4′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid: Synthetic approaches, single crystal X-ray structures and antimicrobial activity of intermediates

Article abstract of DOI:10.1016/j.molstruc.2018.06.086

Two synthetic approaches towards 4′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid, a valuable organic ligand for the preparation of metal-organic frameworks, are reported. The first reaction sequence leading to the target compound comprises the iod

Full text of DOI:10.1016/j.molstruc.2018.06.086

Accepted Manuscript
4′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid: Synthetic approaches, single
crystal X-ray structures and antimicrobial activity of intermediates
Rodinel Ardeleanu, Andrei Dascălu, Sergiu Shova, Alina Nicolescu, Irina Roşca,
Bogdan-Ionel Bratanovici, Vasile Lozan, Gheorghe Roman
PII:
S0022-2860(18)30787-7
10.1016/j.molstruc.2018.06.086
MOLSTR 25373
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 22 February 2018
Revised Date: 20 June 2018
Accepted Date: 21 June 2018
Please cite this article as: R. Ardeleanu, A. Dascălu, S. Shova, A. Nicolescu, I. Roşca, B.-I. Bratanovici,
V. Lozan, G. Roman, 4′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid: Synthetic approaches, single
crystal X-ray structures and antimicrobial activity of intermediates, Journal of Molecular Structure (2018),
doi: 10.1016/j.molstruc.2018.06.086.
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Graphical abstract

ACCEPTED MANUSCRIPT
4
′-(2H-Tetrazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid: Synthetic approaches, single
crystal X-ray structures and antimicrobial activity of intermediates
a
a
a
a
a
Rodinel Ardeleanu , Andrei Dascălu , Sergiu Shova , Alina Nicolescu , Irina Roşca ,
a,b
a,c
a
Bogdan-Ionel Bratanovici , Vasile Lozan *, Gheorghe Roman *
a
Petru Poni Institute of Macromolecular Chemistry, Iaşi 700487, Romania
b
Al. I. Cuza University, Faculty of Chemistry, Iaşi 700506, Romania
c
Institute of Chemistry, Chişinău MD-2028, Republic of Moldova
Abstract: Two synthetic approaches towards 4′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-
carboxylic acid, a valuable organic ligand for the preparation of metal-organic frameworks,
are reported. The first reaction sequence leading to the target compound comprises the
iodination of [1,1′-biphenyl]-4-carboxylic acid, formation of the methyl ester of 4′-iodo-[1,1′-
biphenyl]-4-carboxylic acid, nucleophilic substitution of iodine with cyano, ring closure of
tetrazole, and hydrolysis of the ester function. The second synthetic pathway starts from 4-
bromobenzonitrile, which is converted through Suzuki coupling with 4-carboxyphenylboronic
acid into 4′-cyano-[1,1′-biphenyl]-4-carboxylic acid, which in turn leads to the desired
compound after ring closure of tetrazole. All of the synthesized compounds have been fully
1
13
characterized by IR and H- and C-NMR spectroscopy. Single crystal X-ray structures are
reported for the target compound and for methyl esters of 4′-iodo-[1,1′-biphenyl]-4-carboxylic
acid and 4′-cyano-[1,1′-biphenyl]-4-carboxylic acid. The target compound and the
intermediates showed no antimicrobial activity against Escherichia coli, Staphylococcus
aureus and Candida albicans.
Keywords: Organic ligand; Tetrazole; Multistep synthesis; Single crystal X-ray structure;
Antimicrobial activity.
Corresponding authors:
Dr. Vasile Lozan
Institute of Chemistry, 3 Academiei Str., Chişinău MD-2028, Republic of Moldova
E-mail: vasilelozan@gmail.com

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Dr. Gheorghe Roman
Petru Poni Institute of Macromolecular Chemistry, 41A Aleea Gr. Ghica Vodă, Iaşi 700487,
Romania
E-mail: gheorghe.roman@icmpp.ro

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1
. Introduction
In the last decades, the ongoing search for innovative, high performance compounds in the
field of polymers has led to the rapid development of a novel type of materials generically
designated as metal-organic frameworks (MOFs). These promising multifunctional materials,
which belong to the class of coordination polymers, are compounds that consist of metal ions
(or metal clusters) and organic ligands. These two types building units coordinate in a MOF to
form one-, two-, or three-dimensional structures that are often porous, which makes MOFs
particularly useful for potential industrial applications such as gas storage [1,2], gas
separation [3,4], adsorption-driven heat pumps [5], or catalysis [6,7]. Commercially available
organic linkers have been so far extensively used for the cheap, rapid and efficient preparation
of a large variety of MOFs in large amounts. Nonetheless, the design and preparation of novel
organic ligands has started to be employed by numerous research groups with the view to
produce hitherto unknown porous coordination polymers with potentially interesting
properties. Besides the classical carboxylate ligands, multidentate tetrazolate ligands [8–10]
or combined carboxylate-tetrazolate ligands [11–13] have lately emerged as valuable
alternatives for the synthesis of novel MOFs. One of the most simple combined carboxylate-
tetrazolate ligand is 4′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid 1, which has been
recently used for the synthesis of a cadmium-derived MOF having an intense blue-green
photoluminescence emission at room temperature in the solid state [14], for the preparation of
a Zn-organic framework for highly selective separation of CO [15], and for obtaining
2
luminescent coordination polymers containing either zinc or cadmium [16]. However, the
aforementioned ligand was obtained from 4′-cyano-[1,1′-biphenyl]-4-carboxylic acid using a
2
+
template reaction in the presence of Cd in the first study, while the other two articles only
mention that the required ligand was purchased from commercial sources. Consequently,
there is no available comprehensive report on the synthesis of this valuable ligand from
simple starting materials, and there is no structural characterization for the intermediates and
the final compound. As a part of our program for the development of novel coordination
polymers, the present work aims at correcting this omission by reporting two different
approaches for the synthesis of ligand 1, several X-ray single crystal structures for selected
intermediates and for the target compound. In addition, taking into account the status of
biphenyl as privileged scaffold in medicinal chemistry [17–19], the investigation of the
antimicrobial activity of these compounds has also been undertaken.

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2
2
. Experimental
.1. Materials and methods
Starting
materials
and
reagents
([1,1′-biphenyl]-4-carboxylic
acid
2,
bis[(trifluoroacetoxy)iodo]benzene, 4-bromobenzonitrile 7, 4-carboxyphenylboronic acid,
tetrakis(triphenylphosphine)palladium(0), iodine, copper(I) cyanide, sodium azide,
ammonium chloride, anh. potassium carbonate, 36.5% hydrochloric acid, 98% sulfuric acid,
sodium hydroxide) were obtained from Alfa Aesar (Ward Hill, MA, USA) and were used
without further purification. Most of the solvents (N,N-dimethylformamide (DMF), abs.
methanol, methanol, chloroform, dioxane, ethanol) were purchased from VWR International
(Radnor, PA, USA), only carbon tetrachloride was a product of Chemical Company (Iaşi,
Romania). Mueller–Hinton agar was provided by Merck (Darmstadt, Germany). Melting
points were taken on a MEL-TEMP capillary melting point apparatus and are uncorrected.
NMR spectra were recorded on a Bruker Avance III 400 instrument operating at 400.1 and
1
13
1
00.6 MHz for H and C nuclei, respectively, either in DMSO-d or CDCl . Chemical shifts
6 3
1
13
are reported in ppm relative to the residual solvent peak ( H: 7.26 ppm and C: 77.01 ppm for
1
13
CDCl ; H: 2.51 ppm and C: 39.47 ppm for DMSO-d ). Unambiguous 1D NMR signal
3
6
assignments were made based on 2D NMR homo- and heteronuclear correlations such as
H,H-COSY, H,C-HSQC and H,C-HMBC experiments, which were recorded using standard
pulse sequences in the version with z-gradients, as delivered by Bruker with TopSpin 2.1 PL6
spectrometer control and processing software. Fourier Transform-Infrared (FT-IR) spectra
were taken on a FT-IR Bruker Vertex 70 spectrophotometer in transmission mode, using KBr
pellets. Elemental analysis has been performed on a Vario EL III CHNS analyzer.
2
2
.2. Synthesis
.2.1. 4′-Iodo-[1,1′-biphenyl]-4-carboxylic acid 3. A mixture of [1,1′-biphenyl]-4-carboxylic
acid 2 (13.87 g, 70 mmol), bis[(trifluoroacetoxy)iodo]benzene (30.38 g, 70 mmol) and finely
ground iodine (17.76 g, 70 mmol) in carbon tetrachloride (180 mL) was stirred at room
temperature for 24 h. The resulting solid was filtered, washed with carbon tetrachloride (3×30
mL) and dried under high vacuum to afford the pure product (19.27 g, 85%), mp 315–317 °C
-1
(
lit. mp 310 °C [20]). FT-IR (ATR), 1/υ (cm ): 3107, 2988, 2816, 2673, 2550, 1684, 1607,

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1
7
576, 1551, 1516, 1475, 1425, 1394, 1302, 1198, 1177, 1124, 1063, 997, 951, 868, 822, 770,
1
3
46, 704, 662, 554, 482, 407. H-NMR (400 MHz, DMSO-d ), δ (ppm): 7.55 (d, 2H, J = 12
6
3
3
3
Hz, H-2′), 7.79 (d, 2H, J = 8 Hz, H-2), 7.86 (d, 2H, J = 8 Hz, H-3′), 8.03 (d, 2H, J = 8 Hz,
1
3
H-3), 12.97 (bs, 1H, OH). C-NMR (100 MHz, DMSO-d ), δ (ppm): 95.0 (C-4′), 126.6 (C-
6
2
), 129.1 (C-2′), 129.9 (C-4), 130.0 (C-3), 137.8 (C-3′), 138.4 (C-1′), 143.1 (C-1), 167.0
(
COOH). Anal. Calc. for C H IO : C, 48.17; H, 2.80. Found: C, 48.02; H, 2.72.
13
9
2
2
.2.2. Methyl 4′-iodo-[1,1′-biphenyl]-4-carboxylate 4. To a suspension of 4′-iodo-[1,1′-
biphenyl]-4-carboxylic acid 3 (12 g, 37 mmol) in abs. methanol (300 mL), concentrated
sulfuric acid (7 mL) was added dropwise during 1 h. The reaction mixture was heated at
reflux temperature for 72 h, and then it was allowed to cool to room temperature. The
separated solid was filtered, washed with abs. methanol (2× 20 mL), and dried in an oven at
6
0 °C overnight to give colorless crystals (12.2 g, 97%), mp 192–193 °C (lit. mp 188 °C
-1
[
20]). FT-IR (ATR), 1/υ (cm ): 3456, 2943, 2374, 1780, 1711, 1610, 1576, 1535, 1526, 1516,
1
466, 1435, 1379, 1337, 1286, 1198, 1107, 1063, 999, 949, 862, 820, 764, 694, 582, 501, 457.
1
3
H-NMR (400 MHz, CDCl ), δ (ppm): 3.94 (s, 3H, CH ), 7.36 (d, 2H, J = 8 Hz, H-2′), 7.62
3
3
3
3
3
13
(
d, 2H, J = 8 Hz, H-2), 7.80 (d, 2H, J = 12 Hz, H-3′), 8.10 (d, 2H, J = 8 Hz, H-3). C-NMR
(
100 MHz, CDCl ), δ (ppm): 52.2 (CH ), 94.2 (C-4′), 126.8 (C-2), 129.0 (C-2′), 129.3 (C-4),
3
3
1
30.2 (C-3), 138.5 (C-3′), 139.5 (C-1′), 144.4 (C-1), 166.8 (COOMe). Anal. Calc. for
C H IO : C, 49.73; H, 3.28. Found: C, 49.61; H, 3.21.
14
11
2
2
.2.3. Methyl 4′-cyano-[1,1′-biphenyl]-4-carboxylate 5. A mixture of methyl 4′-iodo-[1,1′-
biphenyl]-4-carboxylate 4 (12 g, 35.5 mmol) and CuCN (4.76 g, 53.25 mmol) in anh. DMF
170 mL) was heated at 120 °C under argon for 3 d. The cooled reaction mixture was then
(
slowly poured into 1.2 L of distilled water under efficient stirring. The resulting solid was
filtered, washed thoroughly with distilled water, and dried in an oven at 105 °C overnight.
The dried material was extracted with chloroform (70 mL), and the suspension was filtered.
Chloroform was removed under reduced pressure to give a yellowish solid (7.8 g, 93%), mp
1
43–144 °C. FT-IR (ATR) 1/υ: 3866, 3744, 3667, 3566, 3366, 3059, 2959, 2374, 2222, 1929,
1
724, 1655, 1603, 1564, 1483, 1427, 1281, 1182, 1105, 1007, 957, 833, 768, 721, 696, 652,
1
5
63, 517, 451, 372. H-NMR (400 MHz, DMSO-d ), δ (ppm): 3.90 (s, 3H, CH ), 7.92 (d, 2H,
6
3
3
3
13
J = 8 Hz, H-2), 7.95-7.99 (m, 4H, H-2′ and H-3′), 8.08 (d, 2H, J = 8 Hz, H-3). C-NMR
100 MHz, DMSO-d ), δ (ppm): 52.2 (CH ), 110.9 (C-4′), 118.6 (CN), 127.4 (C-2), 127.9 (C-
(
6
3
2
′), 129.5 (C-4), 129.8 (C-3), 132.9 (C-3′), 142.6 (C-1), 143.2 (C-1′), 165.8 (COOMe). Anal.
Calc. for C H NO : C, 75.94; H, 4.67; N, 5.90. Found: C, 75.88; H, 4.62; N, 5.83.
1
5
11
2

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2
.2.4. Methyl 4′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-carboxylate 6. A solution of methyl 4′-
cyano-[1,1′-biphenyl]-4-carboxylate 5 (5.35 g, 22.6 mmol), sodium azide (5.53 g, 85 mmol)
and ammonium chloride (4.55 g, 85 mmol) in anh. DMF (130 mL) was heated at 120 °C
under argon for 3 d. The cooled reaction mixture was then slowly poured into 350 mL of
distilled water under efficient stirring. The separated solid material was filtered, washed with
distilled water (3×50 mL), and dried in an oven at 105 °C overnight to give colorless crystals
(5.75 g, 91%), mp 263–265 °C. FT-IR (ATR) 1/υ: 3476, 3074, 2928, 2853, 2679, 2552, 1680,
1
7
7
609, 1578, 1522, 1491, 1423, 1321, 1300, 1180, 1121, 1086, 1030, 997, 922, 899, 876, 833,
1
75, 746, 698, 675, 552, 498. H-NMR (400 MHz, DMSO-d ), δ (ppm): 3.88 (s, 3H, CH ),
6
3
3
3
3
.89 (d, 2H, J = 8 Hz, H-2), 7.96 (d, 2H, J = 8 Hz, H-2′), 8.05 (d, 2H, J = 8 Hz, H-3), 8.16
3
13
(
d, 2H, J = 8 Hz, H-3′). C-NMR (100 MHz, DMSO-d ), δ (ppm): 52.1 (CH ), 124.1 (C-4′),
6 3
1
27.0 (C-2), 127.6 (C-3′), 127.9 (C-2′), 129.0 (C-4), 129.8 (C-3), 141.1 (C-1′), 143.3 (C-1),
1
55.1 (C=N), 165.9 (COOMe). Anal. Calc. for C H N O : C, 64.28; H, 4.32; N, 19.99.
15
12
4
2
Found: C, 64.18; H, 4.28; N, 19.61.
2
.2.5. 4′-(2H-Tetrazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid 1. A mixture of methyl 4′-(2H-
tetrazol-5-yl)-[1,1′-biphenyl]-4-carboxylate 6 (3.55 g, 12.67 mmol), NaOH (2.53 g) and
distilled water (250 mL) were heated at 90 °C until a clear solution was obtained. The cooled
solution was gradually treated with 17% HCl until pH 1-2. The resulting solid was filtered
and thoroughly washed with distilled water until the pH of the washings was neutral. The wet
material was stirred with acetone (70 mL), filtered and dried in an oven at 60 °C overnight to
afford a colorless solid (3.35 g, 95%), which was recrystallized from DMF to give colorless
crystals, mp 316–318 °C. FT-IR (ATR) 1/υ: 3487, 2930, 1676, 1612, 1568, 1518, 1491, 1427,
1
391, 1294, 1182, 1107, 1067, 995, 926, 876, 835, 779, 744, 698, 669, 554, 503, 463, 413.
1
3
3
H-NMR (400 MHz, DMSO-d ), δ (ppm): 7.92 (d, 2H, J = 8 Hz, H-2), 8.01 (d, 2H, J = 8
6
3
3
Hz, H-2′), 8.07 (d, 2H, J = 8 Hz, H-3), 8.13 (d, 2H, J = 8 Hz, H-3′), 13.07 (s, 1H, OH),
1
3
1
1
1
5
2
6.97 (bs, 1H, NH). C-NMR (100 MHz, DMSO-d ), δ (ppm): 123.9 (C-4′), 127.0 (C-2),
6
27.6 (C-3′), 127.9 (C-2′), 130.0 (C-3), 130.3 (C-4), 141.5 (C-1′), 143.0 (C-1), 155.1 (C=N),
67.0 (COOH). Anal. Calc. for C H N O ·2DMF: C, 58.24; H, 5.87; N, 20.38. Found: C,
1
4
10
4
2
8.12; H, 5.77; N, 20.31.
.2.6. 4′-Cyano-[1,1′-biphenyl]-4-carboxylic acid 8. To a solution of 4-bromobenzonitrile 7
(3.1 g, 17 mmol) in dioxane (100 mL) was added a solution of 4-carboxyphenylboronic acid
(4.15 g, 25 mmol) in ethanol (30 mL), followed by a solution of anh. potassium carbonate
(17.39 g, 126 mmol) in deionized water (30 mL). The reaction mixture was degassed by
passing a stream of argon through it for 20 min. After tetrakis(triphenylphosphine)palladium

ACCEPTED MANUSCRIPT
(0.589 g, 0.51 mmol, 3% molar) had been added, the reaction flask was fitted with a
condenser and immersed in an oil bath. The reaction mixture was stirred at 85 °C for 24 h,
and then it was cooled to room temperature before deionized water (100 mL) was added. The
mixture was stirred at room temperature for 1 h, and then it was filtered to remove the
insoluble materials. The solution was treated with 10% HCl until pH 4 under efficient stirring
to give a colorless precipitate, which was collected by filtration, thoroughly washed with
water (300 mL), and dried under reduced pressure at 60 °C. Recrystallization of the solid
from DMF afforded colorless plates (2.6 g, 78%), mp 273–275 °C. FT-IR (ATR) 1/υ: 2669,
2
6
7
550, 2374, 2222, 1803, 1686, 1603, 1568, 1425, 1296, 1182, 1119, 1007, 932, 872, 827, 770,
1
3
98, 555, 515. H-NMR (400 MHz, DMSO-d ), δ (ppm): 7.88 (d, 2H, J = 8 Hz, H-2), 7.93-
6
3
13
.98 (m, 4H, H-2′ and H-3′), 8.06 (d, 2H, J = 8 Hz, H-3), 13.12 (bs, 1H, OH). C-NMR (100
MHz, DMSO-d ), δ (ppm): 110.8 (C-4′), 118.7 (CN), 127.3 (C-2), 127.9 (C-2′), 130.1 (C-3),
6
1
30.8 (C-4), 132.9 (C-3′), 142.3 (C-1), 143.5 (C-1′), 167.0 (COOH). Anal. Calc. for
C H NO : C, 75.33; H, 4.06; N, 6.27. Found: C, 75.22; H, 3.98; N, 6.20.
14
9
2
2
.2.7. 4′-(2H-Tetrazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid 1. A mixture of 4′-cyano-[1,1′-
biphenyl]-4-carboxylic acid 8 (2 g, 8.95 mmol), sodium azide (1.5 g, 23.07 mmol) and
ammonium chloride (1.24 g, 23.1 mmol) in DMF (40 mL) was stirred at 120 °C for 72 h. The
reaction mixture was cooled to room temperature and poured with efficient stirring into
deionized water (300 mL). The solid material was collected by filtration, washed with
deionized water (150 mL), and dried under reduced pressure at 60 °C. Recrystallization from
1
13
DMF afforded colorless crystals (1.9 g, 79%), mp 317–319 °C. The IR, H- and C-NMR
spectra of this compound were identical to those recorded for compound 1 obtained through
the other synthetic route.
2
.3. X-ray crystallography
X-ray diffraction measurements for 1 and 5 were carried out with an Oxford-
Diffraction XCALIBUR E CCD diffractometer equipped with graphite-monochromated
MoKα radiation. Single crystals were positioned at 40 mm from the detector and 155, and 242
frames were measured each for 25, and 5 s over 1° scan width for 1 and 5, respectively.
Intensity data for 4 were collected with Oxford Diffraction SuperNova diffractometer using
hi-flux micro-focus Nova CuKa radiation. The single crystal was positioned at 47 mm from
the detector and 452 frames were measured each for 5 s over 1° scan width. The unit cell
determination and data integration were carried out using the CrysAlis package of Oxford
Diffraction [21]. The structures were solved by direct methods using Olex2 [22] software with

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the SHELXS [23] and refined by full-matrix least-squares on F² with SHELXL-97 [23] using
an anisotropic model for non-hydrogen atoms. All hydrogen atoms were introduced in
idealized positions (dCH = 0.96 Å) using the riding model with their isotropic displacement
parameters fixed at 120% of their riding atom. Positions of hydrogen atoms for the O-H and
N-H groups were located on electron density difference map and refined accounting for the
hydrogen bonds parameters. The molecular plots were obtained using the Olex2 program. The
crystallographic data and refinement details are quoted in Table 1, while bond lengths are
summarized in Table S1 (see Supplementary Material). CCDC-1822343 (1·2DMF), CCDC-
1
822346 (4) and CCDC-1822342 (5) contain the supplementary crystallographic data for this
contribution.
Table 1. Crystallographic data, details of data collection and structure refinement parameters
for compounds 1·2DMF, 4 and 5.
Compound
1·2DMF
4
5
Empirical formula
Formula weight
C H N O
C H INO
C H N O
4
20
24
6
4
14 14
30 22
2
4
12.45
200
339.16
474.50
293(2)
monoclinic
Pc
Temperature/K
Crystal system
Space group
293(2)
orthorhombic
Pca21
monoclinic
P2 /n
1
/
Å
11.9398(12)
8.1451(7)
21.943(2)
90.00
104.273(11)
90.00
2068.1(4)
4
1.325
6.0538(5)
7.3253(6)
27.8702(16)
90.00
90.00
90.00
1235.91(16)
4
3.91242(17)
20.4050(8)
15.2981(5)
90.00
97.002(4)
90.00
b/Å
c/Å
α
/°
β/°
/°
γ
3
V/Å
Z
D /mg/mm
µ
Crystal size/mm
θmin, θ ( )
Reflections collected
1212.18(9)
2
3
1.823
2.574
0.25 × 0.15 × 0.02
6.28 to 50.04
7825
1.300
0.087
0.35 × 0.3 × 0.25
4 to 50.06
14747
clc
-
1
/mm
0.095
3
0.3 × 0.2 × 0.2
3.56 to 50.04
8278
°
mx
Independent reflections 3655 [R = 0.0244 2146 [R = 0.0494] 4301 [R = 0.0275]
int
int
int
Dt/restraints/parameters
GOF
3655/0/276
2146/1/155
4301/2/327
c
1.033
0.0490
0.1146
1.057
0.0364
0.0724
1.043
0.0529
0.1428
R1(I>2σ(I)
b
wR (ll dt)
2
Largest diff.
peak/hole/e Å
0.19/-0.18
0.64/-0.61
-3
0.26/-0.15
b
2
2 2
2 2 1/2
c
2
2 2
1/2
R = Σ||F | − |F ||/Σ|F |. wR = {Σ[w(F −F ) ]/Σ[w(F ) ]} . GOF = {Σ[w(F −F ) ]/(n−p)} , where n is the
1
o
c
o
2
o
c
o
o
c
number of reflections nd p is the total number of parameters refined
2
.4. Biological activity

ACCEPTED MANUSCRIPT
In vitro antimicrobial susceptibility of the target compound 1 and of intermediates 3–6
was evaluated using the guidelines of EUCAST [24]. The three different reference strains
used in this study were E. coli ATCC25922, S. aureus ATCC25923 and C. albicans
ATCC10231. The tests were performed on unsupplemented Mueller–Hinton agar, which was
dispersed in Petri dishes in an even layer of 4.0 mm with a maximum variation of ±0.5 mm.
The inoculum suspension has been prepared by adjusting its density to the density of a
McFarland 0.5 standard by addition of 0.85% NaCl w/v in water or more organisms, to
8
achieve a suspension containing 1×10 CFU/mL for all microorganisms. From each
compound to be tested, a stock solution containing 5 mg/mL was prepared by dissolving the
tested compounds in dimethylsulfoxide. Each compound has been tested at six different
concentrations. The solutions of the tested compounds were obtained by diluting the stock
solutions, with the view to reach final concentrations within the range of 0.156–5 mg/mL.
After the application of the tested compounds, the plates had been incubated at 36 °C ± 1°C
for 24 h. After incubation, the diameters of inhibition zones were measured.
3
3
. Results and discussion
.1. Chemistry
Using commercially available, affordable reagents, two synthetic approaches have
been designed for the preparation of the desired ligand 1. The first approach employs as
starting material a compound having a biphenyl core that is appropriately substituted, whereas
the strategy devised for the second approach involves the construction of the biphenyl core
from suitable substituted benzene derivatives via a Suzuki-Miyaura cross-coupling reaction.
The reaction sequence leading to the target compound 1 through the first approach is given in
Scheme 1. Starting from [1,1′-biphenyl]-4-carboxylic acid 2, intermediate acid 3 is obtained
through nuclear iodination using a procedure previously reported in literature [20]. In the next
step, intermediate acid 3 is converted into the corresponding methyl ester 4, which, in turn, is
subjected to the replacement of iodine with a nitrile group in a typical a Rosemund–von Braun
reaction [25] to afford intermediate 5. The formation of the tetrazole ring in intermediate 6
was accomplished through a [3+2] dipolar cycloaddition between the nitrile 5 and sodium
azide in the presence of ammonium chloride [26]. An initial attempt to conduct the
cycloaddition in the presence of anhydrous ZnCl , as previously reported [27], led to a
2
product containing traces of zinc, whose complete removal proved to be very difficult.
Finally, the base-catalyzed hydrolysis of tetrazole–ester 6 afforded the target compound 1
with a very good total yield of 68% in 5 steps and without chromatographic separation.

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Scheme 1. Synthesis of 4′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid 1. Reagents
and conditions: a) bis[(trifluoroacetoxy)iodo]benzene, I , CCl , rt, 24 h; b) abs. CH OH, conc.
2
4
3
H SO , reflux, 72 h; c) CuCN, anh. DMF, 120 °C, 72 h; d) NaN , NH Cl, anh. DMF, 120 °C,
2
4
3
4
72 h; e) aq. NaOH, 90 °C, several hours.
The second approach towards the preparation of compound 1 is a more
straightforward, two-step synthetic strategy, but, compared to the first approach, it requires
the use of relatively expensive reagents, namely a boronic acid and a palladium-based
catalyst. Thus, in the first step of the reaction sequence, 4-bromobenzonitrile 7 was subjected
to a Suzuki-Miyaura cross-coupling reaction with 4-carboxyphenylboronic acid in the
presence of tetrakis(triphenylphosphine)palladium(0), then, in the second stage, the
intermediate carboxylic acid 8 underwent a [3+2] dipolar cycloaddition with sodium azide in
the presence of ammonium chloride leading to the formation of the tetrazole ring (Scheme 2).
Scheme 2. Alternative synthesis of 4′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid 1.
Reagents and conditions: a) 4-carboxyphenylboronic acid, K CO , Pd[P(C H ) ] , dioxane–
2
3
6
5 3 4
ethanol–water, 85 °C, 24 h; b) NaN , NH Cl, DMF, 120 °C, 72 h.
3
4
The palladium-catalyzed cross-coupling reaction proceeds smoothly even without the use of
expensive Schlenk glassware, as long as air is thoroughly excluded from the reaction mixture,

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and it could be upscaled to easily and steadily provided batches of several grams of
intermediate 8 in a single experiment. With its 62% global yield, this second approach
towards the preparation of the target compound 1 provides a valuable alternative to the first
synthetic strategy described previously in this study.
3
.2. IR spectroscopy
All of the synthesized compounds have been structurally characterized using FT-IR
spectroscopy (see Supplementary Material). Thus, close comparison of the FT-IR spectra of
acid 3 and ester 4 confirmed the conversion of the former into the latter through the shift of
the band associated with the vibration of the double bond of the carbonyl group from 1684
-1
-1
cm in acid 3 to 1711 cm in ester 4. Replacement of iodine in ester 4 with the nitrile group
-1
in ester 5 was proven by the identification of the characteristic band for nitriles at 2222 cm in
the FT-IR spectrum of compound 5, while the value of wavelength number recorded for the
-1
vibration of the carbonyl bond in ester 5 was 1724 cm . The absence in the FT-IR spectrum
of tetrazole–ester 6 of the absorption band associated with the nitrile group confirms the
success of the cycloaddition reaction and the formation of the tetrazole ring. The presence of
-1
the absorption band at 1680 cm in the FT-IR spectrum of the target compound 1, correlated
with the disappearance of the absorption band usually associated with the carbonyl vibration
of the ester function, is suggestive for the hydrolysis of ester 6 to acid 1. As for intermediate
8
, the absorption band for the carbonyl vibration in carboxylic acids can be identified at 1686
-1
cm in its FT-IR spectrum, while the absorption band due to the stretching of the triple bond
-1
in nitriles is found at 2222 cm .
3
.3. NMR spectroscopy
The structure of the synthesized products was also investigated using NMR
spectroscopy. As a general remark, all the compounds reported in this study feature a
biphenyl moiety in their structure, the only difference between compounds 1, 3, 4, 5 and 6
resides in the nature of the substituents attached at positions 4 and 4′ of the biphenyl ring
1
system. Therefore, in the H-NMR spectra of these compounds (see Supplementary Material),
the aromatic protons in the 4,4′-disubstituted biphenyl appear in the region 6-8 ppm as four
doublets presenting a “roof effect”, which is characteristic for para-disubstitution. The exact
chemical shifts values depend on the type of the substituents in each of the compounds 1 and
1
3
3
–6. In the C-NMR spectrum of these compounds, the four signals for the CH groups in the
4
,4′-disubstituted biphenyl moiety are noticeable in the 125–138 ppm range, while the

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chemical shifts values for the quaternary carbons depend heavily on the type of the
substituents attached to them. Specifically, the aromatic protons in intermediate 3 appear in
the proton spectrum of this compound as four doublets in the region 7.53–8.04 ppm, while the
1
3
hydroxyl proton is associated with the very broad signal centered at 12.97 ppm. In the C-
NMR spectrum of 3, a signal corresponding to an aromatic quaternary carbon atom is
detectable at 95 ppm, which is outside the usual range for aromatic carbon atoms. As this
shielding effect is characteristic for elements with many polarizable electrons, such as iodine,
this observation provides the necessary confirmation for the presence of iodine in the structure
of compound 3. Next, the presence of methyl ester function in intermediate 4 was associated
with the intense singlet integrating for three protons at 3.94 ppm in the proton spectrum of this
compound, while the absence in the spectrum of the broad signal assigned to the proton in the
carboxyl function in carboxylic acid 3 offered further proof for the conversion of this group
13
into an ester group. In addition, the signal at 52.2 ppm in the C-NMR spectrum of ester 4
could be assigned to the carbon atom in the methyl group. The introduction of nitrile group in
the structure of ester 5 induces only a minor downfield shift of 0.6 ppm for the protons at C-2′
of the biphenyl ring system compared to the values of the chemical shift for the same protons
1
3
in ester 4. However, comparison of the C-NMR spectra of esters 4 and 5 reveals a few major
changes that are brought about by the presence of the nitrile group in the structure of ester 5.
First, the carbon atom of the nitrile group was assigned the new signal at 118.6 ppm, which
typically appears in that region. Second, the chemical shift value (110.9 ppm) for the
quaternary carbon atom C-4′ onto which the nitrile function is attached in ester 5 shifted
downfield compared to the value recorded for the same protons in 4′-iodo derivative 4. This
shift is usually caused by the π-electron deshielding and polar inductive effects of the cyano
1
group [28, 29]. In the H-NMR spectrum of compound 6, the presence of the tetrazole ring
induces a downfield shift of 1.0 ppm for the protons at position 3′ relative to the value
recorded for the same protons in intermediate 5. The signal for the proton of the tetrazole ring
in tetrazole–ester 6 is very broad, and partially overlaps the four signals associated with the
protons in the biphenyl moiety. The peak at 118.6 ppm, previously assigned to the carbon
1
3
atom in the nitrile group is absent in the C-NMR spectrum of tetrazole–ester 6, and a new
broad signal appears at 155.1 ppm. From the bidimensional H,C-HMBC spectrum, this new
signal was assigned to the quaternary carbon from the tetrazole ring. The chemical shift value
for the quaternary carbon atom C-4′ linked to the tetrazole ring is shifted downfield (124.1
ppm) compared to value for the same carbon atom in ester 5 (110.9 ppm), while an upfield
shift is observed for C-3′. As a result of the hydrolysis of ester 6, a new broad signal, typical

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1
for the proton of the carboxyl group, is observed at 13.07 ppm in the H-NMR spectrum of the
target compound 1. Also, the broad singlet appearing in this downfield region at 16.97 ppm
1
3
was assigned to the proton of the tetrazole ring. C-NMR spectrum of carboxylic acid 1 is
very similar to the carbon spectrum of its methyl ester 6, with the exception of the peak at
5
2.1 ppm assigned to the carbon atom in the methyl ester function, which is now absent. In
the case of intermediate 8, the presence of group of signals in the aromatic region of the
proton spectrum that integrates for eight protons is indicative for the presence of the biphenyl
ring system in the structure of compound 8. In addition, the broad signal centered at 13.12
ppm, characteristic for the proton of the carboxyl group, confirms the success of the Suzuki
coupling. Also, the presence of the nitrile and carboxyl groups in the structure of intermediate
8
is corroborated by the peaks at 118.7 ppm and 167.0 ppm, respectively.
3
.4. Crystal structure of compounds 1, 4 and 5
The solid state structures of the target compound 1 and intermediates 4 and 5 have
been determined by single crystal X-ray diffraction method. Crystals of the target compound
that were suitable for X ray diffraction studies have been obtained by slowly cooling a
1
concentrated solution of this compound in hot DMF. In the case of compounds 4 and 5, X ray
quality single crystals were obtained from their solutions in methanol and chloroform,
respectively, using the slow evaporation technique. All these compounds exhibit a molecular
crystal structure comprising neutral entities, as showing in Figures 1, 2 and 3, respectively.
The bond distances and angles are summarized in Table S1 (see Supplementary Material).
Compounds 4 and 5 crystalize without any solvate molecules, while compound 1 crystalizes
with DMF molecules in 1:2 ratio. The molecule of 1 exhibits a planar configuration, which is
however broken by the rotation of the C8-C12 phenyl ring at 17.464(3)° to the plane formed
by the rest of the atoms. Compound 1 and both solvate DMF molecules are associated via
hydrogen bonding where the N-H and O-H functional groups act as donors of protons (Figure
1
). The molecule of 4 is essentially planar within 0.11 Å, with the maximum deviation at 0.22
Å observed for the methyl group. The crystal of 5 shows the presence of two discrete
chemically equivalent but crystallographic independent molecules in the asymmetric part of
the cell (denoted as A and B). Due to their similarity, only one of the independent molecules
will be characterized in details below. The molecule of 5 features a non-planar structure with
the dihedral angle between two aromatic rings of 38.51 and 37.69° for A and B molecules,
respectively.

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Figure 1. View of the asymmetric part in the crystal 1·2DMF with atom numbering and
thermal ellipsoids at 50% probability level. H-bonds are drawn in black dashed lines.
H-bonds parameters: O2-H···O3 [O2-H 0.82 Å, H···O3 1.75 Å, O2···O3 2.568(2) Å,
O2HO3 171.8°]; N1-H···O4 [N1-H 0.82 Å, H···O4 1.84 Å, N1···O4 2.646(2) Å, ∠ N1HO4
∠
1
55.5°].
Figure 2. X-ray molecular structure of 4 with atom numbering and thermal ellipsoids at 50%
probability level.

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Figure 3. X-ray molecular structure of 5 (molecule A) with atom numbering and thermal
ellipsoids at 50% probability level.
The molecular associates 1·2DMF are assembled in the crystal into one-dimensional
zig-zag supramolecular architectures by π–π stacking interactions between tetrazole and
biphenyl rings of adjacent entities, with a perpendicular distance of 3.459(3) Å and centroid–
to-centroid distance of 3.8478(4) Å. A view of the supramolecular chain is shown in Figure 4.
As shown in Figure 5, the crystal structure is built from the parallel packing of discrete 1D
chains {1·2DMF} along b crystallographic axis.
n
Figure 4. One-dimensional supramolecular architecture in 1·2DMF. H-bonds and centroid-
to-centroid distances are drawn in black and orange dashed lines, respectively. Non-relevant
H-atoms are omitted for clarity.

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Figure 5. Packing diagram for 1·2DMF viewed along b axis.
Due to the presence of aromatic rings in the molecules of 1, 4 and 5, the packing of
these compounds shows common features, based on π-π and C-H···π interactions. A partial
view of the crystal structure for compound 4 is presented in Figure 6. Compared to 1·2DMF,
the driving forces in the packing of 4 are determined by an extended system of C-H···π
contacts involving all aromatic rings. As a result, the main crystal structure motif can be
characterized as a three-dimensional supramolecular architecture.
Figure 6. Partial view of 3D supramolecular network in the crystal structure 4. Non-relevant
H-atoms are omitted. C-H···π contacts are in the range of 2.714÷2.962 Å.

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In the crystal of 5, the neutral entities A and B are arranged separately by π-π
interactions to form supramolecular ribbons of parallel staked molecules, as shown in Figure
7
. The centroid-to-centroid distances are equal to 3.912 Å, being the same for both ribbons,
formed by A and B molecules. In the crystal, the self-assembled ribbons are arranged in
parallel orientation along a crystallographic axis. A partial view of the packing diagram is
presented in Supplementary Material (Figure S20).
Figure 7. π-π stacking in the crystal structure of compound 5. Centroid-to-centroid distances
are shown in dashed-orange lines.
3
.5. Antimicrobial activity
To the best of our knowledge, available data on the antimicrobial activity of
biphenylcarboxylic acids and their close structurally related derivatives is rather scarce.
However, a brief inspection of the recent literature revealed a study that reported promising
antimicrobial activities for a number of hydrazones of biphenylcarboxylic acid hydrazide
[
30]. In addition, a virtual screening, which was followed by experimental evaluations,
established that four biphenylcarboxylic acids act as antivirulence agents against methicillin-
resistant S. aureus by inhibiting the production of the toxins alpha-hemolysin and phenol-
soluble modulin α [31]. In an effort to gain insight into the biological activity of
biphenylcarboxylic acids and esters, the compounds 1 and 3–6 reported in this study have
been subjected to a preliminary in vitro antimicrobial susceptibility test against two reference
strains of bacteria and one reference strain of yeast using the disk diffusion method.

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Unfortunately, none of the tested compounds showed any inhibition of microbial growth
against these three strains at concentrations up to 5 mg/mL. Although compounds 1 and 3–6
could yet exhibit weak antimicrobial activity at higher concentrations, this direction has not
been pursued any further.
4
. Conclusions
′-(2H-Tetrazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid, a valuable organic ligand for
4
the synthesis of metal-organic frameworks, has been obtained through two distinct synthetic
approaches. The first approach leads in five steps to the target compound in a very good yield
of 68%, whereas the second approach affords to the same compound in two steps in 62%
yield. Both approaches are amenable to scale-up, and can provide access to grams of the
target compounds in a single batch. The structures of the target compound and of all the
intermediates have been established using FT-IR and NMR spectroscopy. The solid state
structure of the target compound 1 and intermediates 4 and 5 have been determined by single
crystal X-ray diffraction method. The molecular associates 1·2DMF form one-dimensional
zig-zag supramolecular architectures by π–π stacking interactions between tetrazole and
biphenyl rings of adjacent entities. The main crystal structure motif of 4 can be characterized
as a three-dimensional supramolecular architecture. The crystal of 5 is formed by
supramolecular ribbons of parallel staked molecules. The evaluation of antibacterial activity
of the target compound 1 and of intermediates 3–6 against two bacterial strains and one fungal
strain has shown that these compounds are inactive at concentrations up to 5 mg/mL
Acknowledgment
The financial support of European Social Fund for Regional Development,
Competitiveness 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.
Supplementary material
Spectroscopic data related to this article, the view of the packing diagram in 5 along a
axis and information on the bond distances and angles in the crystals of compounds 1·2DMF,
4
and 5 can be found at http://xxxxxxxxxxx. Crystallography data for compounds 1·2DMF, 4
and 5 has been deposited with the Cambridge Crystallographic Centre. The data can be

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obtained free of charge from CDCC, 12 Union Road, Cambridge CB2 1EZ, UK, Fax (+44)
1
223-336-033, email: deposit@cdcc.cam.ac.uk or http://www.ccdc.cam.ac.uk/getstructures.
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Highlights
•
•
•
•
•
Synthesis of the title compound has been performed through two distinct approaches.
Structural characterization has been performed using IR and NMR spectroscopy.
Single crystal X-ray structures have been determined for two intermediates.
Single crystal X-ray structure has been established for the title compound.
Preliminary antimicrobial activity of the compounds has been evaluated.