Synthesis, structure, computational modeling, and biological activity of two novel bimesitylene derivatives

Article abstract of DOI:10.1007/s11164-018-3611-x

Tetrazole- and nitrile-containing bimesitylene derivatives with potential use in coordination chemistry were synthesized and characterized, and their structural particularities are discussed. For the bimesitylene bistetrazole derivative, geometry optimization was carried out by quantum-chemical calculations using density functional theory together with vibrational frequencies, natural bond orbitals, and highest occupied molecular orbital (HOMO)–lowest unoccupied molecular orbital (LUMO) calculations. The newly synthesized bimesitylene derivatives were also evaluated for their antimicrobial activity against three different reference strains, namely Escherichia coli, Staphylococcus aureus, and Candida albicans.

Full text of DOI:10.1007/s11164-018-3611-x

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-018-3611-x
Synthesis, structure, computational modeling,
and biological activity of two novel bimesitylene
derivatives
1
1
1
1
Lucian G. Bahrin · Lilia Clima · Sergiu Shova · Irina Rosca ·
1
1
1
1
Corneliu Cojocaru · Dana Bejan · Monica C. Sardaru · Narcisa Marangoci ·
Vasile Lozan1 · Alexandru Rotaru1
,2
Received: 10 July 2018 / Accepted: 24 September 2018
©
Springer Nature B.V. 2018
Abstract
Tetrazole- and nitrile-containing bimesitylene derivatives with potential use in coor-
dination chemistry were synthesized and characterized, and their structural particu-
larities are discussed. For the bimesitylene bistetrazole derivative, geometry optimi-
zation was carried out by quantum-chemical calculations using density functional
theory together with vibrational frequencies, natural bond orbitals, and highest
occupied molecular orbital (HOMO)–lowest unoccupied molecular orbital (LUMO)
calculations. The newly synthesized bimesitylene derivatives were also evaluated for
their antimicrobial activity against three diꢀerent reference strains, namely Escheri-
chia coli, Staphylococcus aureus, and Candida albicans.
Keywords Bimesitylene derivatives · Tetrazole · DFT · HOMO–LUMO ·
Antimicrobial activity
Introduction
Biaryls are an important class of derivatives and intermediates, found in many nat-
ural products, such as alkaloids, biologically active compounds (drugs, pesticides,
etc.), and dyes [1]. Moreover, the emergence of metal–organic frameworks as prom-
ising materials with a host of remarkable properties [2] has led to an increase in the
synthesis of functionalized biaryls capable of coordinating metal centers. Bimesi-
tylene, in particular, is an interesting molecule due to the two aromatic rings being
*
Alexandru Rotaru
rotaru.alexandru@icmpp.ro
1
2
“
Petru Poni” Institute of Macromolecular Chemistry, Romanian Academy, 700487 Iasi,
Romania
Institute of Chemistry of Moldova Academy of Sciences, 2028 Chișinău, Republic of Moldova
Vol.:(012
1
3456789)
3

L. G. Bahrin et al.
perpendicular to each other for steric reasons. This means that the four aromatic
hydrogen atoms are arranged at the corners of a tetrahedron, and substituting them
could potentially lead to derivatives capable of forming three-dimensional (3D) net-
works [3]. Currently, only a few functionalized bimesitylene derivatives are known,
including carboxyl-, formyl-, nitrile-, or ethynyl-bearing derivatives [4, 5]. Increas-
ing the number of readily coordinating functionalities grafted onto the bimesitylene
core may prove beneꢁcial not only in the ꢁeld of metal–organic frameworks, but
also for development of new compounds with interesting biological properties. An
increasingly popular functionality, the tetrazole moiety with its electron-rich pla-
nar structural features, has found many uses in pharmaceutical drugs (antibacterial,
antiallergic, antiinꢂammatory, and antifungal) [6], not to mention the recent increase
in use of tetrazole rings as building blocks for design and preparation of functional
metal–organic frameworks [7–9] and metal–organic zeolites [10, 11].
We present herein the synthesis, spectral data, as well as X-ray structure of two
new bimesitylene derivatives, including one structure bearing two tetrazole moie-
ties, with potential uses in coordination chemistry. To better understand the struc-
ture–activity relationship of the new bimesitylene bistetrazole molecule, geometry
optimization was carried out using quantum-chemical calculations with density
functional theory (DFT), together with vibrational frequencies, natural bond orbit-
als, and HOMO–LUMO calculations. The DFT method was chosen due to its great
accuracy and eꢃciency [12–14]. Moreover, it is known that the DFT method ade-
quately takes into consideration electron correlation contributions, which are espe-
cially important in systems containing extensive electron conjugation [15]. Besides
these theoretical investigations, the newly synthesized bimesitylene derivatives were
also tested, and their antimicrobial activity evaluated against three diꢀerent refer-
ence strains, namely Escherichia coli, Staphylococcus aureus, and Candida albi-
cans, revealing that the tetrazole-containing derivative selectively inhibited yeast
growth.
Results and discussion
Synthesis
Synthesis of the target compounds was performed according to Scheme 1.
The ꢁrst step involved homocoupling of mesitylenemagnesium bromide in pres-
ence of iron(III), as previously described [16]. In our case, however, Grignard rea-
gent was generated using magnesium turnings and bromomesitylene 1 in reꢂux-
ing tetrahydrofuran (THF), over a period of 2 h. Upon workup, bimesitylene 2
was obtained as colorless crystals in 60% yield. The next step involved iodination
of 2 using molecular iodine in nitric acid/sulfuric acid mixture [3]. This aꢀorded
3
,3′,5,5′-tetraiodobimesitylene 3 in 85% yield, upon recrystallization of the raw
reaction product from chloroform.
Treatment of iodinated product 3 with copper(I) cyanide aꢀorded the desired
3
,3′,5,5′-tetracyanobimesitylene 4. The reaction was performed in dimethylforma-
mide (DMF) over 24 h at 140 °C, and the desired product was obtained in 70% yield.
1
3

Synthesis, structure, computational modeling, and biological…
Br
1) Mg
) FeCl
I
I
I
I
2
3
, C
2
H
4
Br
2
I , HNO , H SO
2
3
2
4
THF, 60%
3
CH COOH, 85%
1
2
3
N
N
N
NC
NC
CN
HN
CN
CuCN
DMF, 70%
NaN
3 2
, ZnCl
DMF, 30%
CN
NC
NH
N
4
5
N
N
Scheme 1 Synthetic pathways for preparation of bimesitylene bistetrazole 5
Formation of 4 was supported by spectral data. Thus, the 13C nuclear magnetic res-
onance (NMR) spectrum of 4 indicated disappearance of the signal at 105.3 ppm,
corresponding to the four carbon atoms involved in the C–I bonds. Instead, two new
signals were found at 114.5 and 115.4 ppm, corresponding to the aromatic carbon
atoms bound to the CN groups and the carbon atoms of the CN groups, respectively.
−
1
The IR spectrum of 4 revealed the presence of a strong signal at 2224 cm , attrib-
uted to CN groups. Single crystals suitable for X-ray diꢀraction were obtained by
layering pentane over a solution of 4 in dichloromethane.
Cyclization of 4 to bistetrazolyl derivative 5 was performed with sodium azide
and zinc chloride in DMF at 150 °C over 72 h. The relatively low yield of 30% and
the formation of only bistetrazolyl derivative are probably due to a number of fac-
tors, including the steric hindrance of the nitrile groups and the relatively elevated
temperature over a long period of time, which probably caused some decomposi-
tion of the reaction product. In a separate attempt, we increased the reaction time
to 7 days, however, after workup, we were left with a brown residue from which
no single product could be isolated, suggesting that prolonged heating of the tetra-
1
zolyl derivatives led to their decomposition. The H NMR spectrum of 5 displayed
1
3
the presence of the tetrazole proton as a broad singlet at 16.85 ppm, while the
C
NMR spectrum revealed the presence of a new signal at 153.3 ppm, attributed to
the tetrazole carbon atom. In the IR spectrum of 5, a new broad signal appeared at
−1
3
497 cm , corresponding to the N–H groups, as well as the crystallization water
molecules. Single crystals suitable for X-ray diꢀraction were obtained through
recrystallization from ethanol.
X‑ray analysis
The structure of compounds 4 and 5 in solid state was studied by single-crystal
X-ray diꢀraction analysis. Accordingly, compound 4 crystallizes in space group
P2 /n of monoclinic system with one molecular unit of 3,3′,5,5′-tetracyanobimesi-
1
tylene in the asymmetric part, as shown in Fig. 1. As expected, the steric eꢀect
caused by the positions of the methyl groups determines a nonplanar conformation
of the molecule, with dihedral angle between two aromatic rings of 91.74(8)°.
1
3

L. G. Bahrin et al.
Fig. 1 X-ray molecular structure of 4 with atom labeling and thermal ellipsoids at 50% probability level
Fig. 2 One-dimensional supramolecular chain in crystal structure of 4. H-bond parameters: C19–H···N2
[
C19–H, 0.96 Å; H···N2, 2.60 Å; C19···N2 (1.5−x, y−0.5, 0.5−z); ∠C19HN2 155.2°
The crystal packing shows the presence of one-dimensional (1D) supramolecu-
lar chains running along the b axis, sustained by weak H-bonding between CH as
3
donors and nitrile groups as acceptors of protons. The formation of a one-dimen-
sional chain is shown in Fig. 2.
On the other hand, compound 5 crystallizes in C2/c space group of monoclinic
system. It exhibits a molecular crystal structure comprising bistetrazolybimesi-
tylene and water molecules in 1:2.5 ratio. X-ray analysis of compound 5 showed
that the molecule exhibits proper symmetry with twofold axis crosses through
the center of C4–C4′ bond (Fig. 3). Two symmetrically related aromatic rings are
almost perpendicular, being rotated around the common bond at 88.7°, which is
close to that observed for compound 4. The dihedral angle of the planes described
by the phenyl and tetrazole rings is 113.2°.
1
3

Synthesis, structure, computational modeling, and biological…
Fig. 3 X-ray molecular structure of compound 5 with atom labeling and thermal ellipsoids at 50% level
Fig. 4 Partial view of three-dimensional supramolecular network in the crystal structure of 5. H-bond
parameters: N1–H···O1w [N1–H, 0.86 Å; H···O1w, 1.85 Å; N1···O1w (x, –y, 0.5+z) 2.702(3) Å;
∠
N1HO1w, 173.4°]; O1w–H···N4 [O1w–H, 0.85 Å; H···N4, 2.04 Å; O1w···N4 (0.5−x, 0.5 – y, –z),
2
0
.874(3) Å; ∠O1wHN4, 164.9°]; O1w–H···N5 [O1w–H, 0.85 Å; H···N5, 2.12 Å; O1w···N5 (0.5−x,
.5 – y, –z), 2.930(3) Å; ∠O1wHN5, 158.8°]
In the crystal, the components of the structure interact via a O–H···N and N–H···O
hydrogen-bonding system to form a three-dimensional supramolecular network, as
shown in Fig. 4.
1
3

L. G. Bahrin et al.
Fig. 5 Illustration of observed and theoretical molecular structure of compound 5: a single-crystal X-ray
structure (ORTEP view), thermal ellipsoids drawn at 50% probability level; b optimal geometry com-
puted by DFT/B3LYP/6-31+G** method in ground state (all atoms numbering)
A perspective view of molecule 5, together with the data on geometry optimiza-
tion and structural aspects, are presented and discussed below.
Geometry optimization and structural aspects of compound 5
Generally, the ꢁrst point of quantum-chemical calculations requires optimization of
the molecular geometry by energy minimization. In this study, we applied B3LYP/6-
3
1+G** and LSDA/6-31+G** methods for geometry optimization of compound 5.
The DFT-optimized structures were compared with the observed one (X-ray crys-
tal) in terms of root-mean-square deviation (RMSD), a measure of the similitude
between the observed crystal structure and the predicted geometry of a molecule
in terms of atomic positions. The smaller the RMSD, the better the goodness of ꢁt
between the experimental (X-ray) and predicted (DFT) molecular structure. The
explicit mathematical expression for the RMSD estimator is given elsewhere [17,
1
8].
The single-crystal structure determined by X-ray analysis is shown in Fig. 5a,
along with the molecular geometry optimized at B3LYP/6-31+G** level (Fig. 5b).
Full atomic numbering is given for the DFT-optimized geometry (Fig. 5b), as refer-
ence labels for comparison of both structures.
Table 1 presents selected structural parameters (bond lengths, valence, and tor-
sion angles) for comparison between the crystal structure and the predicted molec-
ular geometry of compound 5. The data in Table 1 reveal reasonable agreement
between the crystal structure and predicted geometries (B3LYP/6-31+G** and
LSDA/6-31+G**) in terms of structural parameters.
An explicit comparison between the single-crystal structure and DFT-predicted
geometry is highlighted in Fig. 5, detailing the overlapping plots and corresponding
RMSD values.
As shown in Fig. 6a, the optimized conformation (B3LYP/6-31+G**) ꢁtted
well with the crystal structure. Likewise, Fig. 6b exhibits the computed geometry
(
LSDA/6-31+G**) and the match with the observed structure (X-ray). The over-
lap between the experimental and predicted structure reveals an enhanced RMSD
1
3

Synthesis, structure, computational modeling, and biological…
Table 1 Summary of selected structural parameters: bond lengths (Å), valence angles (°), and torsion
angles (°), for the investigated compound 5
Geometry/structural parametera
Exp. (X-ray)
B3LYP/6-31+G**
LSDA/6-31+G**
b(1C–27C)
b(2C–4C)
1.504(3) Å
1.445(3) Å
1.143(4) Å
1.479(3) Å
1.330(4) Å
0.860(0) Å
1.336(3) Å
1.285(4) Å
1.356(3) Å
1.308(3) Å
1.517(4) Å
1.499(3) Å
179.5(3)°
124.0(2)°
128.1(2)°
107.8(2)°
−91.7(3)°
−91.4(3)°
113.1(3)°
−68.1(3)°
1.505 Å
1.436 Å
1.164 Å
1.480 Å
1.354 Å
1.011 Å
1.351 Å
1.292 Å
1.361 Å
1.324 Å
1.513 Å
1.511 Å
179.04°
125.41°
127.39°
107.19°
−92.41°
−93.97°
110.80°
−68.20°
1.481 Å
1.418 Å
1.171 Å
1.454 Å
1.351 Å
1.021 Å
1.337 Å
1.294 Å
1.341 Å
1.329 Å
1.486 Å
1.489 Å
179.60°
126.41°
127.27°
106.32°
−97.15°
−100.33°
142.25°
−37.14°
b(2C≡10N)
b(3C–14C)
b(14C–12N)
b(12N–13H)
b(12N–11N)
b(11N–9N)
b(9N–7N)
b(7N–14C)
b(6C–19C)
b(8C–15C)
∠(4C–2C–10N)
∠(3C–14C–12N)
∠(3C–14C–7N)
∠(7N–14C–12N)
τ(31C–27C–1C–5C)
τ(32C–27C–1C–6C)
τ(8C–3C–14C–7N)
τ(6C–3C–14C–7N)
ab, bond; ∠, valence angle; τ, torsion angle
Fig. 6 Comparison between observed and theoretical structure of 5 by overlapping; X-ray struc-
ture (blue), and theoretical structures (red) computed by diꢀerent methods: a B3LYP/6-31+G**
(
RMSD=0.211 Å) and b LSDA/6-31+G** (RMSD=0.354 Å). (Color ꢁgure online)
value (0.211 Å) for the B3LYP/6-31+G** model, compared with the LSDA/6-
3
1+G** one (RMSD=0.354 Å). Hence, the hybrid functional B3LYP was better
at predicting the structural parameters of compound 5 in comparison with the local
spin-density approximation (LSDA); For example, according to X-ray structure
1
3

L. G. Bahrin et al.
Fig. 7 Electrostatic properties of molecule 5: a partial atomic charge distribution along with the dipole
moment orientation and b electrostatic potential surface map; computation performed at B3LYP/6-
3
1+G** level
analysis, the torsion angle (6C–3C–14C–7N) was −68.1°, while the prediction given
by B3LYP/6-31+G** was very close, i.e., −68.20° (Table 1). In turn, for the same
dihedral (6C–3C–14C–7N), the LSDA/6-31+G** method suggested a value of
−
37.14° (Table 1), thereby revealing a greater deviation from the observed value.
Consequently, we adopted the B3LYP/6-31G** level of theory as the principal
method to perform additional analysis of molecule 5.
Population analysis, HOMO–LUMO calculation, and reactivity descriptors
In computational chemistry, population analysis provides the distribution of the
partial atomic charges that inꢂuence molecular properties such as the electrostatic
potential, dipole moment, polarizability, vibration modes, and donor–acceptor
behavior [15].
For compound 5, the distribution of partial atomic charges (Mulliken) was calcu-
lated at B3LYP/6-31+G** level and is shown in Fig. 7a. In this diagram, the partial
atomic charge values are highlighted using a color map. The dipole moment orienta-
tion (3.28 D) is rendered as a vector with origin at the biphenyl core (Fig. 7a).
As detailed in Fig. 7a, two carbon atoms (from the tetrazole moieties) have the
most intense negative charge (δ =−1.14, δ =−1.14). In turn, the highest posi-
1
4C
40C
tive charges are attributed to carbons from phenyl groups that are directly connected
to tetrazole moieties (δ =+1.33, δ =+1.33).
3
C
29C
On the basis of the atomic charge distribution, the electrostatic potential surface
(
ESP) surrounding molecule 5 was calculated by integration techniques. Figure 7b
illustrates the mapped isosurface of ESP computed at B3LYP/6-31+G** level. In
this graph, the highest positive ESP regions (blue spots) can be distinguished near
the hydrogen atoms (>N–H) from tetrazole moieties, suggesting sites for nucleo-
philic attack. The moderately negative ESP areas are depicted in Fig. 7b as yellow-
spotted regions that may be discerned near –N=N– bond (in tetrazole) and around
nitrile groups (–C≡N).
1
3

Synthesis, structure, computational modeling, and biological…
Fig. 8 Rendering of frontier
molecular orbitals (HOMO–
LUMO) patterns and associ-
ated bandgap energy value
for molecule 5 (in gas phase);
computations performed at
B3LYP/6-31+G** level
The patterns of the frontier molecular orbitals (HOMO, LUMO) are depicted
in Fig. 8. According to the B3LYP/6-31+G** method, the bandgap energy
(
HOMO–LUMO) was equal to 5.34 eV.
As shown in Fig. 8, the orbital lobes of both the HOMO and LUMO are delo-
calized over the entire molecule, i.e., on the diphenyl core, tetrazole moieties, and
nitrile groups. Such a pattern of molecular orbitals suggests strong intramolecular
electronic conjugation (i.e., a π–π conjugated system).
In addition, we calculated the molecular and reactivity descriptors for mole-
cule 5 according to the methodology presented elsewhere [19–21]. These results
related to molecular properties and global reactivity descriptors are summarized
in Table 2.
Thus, the computational results reveal that molecule 5 belongs to point group
2
(
symmetry) C1, bestowing a molecular surface of 422 Å with heat of formation
3
and polarizability volume equal to 200.73 (kcal/mol) and 48.15 Å , respectively.
Regarding the global chemical reactivity of molecule 5, the following descrip-
tors were calculated: electronegativity of 5.041 eV, chemical hardness of 2.67 eV,
−
1
electrophilicity of 4.76 eV, and chemical softness of 0.187 eV . Note that the
1
3

L. G. Bahrin et al.
Table 2 Summary of molecular and global reactivity descriptors for compound 5; descriptors computed
mainly at B3LYP/6-31+G** level of theory
Molecular/reactivity descriptor
Computed value
C H N (52
Empirical formula
2
2
20 10
atoms, 222
electrons)
Molecular point group (symmetry)
Dipole moment (Debye)
C1
3.2845
11.525
421.98
592.64
1028.59
200.73
48.15
Max. molecular dimension (Å)
Molecular surface area (vdW) (Å )
2
2
Solvent-accessible surface area (SAS) (Å )
3
Molecular volume (from SAS) (Å )
a
Heat of formation (kcal/mol)
Polarizability volume (Å )
3
a
LUMO eigenvalue, εLUMO (eV)
−2.372
−7.711
5.339
7.711
2.372
5.041
−5.041
2.670
0.187
4.76
HOMO eigenvalue, εHOMO (eV)
Energy gap, ΔE =εLUMO – εHOMO (eV)
Ionization potential, I ≈ –εHOMO (eV)
Electron aꢃnity, A ≈–εLUMO, (eV)
Electronegativity, χ= ½(I +A) (eV)
Chemical potential, μ=–χ (eV)
Chemical hardness, η= ½(I – A) (eV)
−
1
Chemical softness, S = ½η (eV
)
2
Electrophilicity index, ω=μ /2η (eV)
Electron-donating power, ω =(3I +A) /16(I – A) (eV)
Electron-accepting power, ω =(I +3A) /16(I – A) (eV)
−
2
7.614
2.573
+
2
aComputed by PM7 semiempirical method (MOPAC)
electron-accepting power of 5 was equal to 2.573 eV, which might be correlated
with the sites for nucleophilic attack identiꢁed on the ESP (Fig. 3b). In contrast,
the electron-accepting power of molecule 5 was equal to 7.614 eV, which might
be associated with the presence of lone-pair electrons from nitrogen atoms.
Antimicrobial activity
The antimicrobial activity was measured by agar disk diꢀusion method, which con-
sists in adding each tested compound to culture medium, preinoculated with micro-
bial suspension, and measuring the inhibition zone after 24 h of incubation. The
tested compounds 4 and 5 showed no antibacterial activity against the reference
strains S. aureus and E. coli, but compound 5 proved to show selective antifungal
activity against C. albicans, especially at concentration of 20 mg/mL. Data on the
average diameters of the inhibition zones are presented in Table 3.
Analyzing the obtained results reveals that intermediate 4 did not show any anti-
microbial activity against C. albicans in comparison with compound 5. This can
1
3

Synthesis, structure, computational modeling, and biological…
1
3

L. G. Bahrin et al.
be explained by the presence of two tetrazole moieties which, due to its structure,
allows the tetrazole derivatives to readily bind to various enzymes or receptors in
living organisms via weak interactions such as coordination bonds, hydrogen bonds,
hydrophobic eꢀect, π–π stacking, van der Waals force, and so on, leading to a broad
spectrum of biological activities [22, 23]. Since C. albicans represents a major
health issue driven by developments in medical care [24], the discovery and identiꢁ-
cation of new drugs and treatment approaches represents a major challenge. Within
this context, taking into account the proven activity of compound 5, various strate-
gies could be developed, including combined loading of compound 5 with an anti-
fungal drug (e.g., propiconazole), to improve its capacity to destroy yeast cells [25].
Conclusions
Two new functionalized bimesitylene derivatives containing nitrile and tetrazolyl
moieties were synthesized and characterized, and their structural particularities are
described and discussed. The crystal packing of compound 4 shows the presence
of one-dimensional supramolecular chains running along b axis, sustained by weak
H-bonding between CH as donors and nitrile groups as acceptors of protons, while
3
in compound 5, the components of the structure interact via a O–H···N and N–H···O
hydrogen-bonding system, forming a three-dimensional supramolecular network.
The computational chemistry approach was applied to compound 5 using DFT
with the B3LYP and LSDA methods and 6-31+G** basis set. The optimized molec-
ular geometries were in good agreement with the observed crystal structure, with
RMSD goodness-of-ꢁt estimator ≤0.354 Å. The patterns of the frontier molecular
orbitals (HOMO, LUMO) indicated obvious delocalization, suggesting a strong π–π
conjugated system. Likewise, population analysis, electrostatic potential, dipole
moment, bandgap energy (HOMO–LUMO), and global reactivity descriptors were
evaluated and are discussed.
The newly synthesized compounds were additionally tested for their antimicro-
bial activity, revealing that bimesitylene derivative 5 displayed antifungal properties
when compared with compound 4. Even though it can be speculated that the tetra-
zolyl moieties are responsible for this, further studies are required to elucidate the
mechanism of action involved.
Experimental
Materials and instrumentation
All commercially available reagents were used without further puriꢁcation. All
chemicals were purchased in their highest purity grade. Proton and carbon nuclear
magnetic resonance (δ , δ ) spectra were recorded on a Bruker Avance DRX
H
C
1
13 19 29
4
00 MHz spectrometer, equipped with a 5-mm four-nuclei ( H/ C/ F/ Si) direct
detection, z-gradient probe. Chemical shifts are referenced to the residual solvent
1
13
signal of dimethylsulfoxide (DMSO)-d6 ( H: 2.51 ppm; C: 39.47 ppm). IR spectra
1
3

Synthesis, structure, computational modeling, and biological…
were recorded on a FTIR Shimadzu or Jasco 660 plus FTIR spectrophotometer.
Mass spectrometry data were obtained using an Agilent 6520 series Accurate-Mass
Quadrupole Time-of-Flight (Q-TOF) LC/MS (positive ion mode). CHN elemen-
tal analysis was performed on a Vario-EL-III elemental analyzer. X-ray diꢀraction
measurements were carried out with an Oxford Diꢀraction XCALIBUR E CCD dif-
fractometer equipped with graphite-monochromated Mo K radiation.
α
Synthesis of bimesitylene 2
Magnesium turnings (0.5 g, 20.6 mmols) were placed in an oven-dried ꢂask, under
nitrogen atmosphere. THF (25 mL) was then added, and the mixture was heated
to reꢂux. Mesityl bromide (3 mL, 20 mmols) was then added in small volumes to
the reaction ꢂask. The resulting solution was reꢂuxed for 2 h, during which the
magnesium reacted completely. After this, a solution of iron chloride (0.3 g, 1.85
mmols) and dibromoethane (1.3 mL, 15 mmols) in diethylether (5 mL) was added
dropwise to the reaction ꢂask, and the resulting solution was reꢂuxed for another
3
h. The mixture thus obtained was allowed to cool down to room temperature, and
aqueous hydrochloric acid (5%, 5 mL) was then added to it. The solution was then
extracted with dichloromethane (3×20 mL), the extracts were combined and dried
over magnesium sulfate, and the solvent was evaporated. The residue thus obtained
was puriꢁed over silica gel, using hexane as eluent, yielding bimesitylene as color-
1
less solid (1.4 g, 60%). H NMR (400 MHz, CDCl ): δ 2.40 (s, 6H, 2CH ), 1.93 (s,
3
3
13
1
2H, 4CH ) ppm. C NMR (100 MHz, CDCl ): δ 137.0, 136.0, 135.5, 128.2, 21.2,
3
3
1
9.9 ppm.
Synthesis of 3,3′,5,5′‑tetraiodobimesitylene 3
To a solution of bimesitylene (0.5 g, 2 mmols) in chloroform (1 mL), iodine (1.18 g,
4
.6 mmols) was added, followed by acetic acid (3 mL) and nitric acid (2 mL). To
this mixture, sulfuric acid (2 mL) was then added dropwise, over 15–30 min. The
solution thus obtained was stirred vigorously at room temperature for 4 h, after
which it was poured over ice–water (100 mL). The precipitate thus obtained was
then ꢁltered, air-dried, and recrystallized from chloroform, yielding 3,3′,5,5′-tetra-
1
iodobimesitylene as colorless crystals (1.26 g, 85%). H NMR (400 MHz, CDCl ):
3
1
3
δ 2.40 (s, 6H, 2CH ), 1.93 (s, 12H, 4CH ) ppm. C NMR (100 MHz, CDCl ): δ
3
3
3
1
37.0, 136.0, 135.5, 128.2, 21.2, 19.9 ppm.
Synthesis of 3,3′,5,5′‑tetracyanobimesitylene 4
To a solution of tetraiodobimesitylene (3.71 g, 5 mmols) in DMF (30 mL), copper(I)
cyanide (2.5 g, 28 mmols) was added, and the resulting mixture was heated to
1
40 °C for 24 h. The resulting solution was then cooled down to room tempera-
ture and poured over aqueous ammonia (25%, 100 mL). The mixture thus obtained
was extracted with dichloromethane (3×50 mL), and the extracts were combined
and dried over magnesium sulfate. The solvent was then evaporated under reduced
1
3

L. G. Bahrin et al.
pressure, and the residue was separated over silica gel, using dichloromethane as
1
eluent, yielding the desired compound as colorless solid (1.25 g, 70%). H NMR
1
3
(
(
400 MHz, CDCl ): δ 2.85 (s, 6H, 2CH ), 2.17 (s, 12H, 4CH ) ppm. C NMR
3 3 3
100 MHz, CDCl ): δ 146.5, 144.3, 136.4, 115.4, 114.5, 20.4, 19.4 ppm. IR (ATR,
3
−1
cm ): 3288 (w), 2926 (m), 2856 (w), 2224 (s), 1767 (w), 1566 (s), 1443 (s),
1
381 (s), 1267 (w), 1024 (m), 953 (m), 744 (w), 662 (m). MS (ESI) m/z Calcd. for
+
C H N [M+H] : 339.1, found: 339.2. Elem. anal. calc. for C H N (338.1): C
2
2
19
4
22 18
4
7
8.08, H 5.36, N 16.56; found: C 78.31, H 5.42, N 16.21.
Synthesis of bistetrazolybimesitylene 5
A suspension of tetracyanobimesitylene (0.68 g, 2 mmols), sodium azide (1.3 g,
2
1
0 mmols), and zinc chloride (0.82 g, 6 mmols) in DMF (50 mL) was heated to
50 °C for 72 h. The mixture was then cooled down to room temperature and poured
over water (20 mL). The pH of the resulting solution was adjusted to 1–2 using 5%
aqueous hydrochloric acid, and the resulting precipitate was ꢁltered and washed
thoroughly with water. The washed precipitate was then redissolved in a solution
of aqueous ammonia (25%, 1 mL) in water (20 mL), and the pH was once again
adjusted to 1–2 using 5% aqueous hydrochloric acid. The newly formed precipitate
was then ꢁltered, washed thoroughly with water, and air-dried, yielding the desired
1
product as light-brown powder (0.25 g, 30%). H NMR (400 MHz, DMSO-d6): δ
1
6.85 (bs, 2H, 2NH), 2.22 (s, 6H, 2CH ), 2.15 (s, 6H, 2CH ), 1.61 (s, 6H, 2CH )
3 3 3
1
3
ppm. C NMR (100 MHz, DMSO-d6): δ 153.3, 142.5, 141.8, 141.5, 137.1, 125.6,
−
1
1
17.2, 113.3, 19.4, 19.3, 18.3 ppm. IR (ATR, cm ): 3497 (bs), 2924 (m), 2854
w), 2750 (w), 2232 (s), 1661 (m), 1580 (s), 1447 (s), 1383 (s), 1244 (s), 1188 (w),
090 (s), 1051 (s), 964 (s), 741 (w), 631 (w). MS (ESI) m/z Calcd. for C H N
(
1
2
2
21 10
+
[
M+H] : 425.1, found: 425.2. Elem. anal. calc. for C H N (424.1): C 62.25, H
2
2
20 10
4
.75, N 33.00; found: C 62.43, H 4.87, N 32.65.
X‑ray crystallography
Crystallographic measurements for 4 and 5 were carried out with an Oxford Dif-
fraction XCALIBUR E CCD diꢀractometer equipped with graphite-monochromated
Mo K radiation. Single crystals were positioned at 40 mm from the detector, and
α
2
40 and 245 frames were measured for 6 and 8 s over 1° scan width for 4 and 5,
respectively. Unit cell determination and data integration were carried out using the
CrysAlis package of Oxford Diꢀraction [26]. The structure was solved by direct
methods using Olex2 [27] software with the SHELXS [3] structure solution pro-
gram and reꢁned by full-matrix least-squares based on and reꢁned by full-matrix
2
least-squares on F with SHELXL-97 [28] using an anisotropic model for nonhy-
drogen atoms. All H atoms attached to carbon were introduced in idealized posi-
tions (d =0.96 Å) using the riding model. Positional parameters of H attached to
CH
O and N atoms were obtained from diꢀerence Fourier syntheses and veriꢁed by the
geometric parameters of the corresponding hydrogen bonds. Drawings of molecules
were obtained using Olex2 program.
1
3

Synthesis, structure, computational modeling, and biological…
−
1
X‑ray data for compound 4 C H N , Mr =338.40
g
mol , size
2
2
18
4
3
0
.35×0.30×0.30 mm , monoclinic, space group P2 /n, a =9.8130(9) Å,
1
3
b =13.1409(11) Å, c =14.7753(12) Å, β=92.706(8)°, V =1903.2(3) Å , Z =4,
−
3
−1
ρ
(
=1.181 g cm , μ(Mo K )=0.072 mm , F(000)=712, 3372 reꢂections in h
α
calcd
−11/11), k (−15/9), l (−17/14), measured in the range 4.16°≤2Θ≤50.04°, com-
pleteness Θ =99.6%, 3372 independent reꢂections, R =0.0460, 241 param-
max
int
eters, 0 restraints, R =0.0691, wR =0.1591, R =0.1104, wR2 =0.1857,
1
obs
2obs
1all
all
−
3
GoF=1.035, largest diꢀerence peak and hole: 0.22/−0.22 e A . CCDC 1834380.
−
1
X‑ray data for compound 5 C H N O , Mr =470.42 g mol , size
2
2
25.1 10 2.55
3
0
.45×0.30×0.25 mm , monoclinic, space group C2/c, a =15.4450(19) Å,
3
b =15.6184(11) Å, c =12.9152(10) Å, β=122.919(7)°, V =2615.3(4) Å , Z =4,
−3
−1
ρ
(
=1.195 g cm , μ(Mo K )=0.084 mm , F(000)=990, 5290 reꢂections in h
α
calcd
−15/18), k (−18/17), l (−15/11), measured in the range 4.08°≤2Θ≤50.06°, com-
pleteness Θ =99.8%, 2301 independent reꢂections, R =0.0243, 160 param-
max
int
eters, 0 restraints, R =0.0632, wR =0.1779, R =0.0771, wR2 =0.1910,
1
obs
2obs
1all
all
−
3
GoF=1.045, largest diꢀerence peak and hole: 0.46/−0.21 e A . CCDC 1834382.
Computational protocol
Computer simulations were performed on an HPC cluster using the Gaussian09
package [29] for electronic structure calculations. Computational outputs were ana-
lyzed in GaussView5 graphical interface software [30] on a Dell Precision work-
station T7910. Density functional theory (DFT) was applied to optimize molecular
geometries using the B3LYP and LSDA methods and double-zeta split-valence basis
set (6-31+G**). The crystal structure (CIF ꢁle) was adopted as input conformation
for geometry optimization of the isolated molecule (in gas phase). The optimized
geometries exhibited no imaginary frequencies, conꢁrming that they represent min-
imum-energy structures. For conformational goodness-of-ꢁt analysis, YASARA-
1
Structure software [31] was employed. In addition, the MOPAC program was used
for computation of some descriptors at the level of PM7 semiempirical theory [32].
Antimicrobial activity
Antimicrobial activity was determined by disk diꢀusion bioassays [33] against
three diꢀerent reference strains, viz. Escherichia coli ATCC25922, Staphylococ-
cus aureus ATCC25923, and Candida albicans ATCC10231. All microorganisms
were stored at −80 °C in 20% glycerol. The bacterial strains were refreshed in Mül-
ler–Hinton broth at 36 °C, and the yeast strain was refreshed on Sabouraud dextrose
agar at 36 °C. Microbial suspensions were prepared with these cultures in sterile
solution to obtain turbidity optically comparable to that of 0.5 McFarland standards,
8
−1
yielding a suspension containing 1×10 colony-forming units (CFU) mL for all
1
http://www.yasara.org—YASARA oꢃcial site (Yet Another Scientiꢁc Artiꢁcial Reality Application).
1
3

L. G. Bahrin et al.
microorganisms. Volumes of 0.5 mL from each inoculum were spread onto Mül-
ler–Hinton agar, and the compound was added after drying of the medium surface.
A sterilized paper disc (6 mm) was placed on the middle of the plate. An aliquot
(
50 μL) of 4 and 5 (concentration 20 mg/mL in DMSO) was added on the paper
disc. To evaluate the antimicrobial properties, growth inhibition was measured after
2
4 h of incubation at 36± 1 °C. All tests were carried out in triplicate to verify the
results. After incubation, the diameters of the inhibition zones were measured.
Acknowledgements Financial support from the European Social Fund for Regional Development, Com-
petitiveness Operational Programme Axis 1—Project “Novel Porous Coordination Polymers with Organic
Ligands of Variable Length for Gas Storage,” POCPOLIG (ID P_37_707, Contract 67/08.09.2016, cod
MySMIS: 104810) is gratefully acknowledged. The research related to computational chemistry is part
of a project that has received funding from the European Union’s Horizon 2020 research and innovation
program under grant agreement no. 667387 WIDESPREAD 2-2014 SupraChem Lab.
References
1
2
3
4
5
6
7
.
.
.
.
.
.
.
J. Hassan, M. Sevignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev. 102, 1359 (2002)
C. Janiak, J.K. Vieth, New J. Chem. 34, 2366 (2010)
J.N. Moorthy, R. Natarajan, P. Venugopalan, J. Org. Chem. 70, 8568 (2005)
W. Lu, Z. Wei, D. Yuan, J. Tian, S. Fordham, H.C. Zhou, Chem. Mater. 26, 4589 (2014)
J.N. Moorthy, R. Natarajan, G. Savitha, P. Venugopalan, Cryst. Growth Des. 6(4), 919 (2006)
C.X. Wei, M. Bian, G.H. Gong, Molecules 20, 5528 (2015)
K. Adil, Y. Belmabkhout, R.S. Pillai, A. Cadiau, P.M. Bhatt, A.H. Assen, G. Maurin, M. Eddaoudi,
Chem. Soc. Rev. 46, 3402 (2017)
8
9
.
.
L.J. Chen, H.B. Yang, M. Shionoya, Chem. Soc. Rev. 46, 2555 (2017)
L.R. Mingabudinova, V.V. Vinogradov, V.A. Milichko, E. Hey-Hawkins, A.V. Vinogradov, Chem.
Soc. Rev. 45, 5408 (2016)
1
1
1
1
1
1
1
1
1
0. M. Eddaoudi, D.F. Sava, J.F. Eubank, K. Adila, V. Guillerm, Chem. Soc. Rev. 44, 228 (2015)
1. Y.X. Tan, F. Wang, J. Zhang, Chem. Soc. Rev. 47, 2130 (2018)
2. V. Karunakaran, V. Balachandran, Spectrochim. Acta A 98, 229 (2012)
3. A. Suvitha, S. Periandy, S. Boomadevi, M. Govindarajan, Spectrochim. Acta A 117, 216 (2014)
4. M. Karabacak, E. Sahin, M. Cinar, I. Erol, M. Kurt, J. Mol. Struct. 886, 148 (2008)
5. I. Sidir, Y.G. Sidir, M. Kumalar, E. Tasal, J. Mol. Struct. 964, 134 (2010)
6. G. Cahiez, C. Chaboche, F. Mahuteau-Betzer, M. Ahr, Org. Lett. 7(10), 1943 (2005)
7. M.F. Zaltariov, C. Cojocaru, S. Shova, I. Sacarescu, M. Cazacu, J. Mol. Struct. 1120, 302 (2016)
8. O.M. Becker, A.D. MacKerell, B. Roux, M. Watanabe, Conformational Analysis, in Computational
Biochemistry and Biophysics (Marcel Dekker, New York, 2001), pp. 69–90
1
2
2
2
2
2
2
9. J. Frau, D. Glossman-Mitnik, Molecules 23(3), 559 (2018)
0. R. Vijayaraj, V. Subramanian, P.K. Chattaraj, J. Chem. Theory Comput. 5(10), 2744 (2009)
1. C.M. Chang, Y.H. Ou, T.C. Liu, S.Y. Lu, M.K. Wang, SAR QSAR Environ. Res. 27(6), 441 (2016)
2. L.L. Dai, S.F. Cui, G.L.V. Damu, C.H. Zhou, Chin. J. Org. Chem. 33, 224 (2013)
3. J. Roh, K. Vavrova, A. Hrabalek, Eur. J. Org. Chem. 31, 6101 (2012)
4. C.G. Pierce, J.L. Lopez-Ribot, Expert Opin. Drug Discov. 8(9), 1177 (2013)
5. B. Minea, N. Marangoci, D. Peptanariu, I. Rosca, V. Năstasă, A. Corciova, C.D. Varganici, A.
Nicolescu, A. Fifere, A. Neamțu, M. Mareș, M. Bărboiu, M. Pinteală, New J. Chem. 40, 1765
(
2016)
2
2
6. CrysAlis RED, Oxford Diꢀraction Ltd., Version 1.171.36.32, 2003
7. O.V. Dolomanov, L.J. Bourhis, R.J.J. Gildea, A.K. Howard, H. Puschmann, J. Appl. Cryst. 42, 339
(
2009)
2
2
8. G.M. Sheldrick, Acta Crystallogr. A A64, 112 (2008)
9. M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, G. Scalm-
ani, V. Barone, B. Mennucci, G.A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H.P. Hratchian,
1
3

Synthesis, structure, computational modeling, and biological…
A.F. Izmaylov, J. Bloino, G. Zheng, J.L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J.
Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J.A. Montgomery, J.E.
Peralta, F. Ogliaro, M. Bearpark, J.J. Heyd, E. Brothers, K.N. Kudin, V.N. Staroverov, R. Kobayashi,
J. Normand, K. Raghavachari, A. Rendell, J.C. Burant, S.S. Iyengar, J. Tomasi, M. Cossi, N. Rega,
J.M. Millam, M. Klene, J.E. Knox, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts,
R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, R.L. Martin, K.
Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador, J.J. Dannenberg, S. Dapprich, A.D. Daniels,
Ö. Farkas, J.B. Foresman, J.V. Ortiz, J. Cioslowski, D.J. Fox, Gaussian 09 (Gaussian Inc., Walling-
ford, CT, 2009)
3
0. R. Dennington, T. Keith, J. Millam, GaussView, Version 5 (Semichem Inc., Shawnee Mission, KS,
2
009)
3
3
3
1. E. Krieger, G. Vriend, Bioinformatics 30, 2981 (2014)
2. J.J.P. Stewart, J. Mol. Model. 19, 1 (2013)
3. D.F. Brown, D. Kothari, J. Clin. Pathol. 28, 779 (1975)
1
3