Structural and theoretical studies of 1,3-Bis-(1,2,3-triazol-1-yl)-propan-2-ol derivatives.

Article abstract of DOI:10.1016/j.molstruc.2020.128864

The crystal structure of three 1,3-Bis-(1,2,3-triazol-1-yl)-propan-2-ol derivatives was determined by X-ray diffraction analyses. The studied compounds presented O[sbnd]H???N hydrogen bonds between hydroxyl group of one molecule with triazolyl nitrogen at

Full text of DOI:10.1016/j.molstruc.2020.128864

Journal Pre-proof
Structural and theoretical studies of
1,3-Bis-(1,2,3-triazol-1-yl)-propan-2-ol derivatives.
Armando Zambrano-Huerta , Joanatan M. Bautista-Renedo ,
Horacio Reyes Data Curation , Diego Mart´ınez-Otero ,
´
´
Ivan Garc´ıa-Orozco , Roberto Carlos Melgar-Fernandez ,
´
Mar´ıa Teresa Ram´ırez-Palma , Nelly Gonzalez-Rivas ,
˜
Erick Cuevas-Yanez
PII:
S0022-2860(20)31189-3
DOI:
Reference:
https://doi.org/10.1016/j.molstruc.2020.128864
MOLSTR 128864
To appear in:
Journal of Molecular Structure
Received date:
Revised date:
Accepted date:
22 April 2020
4 July 2020
8 July 2020
Please cite this article as:
Horacio Reyes Data Curation ,
Armando Zambrano-Huerta ,
Diego Mart´ınez-Otero ,
Joanatan M. Bautista-Renedo ,
´
Ivan Garc´ıa-Orozco ,
´
´
Roberto Carlos Melgar-Fernandez ,
Mar´ıa Teresa Ram´ırez-Palma ,
Nelly Gonzalez-Rivas ,
˜
Erick Cuevas-Yanez , Structural and theoretical studies of 1,3-Bis-(1,2,3-triazol-1-yl)-propan-2-ol
derivatives., Journal of Molecular Structure (2020), doi: https://doi.org/10.1016/j.molstruc.2020.128864
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Highlights:
- The crystal structure of three 1,3-Bis-(1,2,3-triazol-1-yl)-propan-2-ol
derivatives was determined by and analyzed by Single-crystal X-ray
diffraction studies.
- O-H···N and C-H···N interactions in these bistriazoles are detected and
promote the formation of infinite chains which define the crystal network.
- The theoretical Theoretical DFT studies show a high similarity of these
compounds with Fluconazole molecule.

Structural and theoretical studies of 1,3-Bis-
(1,2,3-triazol-1-yl)-propan-2-ol derivatives.
Armando Zambrano-Huerta,1,2,3 Joanatan M. Bautista-Renedo,1,2 Horacio Reyes,4 Diego
Martínez-Otero,1,5 Iván García-Orozco,2 Roberto Carlos Melgar-Fernández,3 María Teresa
Ramírez-Palma,1,2 Nelly González-Rivas1,2 and Erick Cuevas-Yañez1,2*
1Centro Conjunto de Investigación en Química Sustentable UAEM-UNAM. Carretera Toluca-
Atlacomulco Km 14.5, Toluca, Estado de México, 50200, México. Universidad Autónoma del
Estado de México
2Facultad de Química, Universidad Autónoma del Estado de México, Carretera Toluca-
Atlacomulco Km 14.5, Unidad San Cayetano, Toluca, Estado de México, C. P. 50200 México.
3Signa S.A. de C.V., Av. Industria Automotriz No. 301, Zona Industrial Toluca, Toluca, Estado de
México, 50071, México
4División de Ingeniería Química, Instituto de Estudios Superiores de Jocotitlán. Carretera Toluca-
Atlacomulco km 44.8, Ejido de San Juan y San Agustin, Jocotitlán, Edo. México
5Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior S. N., Ciudad
Universitaria, Coyoacán, Ciudad de México, 04510, Mexico
*Corresponding author. Universidad Autónoma del Estado de México. Tel. +52 722 276 66
10; fax: +52 722 180 62 17, e-mail: ecuevasy@uaemex.mx.

Abstract. The crystal structure of three 1,3-Bis-(1,2,3-triazol-1-yl)-propan-2-ol derivatives
was determined by X-ray diffraction analyses. The studied compounds presented O-H···N
hydrogen bonds between hydroxyl group of one molecule with triazolyl nitrogen atom of
another molecule. In addition, other C-H···N interactions between two bistriazole
molecules are observed. These interactions promote the formation of infinite chains which
define the crystal network. The results are in accordance with the solid behavior of
compounds, as evidenced from XRPD and SEM studies. Theoretical studies of molecular
and electronic properties using DFT (Density Functional Theory) revealed a high similarity
of these compounds with Fluconazole molecule.
Keywords. 1,2,3-Triazole, Crystal structure, Density functional theory.
1. Introduction
2-(2,4-Difluorophenyl)-1,3-bis(1,2,4-triazol-1-yl)-propan-2-ol, Fluconazole (1), is one of
the most important drugs used to treat invasive candidiasis as well as other fungal
infections [1-2].
On the other hand, the analysis and determination of the precise solid form of drugs is
important for pharmaceutical industry due to particular solid state structures may change
physicochemical properties in drugs such as solubility, hygroscopicity and mechanical

properties which influence dosing, storage and stability [3-4]. Hence, crystal structure
studies in drugs are highly desirable together to synthetic procedures development.
In this context, the wide antifungal activity of Fluconazole has prompted the development
of crystalline modifications as co-crystals [5-6] and polymorphs [7-11], but also the
synthesis of new Fluconazole derivatives including diverse 1,2,3-triazolyl analogues via
copper-catalyzed azide-alkyne cycloaddition (CuAAC) [12-16], the most used click
reaction.
In a preceding report, we informed a systematic study on the synthesis of 1,3-bis-(1,2,3-
triazol-1-yl)-propan-2-ol derivatives (2, scheme 1) from CuAAC reaction as a novel class
of Fluconazole analogues which display an outstanding selective activity against Candida
albicans and Candida krusei [17]. In relation to this work, we continued our synthetic
studies with emphasis in the crystal and polymorphic behavior of these compounds which
is important to understand and improve biomedical applications. This paper discloses the
crystal structure of three 1,3-Bis-(1,2,3-triazol-1-yl)-propan-2-ol derivatives and other
properties aiming to search and develop new molecules with high antifungal activity.
N
N
N
N
OH
N
N
F
N
N
OH
R
N
N
R
N
N
R
2
F
1
Scheme 1. Structure of Fluconazole 1 and general structure for molecules 2 proposed in
this work.

2. Experimental Section
2.1. General remarks
The starting materials were purchased from Aldrich Chemical Co. and were used without
further purification. Solvents were distilled before use. Silica plates of 0.20 mm thickness
were used for thin layer chromatography. Melting points were determined with a Krüss
1
13
Optronic melting point apparatus and they are uncorrected. H and C NMR spectra were
recorded using a Bruker AVANCE 300; the chemical shifts (δ) are given in ppm relative to
TMS as internal standard (0.00). For analytical purposes the mass spectra were recorded on
a Shimadzu GCMS-QP2010 Plus in the EI mode, 70 eV, 200 °C via direct inlet probe. Only
the molecular and parent ions (m/z) are reported. IR spectra were recorded on a Bruker
TENSOR 27 FT instrument.
For the RX diffraction studies, crystals of compounds 5, 6 and 8 were obtained by slow
evaporation of a dilute dimethyl sulfoxifde solution, and the reflections were acquired with
a Bruker APEX DUO diffractometer equipped with an Apex II CCD detector, Mo-Kα
radiation (λ = 0.71073 Å) at 293 K. Three standard reflections every 97 reflections were
used to monitor the crystal stability. The structure was solved by direct methods
(SHELXS-97) [18] using the shelXle GUI [19]; missing atoms were found by difference-
Fourier synthesis, and refined on F2 by a full-matrix least-squares procedure using
anisotropic displacement parameters using SHELX-97. The hydrogen atoms of the C–H
bonds were placed in idealized positions. The molecular graphics were prepared using
Ortep3, POV-RAY and GIMP [20-21]. Crystallographic data for the structure reported in
this paper have been deposited with the Cambridge Crystallographic Data Centre, CCDC

(No. 2013800 for compound 5, No. 2013802 for compound 6 and No. 2013805 for
compound 8). Copies of available materials can be obtained free of charge on application to
the Director, CCDC, 12 Union Road, Cambridge CB2 IEZ, UK (facsimile: (44) 01223
336033); e-mail: deposit@ccdc.ac.uk.
2.2. General procedure for the synthesis of 1,3-Bis-(4-cyclopropyl-1,2,3-triazol-1-yl)-2-
arylpropan-2-ol derivatives.
1,3-dichloroacetone (2.0 g, 16.0 mmol) was added to a stirred mixture of NaN3 (5.2 g, 7.98
mmol) and acetone (30 mL), and the resulting mixture was stirred at room temperatura for
12-15 h. The mixture was filtered, and the solvent was removed under reduced pressure.
The compound was extracted with methyl tert-butyleter (2 X 30 mL), the organic layers
were joined and dried over Na2SO4 and the solvent was removed under reduced pressure to
yield 1,3-diazido-propan-2-one as a pale solid (2.1 g, 14.34 mmol, 91 %) which was used
without purification.
A solution of 4-fluorophenylmagnesium bromide (3.4 g, 15.91
mmol, 2.0 M in THF) and CH2Cl2 (15 mL) was cooled to -75°C. A solution of 1,3-diazido-
propan-2-one (2.13 g, 15.91 mmol) in CH2Cl2 (15 mL) was added dropwise and the
resulting mixture was stirred under an inert atmosphere at -75°C for 4 h and at room
temperature for 24 h. A saturated solution of NH4Cl (40 mL) was added and the mixture
was stirred for 30 min. The organic layer was separated, and the aqueous phase was
extracted with CH2Cl2 (3 X 15 mL). The organic layers were joined and dried over Na2SO4
and the solvent was removed under reduced pressure to yield the corresponding 1,3-
diazido-2-arylpropan-2-ols 2 and 3 which were used without purification. A solution of
cyclopropylacetylene (1.12 g, 17.0 mmol) in MeOH (15 mL) was added to a solution of the
appropriate 1,3-diazido-2-arylpropan-2-ol (11.43 mmol) in MeOH (10 mL). The mixture

was stirred at room temperature for 5 min, a 2 N solution of NaOH (2 mL, 0.160 g, 4.0
mmol) and CuI (0.3063 g, 2.29 mmol) were successively added, and the resulting mixture
was stirred at room temperature for 24 h. The solvent was removed under reduced pressure
and concentrated NH4OH solution (40 mL) was added and the mixture was stirred for 2 h.
The product was filtered, washed with H2O (20 mL) and cold MeOH (20 mL), and dried
under reduced pressure to afford the corresponding1,3-bis-(4-cyclopropyl-1,2,3-triazol-1-
yl)-2-arylpropan-2-ol derivative which was purified by crystallization.
2.2.1. 1,3-Bis-(4-cyclopropyl-1,2,3-triazol-1-yl)-2-(4-fluorophenyl)-propan-2-ol (5).
Cyclopropylacetylene and 1,3-diazido-2-(4-fluorophenyl)propan-2-ol afforded 1,3-Bis-(4-
cyclopropyl-1,2,3-triazol-1-yl)-2-(4-fluorophenyl)-propan-2-ol (5) as white solid (90 %),
m.p. 235 °C. 1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 2H), 7.4 (d, J = 7.3 Hz, 2H), 7.1 (d,
J = 7.5 Hz, 2H), 6.47 (s, broad, 1H), 4.98 (d, J = 14.1 Hz, 2H), 4.81 (d, J = 14.3 Hz, 2H), ),
2.03 (m, 2H), 1.01 (d, 2H), 0.08 (d, 2H); 13C NMR (75 MHz, DMSO-d6) δ 163.5 (d, 1 X C,
JC-F = 241 Hz), 146.2 (2 X C), 136.9 (1 X C), 128.3 (2 X CH), 125.6 (2 X CH), 115.3 (2 X
CH), 75.1 (1 X C), 57.6 (2 X CH2), 8.2 (4 X CH2), 7.0 (2 X CH); IR (ATR, cm-1): 3164,
3147, 2970, 2948, 1603; MS [EI+] m/z (%): 368 [M]+ (5). HRMS (EI): calcd. For
C19H21FN6O: 368.1761; found: 368.1771.
2.2.2. 1,3-Bis-(4-cyclopropyl-1,2,3-triazol-1-yl)-2-(4-chlorophenyl)-propan-2-ol (6).
Cyclopropylacetylene and 1,3-diazido-2-(4-chlorophenyl)-propan-2-ol afforded 1,3-Bis-(4-
cyclopropyl-1,2,3-triazol-1-yl)-2-(4-chlorophenyl)-propan-2-ol (6) as white solid (80 %),
1
m.p. 240 °C. H NMR (300 MHz, DMSO-d6) δ 7. 68 (s, 2H), 7.66 (d, 4H), 7.52 (d, 4H),
6.41 (s, broad, 1H), 4.89 (d, J = 14.2 2H), 4.63 (d, J = 14.1 Hz, 2H), 2.03 (m, 2H), 1.01 (d,

2H), 0.08 (d, 2H); 13C NMR (75 MHz, DMSO-d6) δ 148.8 (2 X C), 139.9 (1 X C), 137.3 (1
X C), 132.7 (2 X CH), 128.4 (2 X CH), 122.6 (2 X CH), 75.3 (1 X C), 57.6 (2 X CH2), 8.2
(4 X CH2), 7.0 (2 X CH); IR (ATR, cm-1): 3149, 3090, 2970, 2948, 1597; MS [EI+] m/z
(%): 384 [M]+ (5). HRMS (EI): calcd. For C19H21ClN6O: 384.1465; found: 384.1468.
2.3. 1,3-bis(4-phenyl-1,2,3-triazol-1-yl)propan-2-ol (8). According to literature [22], a
solution of 1,3-diazidopropan-2-ol (0.284 g, 2 mmol) in MeOH (3.0 mL), prepared form
epichlorohydrin 7 [23] was added to a stirred mixture of phenylacetylene (0.214 g, 2.1
mmol), a 0.5 N solution of NaOH (0.5 mL, 0.25 mmol) and CuI (0.019 g, 0.1 mmol) in
MeOH (2.0 mL). The reaction mixture was stirred at room temperature for 24h. The
reaction mixture was filtered through celite, and the solvent was removed in vacuo. The
final product was purified by column chromatography (SiO2, hexane/AcOEt 8:2) to afford
compound 8 as a white solid (91%); mp 196-197°C. 1H NMR (CDCl3, 300 MHz) δ 8.53 (s,
2H), 7.85 (d, J = 7.5 Hz, 4H), 7.43 (t, J = 8 Hz, 4H), 7.31 (t, J = 7.5 Hz, 2H), 5.78 (d, J =
5 Hz, 1H), 4.60 (d, J = 10.5 Hz, 2H), 4.41 (d, J = 10.5 Hz, 2H); 13C NMR (CDCl3, 75
MHz) δ 146.1, 130.8, 128.8, 127.7, 125.0, 122.4, 68.2, 53.2; IR (ATR, cm-1): 3220, 3080,
1455, 1600; MS (EI+) m/z (%) 346 [M]+ (100).
2.4. Computational details
With the aim to study the influence of substitutions made on compounds 5 and 6 presented
in Scheme 2, theoretical estimations on the framework of Density Functional Theory, DFT,
were performed at the PBE0/3-21G level of theory implemented in the computational
software NWChem 6.5 [24]. These compounds were compared with hypothetical
substitutions as exemplified in Scheme 2. Global descriptors like ionization potential [25],

IP, electron-affinity [26], EA, and softness [27], , as well as some local descriptors like
dual descriptor [28] denoted as , and Molecular Electrostatic Potential [29], MEP, were
used to characterize the internal reactivity. The obtained results were compared with those
presented for fluconazole structure [30]. For purposes of theoretical analysis, all
substituents in the structures were labeled as S1 and S2. For example, the designation of
compounds 5 and 6 would be 2.D and 2.C.
A= OMe
1=
N
N
N
N
OH
S2
N
N
S1
S1
B= H
C= Cl
S1
2=
3=
S2
D= F
Scheme 2. Proposed structures for theoretical analysis
3. Results and discussion
3.1 Chemistry
Bistriazoles 5 and 6 are representative examples of 1,3-bis-(1,2,3-triazol-1-yl)-propan-2-ol
derivatives bearing a cyclopropyl group with a remarkable antifungal activity against
Candida albicans and Candida krusei strains (MIC= 0.0075 μg/mL for compound 5, and
MIC= 0.04 μg/mL for compound 6). These compounds were obtained from the CuAAC
reaction of cyclopropylacetylene 4 with the corresponding 1,3-diazidopropan-2-ol
derivatives 2 and 3 in presence of catalytic amounts of CuI (scheme 3) [17]. Alcohols 2 and

3 were prepared from 1,3-dichloroacetone 1 which was successively treated with sodium
azide and the corresponding Grignard reagent.
The global yields of these processes were close to 80 %. On the other hand, bistriazole 8
was synthesized according to the literature from epichlorohydrin [22,23].
N
N
N
N
OH
R
N
N
OH
R
O
N3
N3
a, b
c
Cl
Cl
1
4
2 R= F
5 R= F
3 R= Cl
6 R= Cl
Cl
N
N
d, e
N
N
OH
N
N
O
H
7
8
Scheme 3. Reagents and conditions: (a) NaN3, acetone. (b) RC6H4MgBr, THF-CH2Cl2, -
75°C. (c) CuI, NaOH, MeOH. (d) NaN3, NH4Cl, MeOH-H2O. (e) CuI, phenylacetylene,
NaOH, MeOH, RT.
3.2 Crystal Structure Analysis
Suitable crystals of compounds 5, 6 and 8 were obtained from a DMSO solution upon slow
evaporation over several days. Single-crystal X-ray diffraction studies were performed on
these compounds confirming the spectroscopic results. Crystallographic data and structural
refinement parameters of 5, 6 and 8 are summarized in table 1 and selected bond lengths
and angles are shown in table 2.

Table 1. Crystallographic data for structural analysis of compounds 5, 6 and 8.
Crystal data
5
6
8
Empirical formula
Formula weight
C19H21FN6O
368.42
C19H21ClN6O
384.87
C19 H18 N6 O
346.39
Temperature(K)
Radiation type
293(2) K
Mo Kα
296(2) K
Mo Kα
100(2)
Mo Kα
Crystal system
Space group
Monoclinic
P21/c
Orthorhombic
Pbca
Orthorhombic
Pccn
Unit cell dimensions (Ǻ, °)
a
b
c

14.5172(8)
9.5469(5)
14.3270(8)
90
109.261(2)
90
9.7040(7)
14.6585(10)
27.158(2)
90
90
90
3863.1(5)
8
18.06187(17)
5.62359(6)
16.15266(15)


Volume (Ǻ3)
1874.50(18)
4
1640.67(3)
Z
4
1.402
0.746
Density (calculated, Mg/m3)
Absorption coefficient μ (mm-1)
F(000)
1.305
0.760
776
1.323
1.927
1616
728
Crystal size (mm3)
Θ range (deg)
0.519 x 0.229 x 0.201
3.225 to 70.321
-17<=h<=16,
0.291 x 0.156 x 0.125
3.255 to 70.543
-7<=h<=11, -
0.229 x 0.129 x 0.040
4.897 to 69.819
-21<=h<=21, -
Index ranges
0<=k<=11, 0<=l<=17 17<=k<=17, -32<=l<=30 6<=k<=6, -19<=l<=19
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
3454
23880
3662 [R(int) = 0.0435]
3662 / 866 /403
1.035
12848
1552 [R(int) = 0.0145]
1552 / 1 / 126
1.060
3454 [R(int) = ?]
3454 / 117 /276
1.112
Final R indices [I>2sigma(I)]
R1 = 0.0570,
wR2 = 0.1825
R1 = 0.0628,
wR2 = 0.1928
0.274, −0.301
R1 = 0.0536,
wR2 = 0.1634
R1 = 0.0588,
wR2 = 0.1699
0.369, -0.324
R1 = 0.0325,
wR2 = 0.0805
R1 = 0.0334,
wR2 = 0.0811
0.182, -0.183
R indices (all data)
Largest diff. peak and hole (e Å−3)

Table 2. Selected bond lengths and angles of compounds 5, 6 and 8.
Bond
Compound 5
Compound 6
Compound 8
O(1)-H(1)
0.847(17)
0.835(10)
0.839 (8)
C(1)-O(1)
C(1)-C(2)
C(1)-C(8)
C(1)-C(14)
C(8)-N(1)
C(14)-N(4)
N(1)-N(2)
N(2)-N(3)
N(4)-N(5)
N(5)-N(6)
1.417(2)
1.520(3)
1.538(3)
1.548(2)
1.454(3)
1.457(3)
1.329(2)
1.324(3)
1.339(2)
1.316(3)
1.412(2)
1.532(2)
1.536(2)
1.548(3)
1.451(3)
1.454(3)
1.335(2)
1.307(3)
1.354(3)
1.328(6)
1.344(2)
1.525(15)
1.525(15)
1.457(8)
1.457(9)
1.348(14)
1.317(14)
1.348(14)
1.317(14)
Bistriazole 5 crystallized in monoclinic centrosymmetric P21/c space group, with four
molecules in the asymmetric unit. Two of these molecules are mirror images of each other
mainly due to the relative orientation of R1, R2, and R3 rings (5A and 5B, Figure 1).
Taking the C-O bond as the reference of the C1 tetrahedron and the phenyl ring (R1)
toward the front, the CH2-triazole moiety acts as a propeller. In the case of 1A, R1 ring is
quasi-parallel to R3 (dihedral angles R1-R3 = 52.47°), and the R1, R2, and R3 “blades”
twist the propeller clockwise (Λ isomer). On the other case, 1B the R1, R2, and R3

“blades” turn counter-clockwise (Δ isomer). These Δ and Λ enantiomers are present in the
crystal reported structures of the fluconazole [7, 31].
Figure 1. Enantiomers of the crystal structure of compound 5: 5A left, 5B right.
Enantiomers 5A and 5B have an interaction through hydrogen bonding, suggesting a
possible molecular recognition. Three hydrogen bond are observed by the hydroxyl and
H(14) methylene groups of an A-molecule, and the R3-triazolyl ring of a B-molecule. The
O-H···N hydrogen bond between the hydroxyl group of one A-molecule as donor and the
R3-triazolyl N(3) nitrogen atom of one B-molecule as acceptor, is the interaction
commonly observed in different fluconazole polymorphs [6, 7, 10]. Additionally, a C-
H···N hydrogen bond between one of the methylene H(14) hydrogen atom of one A-
molecule and the R3-triazolyl N(2) nitrogen atom. These interactions form infinite arrays
parallel to the c-axis (Figure 2).

Figure 2. Infinite chain formation along b-axis by O-H···N, C-H···N and H···H
interactions in B-molecules of compound 5.
On the other hand, each A-molecule is connected by three C-H···N interactions to its
similar enantiomer molecule. The R2-triazolyl ring by N(5) and N(6) nitrogen atoms
interacts as a donor moiety with a methylene H(14) and phenyl H(7) hydrogen atoms of
other molecule, forming an infinite array parallel to the a-axis, maintaining 21 screw axis
symmetry (Figure 3). The same arrays are forming by the B-molecules.

Figure 3. Infinite chain formation along b-axis by C-H···N interactions, in B-molecules of
compound 5.
The experimental powder X-ray diffraction pattern is in close agreement with the computed
from single crystal X-ray analysis (Figure 4), indicating that powder presents the same
phase observed in the single crystal, and only one polymorph exclusively is yielded. A
noteworthy feature on the powder pattern is the increase of the relative intensities of the
peaks at 12.92, 15.90 and 21.56 2-theta values respecting the single crystal peaks, which
were assigned to hkl reflections (200), (210) and (310), respectively. On the other hand, the
peaks at 20.80, 21.78 and 26.92 2-theta values, corresponding to hkl reflections (113),

(013) and (403) respectively decrease their intensity in respect with single crystal pattern
(Figure 4). This suggests a slightly deformation in the crystalline arrangements of the
powder with respect to the single crystal.
Figure 4. Diffraction patterns of compound 5, blue line: experimental PXRD pattern,
orange line: computed pattern from the single crystal data.
Compound 6 crystallizes in monoclinic centrosymmetric Pbca space group, with eight
molecules in the asymmetric unit. The crystal cell shows the presence of mirror images of
the molecule (Λ and Δ enantiomers). Molecule 6 is similar to 5. The conformation and
bond lengths of both molecules are similar, as shown with the molecular overlay (Figure 5)
and the comparison of torsion angles (Table 2).

Figure 5. Molecular overlay of molecule 5 (light green) and 6 (black).
As shown for compound 5, each Λ enantiomer of compound 6 interacts by hydrogen
bonding with the Δ enantiomer (Figure 6). The R3-triazolyl ring forms two hydrogen bonds
with the hydroxyl group and C14-methylene, as well as an H···H interaction between the
phenyl ring and cyclopropane ring in an infinite array parallel to the b-axis. This interaction
could be important due to cyclopropyl moiety is involved in modulation of drug properties,
such as including potency, receptor subtype selectivity, bioavailability, half-life,
microsomal stability, brain permeability, adaptation to entropically favorable binding,
lipophilicity decreasing, among others, as a result of the small strained cyclopropane ring

structure which increases the applications of a drug molecule to be therapeutically useful in
medicinal chemistry [32-36].
Figure 6. Infinite chain formation along b-axis by O-H···N, C-H···N and H···H
interactions in B-molecules of compound 6.

Each A or B molecule has three CH···N interactions with the same enantiomer, similar to
molecule 5 (Figure 7). In addition, 21 screw symmetry is observed along the a-axis,
forming an infinite array of 2A or 2B molecules. However, the hydrogen bonding for
compound 6 is shorter than those observed for compound 5, in spite of the volume of
fluorine atom versus chloride atom (Table 3). Consequently, hydrogen bonding interactions
are stronger in compound 6 than in compound 5.
Figure 7. Infinite chain formation along a-axis by C-H···N interactions, in B-molecules of
compound 6.

An important fact in compound 6 crystal structure is the presence of a chlorine-oxygen
interaction (Figure 7). The Cl···O distance is 4.812 Å which is shorter than the sum of van
der Waals radii (3.20 Å). In the case of compound 5, the distance F···O (5.036 Å) is larger
than the sum of van der Waals radii (3.00 Å). Thus, the main interaction in the crystal is the
hydrogen bonding as shown above, although the substituent in phenyl ring plays an
important role on the crystal structure. This suggests a possible anion recognition of the
triazolyl rings toward a chloride such as other groups have observed [37-39]. In this
regard, an anion/π-like interaction was evaluated considering the parameters presented in
table 3. The distance of chlorine atom to the computed centroid of R2-triazolyl ring is
shorter than fluorine atom-triazolyl ring distance. Furthermore, the slide-angle β has the
minor value in compound 6, evidencing a strong interaction of chlorine atom with triazolyl
ring.
Table 3. Parameters of the anion/π-like interaction of compounds 5 and 6.
R2…X
X = F (1)
X = Cl (2)
Ω…X (Å)
4.111
Ω…C (Å)
4.483
α (°)
65.5
β (°)
9.47
4.48
3.926
4.516
59.39
The calculated and experimental X-ray diffraction patterns of compound 6 were compared
in order to identify a possible polymorphism. The powder patterns have the same phase and
the relative intensities of the peaks, indicating the presence of only one polymorph similar
to the case of compound 5 (Figure 8).

Figure 8. Diffraction patterns of compound 6, blue line: experimental X-ray powder
diffraction, red line: computed diffraction pattern.
Compounds 5 and 6 were analyzed by SEM to investigate morphologic features. While
SEM micrograph obtained from compound 6 does not present some specific
supramolecular aggregation with irregular shape and size and piled up disorderly (figure
9b), micrograph of compound 5 would suggest the formation of aggregates with a
rectangular-shaped morphology (Figure 9a). The configuration of supramolecular
aggregates with well-defined architectures using 1,3-bis-(1,2,3-triazol-1-yl)-propan-2-ol in
the synthesis of copper complexes has been described and suggests that these compounds
might be candidates as building blocks to integrate specific supramolecular structures [40].

(a)
(b)
Figure 9. SEM micrographs compound 5, (a) X450, 50 μm, and compound 6, (b) X600,
20μm.
On the other hand, compound 8 crystallized in orthorhombic crystalline system in the Pccn
space group. Only a half of molecule is refined, the other half is generated by the symmetry
operation 1/2-x, 3/2-y, +z as observed in Figure 10. The carbon C1 is localized in a 2-fold
rotation axis and a glide plane. The atoms in the alcohol moiety, oxygen O1 and hydrogen
H1a, as well as hydrogen atom bonded to carbon C1 were treated as a disorder in special
position using the PART -1 instruction and the occupancy was fixed in 0.5.

Figure 10. ORTEP diagram for compound 8, Symmetry transformations used to generate
equivalent atoms: 1/2-x, 3/2-y, +z, the atoms O1, H1a and H1 generated by symmetry are
omitted by clarity.
The O-H group forms hydrogen bonds type (a) with a distance of 2.006(12) Å between
hydrogen H1a and nitrogen N(2) (Table 4), along the a-axis forming a unidimensional net
through an infinite array similar to compounds 5 and 6. In general, these hydrogen bonds
can be described as C2,2(12) >a<a forming a 12-membered chain (Figure 11a). A 12-
membered ring is also observed in the packing between two adjacent molecules described
in terms of graph set as R2,2(12) >a>a (Figure 11b).

Table 4. Hydrogen bonds for 8 [Å and °].
D-H...A
d(D-H)
0.84(1)
d(H...A)
d(D...A)
<(DHA)
165(3)
O(1)-H(1A)...N(2)#1
2.006(12)
2.8268(18)
Symmetry transformations used to generate equivalent atoms: #1 x,y-1,z
(a)
(b)
Figure 11. Hydrogen bonds observed in packing of compound 8: a (up) 12-membered
chain, b (down) 12-membered ring.

3.3 Computational analysis
3.3.1. Effects of S1 substituent in the molecular reactivity
In figure 12 are presented some representative optimized structures [24], these structures
shown the formation of an internal hydrogen-bond between the benzyl alcohol and one of
the heterocyclic rings. This conformation inflicts modifications in the internal reactivity of
the molecule. In figure 13, we present the Molecular Electrostatic Potential, MEP, projected
on the electron density for one of the proposed compounds.
Figure 12. Optimized structures for some selected bis-1,2,3-triazoles obteined with the
PBE0/3-21G method.
Molecular Electrostatic Potential, MEP, surfaces illustrate the charge distributions of a
given molecule in a three-dimensional space, allowing to visualize positive, neutral and
negative charge regions. In figure 13, the MEP projected upon an iso-surface of electron
density of compounds 2.D and Fluconazole is presented as example of the behavior of all
compounds studied. Positive, neutral and negative charge regions are indicated in red,
green and blue respectively. The charge distribution presented in MEP shows a positive
region located upon the aromatic hydrogen of one of heterocycles while in the same ring an
irregular negative charge distribution is observed upon aromatic nitrogen atoms of which
one of them participates in the hydrogen bond. In contrast with the behavior of opposite

heterocyclic ring that shown a uniform negative charge distribution of aromatic nitrogens.
Similar results are observed in the MEP of fluconazole structure, so the set of compounds
presented is expected to show similar pharmacological activity to fluconazole. Regarding to
the effect of the S1 substituent, no appreciable influence is observed.
Figure 13. Representative molecular electrostatic potential, MEP, mapped on the electron
density surface with iso value of 0.01 a.u., for the set of proposed structures and for
fluconazole structure calculated with the PBE0/3-21G method. The color scales from blue
to red illustrating the charge distribution with values of -0.005 a.u. to 0.005 a.u.
respectively.
The formation of the intra-molecular hydrogen bond not only is reflected on the MEP
behavior. In figure 14, we present the Dual descriptor projected on the electron density,
where red and blue regions refer to positive and negative values of
meaning of positive and negative values of are related to nucleophilic and electrophilic
sites respectively. Like the charge distribution observed in the MEP, have opposite
. The chemical
reactivity for each heterocyclic ring. Granting electrophilic properties to the hydrogen
acceptor ring and nucleophilic properties to the opposite 1,2,3-triazole. It should be noted

that unlike the MEP, the nature of R1 influences the disposition of the reactive centers of
both heterocyclic rings.
Figure 14. Representative mapped on the electron density surface with iso value of 0.05
a.u., for the set of proposed structures and for fluconazole structure calculated with the
PBE0/3-21G method. The color scales from blue to red refer to values of -0.001 a.u. to
0.001 a.u. respectively.
3.3.2. Effects of S2 substituent in the molecular reactivity
The distribution of the charge density in the MEP seem invariant to S2 nature. Opposite
situation is observed in the reactivity of the aromatic ring measured through , being the
methoxy derivatives the only species with nucleophilic features, while the rest of proposed
structures this ring present electrophilic properties (figure 15).

Figure 15. Representative , mapped on the electron density surface with iso value of
0.05 a.u., for the set of proposed structures and for fluconazole structure calculated with the
PBE0/3-21G method. The color scales from blue to red refer to values of -0.001 a.u. to
0.001 a.u. respectively.
3.3.3. Global properties
Local reactivity description usually results useful for the understanding of a chemical
system. Nevertheless, some other quantities based on the global behavior can be used. An
example of this are the ionization potential, IP, that is a measure of the electron subtraction
of an electron; the electron-affinity, EA, that opposite to IP, is a measure of the electron
acceptor capacity of a system; and the softness, , the deformation capacity of an electron
density. The table 1, concentrates some energetical global parameters calculated at the DFT
framework. For fluconazole structure, it is recognized that its antifungal activity is closely
related to its interaction with the HEME group of the active center of cytochrome P450
protein, through coordination bonds between the Fe+2 atom and one of the nitrogen atoms

of the fluconazole heterocyclic ring. For this reason, it is necessary an electron donor
system. Under this argument, these systems are the molecules with the highest probability
to interact with the active center of cytochrome P450 protein, this due to their low IP value.
However, all systems reported here show better electronic properties regarding to
fluconazole structure.
Table 5. Some quantum global descriptors in eV, where Ionization Potential, PI, Electron
affinity, EA, and Softness, S, of proposed bi-1,2,3-triazoles were calculated at the PBE0/3-
21G method.
System
1.A
IP
EA
S
System
2.D
2.C
3.D
3.B
3.C
F
IP
EA
S
6.8864 0.2888
7.0373 0.3267
7.0793 0.3941
7.0892 0.4265
7.0947 -0.4004
7.3459 -0.3480
7.3640 -0.3757
0.0758
0.0745
0.0748
0.0750
0.0667
0.0650
0.0646
7.3761
7.3819
7.7115
7.7261
7.7391
8.2659
-0.1596
-0.2281
-0.1372
-0.3236
-0.2096
-0.2938
0.0664
0.0657
0.0637
0.0621
0.0629
0.0584
1.B
1.C
1.D
2.A
2.B
3.A
4. Conclusions
Single crystal X ray diffraction studies of 1,3-bis-(1,2,3-triazol-1-yl)-propan-2-ol
derivatives revealed an important O-H···N hydrogen bond between the hydroxyl group and
one triazolyl N(3) nitrogen which is in agreement with theoretical calculations bearing
a
strong resemblance to Fluconazole molecule. For each compound, only one polymorph was
found and to the best of our knowledge, these are the first examples about the crystal
structure of this kind of compounds. Theoretical calculations indicate that a high similarity
can be found between these products and the leading Flucanozole molecule; hence, a good