Synthesis, X-ray characterization, Hirshfeld surface analysis and DFT calculations on tetrazolyl-phenol derivatives: H-bonds vs C–H…π/π…π interactions

Article abstract of DOI:10.1016/j.molstruc.2020.129425

Tetrazoles are nitrogen rich heterocycles with a broad spectrum of medicinal properties and potential for use as drugs. A significant number of FDA approved drugs incorporate the tetrazole moiety indicating the versatile pharmaceutical potential associate

Full text of DOI:10.1016/j.molstruc.2020.129425

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Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis, X-ray characterization, Hirshfeld surface analysis and DFT
calculations on tetrazolyl-phenol derivatives: H-bonds vs
C–H…π/π…π interactions
Asma Bibia, Imtiaz Khanb,∗, Hina Andleeba,c, Jim Simpsond, Muhammad Nawaz Tahire,
Shahid Hameeda,∗, Antonio Fronteraf,∗
a Department of Chemistry, Quaid-i-Azam University, Islamabad-45320, Pakistan
b Department of Chemistry and Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United
Kingdom
c Sulaiman Bin Abdullah Aba Al-Khail – Centre for Interdisciplinary Research in Basic Science (SA-CIRBS), Faculty of Basic and Applied Sciences,
International Islamic University, Islamabad, Pakistan
d Department of Chemistry, University of Otago, P.O. Box 56, Dunedin, 9054, New Zealand
e Department of Physics, University of Sargodha, Sargodha, Pakistan
f Departament de Química, Universitat de les Illes Balears, Crta de Valldemossa km 7.5, 07122 Palma de Mallorca (Baleares), Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Tetrazoles are nitrogen rich heterocycles with a broad spectrum of medicinal properties and potential
for use as drugs. A significant number of FDA approved drugs incorporate the tetrazole moiety indicat-
ing the versatile pharmaceutical potential associated with this heteroaromatic skeleton. Owing to the
higher number of nitrogen atoms and σ-lone pairs, tetrazoles offer the opportunity to control structural
topology through non-covalent interactions. In this perspective, the present research is focused on the
investigation of various non-covalent interactions in a series of tetrazole derivatives (5a–c) incorporating
a linear aliphatic chain (eight to fifteen carbon atoms) at N-2 and with a phenol moiety at the only car-
bon atom of the tetrazole ring. The detailed X-ray crystallographic investigations revealed the formation
of various supramolecular architectures employing non-covalent interactions of a diverse nature. Further
insights into these intermolecular interactions were obtained using Hirshfeld surface analysis and DFT
calculations focusing on the H-bonds, C–H…π and π–π interactions in the structures. These contacts
have been characterized by combining the quantum theory of “atoms-in-molecules” (QTAIM) with the
non-covalent interaction index (NCIplot).
Received 24 August 2020
Revised 5 October 2020
Accepted 7 October 2020
Available online xxx
Keywords:
Non-covalent interactions
Hirshfeld surface analysis, Tetrazoles
DFT calculations
QTAIM
© 2020 Elsevier B.V. All rights reserved.
1. Introduction
delocalization of the negative charge. They also exhibit good mem-
brane penetration and enhanced lipophilicity [8,9], and take a cen-
Tetrazoles are doubly unsaturated five-membered aromatic het-
erocycles featuring one carbon and four nitrogen atoms and are
ranked among the stable heterocycles with highest number of ni-
trogen atoms. However, pentazoles are highly explosive azahetero-
cycles [1]. Tetrazoles can accommodate a maximum of three pen-
dant groups on the ring. Substituted tetrazoles with 6π electrons
may exist in two tautomeric forms shown in I or II (Fig. 1) [2–4].
They show diverse properties such as bioisosterism [5] to car-
boxylic acid and amide functionalities alongside metabolic stability
[6,7] and a good physicochemical character in the form of spatial
tral place in the medicinal chemistry and drug discovery arenas
displaying a plethora of biological applications [10–27]. The phar-
maceutical significance of these heterocycles is well reflected in
the data obtained from Drug Bank [28] indicating 43 drugs with
1H- or 2H-tetrazole moieties, 23 of which are FDA approved [29].
Tetrazoles offer more opportunities to establish hydrogen bonds or
π-stacking with the receptor recognition sites due to the higher
number of nitrogen atoms and σ-lone pairs [30]. Moreover, tetra-
zoles can also be employed as ligands in coordination chemistry
[31,32] and for the synthesis of liquid crystals [33]. Fig. 2 illus-
trates representative examples of drug molecules and liquid crys-
tals highlighting the tetrazole functionality [29,33].
∗
Corresponding authors.
Non-covalent interactions, also known as “supramolecular inter-
actions”, have gained eminence due to their conspicuous role in
E-mail addresses: imtiaz.khan@manchester.ac.uk (I. Khan), shameed@qau.edu.pk
(S. Hameed), toni.frontera@uib.es (A. Frontera).
https://doi.org/10.1016/j.molstruc.2020.129425
0022-2860/© 2020 Elsevier B.V. All rights reserved.
Please cite this article as: A. Bibi, I. Khan, H. Andleeb et al., Synthesis, X-ray characterization, Hirshfeld surface analysis and DFT calcu-
lations on tetrazolyl-phenol derivatives: H-bonds vs C–H…π/π…π interactions, Journal of Molecular Structure, https://doi.org/10.1016/j.
molstruc.2020.129425

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efforts [63–66], in the present study, we report three new tetra-
zole molecules bearing a phenol and an alkylated chain that have
been investigated for the formation of supramolecular assemblies
involving various non-covalent interactions. In particular, the abili-
ties of the tetrazole and phenol moieties as H-bond donor/acceptor
groups and promoting π-stacking are studied and analyzed using
DFT calculations and a combination of QTAIM and NCIplot compu-
tational tools.
Fig. 1. Tautomerism of tetrazole derivatives.
2. Experimental
several leading areas of modern research ranging from supramolec-
ular chemistry to molecular biology [34–37], particularly in drug–
receptor interactions, enzyme inhibition and protein folding [38].
Other applications include the management of the structures of
biomolecules such as proteins and DNA, several host–guest sys-
tems, and enzyme–substrate binding [39,40]. Recognizing the im-
portance of non-covalent interactions such as hydrogen bonding,
halogen bonding, van der Waals forces, π–π stacking, cation–π,
C–H…π, lp–π, anion–π and metallophilic interactions [41–45] in
small organic molecules and proteins, extensive investigations have
been performed [46,47]. Despite their small magnitude such con-
tacts exert a significant impact on structural topology thus affect-
ing several physical and chemical characteristics of bio-systems
[48–52]. Within the field of crystal engineering, an understanding
of crystal packing is sought by a detailed knowledge of intermolec-
ular interactions [47] leading to understanding and control of self-
assembly and molecular recognition [53–55].
2.1. Instrumentation and techniques
The progress of all reactions was monitored by TLC using pre-
coated silica gel-60 F254 TLC plates purchased from Merck (Ger-
many). Melting points of the synthesized compounds were de-
termined in open capillaries using a Gallenkamp melting point
(MPD) apparatus and are uncorrected. The FTIR spectra were per-
formed on a Shimadzu Fourier Transform Infra-Red spectropho-
tometer model 270 using ATR (Attenuated total reflectance) facil-
ity. NMR spectra were recorded on a Bruker Avance 300 MHz spec-
trophotometer. 1H and 13C NMR spectra were obtained using CDCl3
as solvent with reference to TMS as internal standard.
2.2. Substrates and reagents
4-Cyanophenol, sodium azide, ammonium chloride, acetic
anhydride, 1-bromooctane, 1-bromodecane, 1-bromopentadecane
and N,N-dimethylformamide (DMF) were purchased from Sigma-
Aldrich (Germany). Tetrahydrofuran (THF) and methanol were sup-
plied by Lab-Scan (Poland). Silica gel, dichloromethane (DCM), n-
hexane and petroleum ether were purchased from Merck (Ger-
many). Ethyl acetate was purchased from Ridel-de-Haën (USA).
Anhydrous potassium carbonate (K2CO3) and magnesium sulfate
In view of the ubiquitous nature and unique role in diverse
fields, the investigation and understanding of these weak non-
covalent interactions have emerged as one of the major objectives
of contemporary chemistry. Consequently, several researchers have
documented and analyzed various non-covalent interactions using
combined theoretical and experimental methods [56–62] rendering
it an interesting topic of research. In a continuation of our previous
Fig. 2. Representative examples of biologically active drugs (top) and liquid crystals (bottom) highlighting tetrazole functionality.
2

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Scheme 1. Synthetic route to 2,5-disubstituted tetrazoles (5a–c).
(MgSO4) were obtained from WINLAB (USA). Ethanol and acetone
were obtained from commercial sources. The reagents used were
of analytical grade and the commercial solvents were distilled be-
fore use.
2.3.3.1. 4-[(2-Octyl)−2H-tetrazol-5-yl]phenyl acetate (4a). White
solid (yield: 51%); Rf = 0.76 (30% EtOAc in n-hexane); FTIR (neat,
vmax, cm–1): 2942, 2851, 1758, 1613, 1207, 1171, 918; 1H NMR
(300 MHz, CDCl3): δ (ppm) 8.2 (2H, d, J = 8.8 Hz), 7.2 (2H, d,
J = 8.8 Hz), 4.6 (2H, t, J = 7.2 Hz), 2.3 (3H, s), 2.1 (2H, quint,
J = 7.2 Hz), 1.8–1.3 (10H, m), 0.9 (3H, t, J = 6.9 Hz); 13C NMR
(CDCl3): δ (ppm) 169.4, 164.5, 152.3, 128.2, 125.4, 122.3, 53.4, 31.8,
29.5, 29.2, 29.0, 26.5, 22.8, 21.4, 14.2.
2.3. Synthetic chemistry
The numbering of the various starting materials used in these
syntheses is shown in Scheme 1.
2.3.3.2. 4-[(2-Decyl)−2H-tetrazol-5-yl]phenyl acetate (4b). White
solid (yield: 50%); Rf = 0.78 (30% EtOAc in n-hexane); FTIR (neat,
vmax, cm–1): 2951, 2851, 1750, 1614, 1222, 1177, 918; 1H NMR
(300 MHz, CDCl3): δ (ppm) 8.2 (2H, d, J = 8.7 Hz), 7.3 (2H, d,
J = 8.7 Hz), 4.6 (2H, t, J = 7.2 Hz), 2.3 (3H, s), 2.1 (2H, quint,
J = 7.2 Hz), 1.5–1.2 (14H, m), 0.9 (3H, t, J = 7.0 Hz); 13C NMR
(CDCl3): δ (ppm) 169.2, 164.3, 152.1, 128.5, 125.2, 122.1, 53.3, 31.8,
29.6, 29.4, 29.3, 29.2, 28.8, 26.3, 22.6, 21.2, 14.2.
2.3.1. Preparation of 4-(2H-tetrazol-5-yl)phenol (2)
To a stirred solution of 4-cyanophenol 1 (10.0 g, 0.084 mol) in
N,N-dimethylformamide (50 mL) was added sodium azide (22.0 g,
0.340 mol) followed by ammonium chloride (18.0 g, 0.340 mol).
The mixture was heated to 120 °C for 24 h. The reaction mix-
ture was cooled to room temperature, poured onto ice cold wa-
ter (50 mL) and acidified with aqueous HCl to pH 2. The pre-
cipitated solid was filtered and crystallized (ethanol) to afford 4-
(2H-tetrazol-5-yl)phenol 2 in 78% yield [67]. m.p.: 238.0–238.8 °C;
Rf = 0.23 (40% EtOAc in n-hexane); FTIR (neat, vmax, cm–1): 3445,
3254, 3030, 1608; 1H NMR (300 MHz, CDCl3): δ (ppm) 8.1 (2H, d,
J = 6.6 Hz), 7.3 (2H, d, J = 6.6 Hz); 13C NMR (75 MHz, CDCl3): δ
(ppm) 169.4, 152.2, 127.3, 125.5, 122.6.
2.3.3.3. 4-[(2-Pentadecyl)−2H-tetrazol-5-yl]phenyl
acetate
(4c).
White solid (yield: 56%); Rf = 0.83 (30% EtOAc in n-hexane); FTIR
(neat, vmax, cm–1): 2926, 2857, 1753, 1615, 1230, 1169, 914; 1H
NMR (300 MHz, CDCl3): δ (ppm) 8.2 (2H, d, J = 8.7 Hz), 7.3 (2H,
d, J = 8.7 Hz), 4.6 (2H, t, J = 7.2 Hz), 2.3 (3H, s), 2.1 (2H, quint,
J = 7.2 Hz), 1.5–1.2 (24H, m), 0.9 (3H, t, J = 7.0 Hz); 13C NMR
(CDCl3): δ (ppm) 169.1, 164.2, 152.0, 128.5, 125.2, 122.1, 53.3, 31.8,
29.6, 29.4, 29.3, 29.1, 29.0, 28.9, 28.8, 26.5, 26.3, 22.7, 21.2, 19.1,
14.1, 13.7.
2.3.2. Preparation of 4-(2H-tetrazol-5-yl)phenyl acetate (3)
To an ice-cold solution of sodium hydroxide (3 m, 27.6 mL) was
added 4-(2H-tetrazol-5-yl)phenol 2 (5.4 g, 0.033 mol) followed by
acetic anhydride (7.9 mL, 0.083 mol). The reaction mixture was vig-
orously stirred for 30 min and the precipitated solid was filtered,
washed with cold water and crystallized from a mixture of water–
methanol to afford 4-(2H-tetrazol-5-yl)phenyl acetate 3 as a white
solid in 75% yield [67]. m.p.: 186.3–187.4 °C; Rf = 0.33 (40% EtOAc
in n-hexane); FTIR (neat, vmax, cm–1): 3254, 3075, 2938, 2844,
1758, 1613, 1504, 1207; 1H NMR (300 MHz, CDCl3): δ (ppm) 8.1
(2H, d, J = 6.6 Hz), 7.4 (2H, d, J = 6.6 Hz), 2.3 (3H, s); 13C NMR
(75 MHz, CDCl3): δ (ppm) 169.0, 158.0, 153.0, 128.0, 125.2, 122.4,
22.9.
2.3.4. General method for the deprotection reaction
To a stirred solution of 4-[(2-alkyl)−2H-tetrazol-5-yl]phenyl ac-
etate 4a–c (6.2 mmol) in methanol (20 mL) was added KOH
(0.346 g, 6.2 mmol) in water (10 mL) and the resulting mixture
was heated to reflux for 12 h. After completion of the reaction,
the mixture was cooled to room temperature, filtered and volatiles
were removed under reduced pressure. The residue was poured
onto ice (100 g) and acidified with aqueous HCl to pH 2. The pre-
cipitated solid was filtered and recrystallized from ethanol to af-
ford compounds 5a–c [67].
2.3.3. General procedure for the preparation of
4-[(2-alkyl)−2H-tetrazol-5-yl]phenyl acetate (4a–c)
2.3.4.1. 4-[(2-Octyl)−2H-tetrazol-5-yl]phenol
(5a). White
crys-
To a stirred mixture of 4-(2H-tetrazol-5-yl)phenyl acetate 3
(5.0 g, 24 mmol) and anhydrous K2CO3 (3.30 g, 24 mmol) in ace-
tone (40 mL) was added appropriate alkyl halide (24 mmol) and
the mixture was heated to reflux for 48 h. The reaction mixture
was cooled to room temperature and filtered to remove excess
K2CO3. The solvent was removed in vacuo and the product was
crystallized from ethanol [67].
talline solid (yield: 59%); m.p.: 65.5–66 °C; Rf = 0.85 (30% EtOAc
in n-hexane); FTIR (neat, vmax, cm–1): 3363, 2933, 2849, 1615, 1171,
853; 1H NMR (300 MHz, CDCl3): δ (ppm) 7.9 (2H, d, J = 8.7 Hz),
6.9 (2H, d, J = 8.7 Hz), 6.7 (1H, s), 4.2 (2H, t, J = 7.2 Hz), 1.8 (2H,
quint, J = 7.2 Hz), 1.4–1.2 (10H, m), 0.9 (3H, t, J = 5.8 Hz); 13C
NMR (CDCl3): δ (ppm) 165.2, 158.0, 128.8, 120.0, 116.1, 53.4, 31.9,
29.6, 29.3, 28.9, 26.6, 22.8, 14.3.
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˚
2.3.4.2. 4-[(2-Decyl)−2H-tetrazol-5-yl]phenol (5b). White crys-
talline solid (yield: 75%); m.p.: 73.4–76.3 °C; Rf 0.86 (30%
(λ = 0.71073 A). Data collections were controlled by APEX2 soft-
ware [68] with cell refinement and data reduction performed us-
ing SAINT [68]. Multi-scan absorption corrections were applied
using SADABS [69]. The structures were solved with SHELXS-97
[70] and refined by full-matrix least-squares on F2 using SHELXL-
2018/1 [71] and TITAN2000 [72]. All non-hydrogen atoms were as-
signed anisotropic displacement parameters. All H-atoms were po-
sitioned geometrically and refined using a riding model with d(O–
=
EtOAc in n-hexane); FTIR (neat, vmax, cm–1): 3409, 2941, 2854,
1620, 1169, 845; 1H NMR (300 MHz, CDCl3): δ (ppm) 7.9 (2H,
d, J = 8.8 Hz), 7.0 (2H, d, J = 8.7 Hz), 6.7 (1H, s), 4.6 (2H, t,
J = 7.2 Hz), 1.8 (2H, quint, J = 7.2 Hz), 1.4–1.2 (14H, m), 0.9 (3H,
t, J = 5.9 Hz); 13C NMR (75 MHz, CDCl3): δ (ppm) 164.9, 160.8,
128.3, 119.9, 114.8, 53.1, 31.8, 29.6, 29.3, 28.9, 26.4, 22.7, 19.1, 18.7,
14.2.
˚
–
H) = 0.84 A and Uiso= 1.5Ueq(O), d(C H) = 0.93 for aromatic and
˚
˚
0.97 A for CH2 with Uiso= 1.2Ueq(C) and 0.96 A, Uiso= 1.5Ueq(C) for
CH3 atoms. 5b crystallizes in a non-centric space group, P212121,
but the absolute structure cannot be determined reliably, and the
Flack parameter is not reported. All molecular plots and packing
diagrams were drawn using Mercury [73]. Other calculations were
performed using PLATON [74] and the tabular material was pro-
duced using WINGX [75].
2.3.4.3. 4-[(2-Pentadecyl)−2H-tetrazol-5-yl]phenol
(5c). White
crystalline solid (yield: 64%); m.p.: 74–76 °C; Rf = 0.87 (30%
EtOAc in n-hexane); FTIR (neat, vmax, cm–1): 3338, 2930, 2850,
1610, 1174, 855; 1H NMR (300 MHz, CDCl3): δ (ppm) 8.0 (2H,
d, J = 9.0 Hz), 6.9 (2H, d, J = 8.7 Hz), 6.7 (1H, s), 4.6 (2H, t,
J = 7.2 Hz), 2.0 (2H, quint, J = 7.2 Hz), 1.3–1.2 (24H, m), 0.9 (3H,
t, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3): δ (ppm) 164.8, 157.9,
128.5, 119.6, 115.9, 53.2, 31.9, 29.6, 29.4, 29.3, 29.1, 29.0, 28.9, 28.8,
26.5, 26.3, 22.7, 19.1, 19.0, 14.1.
2.6. Theoretical methods
The energies of the complexes included in this study were com-
puted at the PBE1PBE-D3/def2-TZVP level of theory by using the
program Gaussian-16 [76]. The interaction energy (or binding en-
ergy in this work) ꢀE, is defined as the energy difference between
the multicomponent assembly and the sum of the energies of the
monomers, unless otherwise noted. The basis set superposition er-
ror has been corrected using the counterpoise method [77]. For
the calculations we have used the Weigend def2-TZVP [78,79] basis
set and the PBE1PBE DFT functional [80,81]. Grimme’s D3 disper-
sion correction has been used [82,83] to better estimate the π-π
interactions. The MEP (Molecular Electrostatic Potential) surfaces
calculations have been computed using Gaussian-16 software at
the PBE1PBE-D3/def2-TZVP level of theory and using the 0.001 a.u.
2.4. Crystal growth development
Single crystals of compounds 5a–c suitable for X-ray diffraction
analysis were grown at room temperature from ethanol as the sol-
vent.
2.5. X-ray structure determination
Crystallographic data for compounds 5a-c are listed in
Table 1. Diffraction data were collected on a Bruker APEXII CCD
diffractometer using graphite-monochromated Mo-Kα radiation
Table 1
Crystal data and structure refinement for 5a-c.
Compound
5a
5b
5c
Empirical formula
Formula weight
Temperature (K)
C
15H22N4O
C17H26N4O
302.42
C22H36N4O
372.55
274.36
296(2)
296(2)
296(2)
˚
Wavelength (A)
0.71073
0.71073
0.71073
Crystal system
Space group
Monoclinic
Orthorhombic
P212121
Monoclinic
P21/n
P21/n
˚
a (A)
9.7352(5)
13.4508(8)
18.6627(14)
21.5332(17)
90
6.0774(4)
9.6725(7)
37.496(3)
90
˚
b (A)
13.1170(7)
˚
c (A)
12.4010(7)
α (°)
β (°)
γ (°)
90
98.237(2)
90
91.924(3)
90
90
90
3
˚
Volume (A )
1567.23(15)
5405.4(7)
12
2202.9(3)
4
Z
4
Dcalc (g cm−3
)
1.163
1.115
1.123
μ (mm−1
)
0.076
0.072
0.070
Crystal size(mm)
0.42 × 0.34 × 0.30
2.273 to 27.523
−12<=h<=12,
−17<=k<=16,
−16<=l<=15
13,383
0.43 × 0.24 × 0.20
1.444 to 25.497
−16<=h<=14,
−22<=k<=22,
−26<=l<=26
41,463
0.36 × 0.32 × 0.26
2.174 to 26.870
−7<=h<=7,
−12<=k<=12,
−47<=l<=47
18,279
Theta range for data collection (°)
Index
ranges
Reflections collected
Independent reflections
Completeness to theta = 25.242°
Refinement method
3569 [R(int) = 0.0221]
10,075 [R(int) = 0.0723]
100.0%
4748 [R(int) = 0.0373]
100.0%
100.0%
Full-matrix least-squares on F2
0.670 and 0.746
3569 / 0 / 183
1.031
Min. and max. transmission
Data/restraints/parameters
Goodness-of-fit on F2
0.945 and 0.978
10,075 / 0 / 601
0.962
0.975 and 0.982
4748 / 0 / 249
1.026
Final R indices [I >2σ(I)]
R indices (all data)
R1 = 0.0418, wR2 = 0.1094
R1 = 0.0623, wR2 = 0.1232
–
R1 = 0.0526, wR2 = 0.1009
R1 = 0.1445, wR2 = 0.1320
–0.3(10)
R1 = 0.0491, wR2 = 0.1189
R1 = 0.0755, wR2 = 0.1313
–
Absolute structure parameter
Extinction coefficient
–
–
0.0213(14)
−3
˚
Largest difference peak and hole (e A
)
0.162 and −0.187
988,868
0.137 and −0.200
999,009
0.186 and −0.148
999,010
CCDC reference number
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envelope to generate the surface. The NCIPlot [84,85] index and
QTAIM analyses have been performed using the PBE1PBE-D3/def2-
TZVP wave function and the AIMAll program [86].
3.3. Crystal packing
In the crystals, packing is stabilized by a variety of hydrogen
–
bonds, C H…π contacts and a π…π stacking interactions.
3. Results and discussion
3.3.1. Crystal packing of 5a
In the crystal of 5a, classical O1-H1…N4 hydrogen bonds sup-
ported by weaker C2-H2…O1 and C3-H3…N3 hydrogen bonds
form zig-zag chains of molecules along b, Fig. 4. C8-H8A…Cg2 hy-
drogen bonds form inversion related dimers that are linked by
3.1. Synthetic chemistry
The substituted tetrazoles 5a–c were prepared using a four-step
synthetic approach as outlined in Scheme 1. In the first step, 1,3-
dipolar cycloaddition of the azide anion with 4-cyanophenol 1 af-
forded tetrazole 2 in 78% yield which was acetylated using acetic
anhydride to deliver compound 3 in 75% yield. Subsequently, the
alkylation reaction of 3 with different alkyl bromides provided the
corresponding N-2 alkylated tetrazoles 4a-c which on basic hydrol-
ysis afforded the target products 5a-c in 59–75% isolated yields
[67].
–
–
–
the O H…C H…O and C H…N contacts mentioned previously into
chains along c, Fig. 5. Overall, these contacts stack molecules of 5a
along the b axis direction, Fig. S1 in the supplementary material.
3.3.2. Crystal packing of 5b
–
–
–
In the crystal of 5b, O H…N, C H…O and C H…N hydro-
gen bonds from both M1 and M2 molecules of 5b form zig-
zag chains along the a axis direction, Fig. 6, in a fashion rem-
iniscent of the packing found for 5a, (Fig. 4). In contrast, M3
molecules link to one another, albeit in a very similar fashion
with a similar set of hydrogen bonds, also forming zig-zag chains
along a, Fig. 7. M1, M2 and M3 molecules are linked along c
3.2. X-ray crystallography
As background to the structural investigation, a search of the
Cambridge structural database [87] was conducted for the 5-
–
–
by a variety of C H…π contacts reinforced in one instance by a
phenyl-2-propyl-2H-tetrazole, C6 CN4CH2CH2 fragment in organic
π…π interaction between the M1 and M3 tetrazole rings with
compounds. This resulted in 12 hits, none of which had an OH sub-
stituent at any position on the benzene ring. Two of the hits USE-
BUR, (4-(2-ethyl-2H-tetrazol-5-yl)benzyl)phosphonic acid mono-
hydrate [88] and KUVKOC, 1-(((cyclohexyloxy)carbonyl)oxy)ethyl
˚
centroid to centroid distances Cg1…Cg5 3.508(3) A (symmetry
–
operation1-X,−1/2 + Y,1/2-Z), Fig. 8. The C H…π contacts com-
˚
prise C9-H9A…Cg6, H…C = 2.95 A, (symmetry operation, 1-X,
ꢀ
˚
−1/2 + Y, 1/2-Z), C27-H27A…Cg2, H…C = 2.85 A, (symmetry op-
3-((2 -(2-ethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)−2-oxo-2,3-
˚
eration, −1 + X, Y, Z), C43-H43B…Cg2, H…C = 2.91 A, (symme-
dihydro-1H-benzimidazole-4-carboxylate [89] have simple ethyl
substituents on the 2-positions of the tetrazole rings. However
extended alkyl chain substituents are found in MAZHED, 4-[4-
(2-decyl-2H-tetrazol-5-yl)phenyl]−2,6-bis(1,3-thiazol-2-yl)pyridine
[90] and two closely related compounds with hexyl and nonyl
substituents on the tetrazole rings, UFITIO, 4-(2-hexyl-2H-tetrazol-
5-yl)phenyl 4-(hexyloxy)benzoate and UFITEK 4-(2-nonyl-2H-
tetrazol-5-yl)phenyl 4-(nonyloxy)benzoate [67]. The only other
˚
try operation, 1-X, 1/2 + Y, 1/2-Z, C46-H46A…Cg3, H…C = 2.92 A,
(symmetry operation, X, Y, Z), Fig. 8. Cg1, Cg2, Cg3, Cg5 and Cg6
are the centroids of the (N1, N2, N3, N4, C7); (C1—C6); (N5, N6,
N7, N8, C24); (N9, N10, N11, N12, C41) and (C35—C40) rings re-
spectively. These contacts combine to form approximately parallel
sheets of M1, M2 and M3 molecules when viewed along the a axis
direction, Fig. S2 in the supplementary material.
hit with
a single tetrazole ring in the molecule was QIBLOF,
3.3.3. Crystal packing of 5c
butyl 4-(5-phenyl-2H-tetrazol-2-yl)butanoate [91]. The remaining
hits have two tetrazole units in each molecule, link directly to a
central benzene ring with bromoalkane chain of various lengths
substituents on each of the tetrazole rings. Thus SARCAQ [92], has
two bromo–ethyl chains, NUGBEX [93], bromo–propyl, while the
isomeric NEMNAV, and NEMNEZ [94] have bromo–butyl chains.
In the same paper NENNID is reported, with longer bromo–octyl
substituents in each tetrazole ring [94].
In the crystal of 5c, packing is stabilized by a variety of hy-
drogen bonds and a π…π stacking interaction. Strong classical
O1-H1A…N3 form chains of molecules along b. Atom C8 adjacent
to the tetrazole ring acts as a bifurcated donor with chains of
molecules forming along the a axis direction as a result of both
C8-H8A…N4 and C8-H8B…O1 contacts. Finally, weaker C5-H5…O1
hydrogen bonds firm dimers in the ab plane, with the C5-H5…O1
angle of approximately 137.6° Each of these contacts are shown in
Fig. 9. π…π stacking interactions between the benzene and tetra-
zole rings are supported by the O1-H1A…N3 hydrogen bond form-
ing a molecular trimer (Fig. 10) with Cg1…Cg2 centroid to centroid
The three compounds reported here, 4-(2-octyl-2H-tetrazol-5-
yl)phenol, 5a, 4-(2-decyl-2H-tetrazol-5-yl)phenol, 5b, which crys-
tallizes with 3 unique molecules (M1, M2 and M3) in the asym-
metric unit, and 4-(2-pentadecyl-2H-tetrazol-5-yl)phenol, 5c are
closely similar, Scheme 1, and their molecular structures can rea-
sonably be discussed together. Each molecule features a tetrazole
ring substituted on the N atom in the 2-position by beautifully
ordered octyl, 5a, decyl, 5b, and pentadecyl, 5c, alkane chains. In
each case a phenol ring system is bound to the C atom at the 5-
position of the tetrazole ring, Fig. 3(a–c).
˚
distances of 3.6719(9) A. These contacts combine to form well sep-
arated stacks of molecules along the b axis direction (Fig. S3).
3.4. Hirshfeld analysis
Further details of the intermolecular interactions in the three
molecules were obtained using Hirshfeld surface analysis [95] with
surfaces and two-dimensional fingerprint plots generated by Crys-
talExplorer [96].
The tetrazole and phenyl rings in 5a are almost coplanar with a
dihedral angle of 8.01(7)° between them with the O substituent of
˚
the phenol ring positioned 0.033(2) A from the benzene ring plane
(Table 2). The best fit mean plane through the 8 carbon atoms of
˚
the octyl substituent has a deviation of only 0.0642 A and is in-
3.4.1. Hirshfeld analysis of 5a
clined to the tetrazole ring plane by 15.7(1)°. The corresponding
values the three unique molecules of 5b and those for 5c also ap-
pear along Table 2. While most of the angles and deviations are
reasonably similar for all three molecules, the longer alkane is al-
most orthogonal to the plane of the tetrazole ring, unlike values of
less than 16° for the other four molecules.
Fig. 11 shows the Hirshfeld surface of the asymmetric unit of
–
5a. The bold red circles in correspond to classical O H…N hydro-
–
gen bonds with the weaker C H…O contact appears as a faint red
circle.
Fingerprint plots, Fig. 12, show that H…H contacts are by far
the most prolific with significant contributions also coming from
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Fig. 3. (a) The molecular structure of 5a, (b) the three molecules, M1, M2 and M3 that make up the asymmetric unit of 5b and (c) the molecular structure of 5c each
showing the atom numbering schemes and with ellipsoids drawn at the 50% probability level.
Table 2
Metrical data for 5a, 5b and 5c.
˚
˚
Molecule
Tetrazole/benzene angle (°)
O-H oxygen deviation (A)
Cn chain rms deviation (A)
Cn chain/tetrazole ring angle (°)
5a
8.01(7)
0.033(2)
0.011(7)
0.011(8)
–0.007 (7)
0.033(2)
0.0642
0.0870
0.0681
0.0439
0.0658
15.7(1)
5b, M1
5b, M2
5c, M3
5c
13.24(13)
1.708 (15)
11.06(12)
5.27(6)
1.85(13)
4.31(2)
5.34(10)
79.75(6)
Fig. 4. Chains of molecules of 5a along b with hydrogen bonds drawn as cyan dashed lines.
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–
–
Fig. 5. Chains of C H…π dimers along c. Cg2 is the centroid of the C1-C6 benzene ring and these are shown as red spheres, with C H…π hydrogen bonds drawn as red
dashed lines.
Fig. 6. Chains of molecules of 5b along a involving both M1 and M2 molecules of 5b.
Fig. 7. A second set of chains of molecules of 5b along a but in this instance only involving only M3 molecules.
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–
Fig. 8. π…π and C H…π contacts linking M1, M2 and M3 molecules of 5b along c.
Fig. 9. The numerous hydrogen bonds formed by molecules of 5c. O1-H1A…N3, far left, C8-H8A…N4, center top, C5-H5…O1 dimers, bottom center and C8-H8B…O1 hydro-
gen bonds, far right. For clarity, only the H donor and various acceptor atoms are labelled in this figure.
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molecules 1, 2 and 3, M1, M2 and M3 individually. Results of this
latter investigation are shown in the supplementary material (Figs.
S4–S6).
3.4.2.1. Hirshfeld analysis of the asymmetric unit of 5b. Fig. 13
shows the Hirshfeld surfaces for the three molecules that form
–
the asymmetric unit of 5b. Strong O H…N hydrogen bonds (bold
red circles) dominate the surface contacts and are supported by
–
weaker C H…N hydrogen bonds, shown as smaller pale red circles.
Fingerprint plots, Fig. 14, show an even greater dominance
of H…H contacts compared to that of 5a no doubt reflecting
the increased length of the alkyl chains in these molecules. The
H…N/N…H contacts are considerably reduced compared to those
in 5a suggesting a degree if shielding of the tetrazole rings by the
aggregation of the three unique molecules.
Hirshfeld analysis of the individual components of the asym-
metric unit of 5b, molecules M1, M2 and M3, is shown in the
–
–
supplementary data. Again O H…N and weaker C H…N hydrogen
bonds are found on the surfaces of each of the three molecules
(Figs. S4-S6 and the corresponding fingerprint plots in Fig S7–S9).
The three plots of the surfaces of the three unique molecules, per-
haps unsurprisingly, look remarkably similar. Percentage contribu-
tions of interatomic contacts to the Hirshfeld surface for the three
individual molecules of 5b are detailed in Table S1.
3.4.3. Hirshfeld analysis of 5c
–
–
Predictably O H…N and weaker C H…N hydrogen bonds are
also found on the surface of this molecule further reflecting the
close similarity of the three structures (Fig. 15).
Fig. 10. Molecular trimers of 5c formed by π…π stacking interactions between the
–
benzene and tetrazole rings and supported by an O H…N hydrogen bond.
A striking feature of the fingerprint plots for this molecule is
the spectacular increase in the contribution of the H…H contacts
to the included surface area at the expense of the other contacts.
This undoubtedly reflects the significant extension of the alkyl
chain to pentadecyl, providing the opportunity for additional H…H
contacts (Fig. 16).
3.5. Theoretical (DFT) study
The study is focused to the analysis of the H-bonding and π-
stacking interactions observed in the solid state of compounds 5a-
c that have been highlighted above in Figs. 4-10. First of all, we
have computed the MEP surface of compound 5a (Fig. 17), which
also serves as a model of 5b,c, to investigate the most electrophilic
and nucleophilic parts of the molecule. It can be observed that
the most positive MEP value is located at the phenolic H-atom
(+52 kcal/mol) and, remarkably, the positive region is extended to-
ward the aromatic H-atom ortho to the OH substituent, thus also
adequate for interacting with electron rich species. This agrees well
with the H-bonds described in Figs. 5 and 6 for 5a,b. The MEP
values are also positive at the H-atoms of the alkyl chain, espe-
cially those closer to the tetrazole ring. The minimum MEP value
is located, as expected, at the N-atoms of the tetrazole ring, rang-
ing from –32 to –36 kcal/mol. Interestingly, the H-bonds observed
in the solid state of compounds 5a,b are established between the
most positive and negative parts of the molecule. Finally, the MEP
surface also reveals that the phenolic O-atom presents a moder-
ately negative value of –21 kcal/mol. It is interesting to highlight
that the MEP is negative over the phenolic ring (–12 kcal/mol) and
negligible over the tetrazole ring. Therefore, it is expected that the
antiparallel arrangement of these molecules to form π-stacking as-
semblies to minimize possible electrostatic repulsions between the
phenolic rings.
Fig. 11. Hirshfeld surfaces of the asymmetric unit of 5a, mapped over dnorm in the
range –0.5990 to 1.5925 a.u.
Table 3
Percentage contributions of interatomic con-
tacts to the Hirshfeld surface for 5a-c.
Contact
Included surface area (%)
5a
5b
5c
H…H
59.6
14.3
17.1
7.1
1.9
–
65.5
13.2
11.6
7.2
1.2
1.2
0.1
–
74.1
8.1
10.5
3.8
2.4
–
H…C/C…H
H…N/N…H
H…O/O…H
C…N
N…N
N…O
–
0.5
0.3
0.3
C…O
–
C…C
–
–
H…N/N…H and H…C/C…H contacts. Weaker H…O/O…H and C…N
interactions are also found, Table 3.
3.4.2. Hirshfeld analysis of 5b
With three unique molecules in the asymmetric unit of 5b
the Hirshfeld analysis of this structure is more complex. We have
therefore divided the analysis into four sections, examining first
the complete asymmetric unit, followed by each of the unique
Fig. 18 shows two selected dimers (H-bonded and π–stacking)
retrieved from the X-ray structures of compounds 5a,b and one
dimer of compound 5c along with their corresponding binding en-
ergies. Moreover, the QTAIM distributions of critical points (CPs)
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Fig. 12. Full two-dimensional fingerprint plots for the asymmetric unit of 5a, (a), together with (b)-(f) separate contact types and included surface areas for the individual
contacts. These are found to be H…H, H…C/C…H, H…N/N…H, H…O/O…H and C…N contacts.
Fig. 13. Hirshfeld surfaces for the three molecules that comprise the asymmetric unit of 5b, mapped over dnorm in the range –0.6289 to 1.7104 a.u.
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Fig. 14. Two-dimensional fingerprint plots for the asymmetric unit of 5b, (a), together with (b)-(g) separate contact types and included surface areas for the individual
contacts. Minor contacts contributing less than 1% to the total surface area are not shown here but, for completeness, are shown in Table 3. The secondary contacts shown
here are H…H, H…C/C…H, H…N/N…H, H…O/O…H and C…N and N…N contacts.
Fig. 15. Hirshfeld surface of the asymmetric unit of 5c, mapped over dnorm in the range –0.5421 to 1.5181 a.u.
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Fig. 16. Two-dimensional fingerprint plots for 5c, (a), together with (b)-(f) separate contact types and included surface areas for the individual contacts. Minor contacts
contributing less than 1% to the total surface area is not shown here but, for completeness, is shown in Table 3. The secondary contacts shown here are H…H, H…C/C…H,
H…N/N…H and H…O/O…H and C…N contacts.
ciation energy is 5.4 kcal/mol in 5a and 6.1 kcal/mol in 5b, thus
confirming their stronger nature. The π-stacking dimers of com-
pounds 5a and 5b are shown in Figs. 18b and 18d, respectively. The
dimerization energies are very similar (ꢀE2 = –12.0 kcal/mol and
ꢀE4 = –11.8 kcal/mol, for 5a and 5b respectively); however, the
NCIplot surface and QTAIM distribution of CPs reveal some inter-
esting differences. In both compounds the π-π stacking is charac-
terized by two bond CPs that interconnect two atoms of the tetra-
zole rings, however the NCIplot shows that the overlap of the π
systems is significantly greater in 5b (larger green isosurface be-
tween the tetrazole rings) than in 5a. On the contrary, the C–H…π
Fig. 17. MEP surface (0.001 a.u.) of 5a at the PBE1PBE-D3/def2-TZVP level of theory.
interactions are characterized by larger isosurfaces in compound
The values at selected points of the surfaces are given in kcal/mol.
5a than in 5b. Therefore, π-stacking seems to dominate in 5b and
C–H…π interactions dominate in 5a. Each C–H…π interaction is
also confirmed by the QTAIM analysis that shows the existence of
and bond paths overlapped with the NCIplot surfaces of all com-
a bond CP that connects the H-atom to a C-atom of the aromatic
plexes are also indicated. This type of analysis has been recently
ring. In general, both combinations of π-stacking and C–H…π in-
teractions observed in 5a and 5b agree well with the MEP analy-
sis, since the π-stacking involves the tetrazole ring (negligible MEP
over the center of the ring) and the C–H…π interaction involves
the electron rich phenol ring. Finally, the dimerization energy of H-
bonded dimer of 5c presents weaker interaction energy (ꢀE5 = –
6.8 kcal/mol), because only the O–H•••N3 H-bond is established.
Both the QTAIM and NCIplot index evidence the existence of an
additional C–H…H–C interaction that is characterized by a small
green isosurface and a bond CP connecting both H-atoms.
used to analyze a variety of interactions [97-99]. The H-bonded
dimers of compounds 5a and 5b present similar energies (ꢀE1 = –
9.4 kcal/mol and ꢀE3 = –8.9 kcal/mol, respectively) which are
largely due to the formation of three concurrent H-bonds. Each H-
bond is characterized by a bond CP (red sphere) and bond path
interconnecting the H and N/O-atoms. The NCIplot also shows the
corresponding isosurfaces, which are blue for the O–H…N4 H-bond
and green for the C–H…O/N H-bonds, thus confirming their strong
and weak nature, respectively. We have estimated the contribu-
tion of the strong H-bond by using the value of the kinetic en-
ergy density at the bond CP (E = 0.5 x Vr). These values are also
indicated in Fig. 18 and reveal that the O–H…N4 H-bond disso-
Finally, the different π-stacking assembly observed in com-
pound 5c (Fig. 19) has also been analyzed energetically. In the
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Fig. 18. QTAIM distribution of bond and ring CPs (red and yellow spheres, respectively) and the NCIplot isosurface using the gradient cut-off of 0.5 a.u. and color scale −0.04
< ρ < 0.04 a.u. for the dimers of 5a (a,b), 5b (c,d), 5c (e). The interaction energies are also indicated.
Fig. 19. Partial view of the X-ray of 5c with indication of the π–π interactions and the dimerization energy [2 x Dimer(HB) → Tetramer].
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tetramer shown in Fig. 19, the tetrazole and phenol rings stack and
a total of three π–π interactions are established. The dimerization
energy (the H-bonded dimer has been considered as a monomeric
specie for the calculation of ꢀE6) is –17.1 kcal/mol that is signif-
icantly stronger that those π-stacking of compounds 5a and 5b
(Fig. 18), thus compensating the weaker H-bond in 5c.
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–
–
–
–
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Declaration of Competing Interest
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The authors declare that they have no known competing finan-
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for financial support under the Indigenous 5000 PhD Fellowship
program and SRGP Grant No. 2470. J.S. thanks the Chemistry De-
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the MICIU/AEI from Spain for financial support (project number
CTQ2017–85821-R, FEDER funds). We are also grateful to the CTI
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