Structural and energetic aspects of adamantane and memantine derivatives of sulfonamide molecular crystals: Experimental and theoretical characterisation

Article abstract of DOI:10.1039/c8ce00426a

A number of new sulfonamide compounds with adamantane and memantine fragments were synthesised and characterised. Their single crystals were grown and crystal structures were determined. XPac analysis has revealed three sets of isostructural crystals based on adamantane/memantine-specific hydrogen bond patterns. The use of QTAIMC and Hirshfeld surface analysis allowed elucidating the influence of functional groups and molecular arrangement on the strength of inter- and intramolecular non-covalent interactions in crystals and overall packing efficiency. It was found that the bulky memantine fragment hinders the formation of C(4) hydrogen-bonded chains, leading to the formation of dimeric structures with lower stabilisation energy. The layered packing of hydrophobic fragments in the group of isostructural crystals was found to be the most effective for a group of adamantane derivatives of P2₁/c symmetry.

Full text of DOI:10.1039/c8ce00426a

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DOI: 10.1039/C8CE00426A
Journal Name
ARTICLE
Structural and Energetic aspects of Adamantane and Memantine
Derivatives of Sulfonamide Molecular Crystals: Experimental and
Theoretical Characterisation
Received 00th January 20xx,
Accepted 00th January 20xx
Alexander P. Voronina, Tatiana V. Volkovaa, Andrey B. Ilyukhinb, Tatiana P. Trofimovac,d and
German L. Perlovicha,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
number of new sulfonamide compounds with adamantane and memantine fragments were synthesised and
characterised. Their single crystals were grown and crystal structures were determined. XPac analysis has revealed three
sets of isostructural crystals based on adamantane/memantine-specific hydrogen bond patterns. The use of QTAIMC and
Hirshfeld surface analysis allowed elucidating the influence of functional groups and molecular arrangement on the
strength of inter- and intramolecular non-covalent interactions in crystals and overall packing efficiency. It was found that
bulky memantine fragment hinders the formation of C(4) hydrogen-bonded chains, leading to formation of dimeric
structures with lower stabilisation energy. The layered packing of hydrophobic fragments in the group of isostructural
crystals was found to be the most effective for
a group of adamantane derivatives of P21/c symmetry.
extensive review on the biological activity of adamantane
containing mono- and polycyclic pyrimidine derivatives was
published by Shokova and Kovalev16, and Liu et al.17 discussed
38 types of adamantane-containing compounds and makes an
attempt to elucidate the role of the adamantane moiety on
the manifestation of pharmacological activity.
Introduction
Drug
compounds
including
sulfonamide
and/or
adamantane/memantine moieties are an important group of
biologically active agents for different pathologies. Such
compounds
demonstrate
antibacterial,1
anticancer,2
At the same time, the crystallographic studies aimed at
clarification of the crystal structure of newly synthesised
adamantane derivatives are also represented in the literature.
Al-Wahaibi et al.5 described the structures of the synthesised
adamantane-isothiourea hybrid derivatives by single X-ray
crystallographic data. In the study of Saeed et al.18 the
Hirshfeld surface analysis was applied to perform a detailed
analysis of the intermolecular interactions in a series of six
closely related phenyl thiourea species bearing the 1-
antithyroid,3 hypoglycemic,4,5 antimicrobial,5,6 diuretic7,8
,
antivirial9 activity, and also inhibit carbonic anhydrase and
protease.7,10-13 The search for new drugs in the adamantane
series is ongoing and important information devoted to the
study of the pharmacological properties, mechanism of action,
clinical application, marketing study,14 and developing the
delivery systems based on incorporating the adamantane
derivatives15 has been accumulated by now. For example, an
(adamantane-1-carbonyl)group.
A detailed description of
a.G.A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences, 153045
Ivanovo, Russia.
crystal properties including molecular conformational states,
packing architecture, and hydrogen bond networks of a
number of newly synthesised sulfonamides19,20 and
adamantanes21 using graph set notations was published by
Perlovich et al. and the influence of various molecular
fragments on the investigated parameters was emphasised.
The crystal structure, thermophysical and thermodynamic
properties of molecular crystals of sulfonamide derivatives
with an adamantane fragment are described only in several
works.21,22 Published results show that the work on the
synthesis and study of compounds of this class is necessary
and will contribute to the development of a scientific strategy
for the advancement of compounds with improved
pharmaceutical properties from a wide range of structural
analogues and will enable the derivation of structure-property
b.Institute of General and Inorganic Chemistry RAS, 119991 Moscow, Russia.
c. Institute of Physiologically Active Compounds, Russian Academy of Sciences,
142432, Chernogolovka, Russia.
d.Lomonosov Moscow State University, Faculty of Chemistry, 119991 Moscow,
Russia
* To whom correspondence should be addressed:
Telephone: +7-4932-533784; Fax: +7-4932-336237; E-mail glp@isc-ras.ru
Electronic Supplementary Information (ESI) available: CCDC links for crystal
1
structures of compounds
4
10. ORTEP diagrams for crystals of 4-10. Molecular packing of crystals 2, 3, 11, 12,
-
10. H NMR, 13C NMR and IR spectra for compounds
5
-
14. Selected XPac plots of δp against δa for three sets of isostructural crystals. An
XPac map of unique pairs of crystal structures. A sample image and plot of energies
of intramolecular C-H···O and C-H···π contacts against the angle between phenyl
and adamantane fragments. Correlation plots between the N···O distance, minimal
dnorm values and hydrogen bond energies evaluated using Mayo force field and
QTAIMC. 2D fingerprint plots of Hirshfeld surfaces. Numbering of carbon atoms
used in assignment of 13C NMR chemical shifts. A scheme of atoms chosen as
common set of points for XPac analysis. Lists of unique non-covalent interactions
found by QTAIMC in crystal structures of 1-12, 14 with tabulated metric and
charge-density properties. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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DOI: 10.1039/C8CE00426A
ARTICLE
Journal Name
Cl
Cl
Br
Br
Triethylamine (0.04 mol) was added to a stirred suspension of
1-aminoadamantane (
) (or Memantine, R1, R2 = CH3) (0.01
I
mol) in isopropanol (30 ml) at 0°C, followed by solid sulfonyl
chloride (II) (R3 = NO2, Br, CF3) (0.01 mol) over a period of 30
minutes. The 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 colourless oil which was dissolved in ethyl acetate (50
ml), washed with 0.5N HC1 (50 ml), water (50 ml) and dried
SO2
NH
SO2
NH
SO2
NH
SO2
NH
SO2
NH
SO2
NH
H3C
CH3
CF3
H3C
CH3
H3C
NO2
CH3
1
2
3
4
5
6
CF3
NO2
SO2
NH
SO2
NH
SO2
NH
SO2
NH
over MgSO4. The solvent was evaporated by
a rotary
evaporator to afford sulfonamide as a white crystalline solid.
Yields: 80-90%.
H3C
CH3
H3C
CH3
The synthesis procedure of compounds (1) – (4) and (11) – (14)
was described in our previous papers.21,22
7
8
9
10
F
CH3
CH3
F
The compounds were carefully purified by re-crystallizing from
water-ethanol 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 re-crystallisation step until the proton NMR signal
correspondence to the purity of the compound over 98-99 %.
2.1.2 Identification of compounds. 1H NMR spectra were
recorded on Bruker CXP-200 instrument (Germany) with CDCl3
used as a solvent. Solid-state FT-IR spectra were obtained
using the Vertex 80v spectrometer (Germany) in the
wavenumber range of 400 cm-1 – 4000 cm-1 at 2 cm-1 spectral
resolution. Differential scanning calorimetry (DSC) was carried
out using a Perkin-Elmer DSC 4000 differential scanning
calorimeter (USA). DSC runs were performed in a flow of dry
nitrogen (20 ml·min-1) using standard aluminium sample pans
at a heating rate of 10 K·min-1.
SO2
NH
SO2
NH
SO2
NH
SO2
NH
H3C
H3C
CH3
CH3
11
12
13
14
Figure 1. Structural formulae of compounds studied.
relationships with high correlation coefficients.
Our previous work21 studied the structures, packing
architecture, topology of hydrogen bond networks, and
sublimation of 7 adamantane derivatives of sulfonamide. As a
continuation of the study, this work focuses on the
comparative analysis of the published compounds with new
ones: N-Adamantan-1-yl-4-bromo-benzenesulfonamide (5), N-
(3,5-Dimethyl-adamantan-1-yl)-4-bromo-benzenesulfonamide
(6) N-Adamantan-1-yl-4-trifluoromethyl-benzenesulfonamide
The 1H and 13C NMR spectra for newly synthesised compounds
5-10 are presented in Figures 1SI and 2SI, respectively. DSC
(7),
N-(3,5-Dimethyl-adamantan-1-yl)-4-trifluoromethyl-
(8), N-Adamantan-1-yl-4-nitro-
curves of fusion processes are shown in Figure 3SI, and FT-IR
spectra are presented in Figure 4SI. The numeration of carbon
atoms used for the band assignment from the 13C spectra is
presented in Scheme 1SI.
benzenesulfonamide
benzenesulfonamide (9), and N-(3,5-Dimethyl-adamantan-1-
yl)-4-nitro-benzenesulfonamide (10) (Figure 1). The hydrogen-
bonding properties of named compounds are limited by the
presence of bulky hydrocarbon fragments, allowing one to
study the interplay of interactions which govern the molecular
arrangement and packing efficiency in crystal. Hence, the aim
of the present investigation was to analyse the influence of
substituent nature and molecular topology on the molecule
conformational state and the formation of crystal lattice
architecture using a variety of topology-based computational
approaches.
N-Adamantan-1-yl-4-bromo-benzenesulfonamide (5
). 1H NMR
(200 MHz, CDCl3), δ, ppm: 1.54 (m, 6H, AdH), 1.75 (m, 6H,
AdH), 2.00 (br. s., 3H, AdH), 4.82 (br. s., 1H, NH), 7.60 (d, J =
8.60 Hz, 2H, ArH), 7.78 (d, J = 8.60 Hz, 2H, ArH).
13C NMR (50 MHz, δ, CDCl3): 29.60 (C14, C15, C16), 35.94 (C8, C9,
C10), 43.17 (C11, C12, C13), 55.55 (C7), 127.04 (C1), 128.65 (C2, C6),
132.29 (C3, C5), 143.29 (C4).
Tm = 217.7 ± 0.2 °C. . Yield 81.5%. Found (%): C, 52.03; H, 5.29;
N, 3.42. C16H20BrNO2S. Calculated (%): C, 51.90; H, 5.44; N,
3.78.
R1
Experimental
R1
O
O
R3
R3
2.1 Synthesis and identification
S
Cl
H2N
+
N
S
R2
R2
H
O
O
2.1.1 General procedure of the synthesis of the compounds
studied. Synthesis of the novel sulfonamide derivatives was
carried out according to Scheme 1.
III
II
I
Scheme 1. The scheme of synthesis of novel sulfonamides.
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C8CE00426A
N-(3,5-Dimethyl-adamantan-1-yl)-4-bromo-benzenesulfon-
amide (
). 1H NMR (200 MHz, CDCl3), δ, ppm: 0.80 (s, 6H,
2.2 Single crystals preparation
6
Single crystals of compounds 4-10 were grown from 96%
ethanol by slow evaporation. A powder sample of the
substance was fully dissolved at room temperature to yield a
clear solution. The solution was filtered through a 0.22 µm
PTFE syringe filter into a glass vial, then the vial was sealed by
Parafilm® with few small holes pierced and the solvent was
allowed to evaporate at room temperature for 3-5 days. For
compound 13, one did not manage to obtain the diffraction
quality crystals of sufficient size using this method.
2CH3), 1.08 (s, 2H, AdH), 1.25 (m, 4H, AdH), 1.44 (m, 4H, AdH),
1.60 (m, 2H, AdH), 2.07 (m, 1H, AdH), 5.07 (br. s., 1H, NH), 7.65
(d, J = 8.60 Hz, 2H, ArH), 7.80 (d, J = 8.60 Hz, 2H, ArH).
13C NMR (50 MHz, δ, CDCl3): 29.93, 30.09 (C14, C15, C16), 32.63
(2CH3), 41.36, 42.14 (C8, C9, C10), 49.14, 50.12 (C11, C12, C13),
56.97 (C7), 126.91 (C1), 128.49 (C2, C6), 132.18 (C3, C5), 143.12
(C4).
Tm = 170.6 ± 0.2 °C. Yield 68.3%. Found (%): C, 54.53; H, 6.09;
N, 3.44. C18H24 BrNO2S. Calculated (%): C, 54.27; H, 6.07; N,
3.52.
2.3 X-ray diffraction experiments
N-Adamantan-1-yl-4-trifluoromethyl-benzenesulfonamide
(7).
Experimental data from single crystals
on
Bruker SMART APEX2 diffractometer23 (Table 1).
Absorption for and was taken into account by a semi-
empirical method based on equivalents using SADABS
software24 Experimental data from single crystals
and were
obtained on Bruker Oxford Diffraction Xcalibur
diffractometer25 (Table 1). Absorption for
and was taken
5, 7-10 were obtained
1H NMR (200 MHz, CDCl3), δ, ppm: 1.56 (m, 6H, AdH), 1.76 (m,
6H, AdH), 1.99 (br. s., 3H, AdH), 5.00 (br. s., 1H, NH), 7.74 (d, J
= 8.06 Hz, 2H, ArH), 8.03 (d, J = 8.06 Hz, 2H, ArH).
13C NMR (50 MHz, δ, CDCl3): 29.60 (C14, C15, C16), 35.89 (C8, C9,
C10), 43.19 (C11, C12, C13), 55.81 (C7), 120.77 (C1), 126.18 (C2, C6),
127.49 (C3, C5), 133.89 (CF3), 147.73 (C4).
a
1,
3
4
4
6
a
4
6
Tm = 197.7 ± 0.2 °C. Yield 86.5%. Found (%): C, 56.53; H, 5.49;
N, 3.62. C17H20F3NO2S. Calculated (%): C, 56.81; H, 5.61; N,
3.90.
into account by a semi-empirical method based on equivalents
using CrysAlis RED software.25 The structures were determined
using a combination of the direct method and Fourier
syntheses. All the calculations were carried out using SHELXL-
2016 software.26
N-(3,5-Dimethyl-adamantan-1-yl)-4-trifluoromethyl-benzene-
sulfonamide (8
). 1H NMR (200 MHz, CDCl3), δ, ppm: 0.79 (s, 6H,
2CH3), 1.08 (s, 2H, AdH), 1.24 (m, 4H, AdH), 1.45 (m, 4H, AdH),
1.61 (m, 2H, AdH), 2.08 (m, 1H, AdH), 4.83 (br. s., 1H, NH), 7.76
(d, J = 8.32 Hz, 2H, ArH), 8.03 (d, J = 8.32 Hz, 2H, ArH).
13C NMR (50 MHz, δ, CDCl3): 29.99, 30.22 (C14, C15, C16), 32.78
(2CH3), 41.41, 42.21 (C8, C9, C10), 49.28, 50.19 (C11, C12, C13),
57.33 (C7), 120.74 (C1), 126.16 (C2, C6), 127.46 (C3, C5), 133.97
(CF3), 147.66 (C4).
2.4 Calculation procedure
2.4.1 Free molecular volume calculation. The free molecular
volume in the crystal lattice was estimated on the basis of the
X-ray diffraction data and van-der-Waals molecular volume
(Vvdw), calculated by GEPOL: 27
free
V
= (Vcell − Z ⋅V vdw ) / Z
(1)
Tm = 111.6 ± 0.2 °C. Yield 87.5%. Found (%): C, 58.63; H, 6.09;
N, 3.42. C19H24F3NO2S. Calculated (%): C, 58.90; H, 6.24; N,
3.61.
N-Adamantan-1-yl-4-nitro-benzenesulfonamide (9
). 1H NMR
where Vcell is the volume of the unit cell, Z is the number of
molecules in the unit cell.
2.4.2 XPac analysis. The quantitative analysis of packing
similarity was performed using XPac v. 2.0.2.28 This method
allows finding the isostructural supramolecular constructs
within the pairs of crystals by comparing the relative position
and orientation of identical molecular graphs named ‘common
sets of points’ in clusters which imitate the crystal
environment of a molecule. The measure of packing similarity
is the dissimilarity index X, which shows the difference in
angles δa and interplanar angles δp, and stretch parameter D,
which indicates the difference in distances between the
nearest identical fragments. Lattice parameters and positions
of all heavy atoms used in the calculation were taken from the
(200 MHz, CDCl3), δ, ppm: 1.60 (m, 6H, AdH), 1.81 (m, 6H,
AdH), 2.04 (br. s., 3H, AdH), 4.76 (br. s., 1H, NH), 8.10 (d, J =
8.80 Hz, 2H, ArH), 8.35 (d, J = 8.80 Hz, 2H, ArH).
13C NMR (50 MHz, δ, CDCl3): 29.58 (C14, C15, C16), 35.85 (C8, C9,
C10), 43.23 (C11, C12, C13), 56.08 (C7), 124.41 (C2, C6), 128.00 (C1),
128.30 (C3, C5), 149.90 (C4).
Tm = 226.2 ± 0.2 °C. Yield 80.7%. Found (%): C, 57.42; H, 5.69;
N, 8.42. C16H20N2O4S. Calculated (%): C, 57.13; H, 5.99; N, 8.33.
N-(3,5-Dimethyl-adamantan-1-yl)-4-nitro-benzenesulfonamide
(
10). 1H NMR (200 MHz, CDCl3), δ, ppm: 0.80 (s, 6H, 2CH3), 1.09
(s, 2H, AdH), 1.26 (m, 4H, AdH), 1.46 (m, 4H, AdH), 1.62 (m, 2H,
AdH), 2.08 (m, 1H, AdH), 5.12 (br. s., 1H, NH), 8.08 (d, J = 8.60
Hz, 2H, ArH), 8.33 (d, J = 8.60 Hz, 2H, ArH).
13C NMR (50 MHz, δ, CDCl3): 29.99, 30.22 (C14, C15, C16), 32.81
(2CH3), 41.54, 42.17 (C8, C9, C10), 49.31, 50.15 (C11, C12, C13),
57.63 (C7), 124.39 (C2, C6), 127.01 (C1), 128.26 (C3, C5), 149.84
(C4).
X-Ray experiment.
A
cluster of 15 molecules with
intermolecular atom-atom distance shorter than sum of van-
der-Waals radii of contact atoms + 1.5 Å was considered for
each crystal. Medium-level threshold values for parameters δa
and δp were used, which equals 10° and 14°, respectively.
2.4.3 Hydrogen bond energy calculation. The hydrogen
bonding energy was calculated with the help of Mayo et al.29
force field:
Tm = 159.6 ± 0.2 °C. Yield 88.5%. Found (%): C, 59.53; H, 6.49;
N, 7.42. C18H24N2O4S. Calculated (%): C, 59.32; H, 6.64; N, 7.69.
EHB = DHB ⋅[5(Rhb / RDA )12 − 6(Rhb / RDA )10 ]⋅cos4 (θDHA
)
(2)
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ARTICLE
Journal Name
where DHB = 39.7 kJ·mol-1 is a depth of potential well of pair interactions between atoms of different types into the surface
potential at creation of hydrogen bond of H2O dimer; Rhb=2.75 were calculated basing on the normalised distance of
44
Å; RDA, θDHA are the distance and angle between donor and intermolecular contact dnorm between different pairs of
acceptor atoms.
nuclei calculated as:
2.4.4 Solid-state DFT calculations followed by QTAIMC
analysis of periodic electron density. Density functional
theory computations with periodic boundary conditions (solid-
state DFT) were performed in the CRYSTAL14 software
package30 using meta-GGA B3LYP functional in localised 6-
31G(d,p) basis set. The B3LYP/6-31G(d,p) approximation was
proven to provide reliable and consistent results in studying
the intermolecular interactions in crystals.31 Since dispersive
interactions are supposed to contribute significantly into the
stability of the crystal lattice, the D2 empirical correction by
Grimme et al. was used in periodic wavefunction
calculations.32 The unit cell parameters and positions of heavy
atoms determined with high accuracy from low-temperature
X-Ray diffraction experiment were fixed, while the coordinates
of hydrogen atoms were optimised for all structures. Bader
analysis33 of periodic electron density, or QTAIMC34 was
performed in TOPOND14,35 and search for (3;-1) critical points
was conducted between the pairs of atoms within the 5 Å
radius around each symmetry-inequivalent atom in unit cell.
The following electron-density features at the bond critical
point were computed for every non-covalent interaction: (i)
the values of the electron density, ρb, (ii) the Laplacian of the
electron density, 2ρb, and (iii) the positively defined local
electronic kinetic energy density, Gb. The threshold on ρb for
considered interactions was set as 0.003 a.u. since weaker
interactions are too small for determination by existing
experimental and computational methods.34 The energy of the
particular single non-covalent interaction Eint was estimated
using the equation proposed by Mata et al.: 36
di − rvdW de − rvdW
i
e
dnorm
=
+
(5)
rvdW
rvdW
i
e
Here ri and re are the van-der-Waals radii of contact atoms
inside and outside the Hirshfeld surface.
Results and Discussion
3.1 Crystal structure analysis
The results of X-ray diffraction experiments are presented in
Table 1. The numbering of atoms of the considered
compounds was unified and exemplified by compound 3
(Figure 2). Hydrogen bond geometry and graph set notations
of the studied molecules are summarised in Table 2. Thermal
ellipsoids for compounds 4-10 are shown in Figure 5SI.
It would be also interesting to compare the molecular packing
motifs in studied crystals and in the crystals of structurally
similar compounds. For this purpose, we used a row of
thiourea derivatives reported by Saeed et al.18,45-47 and Al-
Wahaibi et al.5 and
a number of adamantane-based
carboxamides reported by various groups and extracted from
Cambridge Structural Database. The crystallographic data and
CSD refcodes for these compounds are listed in Table 1SI. Of
these crystals, 16 adamantane-substituted carboxamides form
C(4), compared to only two structures (VICHAR and VUXCOI)
from this row with dimer organization. However, in case of
structurally different adamantane derivatives of thiourea, the
various types of ring motifs occur in 10 of 11 crystals. The
reasons for this disproportion are clarified below.
−1
E (kJ ⋅ mol ) = 1147 ⋅ G(a.u.)
(3)
int
b
The hydrogen bonds of the selected crystals form networks
with various topological structures. To analyse the hydrogen
bond networks topology, we used graph set notation
terminology introduced by Etter48 and supplemented by
Bernstein.49 The comparative characteristics of the hydrogen
bonds geometry and matrix of the topological graphs
describing hydrogen bond networks topology of the molecular
crystals are presented in Table 2. The topological graphs
Equation (7) yields reasonable Eint values for molecular crystals
with different types of intermolecular interactions: H-bonds,
C−H···O, H···H and π-stacking contacts, etc. 37
Total cohesion energy38 was calculated as sum of energies of
all intermolecular interactions in the asymmetric unit as
described elsewhere:
Elatt
=
E
(4)
∑∑
int, j,i
i
j<i
where Eint,j,i is the energy of
a
particular non-covalent
interaction. Indices j and i denote the atoms belonging to
different molecules. The presented approach provides
reasonable values for single-component39 and two-
component40, 41 molecular crystals.
2.4.5 Hirshfeld surface analysis. The analysis of Hirshfeld
surfaces42 of molecules within the crystal was performed in
CrystalExplorer v.3.1.43 The surface resolution was set to ‘Very
High’. The distances from the Hirshfeld surface to the nearest
nucleus outside and inside the surface (de and di, respectively)
were plotted into a 2D fingerprint map. The contributions from
Figure 2. Unified numbering of atoms of the considered compounds (exemplified
by compound 3)
4 | J. Name., 2012, 00, 1-3
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a
Table 1. Crystal data and structure refinement for 4-10
.
Compound
Formula
CCDC code
crystal system
space group
crystal size, mm
a, Å
4
5
6
7
8
9
10
C18H24ClNO2S C16H20BrNO2S C18H24BrNO2S C17H20F3NO2S C19H24F3NO2S C16H20N2O4S C18H24N2O4S
1590179
monoclinic
P21/c
1590180
monoclinic
P21/c
1590181
monoclinic
P21/c
1590182
monoclinic
C2/c
1590183
monoclinic
P21/c
1590184
monoclinic
P21/c
1590185
monoclinic
P21/c
0.30×0.27×0.25 0.4×0.28×0.2 0.38×0.31×0.29 0.36×0.28×0.2 0.4×0.28×0.2 0.4×0.32×0.2 0.3×0.28×0.24
10.3869(3)
15.4759(3)
11.2824(3)
105.723(3)
1745.75(8)
4
11.0548(8)
6.4659(4)
21.6540(14)
102.382(2)
1511.81(17)
4
10.5014(3)
15.4718(4)
11.3326(3)
106.420(3)
1766.18(9)
4
29.081(2)
6.8576(6)
10.7288(4)
15.5406(6)
11.0672(8)
6.4621(5)
10.5834(3)
15.2084(5)
b, Å
c, Å
β, o
volume, Å3
19.1376(16)
11.6218(5) 21.5494(16) 11.6137(3)
123.701(2) 106.4540(10) 103.132(2) 107.1010(10)
3175.1(4)
8
1858.37(13) 1500.85(19) 1786.66(9)
Z
4
4
4
Dcalc, g·cm-3
radiation
1.346
1.627
1.498
1.504
Mo Kα
1.385
Mo Kα
150(2)
0.216
1.489
Mo Kα
1.355
Mo Kα
Mo Kα
Mo Kα
Mo Kα
150(2)
0.247
150(2)
0.239
120(2)
0.207
T, K
μ, mm-1
100(1)
0.347
150(2)
2.861
150(1)
2.455
Data collection
measured reflections
independent reflections
independent reflections with I >
2σ(I)
7663
3974
16988
5149
16291
7633
21520
4464
27756
6393
18790
4388
21605
5681
3243
3856
5678
3495
5285
3378
4776
Rint
0.0214
29.18
0.0477
32.078
0.0225
35.839
0.0507
28.87
0.033
32.03
0.0455
30.07
0.0333
31.51
o
Θmax
,
Refinement
F2
refinement on
R1 [F2>2σ(F2)]
wR (F2)
F2
F2
F2
F2
F2
F2
0.0394
0.0370
0.0912
1.044
3974
0.0368
0.0968
0.994
5149
0.0366
0.0876
0.998
7633
304
0.0687
0.1875
1.277
4464
0.0473
0.1435
1.124
6393
0.0437
0.1071
1.000
4388
0.115
1.018
5681
322
S
reflections
parameters
(Δ/σ)max
Δρmax, e·Å-3
Δρmin, e·Å-3
304
270
279
309
288
<0.001
0.333
-0.384
295.9
140.5
47.5
0.002
0.518
-0.593
272.9
105.1
38.5
0.002
0.521
-0.736
302.6
138.9
45.9
<0.001
1.224
-0.409
274.8
122.0
44.4
<0.001
0.975
-0.599
305.3
159.3
52.2
<0.001
0.464
-0.388
269.2
106.0
39.4
0.001
0.486
-0.337
301.8
144.9
48.0
vdw , Å3
free , Å3
V
V
, %
β
=V free /V vdw
К =V vdw /Vmol
, %
67.8
72.2
68.5
69.2
65.7
71.8
67.6
a Standard deviations are presented in brackets
occurring in the studied crystals are shown in Scheme 2. group: N-adamantanyl-acetamide50 (refcode: ROLCOK01) and
According to Table 2, all compounds under study can be N-(dimethyladamantanyl)-formamide51 (refcode: VICHAR).
divided into three groups. The first group contains compound Even in such a simple system, the difference in hydrogen bong
1
which does not form N-H···O hydrogen bonds. The second topology is observed: an adamantane derivative forms C(4) H-
group includes the compounds which form hydrogen-bonded bonded chains, while an memantine-based compound is
chains with four involved atoms C(4) ( 11). packed into centrosymmetric dimers (Figure 6SI). Note
Compounds with the adamantane fragment excluding
R22 (8)
belong that for crystal VUXCOI52 with limited conformational mobility
3, 5, 7, 9,
1
to this group. Finally, the third group consists of the also forms dimers instead of chains.
compounds with dimer organisation of hydrogen bonds (with It would be interesting to analyse whether the hydrogen bonds
2
graph set notation
), which have memantine fragment in chains and dimers differ in strength from one another. In
R2 (8)
(2, 4, 6, 8, 10, 12, 14) in their structure. We consider that the order to compare it, the energies of N−H···O bonds were
differences in hydrogen bond motifs are based on steric evaluated using equation (2) (Table 2) as well as using
hindrances that occur in the molecules with the memantine QTAIMC. It was found that the average absolute value of
fragment, so methyl groups impede the formation of C(4) hydrogen bonding energy in chains is somewhat lower than in
infinite chains. The impact of memantine/adamantane dimers (10.6 < 15.3 kJ·mol-1). Besides that it should be noted
substituent on the hydrogen bond topology is confirmed by that the energy of hydrogen bond within the chain in
comparing the crystal structures of compounds consisting only compound 11 is unusually low (-2.6 kJ·mol-1) compared to the
from an adamantane/memantine cage and an alkylamide mean value (-10.6 kJ·mol-1).
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ARTICLE
Journal Name
R2
O2
S
O1
R1
N
H
R1
H
N
R
O2
S
R2
O1
H
H
N
S
O2
S
N
O1
H
R1
N
O1
O2
S
O2
O1
R2
H
O1
N
S
R1
R2
O2
R
Scheme 2. Different hydrogen bond topologies observed in studied crystals: infinite
chains (left) and cyclic dimers (right).
E
Figure 3. Dependence between τ1 and hydrogen bond energy ( HB ) estimated using
equation (2). Numbering corresponds to Figure 1. The red points correspond to the
compounds with C(4) hydrogen bonds topology, whereas the black points – the ones
3.1.1 Molecular conformational analysis. The conformational
states of the investigated molecules depend on the mobility of
the sulfonylamide link, connecting phenyl rings and
R22 (8)
with
topology.
The molecular packing of compounds
similar to one another. For molecules
already described in one of our previous works21 (Figure 7SI a
and b). Figure 4 (a, b, c) shows the packing projections for
. Molecular packing can be presented in the following way.
3
,
5
,
7
,
9
,
11 are very
adamantane fragment. The torsion angle
∠C2-C1-S1-N1 (τ1)
3
and 11 they have been
between the SO2-group and the phenyl motif Ph (C1-C2-C3-C4-
C5-C6) has been chosen to describe the conformational state.
Since the bridge atoms are involved into hydrogen bonding,
we have attempted to find a correlation between the angle τ1
and the strength of a corresponding hydrogen bond (EHB).The
results are displayed in Figure 3. It is not hard to see that as
the hydrogen bond strength gets higher, the τ1 value
decreases. Moreover, τ1 for the substances that form infinite
5, 7,
9
The hydrogen bonds appearing between the sulfonamide
bridges form helicoids parallel to (OY)-axis. The centres of the
helicoids are located in 1/4 and 3/4 of the (OZ) distance. In
turn, the mentioned chains interact with each other in the
crystal by van-der-Waals’s forces (Figure 4a).
C(4) chains (red dots) is higher compared to the dimer-forming
2
The molecules are packed into layers, one of which being
displayed in the (ZOX) plane in Figure 4a. Within the plane, the
alternation of pairs of phenyl and adamantane fragments can
be distinguished in certain directions. In adjacent directions,
the phenyl fragments interact with the same fragment via the
pi-stacking from the one side. The substituents in para-
(
- black dots).
R2 (8)
3.1.2 Packing architecture analysis. As noted above, for
convenience, studied compounds can be divided into three
groups: compounds without hydrogen bonds
(
1
), those
11) and crystals with
10 12 14).
forming infinite chains C(4) (
dimer structure organisation
3, 5, 7, 9,
2
(
2,
4,
6,
8,
,
,
R2 (8)
Table 2. Hydrogen bonds geometry, graph set notations and hydrogen bond energies (EHB) in the studied compounds calculated by different methods
c
d
DH···Aa
[Å]
DH
[Å]
H···A
[Å]
D···A
[Å]
DH···A
[°]
-EHB(Mayo)
[kJ⋅mol-1]
16.5
14.6
17.2
13.3
8.6
EHB(QTAIMC)
Graph
set notation
R22 (8)
[kJ⋅mol-1]
22.9
21.3
24.9
20.1
20.1
14.0
20.1
20.7
23.8
12.7
23.8
23.9
2 b
3 b
4b
5
N1-H1···O1i
N1-H1···O1i
N1-H1···O1i
N1-H1···O1iv
N1-H1···O1i
N1-H1···O1v
N1-H1···O1vi
N1-H1···O1ii
N1-H1···O1iii
N1-H1···O1i
N1-H1···O1i
N1-H1···O1i
0.932
1.992
2.918
172.4
0.891
2.073
2.949
167.7
C(4)
R22 (8)
0.813
2.074
2.880
171.3
0.83(2)
0.86(2)
0.93(3)
0.87(2)
0.819(19)
0.857(18)
0.860
2.16(2)
2.13(2)
2.25(3)
2.11(2)
2.16(2)
2.051(18)
2.373
2.963(2)
2.882(2)
3.136(2)
2.9647(15)
2.9476(18)
2.8975(12)
3.000
163(2)
146.2
C(4)
R22 (8)
6
7
161(3)
168(2)
162.3(18)
169.2(17)
130.1
9.2
C(4)
R22 (8)
8
14.6
13.4
16.4
2.6
9
C(4)
R22 (8)
10
11b
12b
14b
C(4)
R22 (8)
R22 (8)
0.836
2.070
2.900
172.0
16.9
17.1
0.848
2.048
2.891
172.3
a Symmetry codes: (i) x,y,z; (ii) -x,y+1/2,-z+1/2; (iii) -x,-y,-z; (iv) -x+1,y+1/2,-z+1/2; (v) -x+1/2,y-1/2,-z+1/2; (vi) -x+1,-y+1,-z+1;
b Data taken from our earlier work; 21
c Calculated by Mayo equation; 29
d Calculated by QTAIMC34 using equation (3).36
6 | J. Name., 2012, 00, 1-3
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phenyl and adamantane molecular fragments (Figure 5 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
(a)
(a)
(b)
(c)
(b)
(c)
Figure 4. Molecular packing architectures of crystals 5 (a), 7 (b) and 9 (c).
positions are faced in opposite directions above and below the
plane of the considered layer. From the other side the phenyl
ring forms the close contact with the adamantane fragment
stabilised by van-der-Waals interactions. The crystal lattices of
3
,
5
,
9
,
11 are isomorphous within the P21/c space group and
approximately the same unit cell parameters.
The molecular packing in crystals
several common features. For compounds
2,
4,
6,
8
,
10
, 12, 14 has
2, 12 and 14 these
features have been already described by us earlier21 (Figure 8SI
a, b and c). Fig. 5 (a, b, c, d) shows the molecular packing
projections in compounds
The dimers of molecules
4
,
6
,
8
,
10
.
6
are uniformly packed in the plane
(YOZ), i.e. it is not possible to distinguish any anisotropy within
the plane. In a projection parallel to (XOZ) the dimers of
molecules create alternately interlacing layers, composed of
(d)
Figure 5. Molecular packing architectures of crystals 4 (a), 6 (b), 8 (c) and 10 (d).
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parts of the molecules). In its turn, the “adamantane” layer is packing density compared to parent compound
composed in such way that each adamantane motif NO2 (10), –Cl ( ), –Br ( ). The exceptions are the fluorine-based
alternately extends from the layers located above and below. functional groups: –F (14), –CF3 ( ). Similar to the first group, a
This packing looks like interlaced fingers. Such molecular correlation between -parameter and is observed for
packing allows us to conclude that crystal growth from dimer crystals 10 and 12 (Fig. 6, red dotted line).
2: –CH3 (12), –
a
4
6
8
Vvdw
β
2, 4, 6,
saturated solution is carried out by means of delicate 3.1.3 XPac analysis. The XPac method enables to
adjustment of the adamantane fragments into the quantitatively describe the similarity in crystal packing and to
corresponding layers. Crystal structure data gives opportunity provide a basis for the assessment of isostructurality in studied
to calculate a free volume per molecule ( free) in a crystal and crystals. Moreover, the packing similarity may also indicate the
V
= Vfree/Vvdw
This parameter shows how much the free volume increases as the thermodynamic properties.
analyse molecular packing by using β
parameter. common features in intermolecular interactions and hence, in
the molecular van-der-Waals volume grows. The value of the The chosen common set of points for studied compounds
discussed parameter depends on the molecular topology, the includes all heavy atoms of compound
nature of atoms and the availability of hydrogen bond in molecular structure (see Scheme 2SI). For the dataset of 13
networks. The experimental value of -parameter is a result of crystal structures under study, a matrix of [13 × (13 – 1) / 2] =
crystal lattice Gibbs energy minimisation, including both 78 unique pairs of crystals was considered and the packing
enthalpy and entropy terms. The dependence of the dissimilarity index and stretch parameter were
parameter on vdw is shown in Figure 6. The parent compounds investigated for each pair. The results are presented in Figure
1 with no substituents
β
β
-
X
D
V
of considered rows are the substance
substituent (red points) and substance
1
with adamantane 7.
2
with memantine As shown in Figures 9SI and Scheme 3, the results of XPac
fragment (black points). It is easy to see that the packing analysis confirm our empirical suggestions of packing
densities for most compounds of the second group are similarity. Three sets of crystals with the established 3D
significantly lower (i.e. higher
to the first group. The only exception is the crystal
-parameter is comparable to compounds 11. Considering group, C(4) hydrogen-bonded chains and layered packing of
the substances within each group, the following dependencies alternating pairs of adamantane and phenyl fragments.
can be traced: Compounds 11 belong to this group.
For the first group of compounds, the introduction of bulky 2. A set of memantine derivatives with a large substituent in
fragments –CF3 ( ) and –CH3 (11) into the para-position of the phenyl ring (-Cl, -Br, -NO2, -CF3) crystallizing in P21/c space
phenyl ring reduce the packing efficiency with respect to the group. The features of these crystals are dimer
β
-parameter values) compared isostructurality can be isolated (Figure 10SI a, b and c):
6, for which 1. A set of adamantane derivatives crystallizing in P21/c space
β
1, 7,
3, 5, 9,
7
R22 (8)
), –NO2 structure organisation of hydrogen bonds and interlaced
) – increase the molecular packing density in packing of memantine moieties. This group contains
-parameter decreases). Moreover, for the second compounds 10
subgroup of compounds a linear correlation is observed 3. A set of memantine derivatives with small substituent in
between phenyl ring (-F, -CH3) crystallizing in P21/n space group. Like in
-parameter and vdw (Fig. 6, blue dotted line).
For the second group of compounds, the presence of any the previous set, the hydrogen bonds form dimers. The
original compound
) and –Br (
crystal (
1, whereas the substituents –Cl (3
(
9
5
β
4,
6,
8,
.
β
V
R22 (8)
fragment in para-position of the phenyl ring increases the
memantine cages and phenyl rings of adjacent molecules are
packed into a chain-like manner via C-H···C close contacts
along the
group.
a axis. Only two compounds, 12 and 14, build this
Within a row of similarly packed crystals, lowest values of X
(which means highest degree of packing similarity) are
Figure 6. Dependence of β-parameter (Vfree/Vvdw
corresponds to Figure 1. Red points correspond to compounds with adamantane
fragment, whereas the black points – with memantine fragment.
) . The numbering
versus Vvdw
Scheme 3. Diagram showing the structural relationship between 13 adamantane- and
memantine-substituted sulfonamides with crystal structures determined. The
numeration used is consistent with Figure 1.
8 | J. Name., 2012, 00, 1-3
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observed for the pairs of structures with the substituent of explained by shortening of the H···C distance between the
similar size: -Cl – -CH3, -Cl – -Br, -CH3 – -Br, -NO2 – -CF3 etc. 53
contact atoms. Similar trend can be observed for
Additionally, some low-degree packing similarity can be traced intramolecular C-H···O contacts, however, the pair correlation
for all memantine derivatives (hydrogen-bonded dimer coefficient is lower in this case, since the hydrogen-bonding
organisation – 0D supramolecular construct SC0 in pairs with
12 and 14) as well as C(4) chains within the compounds
11 (1D packing similarity in pairs with 7 – SC1 construct). All In the section 3.1 we have supposed that the strength and
2,
activity of C-H groups in the phenyl ring also depends on the
3, 5, 7,
substituent R.
9,
observed low-dimensional motifs correspond to hydrogen topology of hydrogen bonds in crystal affects the conformation
bond patterns, supporting the idea on the structure-forming of the molecule. Basing on the calculated local density of
role of hydrogen bond in crystals. Compound 1, which does kinetic energy at the (3;-1) critical point obtained from the
not form hydrogen bonds, has completely different molecular solid-state DFT, the energies of N-H···O hydrogen bonds were
arrangement in crystal compared to other substances.
determined using the equation (3). Compared to the
Based on the available data on different isostructural motifs, estimation of hydrogen bong strength using the equation (2),
two crystal packing families can be built in a way presented in this approach yields 35-55% higher values of EHB (Table 2).
Scheme 3. It is clearly seen that the introduction of two bulky Such difference is expected, since QTAIMC is performed on the
methyl fragments into the adamantane ring leads to significant periodic wavefunction taken from DFT calculations and
difference in crystal structures, with no common therefore takes into account the effects of crystal
supramolecular constructs between the derivatives of environment, in contrast to the empirical equation (2). At the
adamantane and memantine. Compound
7 with the unique same time, a similar regularity is observed between the
C2/c space group still has the similar to other substituted energies of dimeric and chain-like hydrogen bonding motifs.
adamantanes arrangement of molecules in hydrogen-bonded The average hydrogen bond energy in the dimers is higher
chains. The same synthon isostructurality is observed for P21/c than in chain structures (23 kJ
and P21/n crystals of memantine derivatives. according to QTAIMC) (Table 2). It is easy to trace the
⋅ ⋅
mol-1 against 18 kJ mol-1
Comparing the structural motifs in considered crystals with the dependence between the N···O distance in crystal and the
ones already known in the literature, one should have in mind hydrogen bond energy evaluated from Mayo force field and
the differences in molecular geometry. The conformation of from QTAIMC (Figure 13SI). Only three compounds (
sulfonamides is bent due to pyramidal orientation of the -SO2- 11) do not fit in the considered correlations. This may be
group, while the molecules of carboxamide and thiourea caused by the significant deformation of the (N-H-O) bond
derivatives are essentially planar. Therefore, XPac could not angle in crystals of and 11 (146.2° и 130.0°, respectively) and
find any packing similarity between the compounds presented higher R-factor compared to other crystals for structure
in this article and the ones found in CSD except a few (R[F2>2 (F2)] = 6.87%).
6, 7 and
∠
6
7
σ
occasional adamantane-to-adamantane dimers.
As an alternative method of examination of the properties of
non-covalent interactions in crystals, Hirshfeld surface analysis
was performed. It was found that the minimum value of the
descriptor dnorm in the hydrogen bonding area determined by
Hirshfeld surface analysis, correlates linearly with the N···O
distance in crystal (Figure 14SI). The similar nature of the
3.2. Analysis of non-covalent interactions in crystals
3.2.1. Pattern of non-covalent interactions in crystals. At the
next stage, solid-state DFT calculations followed by Bader
analysis of theoretical periodic electron density were
performed to quantify the contributions into the lattice
stabilisation from different functional groups and packing
motifs. A set of (3;-1) bond critical points corresponding to
particular non-covalent interactions has been found for each
crystal. The results are presented in Tables 2-14SI.
dependencies presented in Figure 14SI and Figure 3, allows
min
using the quantity
as a descriptor for estimation of
(HB)
hydrogen bonding energy derived using the Mayo equation
d
norm
and QTAIMC analysis with accuracy greater than 1 kJ
(Figure 15SI).
⋅
mol-1.
Aside the N-H···O hydrogen bond, the stabilisation of
molecules in the main synthon for most structures comes from
the formation of additional C-H···O bonds with the proximate
hydrogen atom of adamantane cage (in the case of chain
motifs) or phenyl ring (in case of dimeric organisation)
presented in Figure 7. The energy of these interactions is
QTAIMC analysis reveals that the molecules of all considered
compounds contain an intramolecular C-H···O contact
between the adamantane core and one of oxygen atoms of
the sulfo group (Figure 11SI), characterised by a (3;-1) critical
point with ρb = 0.009÷0.015 a.u. The energy of this contact lies
between 9÷13 kJ
increase of interplanar angle Ph-Ad between phenyl and
⋅
mol-1 (absolute value) and increases with the
nearly constant for adamantanes (7-9 kJ
significantly from crystal to crystal within the row of
memantine derivatives (3-9 kJ
mol-1). The mutual orientation
of molecules within a single chain also promotes the formation
of a short C-H···N contact with the energy of 5-7 kJ
mol-1 in
adamantane-based compounds (2 kJ
mol-1 in compound
⋅
mol-1) and changes
adamantane fragments, since the bond angle
becomes closer to 180° (Figure 12SI). For molecules
∠(C-H-O)
1, 3, 7, 9,
⋅
11
and adamantane fragments is also observed with the energy of
3-6 kJ
mol-1. The strength of this interaction is higher for
, 12 a short intramolecular C-H···π contact between phenyl
⋅
⋅
1,
⋅
which does not form hydrogen bonds). This interaction is
absent in crystals of memantine-substituted molecules which
form centrosymmetric dimers. The topology of intermolecular
molecules with lower angle between the planes Ph-Ad in the
molecule (R2 = 0.89) (Figure 12SI), which can be easily
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stabilisation of the crystal lattice present in the literature56. In
present work, the use of Grimme's D2 dispersion correction32
leads to increase of electron density in the Н···Н contact area
and the number of distinguishable bond critical points,
providing a more detailed description of this interaction type.
It is noteworthy that the average energy of interaction
between two nearest adamantane fragments in crystal
estimated using QTAIMC is significantly higher than the
dissociation of isolated adamantane dimer57 (12 versus 6.4
kJ·mol-1). We suppose that this example illustrates the effect of
crystal environment on the non-covalent interaction energy,
since the H···H distances in considered crystals are significantly
shorter than in the gas-phase dimer.
Figure 7. Examples of intermolecular interactions building hydrogen-bonded synthons
of two different types: infinite chain in compound
compound 10 (b). Coloured numbers represent the interaction energies of hydrogen
bonds (blue) and C-H···O/N contacts (green) estimated from QTAIMC in kJ·mol-1
9 (a) and isolated dimer in
Aside from primary synthons and close contacts, the lattices of
studied molecules contain the C-H···O contacts, where phenyl
and adamantane fragments act as donors and oxygen atoms of
.
interactions in the synthon can be demonstrated using the pair
of compounds and 10 with para-nitro substituent in the
phenyl ring (Figure 7). In addition to already named C-H···O
and C-H···N contacts, the oxygen atom in crystals and is
also coordinated by the weaker interactions with total energy
4.7 and 10.3 kJ
mol-1, respectively. Hence, the total energy of
sulfonamide group as well as nitro group in compounds
9 and
9
10. IUPAC includes these interactions into the class of
hydrogen bonds, highlighting their role in stabilisation of
supramolecular structures.58 The energies of these interactions
vary between 3 and 7 kJ·mol-1 and depend on electron
donating or electron withdrawing nature of substituent in the
phenyl ring (Figure 8). The shortest and strongest C-H···O
contacts are observed in structures containing electron
withdrawing groups in the para-position (-Hal, -CF3, -NO2).
5
7
⋅
non-covalent interactions within the chain motif exceeds the
interaction energy within the dimer (average value is 36
against 28 kJ⋅
mol-1).
Their energy can reach up to 9 kJ⋅
mol-1.
The assessment of stabilisation energies coming from the
satellite C-H···O contacts sheds the light on the formation of
chain-like motifs in crystals of compounds in Table 1SI where
adamantane fragment is bound to the carboxamide moiety
and the dimer-like motifs in thiourea derivatives. Indeed, as
the van-der-Waals radius of the sulfur atom is greater than
one of carbon, it can accept more C-H···S contacts to stabilise
the dimeric structure. A simple evaluation of C-H···S contacts
can be made basing only on metric criteria; however, a
thorough QTAIM analysis is needed to be performed for a
more reasonable conclusion.
The Hirshfeld surface analysis performed in paper by Saeed et
al.18 yields in general close results, with H···H contacts and
hydrogen bonds acting as the main stabilising forces in the
crystal. Similar conclusions can be made from the comparative
analysis of the contributions into the PIXEL lattice energy
performed in the work by Al-Wahaibi et al.5.
In the crystals of halogen-substituted compounds 3-6, 14, the
C-H···Hal contacts build about 8-10% of total lattice energy and
up to 20% for compounds
14 SI). Bader analysis also reveals weak (total energy does not
exceed 7 kJ
mol-1) contacts Hal···X, where X = C, O or N. It is
7 and 8 with –CF3 fragments (Table
It is interesting to note that the isolated N-H···O bond
contributes only 10-20% into the lattice energy, which is lower
than its satellite C-H···O contacts in adamantane-based
⋅
compounds (Figure 8). The fact that crystal
1 with no
conventional N-H···O hydrogen bonds in the structure has
sublimation enthalpy close to other compounds in the row21, 22
also suggests that hydrogen bonds do not contribute
significantly to the stabilisation of crystal structure. The
possible explanation of this phenomenon can be the
domination of H···H contacts, so a structure without any
hydrogen bonds would be more thermodynamically
preferable. Other crystals with N-H group not linked to the
hydrogen bond acceptor include HALQER54 and HUGYAK55. The
common feature of these compounds is the absence of free
strong hydrogen bond-accepting substituents not involved into
intramolecular bonds.
25% to 50% of non-covalent interaction energy comes from
close H···H contacts (Figure 8). This type of interactions
dominates in crystals of adamantane-substituted compounds.
Figure 8. Energies of intermolecular interactions between different atom types in
studied compounds calculated by QTAIMC plotted as percentages of lattice energy. The
There are many evidences of attractive nature of 'hydrophobic' numbers display the total contribution of the interaction in kJ·mol-1. X stands for C, N,
and O atoms.
intermolecular Н···Н interactions and their significance for
10 | J. Name., 2012, 00, 1-3
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also interesting to consider the crystal
where close packing of –CF3 groups causes the F···F interaction
to form with energy equal to 8.2 kJ
mol-1. At the same time,
7 with C2/c symmetry,
⋅
the contribution of C-H···O contacts decreases due to the
competition between acceptor sites as well as steric
hindrances. Similar effect was observed by Al-Wahaibi et al.5
upon introduction of the fluorine atom into the molecule of
the isothiourea derivative, when the F···F contacts partially
replaced H···H contacts in the fingerprint plot of the Hirshfeld
surface.
Generally, the introduction of halogen atoms and halogen-
containing groups does not lead to significant changes in total
lattice energy compared to other substituents except the
structures
7
and
8
, where the total contribution from the
mol-1, or 30%
interactions involving fluorine atoms equals 43 kJ
⋅
Figure 9. Energies of intermolecular interactions between different fragments in
studied compounds calculated by QTAIMC plotted as percentages of lattice energy. The
numbers display the total contribution of the interaction in kJ·mol-1. For fragment
numeration, see Scheme 4.
of Elatt value. Though, it should be noted that the precise
description of non-covalent interactions involving halogen
atoms (especially Hal···X and Hal···Hal) using the DFT
calculations with Gaussian-type orbitals requires the use of
diffuse orbitals, the use of which in solid-state calculations is
not straightforward and may lead to problems with SCF
convergence. As a result, the impact of Hal atoms on
theoretical crystal lattice energy can be significantly
overestimated.
considerably higher in compounds containing in their structure
bulky electron donating groups capable of participating in C-
H···X contacts such as -NO2 and -CF3 (ΣEint
(
A
-
С
) = 38-46 kJ
⋅
⋅
⋅
mol-
mol-
mol-
1), less in compounds with -Cl and -Br fragments (32-38 kJ
1) and minimal in crystals with R = -H, -CH3 and -F (24-30 kJ
1) (Figure 9).
According to Etter’s rules, stronger hydrogen bond donors
tend to interact with stronger acceptors59. For this reason, as
well as due to conformation hindrances, the donors of strong
Whereas the contribution of interactions involving fragment
is mostly determined by nature of the substituent in the
phenyl ring, the energy of interactions of fragment with
A
C-H···X (X = O, Hal) contacts with energy above 5 kJ
usually are more polarised C-H groups in the aromatic ring,
while weaker C-H···X bonds (Eint < 5 kJ
mol-1) and C-H···π
⋅
mol-1
С
surroundings depends more on molecular packing. Of three
sets of isostructural crystals described above, the layered
⋅
packing in crystals
efficient from the point of energetic contributions into the
lattice energy (ΣEint ) = 41-47 kJ
mol-1) (Figure 9). This
arrangement is observed only for compounds with
adamantane fragment. However, adamantane derivatives
and crystallise in different space groups and display
substantially lower contribution of fragment into the lattice
energy. Less energetically favourable packing of memantine
cages in isostructural crystals 10 (ΣEint ) = 24-34
kJ·mol-1) is partially compensated by interactions of methyl
groups with fragments and of adjacent molecules, leading
to the contribution of fragment equal to 42-44% of the Elatt
For comparison, in the set consisting of 11 this value
3, 5, 9, 11 with P21/c symmetry is most
interactions are formed are formed by donor groups of the
adamantane cage.
(
С
-С
⋅
3.2.2. The influence of different molecular fragments on the
energy of non-covalent interactions in crystal. Let us consider
the impact of different functional groups on the energy of non-
covalent interactions in studied crystals. For this purpose we
conventionally split the molecule into three fragments:
1
7
С
fragment
fragment
fragment
A
, which consists of phenyl ring with substituent R,
, which includes the sulfonamide group, and
equivalent to adamantane/memantine cage
4,
6,
8,
(С-С
B
C
,
A
B
(Scheme 4). Thus, we get six components of lattice energy,
which describe different interaction types governing the
C
.
3, 5, 9,
molecular packing. In particular, the
the fraction of N-H···O hydrogen bonding, and
represents the efficiency of
adamantane/memantine fragments in crystal.
B
-
B
contribution shows
contribution
packing of
lies in the range 47-53%. Finally, the least efficient packing of
memantine fragments (38-39% of Elatt value) is observed for
crystals 12 and 14 with P21/n symmetry.
C-C
The close breakdown of lattice energy into main contributions
from intermolecular interactions is observed in Hirshfeld
surface analysis. According to this approach, the main
contribution into the crystal lattice comes from dispersive
H···H interactions, which build from 41% to 72% of Hirshfeld
surface area (Figure 10). The H···O contacts including the N-
H···O and C-H···O hydrogen bonds are on the second place.
These contacts occupy approximately 18% of surface area for
Total contribution from the A-C interactions, which reflects the
mutual affinity of phenyl ring and adamantane fragment, is
most crystals and twice as more for the compounds
9 and 10
with -NO2 fragment. For the crystals containing halogen atoms,
a significant contribution comes from the H···Hal interactions
Scheme 4.
A scheme showing the division of molecule into three conventional
fragments.
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ARTICLE
Journal Name
Conclusions
Six new derivatives of sulfonamides with adamantane and
memantine substituents were synthesised and characterised
by 1H and 13C NMR, FT-IR, DSC and element analysis, their
single crystals were grown and crystal structures determined.
All adamantane derivatives excluding the unsubstituted
compound
1 have the C(4) hydrogen-bonded chains in their
crystal structures, while memantine derivatives display the
R22 (8)
dimer organisation of hydrogen bonds possibly due to
steric hindrances. The energies of N-H···O hydrogen bonds in
chain motifs estimated by QTAIMC and Mayo equation are
found to be lower than in dimers. Taking into account the
satellite C-H···O contacts, the total synthon energy behaves in
the opposite manner, with C(4) chains being more
energetically preferable, in agreement with synthon
occurrence for relative compounds in the CSD. A correlation
between the estimated energies of N-H···O hydrogen bonds
and the minimal dnorm parameter in the bonding area was also
established.
Figure 10. Main contributions of intermolecular contacts between atoms of different
types into the Hirshfeld surface for individual molecules within the crystal structures of
the compounds under study.
(above 10%). Other weaker interactions present in crystal
include the Hal···C/O (1-4%) contacts also visible in QTAIMC
analysis and weak C-H···N bonds (0.7-3%) observed only in
adamantane derivatives. For the compounds containing the
nitro group, uncommon O···O and C···O contacts are present
and build up to 6% of total Hirshfeld surface. C···C contacts are
nearly absent in all considered crystal structures, which
indicates the negligibly small influence of π-stacking on the
stability of the crystal structure. These results are in a good
agreement with data obtained by Saeed et al.18 on six
structurally relative adamantane-substituted thioureas.
The dependence of packing efficiency on the nature of the
substituent in the phenyl ring compared to unsubstituted
parent compounds was studied with the help of the
introduced β-parameter. It was found that the introduction of
–Cl, -NO2 and -Br fragments increase the molecular packing
density in crystal of both adamantane and memantine
derivatives, while the bulky -CF3 fragment has the opposite
effect.
The contributions of interactions of different types into the
Hirshfeld surface significantly depend on substituent type, as
presented in Figure 10. Within the pairs of compounds with
the same substituent in the phenyl ring, the memantine
derivatives mostly have higher percentage of H···H
interactions. The crystals with similar substituents (halogen
XPac analysis has revealed three sets of crystals with the
established 3D isostructurality with different packing
arrangement of phenyl and adamantane fragments. No
common supramolecular constructs were found between the
adamantane and memantine derivatives, while the 0D (dimer)
and 1D (chain) hydrogen-bonded motifs persist for all
compounds within these packing families.
atoms in structures 3, 4, 5, 6, 14) also have similar distribution
of contacts. An unusually high contribution of contacts
involving halogen atoms is observed in structures of CF3-
Solid-state DFT calculations followed by QTAIMC analysis of
periodic electron density and Hirshfeld surface analysis
allowed us to quantify the non-covalent interactions in crystals
and their contribution into the lattice energy. The main
contributions into the lattice energy are dispersive H···H
contacts and weak hydrogen bonds. The layered packing of
adamantane fragments in the group of isostructural
adamantane derivatives with P21/c symmetry was found to be
the most efficient, while the group of memantine derivatives
with P21/n symmetry demonstrates the least energetically
favourable packing type.
substituted compounds
7 and 8. Additionally, compound 7
forms a unique intermolecular F···F contact which is absent in
other crystals. QTAIMC analysis also reveals this interaction. In
crystals of molecules
1, 2, 11, 12, which contain in their
structure no substituents capable of specific bonding, the
fraction of H···H contacts is increased.
Fingerprint plots presented in Figures 16SI and 17SI can also
provide some information on the nature of non-covalent
interactions and their relative strength. The position and size
of the side bonding areas in the plot of H···O contacts
corresponding to weak (di, de ≥ 1.6 Å) C-H···O contacts indicate
the ratio of this interactions in the lattice energy.
Characteristic lateral areas, corresponding to specific H···Hal
contacts, are shifted into the region of smaller distances for
shorter H···F contacts and toward the far region for contacts
with more bulky atoms Cl and Br. The size and position of
these areas indicates the bonding energy in these contacts.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The synthetic part of the work has been done within the
framework of 2018 year National Program (№ 0090-2017-
0023). Crystallographic and theoretic pars of the work have
been done within the framework of 2018 year National
12 | J. Name., 2012, 00, 1-3
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30 R. Dovesi, R. Orlando, A. Erba, C. M. Zicovich-Wilson, B.
Civalleri, S. Casassa, L. Maschio, M. Ferrabone, M. De La
Pierre, P. D’Arco, Y. Noël, M. Causà, M. Rérat and B. Kirtman,
Int. J. Quantum Chem., 2014, 114, 1287-1317.
31 S. A. Katsyuba, M. V. Vener, E. E. Zvereva, Z. Fei, R. Scopelliti,
J. G. Brandenburg, S. Siankevich and P. J. Dyson, J. Phys.
Chem. Lett., 2015, 6, 4431-4436.
Program (№ 0092-2014-0005). We thank “the Upper Volga
Region Centre of Physicochemical Research” for technical
assistance with the XRPD experiments. X-ray diffraction studies
were performed at the Centre of Shared Equipment of IGIC
RAS.
32 S. J. Grimme, J. Comput. Chem., 2006, 27, 1787–1799.
33 R. F. W. Bader, Atoms in Molecules - A Quantum Theory.
Oxford University Press: Oxford, 1990.
34 V. G. Tsirelson and R. P. Ozerov, Electron Density and
Bonding in Crystals. Bristol, England / Philadelphia, USA:
Institute of Physics Publishing. 1996.
Notes and references
1
2
J. Drew, Science, 2000, 287, 1960-1964.
T. Owa and T. Nagasu, Exp. Opin. Ther. Patents, 2000, 10
1725-1740.
,
3
4
5
C. W. Thornber, Chem. Soc. Rev., 1979,
A. E. Boyd, Diabetes, 1988, 37, 847-850.
L. H. Al-Wahaibi, H. M. Hassan, A. M. Abo-Kamar, H. A.
Ghabbour and A. A. El-Emam, Molecules, 2017, 22, 710-722.
A. A. El-Emam, K. A. Alrashood, M. A. Al-Omar and A.-M. S.
Al-Tamimi, Molecules, 2012, 17, 3475-3483.
C. T. Supuran and A. Scozzafava, Exp. Opin. Ther. Patents,
2002, 12, 217-242.
C. T. Supuran, A. Scozzafava and A. Casini, Med. Res. Rev.,
2003, 23, 146-189.
8, 563-580.
35 C. Gatti and S. Casassa, TOPOND14 User’s Manual, CNR-ISTM
Milano, Milano, 2014.
36 I. Mata, I. Alkorta, E. Espinosa and E. Molins, Chem. Phys.
Lett., 2011, 507, 185-189.
37 M. V. Vener, E. O. Levina, O. A. Koloskov, A. A. Rykounov, A.
6
7
8
9
P. Voronin and V. G. Tsirelson, Cryst. Growth Des., 2014, 14
4997-5003.
,
38 P. M. Dominiak, E. Espinosa and J. Ángyán, In Modern Charge
Density Analysis; Editors: C. Gatti and P. Macchi, Springer,
Heidelberg, 2012, 387-433.
39 Y. A. Abramov, A. Volkov, G. Wu and P. Coppens, J. Phys.
Chem. B, 2000, 104, 2183-2188.
40 A. N. Manin, A. P. Voronin, A. V. Shishkina, M. V. Vener, A. V.
G. S. Hassana, A. A. El-Emam, L. M. Gad and A. E. M.
Barghash, Saudi Pharm. J., 2010, 18, 123-128.
10 C. T. Supuran and A. Scozzafava, Exp. Opin. Ther. Patents,
2000, 10, 575-600.
11 R. C. Ogden and C. W. Flexner, Protease Inhibitors in AIDS
Therapy; Marcel Dekker: New York, 2001.
12 C. T. Supuran, A. Scozzafava and B. W. Clare, Med. Res. Rev.,
2002, 22, 329-372.
13 A. Scozzafava and C. T. Supuran, J. Med. Chem., 2000, 43
3677-3687.
14 K. Spilovska, F. Zemek, J. Korabecny, E. Nepovimova, O.
Soukup, M. Windisch and K. Kuca, Curr. Med. Chem., 2016,
23, 3245-3266.
15 A. Stimac, M. Sekutor, K. Mlinaric-Majerski, L. Frkanec and R.
Frkanec, Molecules, 2017, 22, 297.
16 É. A. Shokova and V. V. Kovalev, Pharm. Chem. J., 2016, 50
3-15.
17 J. Liu, D. Obando, V. Liao, T. Lifa and R. Codd, Eur. J. Med.
Chem., 2011, 46, 1949-1963.
18 A. Saeed, M. Bolte, M. F. Erben and H. Pérez, CrystEngComm,
2015, 17, 7551-7563.
19 G. L. Perlovich, N. N. Strakhova, V. P. Kazachenko, T. V.
Volkova, V. V. Tkachev, K.-J. Schaper and O. A. Raevsky, Int. J.
Pharm., 2008, 349, 300-313.
20 G. L. Perlovich, A. M. Ryzhakov, V. V. Tkachev, L. Kr. Hansen
and O. A. Raevsky, Cryst. Growth Des., 2013, 13, 4002-4016.
21 G. L. Perlovich, A. M. Ryzhakov, V. V. Tkachev and A. N.
Proshin, CrystEngComm, 2015, 17, 753-763.
22 G. L. Perlovich, T. V. Volkova, A. V. Sharapova, V. P.
Kazachenko, N. N. Strakhova and A. N. Proshin, PCCP, 2016,
18, 9281-9294.
Churakov and G. L. Perlovich, J. Phys. Chem. B, 2015, 119
10466-10477.
,
41 A. O. Surov, A. V. Churakov and G. L. Perlovich, Cryst. Growth
& Des., 2016, 16, 6556-6567.
42 M. A. Spackman and D. Jayatilaka, CrystEngComm, 2009, 11
19-32.
,
,
43 S. K. Wolff, D. J. Grimwood, J. J. McKinnon, M. J. Turner, D.
Jayatilaka and M. A. Spackman, CrystalExplorer, Version 3.1.
University of Western Australia, Crawley, Australia, 2012.
44 J. J. McKinnon, D. Jayatilaka and M. A. Spackman, Chem.
Commun., 2007, 3814-3816.
45 A. Saeed, M. F. Erben and M. Bolte, Spectrochim. Acta A,
2013, 102, 408-413
46 A. Saeed, U. Florke and M. F. Erben, J. Mol. Struct., 2014,
1065, 150-159.
47 A. Saeed, Z. Ashraf and M. F. Erben, J. Simpson, J. Mol.
Struct., 2017, 1129, 283-291.
48 M. C. Etter, J. C. McDonald and J. Bernstein, Acta Cryst. 1990,
B46, 256-262.
49 J. Bernstein, R. E. Davis, L. Shimoni and N-L. Chang, Angew.
Chem. Int. Ed. Engl., 1995, 34, 1555-1573.
50 H.-H. Prohl, A. Blaschette and P. G. Jones, Acta Cryst., 1997,
,
C
53, 1434-1436.
51 L. Wanka, C. Cabrele, M. Vanejews and P. R. Schreiner, Eur. J.
Org. Chem., 2007, 1474-1490.
52 R. Hrdina, F. M. Metz, M. Larrosa, J.-P. Berndt, Y. Y.
Zhygadlo, S. Becker and J. Becker, Eur. J. Org. Chem., 2015,
6231-6236.
23 Bruker (2007). APEX2 and SAINT. Bruker AXS Inc., Madison,
Wisconsin, USA.
24 G. M. Sheldrick, SADABS. University of Göttingen, Germany,
1997.
53 T. Gelbrich, T. L. Threlfall and M. B. Hursthouse,
CrystEngComm, 2012, 14, 5454-5464.
54 J. K. Maurin, W. Lasek, A. Gorska, T. Switaj, A. B. Jakubowska
and Z. Kazimierczuk, Chem. Biodiversity, 2004, 1, 1498-1512.
25 Oxford Diffraction (2009). CrysAlis CCD and CrysAlis RED
Oxford Diffraction Ltd, Yarnton, England.
26 G. M. Sheldrick. Crystal structure refinement with SHELXL.
Acta Cryst., 2015, C71, 3-8.
55 A. A. Fokin, A. Merz, N. A. Fokina, H. Schwertfeger, S. L. Liu, J.
E. P. Dahl, R. M. K. Carlson and P. R. Schreiner, Synthesis,
2009, 909-912.
56 M. V. Vener, A. N. Egorova, D. P. Fomin and V. G. Tsirelson, J.
Phys. Org. Chem., 2009, 22, 177-185.
57 J. Echeverría, G. Aullón, D. Danovich, S. Shaik and S. Alvarez,
27 J. L. Pascual-Ahuir and E. Silla, J. Comput. Chem., 1990, 11
1047-1060.
,
28 T. Gelbrich, D. S. Hughes, M. B. Hursthouse and T. L. Threlfall,
CrystEngComm, 2008, 10, 1328-1334.
29 S. L. Mayo, B. D. Olafson and W. A. Goddard III, J Phys.
Chem., 1990, 94, 8897-8909.
Nature Chemistry, 2011, 3, 323-330.
58 E. Arunan, G. Desiraju, R. Klein, J. Sadlej, S. Scheiner, I.
Alkorta, D. C. Clary, R. H. Crabtree, J. J. Dannenberg, P.
Please do not adjust margins

Please do not adjust margins
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ARTICLE
Hobza, H. G. Kjaergaard, A. C. Legon, B. Mennucci and D. J.
Journal Name
Nesbitt, Pure and Appl. Chem., 2011, 83, 1619-1636.
59 M. C. Etter, Acc. Chem. Res. 1990, 23, 120-126.
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