Synthesis, structural elucidation, characterization and theoretical DFT study of 1-(o-tolyl)biguanidium chloride

Article abstract of DOI:10.1107/S2053229620006336

The structure of the new salt 1-(o-tolyl)biguanidium chloride, C9H14N5 ⁺·Cl^-, has been determined by single-crystal X-ray diffraction. The salt crystallizes in the monoclinic space group C2/c. In this structure, the chloride and biguanidium hydrophilic ions are mostly connected to each other via N-H?N and N-H?Cl hydrogen bonds to form layers parallel to the ab plane around y = and y = . The 2-methylbenzyl groups form layers between these layers around y = 0 and y = , with the methyl group forming C-H?π interactions with the aromatic ring. Intermolecular interactions on the Hirshfeld surface were investigated in terms of contact enrichment and electrostatic energy, and confirm the role of strong hydrogen bonds along with hydrophobic interactions. A correlation between electrostatic energy and contact enrichment is found only for the strongly attractive (N-H?Cl^-) and repulsive contacts. Electrostatic energies between ions reveal that the interacting biguanidium cation pairs are repulsive and that the crystal is maintained by attractive cation?Cl^- dimers. The vibrational absorption bands were identified by IR spectroscopy.

Full text of DOI:10.1107/S2053229620006336

research papers
Synthesis, structural elucidation, characterization
and theoretical DFT study of 1-(o-tolyl)biguanidium
chloride
ISSN 2053-2296
a
a
b
b
Kamel Kaabi, Kacem Klai, Emmanuel Wenger, Christian Jelsch, Fr e´ d e´ ric
c
a
Lefebvre and Cherif Ben Nasr *
Received 28 February 2020
Accepted 11 May 2020
a
Laboratoire de Chimie des Mat e´ riaux, Universit e´ de Carthage, Facul e´ des Sciences de Bizerte, 7021 Zarzouna, Tunisia,
b
c
Universit e´ de Lorraine, CNRS, CRM2, F-54000 Nancy, France, and Laboratoire de Chimie Organom e´ tallique de Surface
LCOMS), Ecole Sup e´ rieure de Chimie Physique Electronique, 69626 Villeurbanne Cedex, France. *Correspondence
e-mail: cherif_bennasr@yahoo.fr
(
Edited by M. Kubicki, Adam Mickiewicz
University, Poland
+
5
ꢁ
The structure of the new salt 1-(o-tolyl)biguanidium chloride, C H N ꢀCl , has
Keywords: hydrogen bonding; IR spectroscopy;
crystal structure; Hirshfeld surface; contact
enrichment ratio; electrostatic potential; bigua-
nidium.
9
14
been determined by single-crystal X-ray diffraction. The salt crystallizes in the
monoclinic space group C2/c. In this structure, the chloride and biguanidium
hydrophilic ions are mostly connected to each other via N—Hꢀ ꢀ ꢀN and N—
1
3
Hꢀ ꢀ ꢀCl hydrogen bonds to form layers parallel to the ab plane around y = and
CCDC reference: 1877569
2
3
y = . The 2-methylbenzyl groups form layers between these layers around y = 0
1
and y = , with the methyl group forming C—Hꢀ ꢀ ꢀꢀ interactions with the
Supporting information: this article has
2
aromatic ring. Intermolecular interactions on the Hirshfeld surface were
investigated in terms of contact enrichment and electrostatic energy, and
confirm the role of strong hydrogen bonds along with hydrophobic interactions.
A correlation between electrostatic energy and contact enrichment is found only
supporting information at journals.iucr.org/c
ꢁ
for the strongly attractive (N—Hꢀ ꢀ ꢀCl ) and repulsive contacts. Electrostatic
energies between ions reveal that the interacting biguanidium cation pairs are
repulsive and that the crystal is maintained by attractive cationꢀ ꢀ ꢀCl dimers.
ꢁ
The vibrational absorption bands were identified by IR spectroscopy.
1
. Introduction
Organic salts have received a lot of attention in recent years
due to their noncovalent interactions, such as hydrogen
bonding, that play significant roles in various fields ranging
from molecular recognition, host–guest chemistry, crystal
engineering, supramolecular chemistry, biochemistry and
pharmaceutical chemistry to materials science (Metrangolo et
al., 2005; Steiner, 2002; Desiraju & Steiner, 2002; Mu et al.,
2
008; Babu & Nangia, 2011; F e´ lix-Sonda et al., 2014). Guani-
dine and its derivatives have been widely used in the manu-
facture of plastics, resins, rubber chemicals, rocket propellants
and disinfectants. They also have biotechnological applica-
tions in the field of protein separation (Pignataro, 2012). The
Galega officinalis plant containing guanidine was used as a
treatment for sugar diabetes in medieval Europe (Bailey &
Campbell, 2007). Biguanides, such as metformin (N,N-di-
methylbiguanide), were synthesized from guanidines in the
1920s and showed antidiabetic properties. Biguanides often
refer to a class of drugs that act as oral antihyperglycemic
agents (Rang et al., 2003); moreover, they are used as analgesic
and antimalarial (Pignard, 1962) drugs. Among the derivatives
of guanidine, o-tolylbiguanide (TBG) is a nontoxic compound
and can be used in solution for topical application (Robert &
Stogniew, 2012) and as a viscosity-lowering agent of protein
solutions in liquid pharmaceutical formulations (Larson et al.,
#
2020 International Union of Crystallography
Acta Cryst. (2020). C76
https://doi.org/10.1107/S2053229620006336 1 of 7

research papers
2
018). TBG has atoms able to generate strong hydrogen
Table 1
Experimental details.
bonding, which plays a very important role in interactions with
biomolecules (Hubberstey & Suksangpanya, 2004). In this
article, we report the first crystal structure of
Crystal data
Chemical formula
+
ꢀClꢁ
9 14 5
C H N
M
r
227.68
Monoclinic, C2/c
1-(o-tolyl)biguanidium chloride, (I) (see Scheme 1), its
Crystal system, space group
Temperature (K)
Hirshfeld surface analysis and a physicochemical character-
ization. The crystal packing is an organic salt network
constructed by hydrogen bonds. The contact enrichments were
computed by Hirshfeld surface analysis in order to evaluate
which contacts play major roles in the stabilization of the
crystal packing.
110
18.4640 (7), 13.7652 (6), 9.3158 (3)
98.847 (4)
2339.54 (16)
8
Mo Kꢂ
0.30
0.23 ꢄ 0.15 ꢄ 0.04
˚
a, b, c (A)
ꢃ
ꢁ
V (A )
( )
˚
3
Z
Radiation type
ꢁ
1
ꢃ (mm
Crystal size (mm)
)
Data collection
Diffractometer
Agilent SuperNova Dual Source
diffractometer with an Atlas
detector
Absorption correction
Multi-scan (CrysAlis PRO; Rigaku
OD, 2015)
0.850, 1.000
Tmin, Tmax
No. of measured, independent and
29979, 3970, 2840
observed [I > 2ꢄ(I)] reflections
R
int
0.063
0.744
˚
ꢁ1
)
(sin ꢅ/ꢆ)max (A
Refinement
2
2
2
R[F > 2ꢄ(F )], wR(F ), S
No. of reflections
0.057, 0.065, 0.97
3970
No. of parameters
No. of restraints
H-atom treatment
192
47
All H-atom parameters refined
0.64, ꢁ0.40
˚
ꢁ3
)
Áꢇmax, Áꢇmin (e A
Computer programs: CrysAlis PRO (Rigaku OD, 2015), SHELXT (Sheldrick, 2015a),
SHELXL (Sheldrick, 2008, 2015b), MoPro (Jelsch et al., 2005) and DIAMOND
(Brandenburg, 1998).
2
. Experimental
2.1. Synthesis and crystallization
An aqueous solution of 37% HCl (40 mg, 0.4 mmol, Sigma–
Aldrich) was added dropwise to a solution of 1-(o-tolyl)-
biguanide (41 mg, 0.4 mmol, Sigma–Aldrich) in ethanol
(
10 ml). After stirring for 45 min, the resultant solution was
left to evaporate at room temperature. Crystals of the title salt,
I), which remained stable under normal conditions of tem-
(
perature and humidity, were isolated after several days and
subjected to X-ray diffraction analysis (yield 73%). Analysis
calculated (%): C 47.43, H 6.15, N 30.74; found: C 45.93, H
5.82, N 28.15.
2.2. Refinement
Crystal data, data collection and structure refinement
details are summarized in Table 1. H atoms were located by
successive differential Fourier syntheses.
The structure was refined with the full-matrix least-squares
procedure using the SHELXL program (Sheldrick, 2015b).
The structure was then refined with the MoPro software
(
&
Jelsch et al., 2005) using the multipolar atom model (Hansen
Coppens, 1978). The X—H bond lengths were elongated
Figure 1
Fourier residual electron density (a) after spherical atom refinement and
according to standard neutron diffraction distances (Allen &
Bruno, 2010). The molecular electron density was transferred
from the ELMAM database of multipolar atoms (Domagała et
(
b) after refinement using the transferred multipolar atom model. The
˚
ꢁ3
contour level is 0.05 e A . The colour key is: blue positive, red negative
and yellow zero.
ꢂ
2
of 7 Kaabi et al. DFT study of 1-(o-tolyl)biguanidium chloride
Acta Cryst. (2020). C76

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+
ꢁ
al., 2012). The TBG ꢀCl salt was set to be electrically neutral,
Table 2
Hydrogen-bond geometry (A, ).
˚
ꢃ
with each ion carrying a unitary formal charge.
When using the multipolar atom model instead of the
spherical one, the r.m.s. Fourier residual electron density was
2
reduced from 0.097 to 0.091 e A , while the wR (F) factor
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
N4—H4ꢀ ꢀ ꢀCl
N5—H5ꢀ ꢀ ꢀCl
N6—H7ꢀ ꢀ ꢀN5
C6—H10ꢀ ꢀ ꢀC8
1.01 (8)
1.01 (9)
1.02 (15)
1.08 (12)
1.01 (9)
1.02 (9)
1.01 (10)
1.02 (15)
1.01 (16)
2.17 (7)
2.37 (9)
2.52 (6)
2.65 (9)
2.44 (6)
2.28 (9)
2.32 (13)
2.34 (18)
1.96 (15)
3.1584 (9)
3.2880 (9)
2.9156 (13)
3.1420 (15)
3.3431 (9)
3.2398 (9)
3.2454 (9)
3.2284 (9)
2.9754 (12)
163 (1)
150 (6)
103 (5)
108 (5)
148 (4)
157 (1)
150 (3)
146 (11)
174 (1)
ꢁ3
˚
diminished from 4.5 to 3.4% (Fig. 1).
i
N3—H1ꢀ ꢀ ꢀCl
i
2
.3. Electrostatic energy calculations
N6—H6ꢀ ꢀ ꢀCl
ii
N5—H3ꢀ ꢀ ꢀCl
The electrostatic energy Eelec was computed with the
iii
N6—H7ꢀ ꢀ ꢀCl
iv
VMoPro module of MoPro software (Jelsch et al., 2005) using
the refined structure with transferred multipolar atom model.
The intermolecular electrostatic interaction energies were
evaluated with the exact potential and multipole methods (EP/
MM) first described by Volkov et al. (2004).
N3—H2ꢀ ꢀ ꢀN2
1
2
1
Symmetry codes: (i) x; y; z þ 1; (ii) x; ꢁy þ 2; z þ
;
(iii) ꢁx þ 1; y; ꢁz þ 2
; (iv)
1
2
3
2
ꢁ
x þ ; ꢁy þ ; ꢁz þ 1.
the absence of imaginary frequencies was checked in order to
verify that the structure corresponded to a true minimum.
A second series of calculations was performed on the most
stable structure, which corresponded to that found by X-ray
diffraction using the B3LYP/6-311++G(p,d) method in order
to obtain results which could be compared to those obtained
previously on neutral TBG. Both a full optimization of all
atoms and an optimization of only the H-atom positions, the
other atoms being at crystallographic positions, were made
and in both cases the electronic properties, such as the ener-
gies and the shapes of the highest occupied molecular orbital
The Eelec value for a contact type was obtained by direct
summation over atomic contacts between the reference and all
the surrounding molecules. To take into account only the
shortest contacts which contribute to the Hirshfeld surface
contacts atom/atom decomposition, a cutoff of the sum of the
˚
van der Waals radii plus 0.3 A was applied to the interatomic
distance. The average Eelec value was obtained by dividing the
summation by the number of contacts.
The dimer electrostatic interaction energies were obtained
by a double summation over atoms a and b constituting the
two moieties [Edimer = Æa Æb E (a ,b )].
i
j
i
j
elec
i
j
(HOMO) and the lowest unoccupied molecular orbital
LUMO), were calculated.
(
2.4. Theoretical calculations
Theoretical calculations were made with the GAUSSIAN09
2.5. IR spectroscopy
software (Frisch et al., 2010) and the B3LYP DFT method. In a
first series of calculations, the different cations resulting from
the protonation of TBG were investigated using the B3LYP/6-
31G(d,p) method in order to determine what was the more
stable species. In all cases, the IR spectrum was calculated and
ꢁ1
The IR spectra were recorded in the range 4000–400 cm
with a PerkinElmer FT–IR 1000 spectrophotometer using
samples dispersed in spectroscopically pure KBr pressed into
a pellet.
2.6. Hirshfeld surface analysis
Fingerprint plots of the contacts in (I) were generated with
the CrystalExplorer3.1 software (Spackman & Jayatilaka,
009). The analysis of contact types and their enrichment were
computed with the MoProViewer program (Guillot et al.,
014). In order to obtain, in one step, the integral Hirshfeld
2
2
+
ꢁ
surfaces around the TBG cation and the Cl anion, they were
computed around an ensemble of two moieties which are not
in contact with each other in the crystal. As the Hc atoms
bound to carbon are hydrophobic and the Hn atoms bound to
nitrogen are more polar, the two atom types have different
interaction propensities and were treated separately.
3
. Results and discussion
3.1. X-ray diffraction study
The main geometrical features of the different chemical
+
ꢁ
entities of the new salt, C H N ꢀCl , (I), are reported in
9
14
5
Tables 1 and 2. X-ray crystal structure analysis reveals that the
complex crystallizes in the monoclinic space group C2/c.
Figure 2
The molecular structure of the title salt, (I), with displacement ellipsoids
drawn at the 40% probability level.
ꢁ
The asymmetric unit of I, shown in Fig. 2, consists of a Cl
+
anion and a 1-(o-tolyl)biguanidium (TGB ) organic cation.
ꢂ
Acta Cryst. (2020). C76
Kaabi et al.
DFT study of 1-(o-tolyl)biguanidium chloride 3 of 7

research papers
This cation does not result only from the protonation of TBG
on one of its N atoms, but also from the migration of one
proton from one N atom to another. This structure has also
been observed previously during the protonation of biguani-
dium chloride ( S¸ erb et al., 2014; Niranjana et al., 2017). The
reaction mechanism of its formation is believed to proceed via
a tautomeric equilibrium leading to the more stable tautomer
form.
Table 3
Comparison between C—N bond distances in 1-(o-tolyl)biguanidium
chloride, (I), and metformin chloride (Niranjana et al., 2017).
(
I)
Metformin chloride
N6—C7
N3—C7
N2—C7
N2—C8
N5—C8
N4—C8
N4—C9
1.3334 (13)
1.3335 (13)
1.3407 (13)
1.3307 (13)
1.3385 (13)
1.3516 (14)
1.4180 (14)
N5—C4
N4—C4
N3—C4
C4—N3
N2—C3
N1—C3
N1—C1(CH3)
1.3398 (3)
1.3407 (4)
1.3332 (3)
1.3332 (3)
1.3372 (4)
1.3376 (4)
1.4590 (4)
1.4566 (5)
Fig. 3 is a representation of the hydrogen bonds around the
+
TBG cation and shows the hydrogen bonds generated
3
N1—C2(CH )
essentially by the amino NH groups which act as donors and
2
ꢁ
the Cl ions which act as acceptors.
The various components of salt (I) are linked to each via
N—Hꢀ ꢀ ꢀCl and N—Hꢀ ꢀ ꢀN hydrogen bonds (Table 2), and
they are arranged so as to form cavities along the c direction at
˚
.4566 (3)/1.4590 (3) A in metformin; this is explained by the
1
different chemical natures of the substituents on the N4 atom.
In the crystal lattices of both salts, the molecules are
arranged by ‘pairs’ of molecules symmetrically related by a
centre of inversion.
1
1
x = and y = (Figs. S1 and S2 in the supporting information).
Within the organic cation, an examination of the C—N bond
2
2
˚
lengths of the aliphatic group gives a mean value of 1.338 A
(Table S1 in the supporting information). They are short for
C—N single bonds, but still not quite as contracted as one
would expect for a fully established C N double bond. All
these bond-length features are consistent with an imino
resonance form (Yang et al., 1995; Grobelny et al., 1995) and
suggest a great contribution from it to the stability of (I).
The values of the C—N bond lengths in (I) are close to
those of metformin chloride ( S¸ erb et al., 2014; Niranjana et al.,
3.2. Contacts analysis
A Hirshfeld surface analysis was undertaken to further
characterize the nature of the intermolecular contacts
(
Table 4). The spikes in the fingerprint plots at short contact
distances correspond to Nꢀ ꢀ ꢀH and Clꢀ ꢀ ꢀH hydrogen bonds
Fig. 5). The enrichment ratio (Jelsch et al., 2014, 2015) is a
(
powerful tool to deduce which type of contacts are over- or
under-represented in the crystal packing. The contact enrich-
ment EXY between chemical species X and Y is the ratio
between the actual contacts CXY in the crystal and the RXY
2017) (Table 3). Fig. 4 shows that the C—N distances are
clustered in two groups. The first group of hybridized bonds
+
has a mean C—N distance of 1.339 A in TBG and 1.337 A in
˚
˚
+
metformin. The dispersion of values is much larger in TBG ,
‘random’ contacts, computed as if all types of contacts had the
˚
with a sample standard deviation (ssd) of 0.008 A compared to
˚
a value of 0.003 A in metformin. The second group concerns
same probability to form. RXY values are obtained from
probability products RXY = S ꢀS , where S is the proportion
X
Y
X
N4—C bonds and has much less agreement between the two
=
of X on the Hirshfeld surface. The Clꢀ ꢀ ꢀHn strong hydrogen
+
molecules as N—Ctolyl = 1.418 (2) A in TBG and N—C
˚
methyl
Figure 4
Scatterplot of the C—N distances in TBG and metformin chloride
(Niranjana et al., 2017).
+
Figure 3
Representation of the hydrogen bonds around the TBG cation in (I).
+
ꢂ
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Table 4
Analysis of contacts on the Hirshfeld surface.
Table 5
Electrostatic energy (kJ mol ) between the TBG cations and the
neighbouring cations in direct contact.
ꢁ
1
+
Reciprocal contacts Xꢀ ꢀ ꢀY and Yꢀ ꢀ ꢀX are merged. The second line shows the
chemical content on the surface. The % of contact types between chemical
species are given in the next five lines, followed by their enrichment ratios. The
major contacts, as well as the most enriched ones, are highlighted in bold. The
lower part of the table gives the contact enrichment when the N atom with
1
The summation was performed by attributing a coefficient to the involutional
2
symmetry operators ꢄ and a unitary weight to the others.
Symmetry code
Energy
Coefficient
lone pair Nlp is distinguished from the other nitrogen Nh atoms (NH and NH
groups).
2
TBG+ꢀ ꢀ ꢀClꢁ
1
2
x, y, z
x, y, z + 1
x, ꢁy + 2, z +
ꢁ385
ꢁ410
ꢁ369
ꢁ369
126
216
245
135
138
141
60
ꢁ472
1
1
1
2
1
1
1
2
Atom
Hn
C
N
Cl
Hc
1
2
ꢁ
x + 1, y, ꢁz +
+
+
1
2
Surface %
Hn
C
27.3
4.4
6.4
4.9
19.3
8.1
15.5
29.8
TBG ꢀ ꢀ ꢀTBG
x, ꢁy + 1, z ꢁ
1
ꢁx + 1, y, ꢁz +
ꢁx + 1, y, ꢁz +
2
2
3
1
5.0
1.1
% contacts
2
2
1
2
N
0
ꢁx + 1, ꢁy + 1, ꢁz + 1
Cl
Hc
Hn
C
N
Cl
Hc
27.3
7.8
1.2
18.7
1.2
7.1
0.2
3.8
ꢁx +
1
2
1
2
1
, y ꢁ
1
2
, ꢁz +
1
2
1
1
2
1
3
2
3
11.0
ꢁx + , ꢁy + , ꢁz
0.58
0.62
1.24
2.92
0.48
ꢁx + , ꢁy + , ꢁz + 1
2
2
2
1.43
0.42
0.19
1.69
Enrichment
Sum
0
0.48
1.68
0.08
0.38
1.25
contact types. The Eelec values were averaged for all Xꢀ ꢀ ꢀY
contacts where the dXY distance is shorter than the sum of the
and
Atom
Hn
C
Nlp
Nh
Cl
Hc
˚
van der Waals radii plus 0.3 A. The scatterplot of E
elec
Nlp
Nh
2.37
0.39
0.05
0.36
0
0
0
0
0
0.88
0.98
2.24
enrichment ratios is shown in Fig. 6.
The Clꢀ ꢀ ꢀHn strong hydrogen bond is by far the most
ꢁ
1
energetic contact type (average of ꢁ172 kJ mol ), followed
ꢁ
1
bonds are the most abundant and the most enriched contact
types. The hydrophobic Hc atoms form mostly C—Hꢀ ꢀ ꢀꢀ
by Nꢀ ꢀ ꢀHn (average of ꢁ33 kJ mol for three contacts). If
iv
only the N3—H2ꢀ ꢀ ꢀN2 strong hydrogen bond involving the
2
interactions with the C and N sp atoms of the tolyl and
N atom with an electron lone pair is considered (N6—
H7ꢀ ꢀ ꢀN5 excluded), the Nꢀ ꢀ ꢀHn energy reaches ꢁ58 kJ molꢁ
and the enrichment is 2.37. On the other side of the scatter-
1
biguanide moieties. The nonpolar contacts Hcꢀ ꢀ ꢀHc, Cꢀ ꢀ ꢀC
and Hcꢀ ꢀ ꢀC are all over-represented due to the presence of
hydrophobic layers in the crystal packing.
In order to analyze correlations with enrichment ratios, the
electrostatic energy Eelec, derived from the transferred
multipolar atom model, was computed for the different
ꢁ
ꢁ
plot, the Cl ꢀ ꢀ ꢀCl interaction is very unfavourable energe-
tically and is strongly under-represented.
Figure 6
ꢁ
1
Scatterplot of the average electrostatic energy Eelec (kJ mol ) and the
enrichment ratio for the different contact types. For Clꢀ ꢀ ꢀC, Nꢀ ꢀ ꢀN and
Clꢀ ꢀ ꢀCl, as there was no contact shorter than the sum of the van der Waals
˚
Figure 5
Fingerprint plots of the contacts at the Hirshfeld surface. The scales on
the axes are from 0.6 to 2.4 UNITS?.
radii plus 0.3 A, the energy was computed for two ‘spherical’ atoms at this
distance. Hydrophobic contacts are in bold, while contacts between
charged atoms are in purple.
ꢂ
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Kaabi et al.
DFT study of 1-(o-tolyl)biguanidium chloride 5 of 7

research papers
Table 6
Calculated energies of the possible cations obtained by protonation of
3.3. Theoretical study
As the molecule can potentially have seven forms, corre-
sponding to different protonation of the N atoms (Scheme 2),
theoretical studies were carried out with the GAUSSIAN09
software (Frisch et al., 2010) using the B3LYP/6-31+G*
method. The structures were fully optimized and the absence
of imaginary frequencies was checked, determining if they
correspond to real minima.
1-(o-tolyl)biguanide.
Relative energy versus
ꢁ
1
structure 6 (kJ mol )
Structure
Absolute energy (Ha)
1
2
3
4
5
6
7
ꢁ624.898406392
ꢁ624.903083434
ꢁ624.916688817
ꢁ624.954584111
ꢁ624.966125315
ꢁ624.986333171
ꢁ624.964705612
230
216
182
83
52
0
55
Besides the strong hydrogen bonds, the only enriched
contacts are the three hydrophobic interactions (Hcꢀ ꢀ ꢀHc,
Cꢀ ꢀ ꢀC and Cꢀ ꢀ ꢀHc) and the Nꢀ ꢀ ꢀHc contacts. The E
elec-
trostatic energies of these four enriched interactions are
however very small (Fig. 6). If one omits the most attractive
elec
ꢁ
ꢁ
ꢁ
(
Cl ꢀ ꢀ ꢀHn and Nꢀ ꢀ ꢀHn) and most repulsive (Cl ꢀ ꢀ ꢀCl )
interactions, the weaker contacts show globally no clear
correlation between enrichment and Eelec values (Fig. 6).
ꢁ
The biguanidium cation interacts directly with four Cl
anions and the electrostatic energies computed between the
two moieties are similar and in the range from ꢁ369 to
ꢁ
1
410 kJ mol (Table 5). On the other hand, there are seven
ꢁ
+
+
independent TBG ꢀ ꢀ ꢀTBG dimers in the crystal packing. The
+
interaction energies between interacting TBG cations
E
elec
ꢁ
1
are in the range from 60 to 245 kJ mol , which indicates that
all these dimers are repulsive from an electrostatic point of
view. In the energy sum over all contacts, the involutional
symmetry operators were counted with a half weight, as non-
involutional symmetries ꢄ represent two reciprocal contacts
1
(
ꢄ and ꢄ ). The summation leads to an attractive E energy
elec
ꢁ1
+
of ꢁ472 kJ mol between a TBG cation and its nearest
neighbours.
The energy values are listed in Table 6. As observed
experimentally, the most stable structure is 6, where the
proton has moved on one N—H group and where the two
C
N double bonds are conjugated. Structure 5, where the
two C N bonds are also conjugated, and structure 7 have the
ꢁ
1
same energy, which is ca 50 kJ mol greater than that of
ꢁ
1
structure 6. Structure 4 has an energy which is ca 80 kJ mol
greater. Finally, the structures resulting from the protonation
of the amine groups are far less stable (with an energy at least
ꢁ
1
80 kJ mol greater than that of structure 6).
1
A more detailed analysis was then performed on structure 6
using the B3LYP/6-311++G(d,p) method. Fig. 7 shows the
HOMOs and LUMOs for (I) after full optimization. Clearly,
the HOMOs are localized primarily on the aromatic ring,
while the LUMOs are located on the N atoms. The HOMO
and LUMO energies are ꢁ9.79 and ꢁ4.98 eV, respectively.
The value of the energy separation between the HOMO and
LUMO orbitals, called the energy band gap, is 4.81 eV. This
large HOMO–LUMO energy gap implies a high kinetic
stability and a low chemical reactivity of the molecular system.
Figure 7
Frontier orbitals in (I) calculated at the B3LYP/6-311++G(d,p) level.
ꢂ
6
of 7 Kaabi et al. DFT study of 1-(o-tolyl)biguanidium chloride
Acta Cryst. (2020). C76

research papers
3.4. Molecular electrostatic potential (MEP) analysis
The MEP of (I) was computed at the B3LYP/6-31++G(d,p)
level and is shown in Fig. 8. The MEP is used to predict the
molecular reactive behaviour towards electrophilic and
nucleophilic attack and defined sites of the electrophile and
nucleophile. The electrostatic potential maps are colour coded
and are subdivided into many regions where those various
colours are used to identify different potentials. Intermediate
potentials are assigned colours according to the following
colour spectrum: red < orange < yellow < green < blue. As
seen from Fig. 8, the positive region is localized on the N
atoms, while the negative region is located inside the aromatic
ring.
Figure 8
MEP surface of (I) calculated at the B3LYP/6-311++G(d,p) level.
4
. Conclusion
Desiraju, G. R. & Steiner, T. (2002). In The Weak Hydrogen Bond in
Structural Chemistry and Biolog. Oxford University Press.
Domagała, S., Fournier, B., Liebschner, D., Guillot, B. & Jelsch, C.
(2012). Acta Cryst. A68, 337–351.
F e´ lix-Sonda, B. C., Rivera-Islas, J., Herrera-Ruiz, D., Morales-Rojas,
H. & H o¨ pfl, H. (2014). Cryst. Growth Des. 14, 1086–1102.
Frisch, M. J., et al. (2010). GAUSSIAN09. Revision D.01. Gaussian
Inc., Wallingford, CT, USA. https://gaussian.com/.
Grobelny, R., Glowiak, T., Mrozinski, J., Baran, W. & Tomasik, P.
(1995). Pol. J. Chem. 69, 559–565.
Guillot, B., Enrique, E., Huder, L. & Jelsch, C. (2014). Acta Cryst.
A70, C279.
Hansen, N. K. & Coppens, P. (1978). Acta Cryst. A34, 909–921.
Hubberstey, P. & Suksangpanya, U. (2004). Struct. Bond. 111, 33–
83.
Jelsch, C., Ejsmont, K. & Huder, L. (2014). IUCrJ, 1, 119–128.
Jelsch, C., Guillot, B., Lagoutte, A. & Lecomte, C. (2005). J. Appl.
Cryst. 38, 38–54.
Jelsch, C., Soudani, S. & Ben Nasr, C. (2015). IUCrJ, 2, 327–340.
Larson, A. M., Love, K., Weight, A. K., Crane, A., Langer, R. S. &
Klibanov, A. M. (2018). US Patent No. 9925263.
Metrangolo, P., Neukirch, H., Pilati, T. & Resnati, G. (2005). Acc.
Chem. Res. 38, 386–395.
In summary, a novel 1-(o-tolyl)biguanidium chloride salt has
been successfully synthesized at room temperature by slow
evaporation. The enrichment ratio, derived from the Hirshfeld
contact surface analysis, allows the determination of which
types of contacts are over or under-represented. The crystal
packing is stabilized by intermolecular N—Hꢀ ꢀ ꢀCl and N—
Hꢀ ꢀ ꢀN strong hydrogen bonds, as well as C—Hꢀ ꢀ ꢀꢀ and N—
Hꢀ ꢀ ꢀN interactions, which are all quite over-represented. The
2
N sp atoms form most likely C—Hꢀ ꢀ ꢀN interactions on the
2
two sides of the sp plane. There is an anticorrelation between
contact enrichment and electrostatic energy only for the
strongest attractions and the most repulsive interaction.
According to the enrichment values, it can be inferred that the
ꢁ
Cl ꢀ ꢀ ꢀHn and Nꢀ ꢀ ꢀHn strong hydrogen bonds, the avoidance
ꢁ
ꢁ
of Cl ꢀ ꢀ ꢀCl contacts and the three hydrophobic interaction
+
types are the driving forces in the stabilization of the TBG /
ꢁ
Cl crystal packing. Eelec values between interacting dimers
(Table 5) show that all cation dimers are repulsive, which is
more than compensated for by the attractive cation–anion
dimers which maintain the crystal cohesion. Moreover, the
HOMO–LUMO energy gap suggests a good stability of this
compound.
Mu, Z., Shu, L., Fuchs, H., Mayor, M. & Chi, L. (2008). J. Am. Chem.
Soc. 130, 10840–10841.
Niranjana Devi, R., Jelsch, C., Israel, S., Aubert, E., Anzline, C. &
Hosamani, A. A. (2017). Acta Cryst. B73, 10–22.
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Pignataro, B. (2012). Editor. In New Strategies in Chemical Synthesis
and Catalysis. Chichester, UK: Wiley.
Acknowledgements
The Secretary of State for Scientific Research and Technology
of Tunisia is acknowledged for a visiting grant to KK. We
Rang, H. P., Dale, M. M., Ritter, J. M. & Moore, P. K. (2003). Editors.
In Pharmacology. Edinburgh: Churchill Livingstone.
Rigaku OD (2015). CrysAlis PRO. Rigaku Oxford Diffraction Ltd,
Yarnton, Oxfordshire, England.
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10639.
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122.
Sheldrick, G. M. (2015a). Acta Cryst. A71, 3–8.
Sheldrick, G. M. (2015b). Acta Cryst. C71, 3–8.
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32.
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Volkov, A., Koritsanszky, T. & Coppens, P. (2004). Chem. Phys. Lett.
391, 170–175.
2
thank the PMD X X-ray diffraction facility of the Institute
Jean Barriol, University of Lorraine, for X-ray diffraction
measurements, data processing and analysis, and providing
reports for publication: (http://crm2.univ-lorraine.fr/lab/fr/
services/pmd2x).
References
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Germany.
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ꢂ
Acta Cryst. (2020). C76
Kaabi et al.
DFT study of 1-(o-tolyl)biguanidium chloride 7 of 7

supporting information
supporting information
Acta Cryst. (2020). C76 [https://doi.org/10.1107/S2053229620006336]
Synthesis, structural elucidation, characterization and theoretical DFT study of
-(o-tolyl)biguanidium chloride
1
Kamel Kaabi, Kacem Klai, Emmanuel Wenger, Christian Jelsch, Frédéric Lefebvre and Cherif Ben
Nasr
Computing details
Data collection: CrysAlis PRO (Rigaku OD, 2015); cell refinement: CrysAlis PRO (Rigaku OD, 2015); data reduction:
CrysAlis PRO (Rigaku OD, 2015); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to
refine structure: SHELXL (Sheldrick, 2008, 2015b) and MoPro (Jelsch et al., 2005); molecular graphics: DIAMOND
(
Brandenburg, 1998).
-[Amino(iminiumyl)methyl]-1-(2-methylphenyl)guanidine chloride
Crystal data
2
+
−
C
M
9
H
14
N
5
·Cl
F(000) = 960
= 1.293 Mg m
−3
r
= 227.68
D
x
Monoclinic, C2/c
Hall symbol: -C 2yc
a = 18.4640 (7) Å
b = 13.7652 (6) Å
c = 9.3158 (3) Å
β = 98.847 (4)°
Mo Kα radiation, λ = 0.71073 Å
Cell parameters from 8409 reflections
θ = 3.7–32.4°
µ = 0.30 mm
T = 110 K
−1
Prism, white
0.23 × 0.15 × 0.04 mm
3
V = 2339.54 (16) Å
Z = 8
Data collection
Agilent SuperNova Dual Source
diffractometer with an Atlas detector
Radiation source: fine-focus sealed tube
Mirror monochromator
29979 measured reflections
3970 independent reflections
2840 reflections with > 2.0σ(I)
R
int = 0.063
ω scans
θmax = 31.9°, θmin = 3.7°
Absorption correction: multi-scan
h = −27→27
k = −19→20
l = −13→13
(
CrysAlis PRO; Rigaku OD, 2015)
T
min = 0.850, Tmax = 1.000
Refinement
2
Refinement on F
Primary atom site location: structure-invariant
direct methods
Secondary atom site location: difference Fourier
map
Least-squares matrix: full
R[F > 2σ(F )] = 0.057
2
2
2
wR(F ) = 0.065
S = 0.97
Hydrogen site location: difference Fourier map
All H-atom parameters refined
3970 reflections
192 parameters
47 restraints
2
2
w = 1/[2.1*σ (F
o
)]
(Δ/σ)max = −0.002
Acta Cryst. (2020). C76
sup-1

supporting information
−3
−3
Δρmax = 0.64 e Å
Δρmin = −0.40 e Å
Special details
2
2
2
Refinement. Refinement of F against reflections. The threshold expression of F > 2sigma(F ) is used for calculating R-
2
factors(gt) and is not relevant to the choice of reflections for refinement. R-factors based on F are statistically about
twice as large as those based on F, and R-factors based on ALL data will be even larger.
A single crystal was carefully selected under a polarizing microscope in order to perform its structural analysis. X-ray
diffraction data were collected on a SuperNova (Dual, Cu at zero Atlas) diffractometer at 110 K, using graphite-
monochromated Mo Kα = 0.71073 Å radiation. The structure was solved using a direct method with the SHELXT
program The structure was refined using the full-matrix least-squares procedure using the SHELXL program (Sheldrick,
2
008; Sheldrick 2015). The drawings were made with Diamond (Brandenburg, 1998). Crystal data and experimental
parameters used for the intensity data collection are summarized in Table 1.
2
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å )
x
y
z
Uiso*/Ueq
Cl
0.414821 (13)
0.33610 (4)
0.30580 (4)
0.3193 (6)
0.257 (10)
0.36565 (5)
0.3785 (6)
0.39543 (5)
0.3896 (7)
0.4122 (6)
0.41948 (5)
0.4310 (6)
0.460 (10)
0.35465 (5)
0.36674 (5)
0.35099 (6)
0.39317 (6)
0.29635 (6)
0.2707 (5)
0.28159 (7)
0.240 (10)
0.37666 (7)
0.410 (10)
0.45508 (6)
0.4772 (4)
0.499 (10)
0.4374 (4)
0.32202 (8)
0.3110 (6)
0.88578 (2)
0.78604 (6)
0.81756 (7)
0.8406 (9)
0.7853 (8)
0.75392 (7)
0.7843 (8)
0.90299 (7)
0.957 (10)
0.9204 (8)
0.86368 (8)
0.8816 (9)
0.8615 (10)
0.82389 (8)
0.81496 (8)
0.65283 (8)
0.59042 (9)
0.61761 (8)
0.667 (10)
0.51917 (10)
0.4912 (5)
0.49095 (9)
0.4425 (4)
0.62439 (8)
0.692 (10)
0.5723 (4)
0.6349 (7)
0.45601 (8)
0.379 (10)
−0.04433 (3)
0.42786 (10)
0.65219 (9)
0.756 (10)
0.6192 (12)
0.20089 (10)
0.109 (10)
0.29973 (9)
0.3710 (9)
0.204 (10)
0.01974 (2)
0.01757 (7)
0.01997 (8)
0.0244 (2)*
0.0244 (2)*
0.01987 (8)
0.0244 (2)*
0.02277 (8)
0.0280 (3)*
0.0279 (3)*
0.02504 (8)
0.0302 (3)*
0.0302 (3)*
0.01720 (8)
0.01704 (8)
0.02048 (9)
0.02626 (11)
0.02776 (11)
0.0335 (3)*
0.03686 (13)
0.0449 (4)*
0.03765 (14)
0.0464 (5)*
0.03502 (12)
0.0523 (5)*
0.0523 (5)*
0.0522 (5)*
0.04085 (15)
0.0506 (5)*
N2
N3
H1
H2
N4
H4
N5
H3
H5
N6
H6
H7
C7
C8
C9
C1
C2
H8
C3
H9
C4
H14
C6
H10
H11
H12
C5
H13
0.61097 (9)
0.718 (10)
0.5498 (9)
0.56102 (12)
0.31484 (12)
0.20189 (13)
0.29875 (14)
0.09368 (13)
0.0104 (8)
0.08305 (15)
−0.0010 (9)
0.28582 (15)
0.3608 (9)
0.40909 (13)
0.3770 (9)
0.4226 (10)
0.513 (10)
0.17956 (18)
0.1731 (12)
Acta Cryst. (2020). C76
sup-2

supporting information
2
Atomic displacement parameters (Å )
11
22
33
12
13
23
U
U
U
U
U
U
Cl
0.02111 (12)
0.0193 (4)
0.0189 (4)
0.0276 (5)
0.0334 (5)
0.0196 (4)
0.0177 (5)
0.0193 (5)
0.0228 (5)
0.0272 (6)
0.0296 (6)
0.0390 (7)
0.0437 (8)
0.0337 (7)
0.0487 (8)
0.02624 (15)
0.0218 (5)
0.0286 (6)
0.0197 (5)
0.0224 (5)
0.0427 (7)
0.0217 (6)
0.0187 (6)
0.0209 (6)
0.0225 (6)
0.0275 (7)
0.0318 (8)
0.0253 (7)
0.0381 (8)
0.0216 (7)
0.01251 (14)
0.0124 (5)
0.0135 (5)
0.0135 (5)
0.0140 (5)
0.0132 (5)
0.0128 (6)
0.0136 (6)
0.0198 (6)
0.0309 (7)
0.0267 (7)
0.0411 (9)
0.0470 (10)
0.0322 (8)
0.0554 (11)
0.00064 (10)
−0.0053 (4)
−0.0043 (4)
−0.0037 (4)
−0.0096 (4)
−0.0091 (4)
−0.0026 (4)
−0.0030 (4)
−0.0025 (4)
0.0004 (5)
−0.0071 (5)
−0.0097 (6)
0.0036 (6)
0.0062 (6)
−0.0071 (6)
0.00457 (9)
0.0050 (3)
0.0061 (4)
0.0070 (4)
0.0085 (4)
0.0040 (4)
0.0044 (4)
0.0040 (4)
0.0097 (4)
0.0100 (5)
0.0061 (5)
0.0104 (6)
0.0164 (7)
0.0015 (6)
0.0184 (7)
0.00235 (11)
−0.0019 (4)
−0.0024 (4)
−0.0023 (4)
−0.0021 (4)
−0.0041 (5)
−0.0013 (5)
−0.0014 (5)
−0.0023 (5)
0.0019 (6)
−0.0101 (6)
−0.0136 (7)
0.0058 (7)
0.0058 (6)
−0.0103 (7)
N2
N3
N4
N5
N6
C7
C8
C9
C1
C2
C3
C4
C6
C5
Geometric parameters (Å, º)
N2—C8
N2—C7
N3—C7
N3—H1
N3—H2
N4—C8
N4—C9
N4—H4
N5—C8
N5—H3
N5—H5
N6—C7
N6—H7
N6—H6
1.3306 (13)
C9—C1
1.3938 (16)
1.3405 (14)
1.3335 (12)
1.01 (9)
1.01 (16)
1.3516 (14)
1.4179 (14)
1.01 (8)
1.3385 (13)
1.01 (10)
1.01 (9)
1.3334 (13)
1.02 (15)
1.02 (9)
C9—C2
C1—C4
C1—C6
C2—C3
C2—H8
C3—C5
C3—H9
C4—C5
C4—H14
C6—H11
C6—H10
C6—H12
C5—H13
1.3986 (15)
1.4039 (17)
1.4902 (17)
1.3826 (16)
1.08 (9)
1.384 (2)
1.08 (11)
1.3863 (19)
1.08 (9)
1.08 (14)
1.08 (12)
1.08 (9)
1.08 (14)
C8—N2—C7
C7—N3—H1
C7—N3—H2
H1—N3—H2
C8—N4—C9
C8—N4—H4
C9—N4—H4
C8—N5—H3
C8—N5—H5
H3—N5—H5
C7—N6—H7
C7—N6—H6
122.46 (8)
120 (4)
120 (8)
120 (2)
125.79 (8)
115 (4)
118.7 (6)
121 (7)
119 (1)
C9—C1—C4
C9—C1—C6
C4—C1—C6
C9—C2—C3
C9—C2—H8
C3—C2—H8
C2—C3—C5
C2—C3—H9
C5—C3—H9
C1—C4—C5
C1—C4—H14
C5—C4—H14
116.95 (10)
123.10 (9)
119.91 (10)
120.24 (10)
119 (3)
120 (7)
119.24 (10)
121 (2)
120 (4)
121.61 (11)
117 (2)
119 (4)
120 (9)
119 (1)
122 (6)
Acta Cryst. (2020). C76
sup-3

supporting information
H7—N6—H6
N2—C7—N6
N2—C7—N3
N6—C7—N3
N4—C8—N2
N4—C8—N5
N2—C8—N5
N4—C9—C1
N4—C9—C2
C1—C9—C2
120 (4)
C1—C6—H11
C1—C6—H10
C1—C6—H12
H11—C6—H10
H11—C6—H12
H10—C6—H12
C3—C5—C4
111 (7)
111 (2)
111 (3)
107 (6)
108 (4)
108 (2)
120.43 (11)
120 (5)
119 (3)
124.79 (8)
117.54 (8)
117.61 (8)
118.60 (8)
116.01 (8)
125.27 (8)
121.39 (9)
116.92 (9)
121.48 (10)
C3—C5—H13
C4—C5—H13
N2—C8—N4—C9
N2—C8—N4—H4
N2—C8—N5—H3
N2—C8—N5—H5
N2—C7—N6—H7
N2—C7—N6—H6
N2—C7—N3—H1
N2—C7—N3—H2
N3—C7—N2—C8
N3—C7—N6—H7
N3—C7—N6—H6
H1—N3—C7—N6
H2—N3—C7—N6
N4—C8—N2—C7
N4—C8—N5—H3
N4—C8—N5—H5
N4—C9—C1—C4
N4—C9—C1—C6
N4—C9—C2—C3
N4—C9—C2—H8
H4—N4—C8—N5
H4—N4—C9—C1
H4—N4—C9—C2
N5—C8—N4—C9
N5—C8—N2—C7
N6—C7—N2—C8
C8—N4—C9—C1
−16.30 (15)
166 (2)
−8 (4)
−173 (3)
−5 (4)
−171 (2)
175 (2)
0 (5)
156.67 (15)
172 (4)
6 (2)
−2 (2)
C8—N4—C9—C2
C9—C1—C4—C5
C9—C1—C4—H14
C9—C1—C6—H11
C9—C1—C6—H10
C9—C1—C6—H12
C9—C2—C3—C5
C9—C2—C3—H9
C1—C9—C2—C3
C1—C9—C2—H8
C1—C4—C5—C3
C1—C4—C5—H13
C2—C9—C1—C4
C2—C9—C1—C6
C2—C3—C5—C4
C2—C3—C5—H13
H8—C2—C3—C5
H8—C2—C3—H9
C3—C5—C4—H14
H9—C3—C5—C4
H9—C3—C5—H13
C4—C1—C6—H11
C4—C1—C6—H10
C4—C1—C6—H12
H14—C4—C1—C6
H14—C4—C5—H13
C6—C1—C4—C5
127.35 (15)
1.41 (17)
180 (9)
−143 (9)
−24 (1)
96 (5)
−0.72 (17)
−179 (10)
1.78 (17)
−170 (1)
−0.44 (19)
180 (1)
−2.07 (16)
175.84 (17)
0.07 (19)
180 (1)
171 (2)
−7 (11)
−179 (10)
179 (13)
−2 (13)
−178 (5)
157.09 (14)
168 (4)
3 (2)
−176.71 (15)
1.20 (15)
176.65 (15)
4 (2)
−10 (2)
120 (2)
35 (9)
154 (1)
−86 (5)
2 (13)
2 (13)
−176.57 (18)
−55 (2)
167.49 (15)
−27.08 (15)
−26.32 (16)
−57.78 (16)
Hydrogen-bond geometry (Å, º)
D—H···A
D—H
H···A
D···A
D—H···A
N4—H4···Cl
N5—H5···Cl
N6—H7···N5
C6—H10···C8
1.01 (8)
1.01 (9)
1.02 (15)
1.08 (12)
1.01 (9)
1.02 (9)
2.17 (7)
2.37 (9)
2.52 (6)
2.65 (9)
2.44 (6)
2.28 (9)
3.1584 (9)
3.2880 (9)
2.9156 (13)
3.1420 (15)
3.3431 (9)
3.2398 (9)
163 (1)
150 (6)
103 (5)
108 (5)
148 (4)
157 (1)
i
N3—H1···Cl
i
N6—H6···Cl
Acta Cryst. (2020). C76
sup-4

supporting information
ii
N5—H3···Cl
N6—H7···Cl
1.01 (10)
1.02 (15)
1.01 (16)
2.32 (13)
2.34 (18)
1.96 (15)
3.2454 (9)
3.2284 (9)
2.9754 (12)
150 (3)
146 (11)
174 (1)
iii
iv
N3—H2···N2
Symmetry codes: (i) x, y, z+1; (ii) x, −y+2, z+1/2; (iii) −x+1, y, −z+1/2; (iv) −x+1/2, −y+3/2, −z+1.
Acta Cryst. (2020). C76
sup-5