, S.
Nꢀ(3,5ꢀDimethylꢀadamantanꢀ1ꢀyl)ꢀ4ꢀfluoroꢀbenzenesulfonamide
(6)
65 1H NMR (200 MHz, CDCl3), δ, ppm:0.73 (s, 6H, 2CH3), 1.02 (s,
2H, AdH), 1.10 ꢀ 1.29 (m, 4H, AdH), 1.31 ꢀ 1.53 (m, 4H, AdH),
1.53 ꢀ 1.70 (m, 2H, AdH), 1.90 ꢀ 2.12 (m, 1H, AdH), 4.70 (br. s.,
1H, NH), 6.95 ꢀ 7.22 (m, 2H, ArH), 7.78 ꢀ 8.03 (m, 2H, ArH).
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DOI: 10.1039/C4CE02076F
Mp 137.3 ± 0.2 °C. Anal. (C18H24FNO2S) C, H, N, S.
Nꢀ(3,5ꢀDimethylꢀadamantanꢀ1ꢀyl)ꢀ4ꢀmethylꢀbenzenesulfonamide
(7)
whereas the sublimation entropy at the given temperature
calculated from the following relation:
T is
1H NMR (200 MHz, CDCl3), δ, ppm: 0.77 (s, 6H, 2CH3), 1.06 (s,
2H, AdH), 1.12 ꢀ 1.32 (m, 4H, AdH), 1.32 ꢀ 1.55 (m, 4H, AdH),
1.55 ꢀ 1.67 (m, 2H, AdH), 1.98 ꢀ 2.11 (m, 1H, AdH), 2.42 (s, 3H,
ArCH3), 4.68 (br. s., 1H, NH), 7.16 ꢀ 7.35 (d, J = 7.83 Hz, 2H,
ArH), 7.78 (d, J = 7.83 Hz, 2H, ArH). Mp 162.4 ± 0.2 °C. Anal.
(C19H27NO2S) C, H, N, S.
ꢀSsTub
=
(
ꢀHsTub − ꢀGsTub )/
T
(3)
P
P / P0 ) , where is the standard pressure
0
5
with ꢀGsTub = −RT ln(
105 Pa
60 of 1
⋅
For experimental reasons, the sublimation data are obtained at
elevated temperatures. However, in comparison with effusion
methods, the temperatures are much lower, which makes
extrapolation to room conditions easier. In order to further
65 improve the extrapolation to room conditions, we estimated the
heat capacities ( C2p9,c8r ꢀvalue) of the crystals using the additive
scheme proposed by Chickos et al.27 Heat capacity was
introduced as a correction for the recalculation of the sublimation
10
Single crystals preparation
Single crystals of compounds 1 and 3 were grown from an
ethanol solution by slow evaporation. Single crystals of
substances 4, 5 and 6 were prepared from an isopropyl solution
15 (the initial composition 20:1 v/v) by slow evaporation. Finally,
single crystals of 7 were yielded from an (isopropyl ethanol –
ethyl acetate) solution by slow evaporation.
enthalpy
ꢀ ꢀ
HsTub ꢀvalue at 298 K ( Hs2u9b8 ꢀvalue), according to the
70 equation27:
298
sub
HsTub
+
ꢀHcor
=
Methods
ꢀH
=
ꢀ
20 Xꢀray diffraction experiments. Singleꢀcrystal Xꢀray measurements
were carried out using a Nonius CADꢀ4 diffractometer with
graphiteꢀmonochromated Mo Kα radiation (λ = 0.71069 Å). The
intensity data were collected at 25° C by means of a ωꢀ2θ
scanning procedure. The crystal structures were solved using
25 direct methods and refined by means of a fullꢀmatrix leastꢀ
squares procedure. CADꢀ423 was applied for data collection, data
reduction and cell refinement. The SHELXSꢀ97 and SHELXLꢀ97
programs24 were used to solve and to refine structures,
respectively.
298
p,cr
=
ꢀ
HsTub +(0.75+0.15
⋅
C
)
⋅
(Tꢀ298.15)
(4)
Differential scanning calorimetry. Differential scanning
calorimetry (DSC was carried out using a PerkinꢀElmer Pyris 1
)
75 DSC differential scanning calorimeter (Perkin Elmer Analytical
Instruments, Norwalk, Connecticut, USA) with Pyris software for
Windows NT. DSC runs were performed in an atmosphere of
flowing (20 ml
using standard aluminum sample pans and at a heating rate of 10
minꢀ1. The accuracy of weight measurements was
0.005 mg.
⋅
minꢀ1) dry helium gas of high purity 99.996%
80
K
⋅
±
30
The DSC was calibrated with an indium sample from Perkinꢀ
Sublimation experiments. Sublimation experiments were carried
out by the transpiration method as was described elsewhere.25 In
brief: a stream of an inert gas passes above the sample at a
constant temperature and at a known slow constant flow rate in
35 order to achieve saturation of the carrier gas with the vapor of the
substance under investigation. The vapor is condensed at some
point downstream, and the mass of sublimate and its purity are
determined. The vapor pressure over the sample at this
temperature can be calculated by the amount of the sublimated
40 sample and the volume of the inert gas used.
Elmer (P/N 0319ꢀ0033). The value determined for the enthalpy of
fusion corresponded to 28.48 J
⋅
gꢀ1 (reference value 28.45 J
C (n=10).
⋅
gꢀ1).
The melting point was 156.5 0.1
±
°
85
Calculation procedure. The free molecular volume in the crystal
lattice was estimated on the basis of the Xꢀray diffraction data
and van der Waals molecular volume (Vvdw), calculated by
GEPOL28:
free
90
V
=
(Vcell
−
Z
⋅
V
vdw)/
Z
(5)
The equipment was calibrated using benzoic acid. The standard
value of sublimation enthalpy obtained here was ꢀHs0ub = 90.5 ±
0.3 J⋅molꢀ1. This is in good agreement with the value
where Vcell is the volume of the unit cell, Z is the number of
molecules in the unit cell.
recommended by IUPAC of ꢀHs0ub = 89.7
± 0.5 J⋅
molꢀ1.26 The
Nonꢀbonded van der Waals interactions of crystal lattice energy
were calculated as a sum of atomꢀatom interactions with the help
45 saturated vapor pressures were measured 5 times at each
temperature with the standard deviation being within 3ꢀ5 %.
Because the saturated vapor pressure of the investigated
compounds is low, it can be assumed that the change of the vapor
heat capacity with the temperature is so small that it can be
50 neglected. The experimentally determined vapor pressure data
may be described in (lnP;1/T) coꢀordinates in the following way:
95 of Gavezzotti et al.29 force field and cutꢀoff radius 16 Ǻ.
Physicochemical descriptors applied in the analysis of solubility
and transfer processes were estimated by means of the program
HYBOT (HYdrogen BOnd T
hermodynamics).30
Results and Discussion
ln(P) = A+ B /T
(1)
100 Crystal Structure Analysis
The results of Xꢀray diffraction experiments are presented in
Table 1. The numbering of atoms of the considered compounds
The value of the sublimation enthalpy is calculated by the
ClausiusꢀClapeyron equation:
was unified and exemplified by compound
bond geometry and graph set notations of the molecules studied
4 (Fig. 2). Hydrogen
55
ꢀHsTub = RT 2 ⋅∂(ln
P
)/
∂
(T
)
(2)
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are summarized in Table 2
Table 1 Crystal lattice parameters of the substances under investigationa
1
3
4
5
6
7
CCDC code
crystal system
space group
crystal size, mm
a, Å
1028779
orthorhombic
Pca21
1028778
monoclinic
P21/c
1028780
monoclinic
P21/c
1028783
monoclinic
P21/n
1028782
monoclinic
P21/n
1028781
monoclinic
P21/n
0.38×0.34×0.22 0.31×0.26×0.20 0.40×0.35×0.15 0.40×0.37×0.30 0.45×0.40×0.35 0.43×0.27×0.15
11.977(1)
10.516(1)
11.290(1)
90.00
11.189(2)
6.536(1)
21.527(4)
90.00
11.0510(4)
6.4458(3)
21.4660(8)
90.00
9.3350(2)
11.5770(2)
15.7703(3)
90.00
10.5261(1)
11.5499(1)
14.1017(4)
90.00
10.8028(3)
11.6083(3)
14.0725(4)
90.00
b, Å
c, Å
α, °
100.587(2)
90.00
1675.31(6)
4
95.824(3)
90.00
1755.61(8)
4
90.00
90.00
1422.0(2)
4
1.361
102.41(3)
90.00
1537.5(5)
4
102.427(3)
90.00
1493.2(1)
4
97.386(2)
90.00
1700.20(8)
4
β, °
γ, °
volume, Å3
Z
Dcalc, g·cmꢀ3
1.319
1.449
1.267
1.318
1.262
Mo Kα
Mo Kα
radiation
Mo Kα
293(2)
0.229
Mo Kα
293(2)
0.215
Mo Kα
150.0(1)
0.399
Mo Kα
150(1)
0.209
150(1)
0.20
100(1)
0.19
T, K
ꢁ, ммꢀ1
Data collection
measured
1789
1458
1365
3097
3010
2331
7450
3990
3442
8683
4475
3753
8870
4527
3840
9233
4679
4098
reflections
independed reflections
independed reflections with
> 2σ(I)
Rint
0.029
25.0
0.010
26.0
0.016
29.1
0.018
29.1
0.015
29.1
0.021
29.1
θ
max , °
Refinement
refinement on
R[F2>2σ(F2)]
F2
F2
F2
F2
F2
F
0.0355
0.0299
0.0468
0.0361
0.0381
0.0356
ωR(F2)
S
0.0989
1.021
4679
0.0733
1.067
1458
0.1609
1.030
3010
0.0924
1.067
3990
0.1038
1.046
4475
0.0925
1.045
4527
reflections
parameters
(ꢀ/σ)max
185
192
190
196
208
211
<0.001
0.381
ꢀ0.431
295.7
<0.001
0.197
ꢀ0.131
<0.001
0.626
ꢀ0.434
<0.001
0.363
ꢀ0.424
0.001
0.341
ꢀ0.421
280.2
<0.010
0.300
ꢀ0.364
ꢀρmax, e⋅ Åꢀ3
ꢀρmin, e⋅ Åꢀ3
V vdw , Å3
246.3
109.2
44.3
263.6
120.8
45.8
265.1
108.2
40.8
282.8
142.2
50.3
free , Å3
138.6
49.5
66.9
143.2
48.4
67.4
V
free
β
=
V
/
V vdw , %
К =V vdw /Vmol , %
69.3
68.6
71.0
66.5
a Standard deviations are presented in brackets;
5
The hydrogen bonds of the selected crystals create hydrogen
10 bond networks with various topological structures. To analyze
hydrogen bond networks topology, we used graph set notation
terminology introduced by Etter31 and supplemented by
Bernstein32. The comparative characteristics of the hydrogen
bonds geometry and matrix of the topological graphs describing
15 hydrogen bond networks topology of the molecular crystals are
presented in Table 2. The topological graphs occurring in the
studied crystals are shown in Scheme 2. Two compounds (
3 and
4
) create hydrogen bond networks including infinite chains with
four included atoms C(4), whereas three substances (5, 6 and 7)
20 generate dimers with set graph notation R22 (8) .
Fig. 2 Unified numbering of atoms of the considered compounds
(exemplified by compound 4)
4
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Table 2 Hydrogen bonds geometry and graph set notations of the molecules studied
DH…Aa
N1ꢀH1…O1i
N1ꢀH1…O1i
N1ꢀH1…O1i
DH
0.860
0.891
0.932
H…A
2.373
2.073
1.992
D…A
3.000
2.949
2.918
DH…A
130.1
167.7
Graph set notation
3
4
5
C(4)
C(4)
R22 (8)
R22 (8)
R22 (8)
172.4
6
7
N1ꢀH1…O1i
N1ꢀH1…O1i
0.848
0.836
2.048
2.070
2.891
2.900
172.3
172.0
a symmetry code: (i) x,y,z.
fragment
∠PhꢀAd (the acute angle between the leastꢀsquare
R2
O2
R
planes through the phenyl ring C1ꢀC2ꢀC3ꢀC4ꢀC5ꢀC6 and the
20 plane including atoms С7ꢀС13ꢀС14ꢀС10). Experimental values of
the angles are summarized in Table 3.
S
O1
R1
N
H
R1
H
N
O2
As it follows from Table 3, the molecules of compounds
have very similar conformational states. Moreover, the
conformational states of and are similar as well.
The experimental values τ1 (a), τ1 + τ2 (b) and
versus the free volume per molecule in the crystals (
presented in Fig. 3 (a,b,c). It should be noted that compound
3 and
S
R2
4
O1
H
N
O2
S
N
O1
H
5
,
6
7
O1
S
O2
25
∠
V
PhꢀAd (c)
H
free ) are
R1
N
1
S
O2
O1
falls out of the obtained regularities. This observation may be
connected to the fact that no hydrogen bond networks are created
R2
R
H
O1
30 in crystal
1 in contrast to the other compounds, where SO2ꢀ and
N
S
R1
NHꢀ groups participate in building of these bonds. It is evident
that an increase in the free volume per molecule in the crystals
R2
O2
R22 (8)
C(4)
reduces τ1, (τ1 + τ2) and
∠PhꢀAd which tend to reach the values
Scheme 2
corresponding to the unstrained state. Thus, the flexibility of the
35 bridge connecting the phenyl ring with the adamantane motif is
very sensitive both to the free volume and to the availability of
the hydrogen bonds in which the bridge takes part.
5
Molecular conformational analysis
The conformational states of the molecules under investigation
depend on the mobility of the bridge, connecting phenyl rings and
adamantane fragment. Three parameters (as those used by
Perlovich et al.33) have been chosen to describe the
Table 3 Some parameters (°) describing molecular conformational states
in the crystals studied
10 conformational state: the angle between the SO2ꢀgroup and the
phenyl motif Ph (C1ꢀC2ꢀC3ꢀC4ꢀC5ꢀC6) C2ꢀC1ꢀS1ꢀN1 (τ1) and
the angle C1ꢀN1ꢀS1ꢀC7 (τ2), describing the S1ꢀN1 bond
mobility (Fig. 2). In addition to the noted angles, we introduced
an angle equal to the sum of the dihedral angles (∑τi = τ1+τ2),
15 which describes the integral flexibility of the bridge connecting
the phenyl ring with the adamantane motif. Moreover, we
introduced an angle between the phenyl ring and adamantane
τ1 + τ2
111.2
134.6
135.1
128.9
126.3
120.9
Compound
τ1
τ2
∠PhꢀAd
99.3
105.4
105.4
95.7
∠
1
3
4
5
6
7
28.2
58.2
58.8
53.8
47.6
46.4
83.0
76.4
76.3
75.1
78.7
74.5
∠
94.7
91.4
40
a
b
c
Fig. 3 The experimental values τ1 (a), τ1 + τ2 (b) and
∠
PhꢀAd (c) versus the free volume per molecule (
V
free ) in the crystal lattices
studied
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ARTICLE TYPE
It should be mentioned that if compounds with the same
adamantane fragment ( and ) are taken into consideration,
the following peculiarities of their conformational states are
observed (Fig. 4). Substances and (Fig. 4 b, c) have a similar
Molecular packing
3
can be presented in the following way.
5
,
6
7
The hydrogen bonds, appearing between the sulfonamide bridges,
form helicoids which are parallel to (OY)ꢀaxis. The centers of the
helicoids are located in 1/4 and 3/4 of the distance (OZ). In turn,
6
7
5
location of the methyl groups at the adamantane motif in relation 35 the mentioned chains interact with each other in the crystal by
to the axis imaginably drawn through the (N1ꢀC7) bond and
perpendicularly oriented to the plane of the Fig.4. In contract, the
van der Waals’s forces (Fig. 6 a). The molecular packing
architecture of compound
(Fig. 6 b).
4
is very similar to the previous case
adamantane motif of substance
5 is rotated 120° clockwise in
comparison with and (Fig. 4 а).
6
7
10
a
b
c
Fig. 4 Conformational states of the molecules 5 (a), 6 (b) and 7 (c) in the
crystal lattices studied (Hꢀatoms are omitted)
Packing architecture analysis
As it was noted above, the compounds studied can be for
15 convenience divided into three groups: compounds without
hydrogen bonds (
1
), those forming infinite chains C(4) (
3
).
,
4) and
a
crystals with dimer structure organization R22 (8)
(
5
,
6,
7
Molecular packing architecture of crystal
1 can be presented as
a zigzag layers packing (Fig. 5). Inside a layer the molecules are
20 generally packed due to interactions between the adamantane
motifs, which create the “core” of the zigzag. The sulfonamide
phenyl fragments “decorate” the adamantane “core” alternately
sticking out on different sides from the “core”. Molecules within
the layer interact with each other by van der Waals’s forces. In
25 turn, the layers interact with each other by van der Waals’s forces
as well. The sulfonamide phenyl fragments of each layer fill the
cave of the adjacent layer topologically making the crystal lattice
packing ultimately compact.
b
40 Fig. 6 Molecular packing architectures of crystals 3 (a) and 4 (b). Rhombs
correspond to the centers of the helicoids
Finally, the third group of the compounds (5, 6, 7) includes
crystals with dimer molecular organization. Various projections
of the dimers under investigation are shown in Fig. 1ESI. As it
45 was noted above, adamantane motif
relation to the (N1ꢀC7) bond, in comparison with
5
is rotated clockwise in
and . This
6
7
fact affects the geometric structure of the dimers (the orientation
of the phenyl groups in relation to the plane where the hydrogen
bonds with graph set notation R22 (8) are located). The described
30
Fig. 5 Molecular packing architecture of crystal 1
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effects, in their turn, influence the molecular packing architecture
of the crystals. Fig. 7 and 8 show different projections of the
molecular packing of compounds and , respectively. The
and are very
6
7
molecular packing architectures of substances
similar.
6
7
5
The dimers of molecules
6 are uniformly packed in the plane
(YOZ), i.e. it is not possible to distinguish any anisotropy within
the plane). However, in a projection parallel to (XOZ), one can
observe alternately interlacing layers, composed of phenyl and
10 adamantane molecular fragments (Fig. 7 b). The adamantane
motifs extend from the sulfonamide phenyl fragments of the
selected dimer into the adjacent layers (above and below the
imaginary plane formed by the phenyl parts of the molecules).
b
Fig. 8 Projections of molecular packing of crystal 7 on the planes (YOZ)
– a and (XOZ) – b.
In its turn, the “adamantane” layer is composed in such a way
20 that each adamantane motif alternately extends from the layers
located above and below. This packing looks like interlaced
fingers. It is this molecular packing that allows us to conclude
that crystal growth from dimer saturated solution is carried out by
means of delicate adjustment of the adamantane fragments into
25 the corresponding layers. Similar conclusions can be made for
compound
7 (Fig. 8 a, b).
Molecular packing architecture of compound
that of the two previous compounds (Fig. 9 a, b).
5 is similar to
a
a
b
15 Fig. 7 Projections of molecular packing of crystal 6 on the planes (YOZ)
– a and (XOZ) – b.
b
30 Fig. 9 Projections of molecular packing of crystal 5 on the planes (XOZ)
– a and (201)– b
It is especially obvious in a projection on the plane (XOZ) (Fig. 9
a) containing a layered structure with alternately interlacing
layers, composed by phenyl and adamantane molecular
35 fragments. However, in contrast to the previous molecular
packing, a subdivision of the adamantane motifs into pairs is
a
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observed within the layer. This observation can probably be
explained by the rotation of the adamantane fragment (see
above), where the methyl groups are situated on the periphery of
between the crystal structures of the substances and their
sublimation thermodynamic functions (see below). Introducing
substitutes COOHꢀ, 2ꢀdiꢀNO2 and 2,2ꢀOHꢀ, CH3ꢀ into the
these pairs and promote such decoration of the layer. It is most 30 adamantane molecule leads to denser molecular packing in the
5
probably this structurization that allows one of the molecular
packing projections to be represented as a zigzag layer structure
(Fig. 9 b).
crystals (βꢀparameter decrease). In turn, introducing substitutes 1ꢀ
OHꢀ, 1ꢀBrꢀ, 1ꢀCOCH3ꢀ and 1ꢀCON(CH3ꢀ)2ꢀ results in a decrease
in the molecular packing density. It should be mentioned that
both groups contain crystal structures with hydrogen bond
Crystal structure data gives opportunity to calculate a free
volume per molecule (
10 packing by using
V
free ) in a crystal and analyze molecular 35 networks. Therefore, the observed molecular packing changes are
free
β
=
V
/
V vdw parameter. This parameter
not connected with the factor.
shows how much the free volume increases as the molecular van
der Waals’s volume grows. The value of the discussed parameter
depends on the molecular topology, the nature of atoms and the
Similar analysis can be done for compound 1 (as the initial
one) and its derivatives ꢀ
3 and 4. Introducing a Clꢀ atom at the
paraꢀ position of the phenyl motif leads to an increase in the
availability of hydrogen bond networks. The experimental value 40 molecular packing density of the crystal, whereas introducing a
15 of ꢀparameter is a result of crystal lattice Gibbs energy methyl group at the same position produces the opposite effect. It
minimization, including both enthalpic and entropic terms. should be mentioned, that compound has no hydrogen bonds
The dependence of the
ꢀparameter on V vdw is shown in Fig.
10.
β
1
β
unlike the other two substances where infinite chains are
observed.
45
If the crystal structures of adamantane and compound 1 are
compared, introducing a phenyl sulfonamide fragment into 1ꢀ
position does not practically lead to any changes in the molecular
packing density. Adding two methyl groups to the adamantane
fragment of molecule
1 (which results in the formation of
50 compound ( )) leads to an essential reduction in the molecular
5
packing density. Moreover, hydrogen bond networks are formed
in the crystal structure. Introducing a methyl group at the paraꢀ
position of the phenyl ring of molecule
formation of compound ( )) leads to a decrease in the molecular
55 packing density of the crystal, whereas adding an Fꢀ atom
(compound ) has the opposite effect. The considered crystals
5 (which results in the
7
6
also have hydrogen bond networks. Thus, the molecular packing
densities of the crystals with adamantane motifs significantly
depend on the molecular topology and substituents nature.
20
Fig. 10 Dependence βꢀparameter (Vfree/Vvdw) versus Vvdw (adam –
Adamantane; iꢀRꢀ ꢀ iꢀRꢀAdamantane). Numbering correcponds to the
compounds studied (red color points).
60 Sublimation Characteristics
The temperature dependences of saturated vapor pressure of 1, 2,
3, 4, 6, 7 are shown in Table 1ESI. The thermodynamic functions
of sublimation and fusion processes of the selected substances are
presented in Table 4.
Beside the crystal structures studied in this work, we selected
structures of adamantane and their derivatives from CSD,34 the
25 sublimation characteristics of which had been earlier described in
literature. This step was aimed at finding out the regularities
65
Table 4. Thermodynamic characteristics of sublimation and fusion processes of the compounds studied
1
2
3
4
6
7
298
58.2
59.6
59.8
70.2
65.2
58.8
ꢀ
ꢀ
ꢀ
G
[kJ⋅molꢀ1]
sub
H sTub [kJ⋅molꢀ1]
119.1 ± 0.8
123.6 ± 0.8
373.2
116.5 ± 1.2
121.4 ± 1.2
389
120.1 ± 1.4
126.2 ± 1.4
392.9
108.8 ± 1.8
115.1 ± 1.8
462.8
115.4 ± 1.6
120.8 ±1.6
451
148.1 ± 1.3
154.4 ± 1.3
400.8
298
sub
H
[kJ⋅molꢀ1]
C2p9,c8r [J⋅molꢀ1⋅Kꢀ1]a
298
sub
62.2
[kJ⋅molꢀ1]
64.0
61.6
84.2
61.0
56.3
T
⋅ꢀS
298
209 ± 7
282 ± 8
ꢀS
[J⋅molꢀ1⋅Kꢀ1]
215 ± 6
207 ± 6
205 ± 6
189 ± 7
sub
ςH [%]b
ς
66.0
34.0
65.9
34.1
66.3
33.7
64.7
35.3
67.4
32.6
67.2
32.8
TS [%]b
410.4 ± 0.2
Tm [K]
437.8 ± 0.2
25.9 ± 0.5
397.4 ± 0.2
14.7 ± 0.5
37.0
419.3 ± 0.2
18.8 ± 0.5
44.8
459.9 ± 0.2
25.3 ± 0.5
55.0
435.5 ± 0.2
29.6 ± 0.5
68.0
ꢀHTfus [kJ⋅molꢀ1]
ꢀSTfus [J⋅molꢀ1⋅Kꢀ1]c
29.8 ± 0.5
72.6
59.2
8
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a C2p9,c8r has been calculated by Chikcos additive scheme27 the error of the calculation procedure corresponds to significant digit;
298
sub
298
sub
298
sub
298
sub
298
sub
298
sub
bςH = (ꢀ
H
/(ꢀ
H
+T⋅ꢀ
S
))⋅100%; ςTS = (T⋅ꢀ
S
/(ꢀ
H
+T⋅ꢀ
S
))⋅100%;
c ꢀSTfus = ꢀHTfus /Tm
;
5
Unfortunately, the sublimation thermodynamic characteristics of
the studied class of compounds are not directly connected to the
characteristics and fusion processes of adamantine and its
derivatives, which are used in this analysis. The experimental
298
characteristics of crystal lattice structure such as Vmol, Vfree and
β
ꢀ
20 data of sublimation Gibbs energies (
ꢀG
ꢀ a) and enthalpies
sub
parameter. Nevertheless, we tried to find a correlation of the
( ꢀ
Hs2u9b8 ꢀ b) versus Vvdw are presented in Fig. 11. It is evident that
obtained thermodynamic functions and van der Waals’s
our assumptions have been confirmed because a correlation was
observed between the discussed values. Moreover, Gibbs
energies can be described by the following correlation equation
10 molecular volumes (Vvdw). The choice of this parameter as a
descriptor was determined by the following reasons. Firstly, this
value can be easily calculated on the basis of the structural 25 with good correlation characteristics:
formula of a substance. Secondly, the dominant interactions
298
sub
ꢀG
=
(
−
13.2
±
5.1)
+
(0.259
±
0.024)
⋅
V vdw
(6)
between the molecules of the chosen class in the crystal lattice
15 are the nonꢀspecific (van der Waals) interactions. Table 2ESI
(supporting information) summarizes the literature data and
references used about the sublimation thermodynamic
R = 0.922;
σ
= 6.39; n=23
a
b
298
sub
298
sub
Fig. 11 Dependencies of sublimation Gibbs energies (
ꢀG
ꢀ a) and enthalpies (
ꢀH
ꢀ b) versus Vvdw
30 Moreover, we tried to analyze the sublimation characteristics by
contributions of various motifs of the studied molecules into the
crystal lattice packing energy. In order to make the results of the
calculations comparable to each other, we divided the selected
HYBOT (HYdrogen BOnd
descriptors.30 The statistical analysis of the experimental data
shows that the descriptors indicating polarizability (
Thermodynamics) physicochemical
α
/Å3) of the 50 molecule into three fragments for convenience (Scheme 3). The
molecule (a contribution made by nonꢀspecific interactions in the
35 crystal lattice) and the sum of Hꢀbond acceptor factors ( ΣCa ) (a
contribution made by specific interactions in the crystal lattice)
are the best to describe the selected characteristics. The
correlation equation can be presented as:
first one (I) includes the phenyl ring together with substitutes (if
there are any). The second fragment (II) includes the sulfonamide
bridge. Finally, the third fragment consists of the adamantane part
with substituents.
55
R1
298
ꢀG
= (ꢀ8.8 ± 3.5) + (1.69 ± 0.17)·
α
+ (4.2 ± 1.4)·
=4.81; F=113.8; n=23
= (14.0 ± 7.2) + (2.71 ± 0.33)· + (6.3 ± 1.9)·
=10.8; F=67.9; n=30
Σ
(Ca)
(7)
sub
O
R3
N
S
40
R=0.959; σ
R2
H
O
298
sub
ꢀH
α
Σ(Ca)
(8)
I
II
III
R=0.913;
σ
Scheme 3
Thus, all the sublimation thermodynamic functions of the
compounds belonging to the selected class can be estimated
45 based on the compound structural formula alone.
The calculation results of the fragments contributions (with the
hydrogen bonds energies taken into account) to the total packing
60 energy versus
β
ꢀparameter are presented in Fig. 12.
At the next stage of the investigation, we tried to estimate the
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Fig. 12 Molecular fragments contributions (with the hydrogen bonds
energies taken into account) to the total packing energy versus βꢀ
Fig. 13 Dependence of the experimental melting points versus the free
volumes per molecule (
free ) in the crystal lattices studied
V
parameter (
V
free /V vdw ). The red points correspond to the sum of the
5
contribution made by fragments I and II
Conclusions
The red points correspond to the sum of the contribution made by
fragments I and II. These energy contributions are comparable to
the analogous contributions made by the big adamantane motif.
Firstly, it should be noted that the discussed energetic terms can
10 be ranged in the following way: E(II) < E(I) < E(III). Moreover,
the energy term of the adamantane motif (for all the studied
substances) is 1.5 times higher than that of the phenyl term (I).
The sum of the first and second terms usually exceeds the
analogous term of the adamantane motif (red points). When the
15 crystal lattice molecular packing density reaches the critical value
(in our case β* ≈ 49.5 %), the sum of the packing terms of
fragments I and II, on the one side, and the packing term of the
45 The crystal structures of six adamantane derivatives of
sulfonamides have been solved by Xꢀray diffraction experiments.
Comparative analysis of molecular conformational states has
been carried out. It has been established that the mobility of the
bridge connecting the phenyl and the adamantine fragments is
50 very sensitive both to the free volume per a molecule in a crystal
and to the presence of hydrogen bonds in which the bridge is
involved. As the free volume per molecule in a crystal grows, the
values τ1, (τ1 + τ2) and ∠PhꢀAd decrease tending to the most
unstrained state.
55
Parameter β has been introduced to describe the molecule
packing density in crystals. Based on the Xꢀray results obtained
in this study and those taken from other works, we analyzed the
influence of the molecule topology and substituents nature on βꢀ
parameter for the crystals of this class. The molecular packing
adamantine motif, on the other side, (5, 6) are comparable. In
other words, before the packing density reaches the critical value,
20 the dominant contributions to the packing energy are made by the
adamantane fragments. When the critical value is reached, the
adamantine fragment competitors start making energy
contributions to the packing energy.
60 architecture of the selected crystals may be for convenience
divided into three different groups.
The thermodynamic aspects of sublimation processes of the
compounds were studied by determining the temperature
dependence of vapor pressure using the transpiration method. A
65 regression equation connecting the sublimation Gibbs energies
and van der Waals’s molecular volumes was derived. Moreover,
correlations between the sublimation thermodynamic functions
and physicoꢀchemical descriptors such as ΣCa (descriptor
indicating the sum of Hꢀbond acceptor factors – specific
70 interactions) and polarizability of the molecule (nonꢀspecific
interactions) were revealed.
In our previous works,35 we found out a correlation between
25 the melting points and free volumes per molecule in crystal
lattices. The physical sense of such observation is connected to
the fact that the free volume plays the role of crystal defects
which, as a rule, determine fusion and sublimation processes.36
For these regularities to be obtained the analyzed molecular
30 structures should be similar and the crystal lattices of the
compounds should have similar hydrogen bond networks. Taking
into account this fact, we added 1ꢀOHꢀAdamantane (RefCode
Adamol)34 to the studied compounds as the selected crystal
The thermophysical characteristics of fusion processes of the
molecular crystals were obtained and analyzed. A relationship
between the melting points of the studied substances and the free
75 volumes per molecule in the crystal lattices was evaluated. It was
identified that an increase in the free volume per molecule in a
crystal results in a decrease in the compounds melting points.
The influence of various molecular fragments on crystal lattice
energy was analyzed. When the molecule packing density in a
80 crystal reaches the critical value (in this case β* ≈ 49.5 %), the
energy contributions to the packing energy made by the sum of
fragments I (phenyl ring) and II (bridge), on the one side, and the
adamantine fragment, on the other, are comparable. In other
structure has the same helicoids as crystals
3 and 4. Compound 1
35 was excluded from consideration as there are no hydrogen bond
networks in its crystals. Fig. 13 shows the dependence of the
experimental melting points on the free volumes per molecule. As
it follows from Fig. 13, an increase in the free volumes per
molecule in the crystals results in the melting point values
40 reduction.
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words, before the packing density reaches the critical value, the
dominant contributions are made by the adamantine fragments.
When the critical value is reached, contributions are made by the
adamantine fragment competitors determining the packing
energy.
70
5
Acknowledgment
This work was supported by the Russian Scientific Foundation
(№14ꢀ13ꢀ00640). We thank “the Upper Volga Region Centre of
Physicochemical Research” for technical assistance with DSC
10 experiments.
28. J.L. PascualꢀAhuir, E. Silla, J. Comput. Chem., 1990, 11, 1047.
80 29. A. Gavezzotti, and G. Filippini, Energetic aspects of crystal packing:
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Notes and references
a Krestov’s Institute of Solution Chemistry, Russian Academy of Sciences,
153045 Ivanovo, Russia. Fax: +7 4932 336237; Tel: +7 4932 533784; Eꢀ
mail: glp@iscꢀras.ru
85
(Hydrogen Bond Thermodynamics) program package, Registration
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Sciences, 142432, Chernogolovka, Russia.
c Laboratory of Structural Chemistry, Institute of Problems of Chemical
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† Electronic Supplementary Information (ESI) available: [The cif files of
20 the 1, 3ꢀ7 compounds. Temperature dependences of saturation vapor
pressure of the substances studied. Thermodynamic characteristics of
sublimation and fusion processes of adamantane derivatives selected from
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25 ‡ Footnotes should appear here. These might include comments relevant
to but not central to the matter under discussion, limited experimental and
spectral data, and crystallographic data.
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DOI: 10.1039/C4CE020176F
Adamantane Derivatives of Sulfonamide Molecular Crystals: Structure, Sublimation
Thermodynamic Characteristics, Molecular Packing, Hydrogen Bonds Networks
German L. Perlovich*,†,‡, Alex M. Ryzhakov†,‡, Valery V. Tkachev‡,§, Alexey N. Proshin‡
†Krestov’s Institute of Solution Chemistry, Russian Academy of Sciences, 153045 Ivanovo, Russia;
‡Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432, Chernogolovka, Russia;
§Laboratory of Structural Chemistry, Institute of Problems of Chemical Physics, Russian Academy of Sciences,
142432, Chernogolovka, Russia;
The crystal structures of six adamantane derivatives of sulfonamides have been determined by X-ray diffraction and
their sublimation and fusion processes have been studied. Correlations between the sublimation thermodynamic
functions and physico-chemical descriptors were revealed.
*
To whom correspondence should be addressed:
Telephone: +7-4932-533784; Fax: +7-4932- 336237; E-mail glp@isc-ras.ru