ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 10, pp. 2177–2182.

© Pleiades Publishing, Ltd., 2018.

Synthesis, Characterization, and Phytotoxic

and Antifungal Activities of Biphenyl Derivatives1
Q. Alia, M. Irshada*, A. Asghara
a
Division of Science and Technology, University of Education, Township Campus, Lahore, Pakistan
*e-mail: misbah-irshad@ue.edu.pk; misbahchatha@hotmail.com

Received July 28, 2018

Abstract―Three series of biphenyl derivatives are synthesized, characterized and evaluated for Lemna minor
phytotoxicity and antifungal activity. The synthetic biphenyl analogues 2c and 6c demonstrate significant
activity, while compounds 4b and 6b demonstrate high activity. The compounds 2c and 6c can be considered
as biaryl-based potential phytotoxic agents. According to in vitro antifungal bioassay the compounds 2b, 2e,
and 6b demonstrate moderate activity.
Keywords: biphenyl derivatives, 1H NMR, Lemna minor phytotoxicity, antifungal activity
DOI: 10.1134/S1070363218100249

INTRODUCTION monitored by TLC. Most of the compounds were

Biphenyl containing compounds found applications
in various areas, including pesticides [1], chiral separa-
tion [2], catalysis in asymmetric synthesis [3], oxygen-
binding of molecules [4], and bleaching [5–7].
Biphenyl derivatives demonstrate a broad spectrum of
biological activities: antimicrobial [8, 9], anti-inflam-
matory [10], antihypertensive [11], antiviral [12],
anticancer [13], diuretic [14], and antidiabetic [15].
In the current study we targeted synthesis and phyto-
toxic screening of a variety of biphenyl derivatives
containing different moieties at the positions 2, 3 and 4.
RESULTS AND DISCUSSION
Three different approaches to the synthesis of
biphenyl analogues by nucleophilic substitution
reactions were used. According to the first method,
[1,1'-biphenyl]-2,2'-diol was treated with a variety of
bromo-substituted compounds (Scheme 1). According
to the second method four different products were
synthesized by treating [1,1'-biphenyl]-4,4'-diol with
4-nitrobromobenazldehyde followed by reduction of
the semi-product 4a to 4b. [1,1'-Biphenyl]-4,4'-diol
was also treated with 1,3-dibromopropane and
propargyl bromide (Scheme 2). In the third approach,
treatment of Fast Blue B salt by potassium iodide gave
three products (Scheme 3). The reactions were
1
The text was submitted by the authors in English.
obtained in crystalline form. The structures of biphenyl
analogues were characterized by 1H NMR and mass
spectrometry.
The tested phytotoxic effect of the synthesized
compounds was determined to be dose dependent (5,
50, and 500 μg/mL) towards Lemna fronds prolifera-
tion (Table 1).
Compounds 2c and 6c demonstrated significant
activity (≥70% inhibition) at all concentrations.
Compounds 4b and 6b showed good activity (60–
69%) at concentration 500 μg/mL. Compounds 2d, 4a,
6a demonstrated moderate activity (40–59%).
Compounds 1, 2a, 2b, 2e, 4c, and 4d exhibited low
activity (0–39%). The accumulated data indicated that
biphenyl derivatives containing ether substituents in
positions 2 and 3 demonstrated higher phytotoxic
effect than the other products.
In vitro antifungal tests of the synthesized biphenyl
derivatives demonstrated that the compounds 2b and
2e were moderate moderately active against some
fungal strains (Table 2).
EXPERIMENTAL
1
H NMR spectra were measured on an Avance
Bruker AM 300 MHz. Electron impact mass spectra
(EIMS) were measured on a Finnigan MAT-311A.
TLC was performed on pre-coated silica gel aluminum

2177
2178 ALI et al.

Scheme 1. Synthesis of [1, 1'-biphenyl] -2,2'-diol derivatives 2a–2e.

O OH
O O

O O

O
Br
O TFA
O O
Acetone, K2CO3
O O
O OH

2a 2b

13.4 mmol Br
O
HO O
Br
Br Br
Ethanol, K2CO3 2c
OH
O
1 5.37 mmol

2d

O O
O O
Br
O O O O
Acetone, K2CO3

2e

plates (Kieselgel 60, 254, E. Merck). Chromatograms
were visualized under UV light at 254 nm.
Synthesis of biphenyl derivatives of [1,1'-bi-
phenyl]-2,2'-diol (1). Compound 1 (250 mg, 1.34 mmol)
was dissolved in 15 mL of acetone followed by
addition of K2CO3 (1.5 g, 10.21 mmol) and tert-butyl
bromoacetate (2 mL, 13.4 mmol). The reaction mixture
was stirred at room temperature for 3 h. The product
2a was purified by column chromatography (hexane:
dichloromethane, 6 : 4), yield 84%. Stirring of com-
pound 2a (100 mg, 0.30 mmol) with TFA for 1 h,
followed by work up with hexane and toluene gave
product 2b (yield 90%). Compound 2c was syn-
thesized by refluxing the mixture of 1,3-dibromo-
propane (1.3 mL, 13.4 mmol) with compound 1
(500 mg, 2.68 mmol) and K2CO3 (1 g, 7.16 mmol) in
20 mL of ethanol (yield 50%). Compound 2d was

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 SYNTHESIS, CHARACTERIZATION, AND PHYTOTOXIC AND ANTIFUNGAL ACTIVITIES 2179

Scheme 2. Synthesis of [1,1'-biphenyl]- 4,4'-diol derivatives 4a–4d.

Br Br

Br O O Br
Ethanol, K2CO3

4c

O2N O O NO2

4a

HO OH + Br NO2 SnCl2, HCl

DMF K2CO3
3
H2N O O NH2

4b

Ethanol, K2CO3
O O

Br
4d

Scheme 3. Synthesis of Fast blue B salt derivatives 6a–6c.

I I

O
6a
O
O
+ KI I
+
Cl N2 N2 Cl− ZnCl2 H 2O
O
O 6b

Fast blue B salt O

O
6c

RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 10 2018

2180 ALI et al.

Table 1. Phytotoxic activity of biphenyl derivatives

Comp. no. Concentration, μg/mL Growth regulation, % Comp. no. Concentration, μg/mL Growth regulation, %
1 500 15 2a 500 20
50 10 50 15
5 05 5 10
2b 500 15 2c 500 80
50 10 50 75
5 5 5 70
2d 500 50 2e 500 35
50 35 50 30
5 35 5 15
4a 500 50 4b 500 60
50 30 50 50
5 15 5 25
4c 500 35 4d 500 23
50 30 50 17
5 15 5 0
6a 500 50 6b 500 60
50 25 50 45
5 15 5 35
6c 500 90
50 80
5 75

Table 2. In vitro antifungal bioassay of biphenyl derivatives (% inhibition)

Compound
Fungus
2a 2b 2c 2d 2e 4a 4b 4c 4d 6a 6b 6c Miconazole
Trichophyton – – – – 20 – – 10 – – – 20 –
longifusus
Candida albican – – – – – – – – – – – – 110.80
Aspergiluus flavis 30 30 05 – 30 20 20 – 10 20 10 40 20.20
Microsporum 10 10 40 30 – – 10 40 20 98.40
canis
Fusarium solani 10 50 20 20 30 10 20 10 20 40 30 10 73.25
Candida glabrata – – – – – – – – – – – – 110.80

obtained by refluxed overnight the mixture of biphenyl-
2,2'-diol (1 g, 5.37 mmol) dissolved in acetone
(20 mL) with K2CO3 (3 g, 21.48 mmol) and 1,3-
dibromopropane (0.5 mL, 5.37 mmol). Silica gel
column chromatography (hexane : CH2Cl2, 1 : 1) gave
the pure product 2d, yield 65%. Compound 2e was
obtained by stirring the reaction mixture consisting of
2,2'-dihydroxy biphenyl (1 g, 5.37 mmol) dissolved in
150 mL of acetone (3 g, 21.48 mmol) of K2CO3, and
0.56 mL (5.37 mmol) of ethylbromoacetate at 55°C for
8 h (yield 60%).
Di-tert-butyl-2,2'-(biphenyl-2,2'-diyldioxy)di-
acetate (2a). Colorless crystals, yield 84%. 1H NMR
spectrum, δ, ppm: 1.42 s [18H, C(CH3)3], 4.45 s (4H,
PhOCH2), 6.82 d (2H, J = 8.1 Hz, Ph-H), 7.02 t (2H,
J = 7.2 Hz, Ph-H), 7.25 m (2H, J = 1.5 Hz, Ph-H), 7.36
d (2H, J = 1.4 Hz, Ph-H). EIMS: m/z: 414 [M]+.

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 SYNTHESIS, CHARACTERIZATION, AND PHYTOTOXIC AND ANTIFUNGAL ACTIVITIES
2,2'-[Biphenyl-2,2'-diylbis(oxy)]diacetic acid (2b).
Colorless crystals, yield 90%. 1H NMR spectrum, δ,
ppm: 4.56 s (4H, PhOCH2), 6.94 d (2H, J = 8.1 Hz,
Ph-H), 7.01 t (2H, J = 7.2 Hz, Ph-H), 7.26 d (4H, J =
7.8 Hz, Ph-H). EIMS: m/z: 302 [M]+.
2,2'-Bis(3-bromopropoxy)biphenyl (2c). Colorless
powder, yield 50%. 1H NMR spectrum, δ, ppm: 2.12 m
(4H, PhOCH2CH2CH2Br), 3.32 t (4H, J = 6.3 Hz,
PhOCH2CH2CH2Br), 4.03 t (4H, J = 5.7 Hz,
PhOCH2CH2CH2Br), 7.05 d.d (4H, J = 15.6, 7.5 Hz,
Ph-H),7.29 d.d (4H, J = 15.6, 7.8 Hz, Ph-H). EIMS:
m/z: 426 [M]+.
7,8-Dihydro-6H-dibenzo(f,h)-1,5-dioxonine (2d).
Colorless powder, yield 60%. 1H NMR spectrum, δ,
ppm: 1.98 m (2H, PhOCH2CH2CH2OPh), 4.35 t (4H,
J = 5.1 Hz, PhOCH2CH2CH2OPh), 7.11 t (4H, J =
6.6 Hz, Ph-H), 7.32 m (4H, Ph-H). EIMS: m/z: 226 [M]+.
Diethyl-2,2'-(biphenyl-2,2'-diylbis(oxy))diacetate
(2e). Colorless crystals, yield 65%. 1H NMR spectrum,
δ, ppm: 1.22 t (6H, J = 7.2 Hz, COOCH2CH3 ), 4.22 q
(4H, COOCH2CH3), 4.55 s (4H, PhOCH2), 6.85 d (2H,
J = 8.4 Hz, Ph-H), 7.04 t (2H, J = 7.5 Hz, Ph-H), 7.29
ddd (2H, J = 7.5, 7.5, 5.1 Hz, Ph-H). EIMS: m/z: 358
[M]+.
Synthesis of biphenyl analogues based on [1,1'-
biphenyl]-4,4'-diol (3). Compound 3 (250 mg,
1.25 mmol) was dissolved in 20 mL of DMF and
mixed with 1.5 g (10.21 mmol) of K2CO3 and 1.40 g
(7.0 mmol) of 4-nitrobromobenzene. The reaction
mixture was stirred at 120°C for 12 h; H2O (50 mL)
was added to quench the reaction. The separated crude
product was purified by column chromatography
(hexane : ethyl acetate, 6 : 4) affording 4a. The
compound 4a (100 mg, 0.233 mmol) was reduced by
stirring in a mixture with 15 mL of HCl and 315 mg
(1.398 mmol) of SnCl2 at 60°C for 3 h. Potassium
carbonate (10 mL, 2 M) was added to quench the
reaction. The isolated compound 4b was purified by
column chromatography (CH2Cl2 : hexane, 3 : 7).
Refluxing of compound 3 (50 mg, 0.25 mmol) with
345 mg (2.5 mmol) of K2CO3 and 0.21 mL (2 mmol) of
dibromopropane in 15 mL of ethanol for 6 h gave the
product 4c. The product was extracted by CH2Cl2
(50 mL) and purified by column chromatography
(CH2Cl2 : hexane, 4 : 6). Compound 4d was obtained
by refluxing a mixture of 100 mg (0.50 mmol) of
compound 3 with K2CO3 (345 mg, 2.5 mmol) and
propargyl bromide (0.2 mL, 2 mmol) in 20 mL of
ethanol for 2 h.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 10 2018
2181
4,4'-Bis(4-nitrophenoxy)biphenyl (4a). Light yellow
crystals, yield 70%. 1H NMR spectrum, δ, ppm: 7.06 d
(4H, J = 9.3 Hz, Ph-H), 7.16 dt (4H, J = 8.6 Hz, Ph-H),
7.62 d (4H, J = 8.7 Hz, Ph-H), 8.21 d (4H, J = 9 Hz,
Ph-H). EIMS: m/z: 428 [M]+.
4,4'-(Biphenyl-4,4'-diylbisoxy)dianiline (4b). Colorless
powder, yield 63%. 1H NMR spectrum, δ, ppm: 3.56 s
(4H, NHarom), 6.66 d (4H, J = 8.6 Hz, Ph-H), 6.88 d
(4H, J = 8.0 Hz, Harom), 6.95 d (4H, J = 8.6 Hz, Ph-H),
7.43 d (4H, J = 8.7 Hz, Ph-H). EIMS: m/z: 368 [M]+.
4,4'-Bis(3-bromopropoxy)biphenyl (4c). Colorless
solid, yield 70%. 1H NMR spectrum, δ, ppm: 2.32 m
(4H, PhOCH2CH2CH2Br), 3.60 t (4H, PhOCH2CH2·
CH2Br), 4.12 t (4H, -PhOCH2CH2CH2Br), 6.94 d (4H,
J = 6.6 Hz, Ph-H), 7.45 d (4H, J = 6.3 Hz, Ph-H).
EIMS: m/z: 428 [M]+.
4,4'-Bis(prop-2-ynyloxy)biphenyl (4d). Colorless
solid, yield 84%. 1H NMR spectrum, δ, ppm: 2.51 t
(2H, PhOCH2C≡CH). 4.70 d (4H, J = 2.4 Hz,
PhOCH2C≡CH), 7.01 d (4H, J = 8.8 Hz, Ph-H), 7.46 d
(4H, J = 6.6 Hz, Ph-H). EIMS: m/z: 262 [M]+.
Synthesis of biphenyl derivatives based on Fast
Blue B salt. KI mixture (28 g, 0.17 mmol) in 200 mL
of water with Fast Blue B salt (10.00 g, 21.0 mmol)
was stirred at room temperature for 12 h. The
separated crude product was purified by column
chromatography (CH2Cl2 : hexane, 1 : 4) affording
compound 6a. Additionally, fine crystals of 6b and 6c
were also obtained by column chromatography.
4,4'-Diiodo-3,3'-dimethoxybiphenyl (6a). Yellow
crystals, yield 70%. 1H NMR spectrum, δ, ppm: 3.92 s
(6H, PhOCH3), 6.88 d.d (2H, J = 6, 1.5 Hz, Ph-H),
6.94 d (2H, J = 1.5 Hz, Ph-H), 7.79 d (2H, J = 6 Hz,
Ph-H). EIMS: m/z: 465.6 [M]+.
4-Iodo-3,3'-dimethoxybiphenyl (6b). Colorless
crystals, yield 25%. 1H NMR spectrum, δ, ppm: 3.85 s
(3H, PhOCH3), 3.92 s (3H, PhOCH3), 6.90 m (1H,
Ph-H), 6.92 d.d (1H, J = 3.3, 7.9, Ph-H), 7.00 d (1H,
J = 1.8 Hz, Ph-H), 7.07 t (1H, J = 2.1 Hz, Ph-H), 7.13
d.d (1H, J = 6.6, 1.2 Hz, Ph-H), 7.36 t (1H, J = 8.1 Hz,
Ph-H), 7.8 d (1H, J = 7.9 Hz, Ph-H). EIMS: m/z: 340
[M]+.
3,3'-Dimethoxybiphenyl (6c). Colorless fine crystals,
yield 20%, 1H NMR spectrum, δ, ppm: 3.84 s (6H,
PhOCH3), 6.87 d.d (2H, J = 7.8,1.8 Hz, Ph-H), 7.14 m
(4H, Ph-H), 7.34 t (2H, J = 7.8 Hz, Ph-H). EI-MS:
m/z: 214.
2182
Lemna minor assay. Lemna minor (20 L) in each
flask, 20 mL of E-medium and the reference drug were
mixed together. After 7 days of storage in a growth
cabinet, counting of number of fronds per flask was
carried out. The results obtained were analyzed as
growth regulation (%) or mortality (%) with reference
to the negative control [16].
Antifungal bioassay of synthesized biphenyl
derivatives. Biphenyl derivatives were evaluated for
antifungal activity by using the agar tube dilution
method [17]. Candida albican (ATCC 2091),
Aspergiluus flavis (ATCC 32611), Microsporum canis
(ATCC 11622), Fusarium solani (ATCC 11712), and
Candida glabrata (ATCC 90030) were employed for
antifungal screening of the synthesized compounds.
The samples to be screened for antifungal bioassay
were incubated at 27–29°C for 7–10 days. The media
supplemented with DMSO and a reference drug was
used as negative and positive controls, respectively.
Growth in the media was determined by measuring
linear growth (mm) and percent of inhibition was
calculated with reference to the negative control.
CONCLUSIONS
Synthesis of three series of biphenyl derivatives
was carried out by using general synthetic routes
involving nucleophilic substitution reactions.
Compounds 2c and 6c demonstrated significant
phytotoxic activity (≥70% inhibition) at all
concentrations. The other products demonstrated good
to moderate activity. The synthesized biphenyl
derivative 2b demonstrated moderate antifungal
activity against F. solani.
CONFLICT OF INTERESTS
No conflict of interests was declared by the authors.
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