Synthesis, characterization, antibacterial activity and molecular docking studies on triazolophanes with benzophenone and S(-)-BINOL functionalization at the intra annular position

Article abstract of DOI:10.1080/00397911.2020.1781182

Triazolophanes with benzophenone and S(-)-BINOL functionalization at the intra annular position have been synthesized by the click reaction of 4,4′-bis(azidomethyl) benzophenone with the corresponding bispropargyloxy compounds. The newly synthesized triazolophanes were characterized by spectral and analytical methods. Triazolophane with S(-)-BINOL and benzophenone functionality at the intra annular position shows good target binding ability in molecular docking studies and also better antibacterial activity against all the four tested pathogens viz. Staphylococcus aureus, Bacillus subtilis, Salmonella typhimurium, and Escherichia coli bacteria.

Full text of DOI:10.1080/00397911.2020.1781182

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis, characterization, antibacterial
activity and molecular docking studies on
triazolophanes with benzophenone and S(-)-BINOL
functionalization at the intra annular position
Velautham Saravanan & Perumal Rajakumar
To cite this article: Velautham Saravanan & Perumal Rajakumar (2020): Synthesis,
characterization, antibacterial activity and molecular docking studies on triazolophanes with
benzophenone and S(-)-BINOL functionalization at the intra annular position, Synthetic
Communications
To link to this article: https://doi.org/10.1080/00397911.2020.1781182
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https://doi.org/10.1080/00397911.2020.1781182
Synthesis, characterization, antibacterial activity and
molecular docking studies on triazolophanes with
benzophenone and S(-)-BINOL functionalization at the intra
annular position
Velautham Saravanan and Perumal Rajakumar
Department of Organic Chemistry, University of Madras, Chennai, India
ABSTRACT
ARTICLE HISTORY
Received 7 March 2020
Triazolophanes with benzophenone and S(-)-BINOL functionalization
at the intra annular position have been synthesized by the click reac-
tion of 4,40-bis(azidomethyl) benzophenone with the corresponding
bispropargyloxy compounds. The newly synthesized triazolophanes
were characterized by spectral and analytical methods.
Triazolophane with S(-)-BINOL and benzophenone functionality at
the intra annular position shows good target binding ability in
molecular docking studies and also better antibacterial activity
against all the four tested pathogens viz. Staphylococcus aureus,
Bacillus subtilis, Salmonella typhimurium, and Escherichia coli bacteria.
KEYWORDS
Antibacterial; click
chemistry; molecular
docking; triazolophane
GRAPHICAL ABSTRACT
Synthesis and antibacterial activity of triazolophanes against S.
aureus, B. subtilis S. typhimurium, and E. coli bacteria.
Introduction
Cyclophanes with heterocyclic ring systems possess a binding site for metal ions[1] and
propitiate the properties as molecular hosts. Molecular recognition in supramolecular
chemistry,[2] play a vital role in a biological system involving host–guest interactions.
CONTACT Perumal Rajakumar
perumalrajakumar@gmail.com
Department of Organic Chemistry, University of
Madras, Maraimalai (Guindy) Campus, Chennai 600025, India.
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

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V. SARAVANAN AND P. RAJAKUMAR
Molecular recognition in supramolecular chemistry is regulated by non-covalent inter-
molecular interactions such as hydrogen bonding, metal coordination, hydrophobic p–p
stacking, van der Waals’ and electrostatic interactions. Cyclophanes with a preorganized
cavity can interact through hydrogen bonding with various guest molecules[3]
Cyclophanes can function as selective probes for various guest molecules through non-
covalent interactions as well as by forming inclusion complexes. Cyclophanes with bind-
ing sites for metal ions can function as a molecular host.[4]
Macrocyclic systems with triazole unit have attracted the synthetic chemists because
of their various applications in supramolecular chemistry. Triazolophanes[5] are the new
class of cyclophanes containing 1,2,3-triazole motif, which can exhibit strong interac-
tions with halides, transition metal ions, and neutral molecules,[6] and are also of bio-
logical importance.[7] Triazolophanes are a new motif that can participate in multiple
non-covalent interactions such as metal coordination,[8] anion recognition,[9] self-assem-
bly,[10] and also can exhibit wide applications in biology if used in the synthesis of rigid
cavity cyclophanes and hence can have the ability to form complexes with a selectivity
that can sharply change the spectral properties. Triazolophane moiety functions as mul-
tiple targets due to their auspicious properties such as solubility, bioavailability, hydro-
philic and pharmacophoric nature. Further, triazole moiety can enhance the
hydrophilicity and binding with macromolecules as seen in drug molecules such as sil-
denafil, imatinib.[11,12]
Cu(I)-catalyzed azide-alkyne (CuAAC)[13] click chemistry is used for the synthesis of
1,2,3-triazoles regioselectively, which could be a very interesting and promising method.
1,2,3-triazole unit finds their due to the many applications in biology as well as in
material science[14] S(-)-BINOL and benzophenone are used in electron transfer and
electron exchange devices and also have been widely used in various fields such as tex-
tile, drug synthesis,[3] lubricant additives,[12] flavoring agents,[15] personal care,[16] plas-
tics,[14] pharmaceuticals,[17] household products and for the synthesis of antibacterial
agent,[18] and so on. However, the biological activity of the triazolophanes is rarely
reported.[19] Triazolophanes with BINOL and benzophenone could furnish supra-
molecular sensing, recognition, and self-assembling properties. We wish to report herein
the synthesis, characterization, and antibacterial activity of the new class of triazolo-
phanes 1–6 obtained from the suitable azide and terminal alkyne by click reaction
(Fig. 1).
Results and discussion
Triazolophanes 1–6 can be synthesized by the reaction of the corresponding bispropar-
gyloxy precyclophane with various bisazides. The corresponding bispropargyloxy precy-
clophane can be obtained by the reaction of bis(4-(bromomethyl)phenyl) methanone
with propargyl alcohol. In order to synthesis the triazolophanes 1–6 using click chemis-
try, synthesis of the azides 9, 11, and the alkynes 10, 12, 14. is focused. Synthesis of the
precyclophanes 9, 10, 11, 12, and 14 is shown in Scheme 1. Reaction of 4-methyl
benzoyl chloride with toluene in the presence of anhydrous AlCl3 at 0 ꢀC to room tem-
perature (rt) afforded 4, 40-dimethylbenzophenone 7 in 85% yield. Reaction of 4,40-
dimethylbenzophenone 7 with 2.1 equiv. of NBS in the presence of benzyl peroxide in

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Figure 1. Molecular structure of triazolophanes 1–6 with S(-)-BINOL and benzophenone functionaliza-
tion at the intra annular position.
CCl4 gave bis(40-(bromomethyl)phenyl) methanone 8 in an 85% yield. Further, azida-
tion of 8 with 2.1 equiv. of NaN3 in a mixture of acetone water (4:1) at 60 ꢀC gave
bis(40-(azidomethyl)phenyl) methanone 9 in 72% yield. Propargylation of bromomethyl
compound 8 with 2.1 equiv. of propargyl bromide in the presence of K2CO3 in dry
DMF gave bis(40-(propargylmethyl)phenyl methanone 10 in 72% yield.
The reaction of 1.0 equiv. of the bisazide 9 and the bispropargyloxy compound 10 with
1.0 equiv. of p-Tolylsulphonyl hydrazide in a mixture of toluene-ethanol (2:3) gave the pre-
cyclophanes 11 and 12 in 60 and 62% yields, respectively. (Scheme 1). Having successfully
synthesized the precyclophanes 11 and 12, synthesis of bispropargyloxy S (-) BINOL 14 was
then focused on. The reaction of 1.0 equiv. of S (-)BINOL with 2.1 equiv. of propargyl brom-
ide in the presence of K2CO3 in dry DMF gave the bispropargyloxy BINOL 14 in 75% yield.

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V. SARAVANAN AND P. RAJAKUMAR
Scheme 1. Reagents and conditions: (i) Toluene, Anhydrous AlCl3, DCM, 0 ꢀC to rt, 3 h, 7 (85%), (ii)
2.1 equiv. of NBS, dry CCl4, BPO, reflux, 12 h, 8 (85%). (iii) 2.5 equiv. of NaN3, acetone/H2O, (4:1)
60 ꢀC, 3 h, 9 (72%). (iv) 2.1 equiv. of propargyl bromide, dry DMF, rt, 24 h 10 (72%). (v) P-
Tosylhydrazide, (1.0 equiv.), Toluene/ethanol (2:3), rt, N2, 24 h, 11 (60%),12 (62%). (vi) 2.1 equiv. of
propargyl bromide, dry DMF, rt, 24 h, 14 (75%).
Synthesis of the triazolophanes 1, 2, 3, 4, 5, and 6 is shown in Scheme 2. The reac-
tion of 1.0 equiv. of the bisazide 9 with 1.0 equiv. of each of the bispropargyloxy deriva-
tives 10, 12, and 14 in the presence of CuSO4ꢁ5H2O (5 mol%) and NaAsc (10 mol%) in
a mixture of THF-H2O (3:1) at rt under click reaction conditions gave the triazolo-
phanes 1, 3 and 5 in 35, 25, and 62% yields, respectively. Similarly, the reaction of 1.0
equiv. of the hydrazide 11 with 1.0 equiv. of each of the propargyloxy derivative 12 and
14 gave the triazolophanes 4 and 6 in 65%, and 30% yields, respectively (Scheme 2).
However in the case of the coupling between the azide 9 and the bispropargyloxy
ketone 10, 2:2 oligomer 2 was also obtained in 41% yield. But the formation of such
oligomers is not observed in the other coupling reactions.
1
The H NMR spectrum of the triazolophane 1 displayed three singlets at d 4.70, 4.74,
and 5.63 for the O-CH2, N-CH2, and benzylic protons, respectively, in addition to the
signals for the aromatic protons in the region at d 7.29–7.81. The 13C NMR spectrum
of the triazolophane 1 showed signals at d 53.6, 63.9, and 71.9 for the O-CH2, N-CH2,
and benzylic carbon and the aromatic carbons appeared in the region at d 122.7–145.6
and the ester carbonyl carbon appeared at d 196.1.

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Scheme 2. Reagents and conditions: (i) CuSO4.5H2O (5 mol%), sodium ascorbate (10mol%), H2O/THF
(1:1), rt, 10 h. 1 (35%), 2 (41%), 3 (25%), 4 (65%). 5 (62%), 6 (30%).
The mass spectrum of the triazolophane 1 showed the molecular ion peak at m/z 610
[Mþ]. Further, the structure of the triazolophane 1 was also confirmed from the analyt-
ical data. Similarly, the structure of the triazolophanes 2, 3, 4, 5, and 6 were character-
ized by spectral and analytical data. (Supplementary Information)
Antibacterial activity of the triazolophanes 1–6
The emergence of drug resistance in bacteria makes it difficult to control both commu-
nity and hospital-acquired infections. Hence, there is a need to develop new antibacter-
ial drugs. As a result of the drug resistance, there is a major threat to global health and
the available drugs will no longer be effective in treating infections due to increasing
drug resistance against bacteria. As one of the approaches to screen for the new antibac-
terial agents that may inhibit and also act as drug targets through a unique binding, we
studied the antibacterial activity of the newly synthesized triazolophanes, which is also
supported by docking studies.
The antibacterial activity of the newly synthesized cyclophanes was investigated by
the Agar well diffusion method against Gram-positive bacteria (aureus and subtilis) and
Gram-negative bacteria (typhi and coli) strains. All the cyclophanes at various concen-
trations viz. 50, 100, and 150 mg/mL were dissolved in DMSO. In brief, the incubated
bacterial cultures were swabbed on MHA plates and different concentrations of samples
were loaded into the well. Streptomycin 25 mg/mL was used as the stranded control and
the plates were maintained overnight at 37 ꢀC. After the incubation, a clear zone
appeared around the well and was measured as a zone of inhibition against bacteria.
Figure 2 shows the zone of inhibition when the triazolophanes are tested by Agar
well diffusion method against both Gram-positive and Gram-negative bacteria. 10%
DMSO in water is used as the control which did not show inhibition against all the
tested bacteria. At higher concentrations, all the triazolophanes significantly inhibited

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V. SARAVANAN AND P. RAJAKUMAR
Figure 2. Antibacterial activity of triazolophanes 1, 2, 3, 4, 5, and 6 against both Gram positive (S.
aureus) and Gram negative (S. typhimurium and E. coli) bacteria strains. Zone of inhibition in mm
diameter (a) 50 mg, (b) 100 mg, (c) 150 mg, (d) 25 mg standard (Streptomycin) and (e) 10%
DMSO (control).

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Table 1. Antibacterial activity of Triazolophanes 1–6.
Zone of inhibition in mm
Gram Positive bacteria
Staphylococcus aureus Bacillus subtilis
Gram Negative bacteria
Salmonella typhi
Escherichia coli
Triazolophane
a
b
c
d
e
a
b
c
d
e
a
b
c
d
e
a
b
c
d
e
1
2
3
4
5
6
NA 7.5
4.5
NA 1.5
9
8
2
13 NA 10 11 12 13 NA 1.5
10 NA 10 12 13 14 NA 3.5 4.5
3
5.5
7
8
8
9
NA 10 12 13 14 NA
NA 10 11 12 13 NA
NA 10 11 12 13 NA
2
9
7
9
8
NA 11 13 14 15 NA NA NA 1.5
NA 4.5 5.5
NA 11 12 13 15 NA NA
NA 11 12 14 15.5 NA 2.5 4.5
NA 10 11.5 13 14 NA NA
6
8
7
10 NA 10 11 12 12.5 NA
NA 11 12 13 14.5 NA
5.0
7
8
6
8
2.0 4.5
9
11 13 NA 11 12 12 14 NA
(a) 50 mg, (b) 100 mg, (c) 150 mg, (d) 25 mg of the standard drug (streptomycin) and (e) 10% DMSO (negative control).
NA: nil activity.
the growth of both Gram-positive and Gram-negative bacteria. The inhibition of the
bacterial growth was directly proportional to the concentration of the triazolophanes.
All the tested cyclophanes inhibit the growth of bacteria subtilis and coli effectively.
The average diameter of the inhibition zones of the triazolophanes is determined and
listed in Table 1. These values indicate that the inhibition zone increases with an
increase in the concentration of the triazolophanes from 50–150lg/mL in 10% DMSO
water medium. The present study clearly shows that the triazolophanes are solely
responsible for the antibacterial activity against both Gram-positive (Staphylococcus aur-
eus) and Gram-negative (Salmonella typhimurium) bacteria.[20]
The antibacterial mechanism of samples can be attributed due to the formation of
reactive oxygen species (ROS), which results in cell death. It has been reported[21] that
the rupture of the bacterial outer membrane can weaken the cells, which is caused by
the interaction of the sample surface with bacterial membrane.
Triazolophane 5 shows better antibacterial activity against aureus at all tested con-
centration and all the synthesized triazolophanes show good antibacterial activity at
the concentration of 100 lg/mL and the zone of inhibition is almost equal to that of
the standard drug viz. Streptomycin. All the triazolophanes 1–6 exhibit almost equal
antibacterial effect to that of the standard viz. streptomycin at a concentration
100 lg/mL. However, most of the triazolophanes show poor antibacterial activity or
nil activity at the lower concentration of 50 lg/mL with respect to the microorganism
Salmonella typhi and at higher concentration of the 100 lg/mL Triazolophanes 2, 5
and 6 at concentration of 150 lg/mL show almost equal activity to that of the stand-
ard viz., streptomycin. The antibacterial activity of all triazolophanes 1–6 is compar-
able to that of the standard even at a lower concentration of 50 lg/mL with respect
to bacterial Escherichia coli. The antibacterial activity against the bacteria E. coli at
higher concentration viz. 100 lg/mL is almost the same as that of a lower concentra-
tion viz. 50 lg/mL. Hence, with respect to E. coli bacteria, the antibacterial activity is
dose-independent. From the above observation, triazolophanes 5 and 6 show better
antibacterial activity against all the four tested pathogens than that of the triazolo-
phanes 1, 2, 3, and 4. Triazolophanes 1, 2, 4, 5, and 6 show antibacterial activity
against S. aureus at a higher concentration of 150 mg comparable to that of the

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V. SARAVANAN AND P. RAJAKUMAR
Table 2. Molecular docking of triazolophanes 1, 3, 4, 5, and 6 with target proteins (PDB-3U2D).
Cyclophanes
1
Glide score
Glide energy (kcal/mol)
Hydrogen bond interactions D–H … A
Distance (Å)
ꢂ4.164
ꢂ60.007
(SER-129) O–H … N
(THR-173) O–H … O
(ASN-54) N–H … O
C–H … O (TYR-63)
(ARG-84) N–H … N
(THR-173) O … O
2.7
3.0
3.0
2.9
3.2
2.7
3
ꢂ8.410
ꢂ74.450
4
5
6
ꢂ4.232
ꢂ7.556
ꢂ4.274
ꢂ67.671
ꢂ68.065
ꢂ51.921
standard drug viz., streptomycin. All the synthesized triazolophanes 1–6 show concen-
tration-independent antibacterial activity toward Bacillus subtilis and comparable to
that of the standard. Triazolophanes 2, 4, 5, and 6 show antibacterial activity agent
Salmonella typhi comparable to that of the standard only at a higher concentration of
150 mg. The antibacterial activity of the triazolophanes 1–6 is concentration-
dependent with respect to E. coli and comparable to that of the standard
Molecular docking study on triazolophanes 1, 3, 4, 5, and 6
The molecular docking study helps us to find the interactions between ligand/com-
pound with a protein of interest (target).[22] The binding of any ligand in the active
pocket of the protein inhibits the catalytic functions. Further, molecular docking could
explain the mode of action of the ligands that bind to the target proteins. Hence, the
synthesized triazolophane derivatives 1, 3, 4, 5, and 6 have been subjected to molecular
docking studies with the target protein of S. aureus GyrB. A molecular docking study
was carried out using the Schrodinger suite. DNA gyrase is an essential enzyme in bac-
teria.[23] The inhibition of DNA gyrase results in disruption of DNA synthesis and sub-
sequently cell death. DNA gyrase consisting of the subunits GyrA and GyrB and is one
of the members of the type II family of topoisomerases that control the topological state
of DNA in cells.[24] This enzyme plays a vital role in the replication of DNA by cou-
pling with the ATP, which helps the supercoiling of the DNA. It has been known as a
fascinating target for antibacterial drugs.[25] The 3D structure of S. aureus GyrB was
taken from the protein data bank (PDB ID: 3U2D), in which the crystal structure was
solved at 1.85 Å resolution. Staphylococcus aureus GyrB protein was prepared and
refined by protein preparation module and their energy minimized using default con-
€
straint of 0.3 Å RMSD and OPLS 2005 force field. (Schrodinger suite). ASP-81, ARG-84,
ARG-144, and THR-173 are the active site residues of the protein. The synthesized tria-
zolophanes derivative structures were built using Maestro v9.1 and geometrically mini-
€
mized using OPLS_2005 force field by LigPrep module of Maestro 9.1 (Schrodinger
suite). LigPrep produces a minimized low-energy 3D conformation of each input struc-
ture with various ring conformations, ionization states, and tautomer using various cri-
teria including molecular weight and types of functional groups present.
The triazolophanes 1, 3, 4, 5, and 6 show excellent binding with the amino acids
in the active pocket of the protein with good binding energy and docking score, and

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Figure 3. Pymol view of the interaction between triazolophane 3 and S. aureus GryB.
the results are tabulated in Table 2. However, the docking study could not be car-
ried out with the triazolophane 2 due to its larger size and higher molecular mass.
Among the five derivatives, the triazolophane 5 closely binds with the active site of
the target protein. The sulphonyl group on the right side of the triazolophane 3 forms
hydrogen bonding interaction with the side chain of the hydroxyl group of THR-173
(2.7 Å). An additional nitrogen atom of triazolophane 3 has a hydrogen bond inter-
action with the nitro group of ARG-84 (3.2 Å) as shown in Figure 3. Triazolophane 3
has the highest glide score of ꢂ8.410 and glide energy of ꢂ74.450 with the target pro-
tein of S. aureus GryB as shown in Table 2. The carboxyl group of the triazolo-
phane 1 shows hydrogen bond interaction with the side chain of the hydroxyl group
of THR-173 (3.0 Å). However, the triazolophanes 4 and 6 do not bind with the
active site of the target protein S. aureus GryB. Pymol view of the interaction
between the triazolophanes 3, 1, 4, 5, and 6 and S. aureus GryB is shown in
Figures 3–7, respectively.
Experimental
General information
All the reagents and solvents were commercially available in the best grade and used
without further purification. The melting points were determined using a Toshiwal
1
melting point apparatus by open capillary tube method and are uncorrected. The H
and 13C NMR spectra were recorded on a Bruker 300 MHz NMR spectrometer. The

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V. SARAVANAN AND P. RAJAKUMAR
Figure 4. Pymol view of the interaction between triazolophane 1 and S. aureus GryB.
Figure 5. Pymol view of the interaction between triazolophane 4 and S. aureus GryB.

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Figure 6. Pymol view of the interaction between triazolophane 5 and S. aureus GryB.
Figure 7. Pymol view of the interaction between triazolophane 6 and S. aureus GryB.
chemical shifts are reported in ppm (d) with TMS as an internal standard and the cou-
pling constants (J) are expressed in Hz. Elemental analyses were performed on a
Perkin-Elmer 240B elemental analyzer. Electrospray ionization mass spectra (ESI-MS)
were recorded with an LCQ AD mass spectrometer.

12
V. SARAVANAN AND P. RAJAKUMAR
General procedure for the Cu (I) catalyzed click reaction (procedure A)
A mixture of acetylenic derivative (1.0 mmol, 1 equiv.) and azido derivative (1.1 mmol,
1.1 equiv.) was dissolved in THF/H2O (1:1; 8 mL) and added sodium ascorbate
(0.4 mmol, 0.4 equiv.) followed by CuSO4.5H2O (0.2 mmol, 0.2 equiv.). The reaction
mixture was stirred overnight at rt. The solvent was evaporated and the crude product
was dissolved with EtOAc (2 ꢃ 100 mL), washed with NH4Cl solution (50 mL) and brine
solution (50 mL), dried over Na2SO4 and concentrated to give a residue, which was
purified by column chromatography (SiO2), using the eluent as mentioned under
each compound.
General procedure for the synthesis of bispropargyloxy compound by O-
alkylation (procedure B)
A mixture of 1.0 equiv. of the dihydroxyl compound and 2.2 equiv. of propargyl brom-
ide with potassium carbonate (3.0 equiv.) in anhydrous DMF (5 mL) was stirred at
60 ꢀC for 48 h under nitrogen. The reaction mixture was allowed to cool to rt and
poured into ice water (500 mL) and extracted with CHCl3 (2 ꢃ 100 mL) and the com-
bined organic layer was washed with water (2 ꢃ 50 mL) brine (50 mL) and dried over
anhydrous Na2SO4 The crude product obtained after the removal of the solvent, was
subjected to column chromatography over SiO2 using hexane:CHCl3 (1:2) as the eluent
to give the corresponding bispropargyloxy compound.
General procedure for the conversion of dendritic chloride to azide (procedure C)
Dendritic chloride (1.0 mmol, 1.0 equiv.) was dissolved in a mixture of acetone:water
(4:1; 8 mL) and added NaN3 (1.5 mmol, 1.5 equiv.), and the mixture was heated to
60 ꢀC for 3 h. The reaction mixture was cooled to rt, acetone was evaporated, diluted
with water (100 mL), and extracted with EtOAc (2 ꢃ 100 mL). The organic layer was
washed with saturated NaCl (100 mL), dried over Na2SO4 and evaporated to give the
corresponding azido compounds.
Bis(4-(bromomethyl)phenyl) methanone (8)
Bis(4-(bromomethyl)phenyl) methanone (8) was obtained by the radical bromination of
di-p-tolylmethanone (2.6 g, 15.3 mmol) using NBS (1.6 g, 30.6 mmole) in CCl4(100 mL)
in the presence of pinch of benzyl peroxide as per the reported procedure. Yield: 85%.
Bis(4-(azidomethyl)phenyl) methanone (9)
Following the general procedure C, bis(4-(azidomethyl)phenyl) methanone (9) was
obtained as white solid by the reaction of bis(4-(bromomethyl)phenyl) methanone
(5.6 g, 15.3 mmol) with sodium azide (3.0 g, 45.9 mmol) in acetone at 60 ꢀC for 8 hr.
1
Yield: 3.2 g, 72%, mp: 120 ꢀC. H NMR: (300 MHz, CDCl3): dH 4.46 (s, 4H); 7.45 (d,
4H, J ¼ 8.1 Hz); 7.82 (d, 4H, J ¼ 8.1 Hz); 13C NMR: (75 MHz, CDCl3) dc 54.3, 126.5,

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127.9, 130.6, 137.3, 140.1, 195.6. MS (ESI): m/z ¼ 293 [M þ 1]. Anal. Calcd. For
C15H12N6 O: C, 61.64; H, 4.14; N, 28.75. Found: C, 61.52; H, 4.28; N, 28.68.
Bis(40-(propargylmethyl)phenyl methanone (10)
A mixture of bis (4-(bromomethyl) phenyl) methanone (1.5 g, 0.004 mmol, 1.0 equiv.),
propargyl alcohol (0.91 g, 0.016 mmol, 2.1 equiv.) and K2CO3 (3.0 equiv.) in DMF
(10 mL) was stirred at rt for 24 h. After completion of the reaction, the reaction mixture
was poured into water and the residue was extracted with CH2Cl2 (3 ꢃ 100 mL). The
combined organic layers were washed with brine (2 ꢃ 100 mL), dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The residue obtained was purified by col-
umn chromatography with silica gel using CHCl3:Hexane (4:1) as the eluent to give the
1
diyne 10 as white solid, Yield: 3.2 g, 72%, mp: 120 ꢀC. H NMR: (300 MHz, CDCl3): dH
2.51 (t, 2H, J ¼ 2.4 Hz); 4.24 (d, 4H, J ¼ 2.1 Hz); 4.69 (s, 4H); 7.48 (d, 4H, J ¼ 7.8 Hz);
7.79 (d, 4H, J ¼ 7.8 Hz); 13C NMR: (75 MHz, CDCl3): dC 57.6, 70.9, 75.0, 79.3, 127.5,
130.3, 137.1, 142.1, 196.0. ESI-MS: m/z ¼ 318 [Mþ]. Elemental Anal. Calcd for
C21H18O3: C, 79.22; H, 5.70%. Found: C, 79.19; H, 5.69%.
N’-(bis(4-(azidomethyl)phenyl)methylene)-4-methylbenzenesulfonohydrazide (11)
Following the general procedure C, N0-(Bis(4-(azidomethyl)phenyl)methylene)-4-methyl-
benzenesulfonohydrazide 11 was obtained as white solid by the reaction of bis(4-(azido-
methyl)phenyl) methanone 9 (2.5 g, 15.3 mmol) with p - tosylhydrazide (3.0 g,
45.9 mmol) in toluene, ethanol at rt for 24 h. Yield: 60%, mp: 180 ꢀC. 1H NMR:
(300 MHz, CDCl3): dH 2.44 (s, 3H); 4.31 (s, 2H); 4.46 (s, 2H); 7.16 (q, 2H) 7.26 (q, 2H);
7.36 (s, 2H); 7.48 (q, 4H); 7.16 (q, 2H); 13C NMR: (75 MHz, CDCl3) dc 21.6,54.2, 54.3,
127.0, 129.9, 128.0, 128.8, 129.3, 129.7, 130.8, 135.3, 136.3, 137.2, 137.9, 144.3, 153.0.
MS (ESI): m/z ¼ 460 [M þ 1]. Anal. Calcd. For C22H20N8O2S: C, 57.38; H, 4.38; N,
24.33. Found: C, 57.34; H, 4.39; N, 24.35.
N’-(bis(4-((prop-2-ynyloxy)methyl)phenyl)methylene)-4 methyl benzene
sulfonohydrazide (12)
Following the general procedure A, N0-(Bis(4-((prop-2-ynyloxy)methyl)phenyl)methy-
lene)-4 methyl benzene sulfonohydrazide 12 was obtained as white solid from Bis(40-
(propargylmethyl)phenyl methanone (10) and p-tolylsulphonyl hydrazide. Yield: 62%,
1
mp: 180 ꢀC. H NMR: (300 MHz, CDCl3): dH 2.44 (t, 3H, J ¼ 2.4 Hz); 2.47 (s, 1H); 2.52
(t, 1H, J ¼ 2.1 Hz); 4.16 (s, 2H) 4.28 (s, 2H); 4.58 (s, 2H); 4.68 (s, 2H); 7.12 (s, 2H); 7.28
(s, 1H) 7.34 (d, 2H) 7.42 (m, 2H); 7.53 (m, 3H) 7.86 (d, 2H); 13C NMR: (75 MHz,
CDCl3) dc 21.6, 57.8, 74.8, 75.1, 79.4, 125.3, 127.9, 128.4, 128.5, 128.7, 129.1, 129.7,
135.4, 136.0, 139.2, 139.8, 144.2, 153.8. MS (ESI): m/z ¼ 486 [M þ 1]. Anal. Calcd. For
C28H26N2O4: C, 69.11; H,5.39; N, 5.76. Found: C, 69.22; H, 5.45; N, 5.85.

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V. SARAVANAN AND P. RAJAKUMAR
Bis (propargylic) S(-)- binaphthyl ether (14)
Following the general procedure B, the bispropargylic ether 14 was obtained as white
solid from S(-)-BINOL and propargl bromide. Yield: 75%, mp: 104 ꢀC. 1H NMR:
(300 MHz, CDCl3): dH 2.38 (t, 2H, J ¼ 2.1 Hz); 4.57 (s, 4H); 7.14 (s, 4H), 7.32 (d, 2H,
J ¼ 8.4 Hz); 7.54 (d, 2H, J ¼ 8.1 Hz); 7.57 (t, 2H, J ¼ 7.1 Hz); 7.86 (t, 2H, J ¼ 7.2 Hz); 7.96
(d, 2H, J ¼ 9.0 Hz); 13C NMR: (75 MHz, CDCl3) dc 57.3, 55.3, 79.3, 116.1, 120.6, 124.1,
125.6, 126.4, 127.9, 129.4, 129.8, 304.0, 153.2. MS (ESI): m/z ¼ 293 [M þ 1]. Anal. Calcd.
For C26H18O2: C, 86.20; H, 5.06. Found: C, 86.36; H, 5.20.
Triazolophane 1
Following the general procedure A, the triazolophane 9 was obtained as yellow solid
from the precyclophane 10 (0.3 g, 0.65 mmol) and the bisazide 9 (0.16 g, 0.65 mmol).
1
Yield: 35%, mp: 104 ꢀC. H NMR: (300 MHz, CDCl3): dH 4.70 (s, 4H); 4.74 (s, 4H); 5.63
(s, 4H); 7.37 (d, 4H, J ¼ 7.8 Hz); 7.59 (s, 4H); 7.66 (s, 2H); 7.71 (t, 4H, J ¼ 10.5 Hz); 7.79
(t, 4H, J ¼ 7.8 Hz); 13C NMR: (75 MHz, CDCl3) dc 54.3, 64.0, 71.9, 122.7, 126.5, 127.5,
127.9, 130.3, 136.5, 136.9, 140.3, 143.0, 145.5, 195.1, 195.3. MS (ESI): m/z ¼ 610 [M þ 1].
Anal. Calcd. For C36H30N6O4: C, 70.81; H,4.95; N, 13.76. Found: C, 70.93; H,5.07;
N, 13.88.
2:2 Oligomeric triazolophane 2
The triazolophane 2 was also obtained obtained as yellow solid from the precyclophane
1
10 (0.3 g, 0.65 mmol) and the bisazide 9 (0.16 g, 0.65 mmol). Yield: 41%, mp: 104 ꢀC. H
NMR: (300 MHz, CDCl3): dH 4.69 (d, 8H, J ¼ 2.7 Hz); 4.73 (s, 8H); 5.62 (s, 8H); 7.38 (d,
8H, J ¼ 8.1 Hz); 7.45 (t, 8H, J ¼ 7.5 Hz); 7.59 (s, 4H); 7.69 (t, 8H, J ¼ 7.8 Hz); 7.78 (d,
8H, J ¼ 6.9 Hz); 13C NMR: (75 MHz, CDCl3) dc 53.6, 64.0, 71.9, 122.7, 126.5, 127.9,
130.2, 130.7, 137.5, 142.1, 143.0, 143.3, 145.5, 195.0, 195.1. MS (ESI): m/z ¼ 1220
[M þ 1]. Anal. Calcd. For C75H60N12O8: C, 70.81; H,4.95; N, 13.76. Found: C, 70.96;
H,4.99; N, 13.84.
Triazolophane 3
Following the general procedure A, the triazolophane 3 was obtained as yellow solid
from the precyclophane 12 (0.3 g, 0.65 mmol) and the bisazide 9 (0.16 g, 0.65 mmol).
1
Yield: 25%, mp: 104 ꢀC. H NMR: (300 MHz, CDCl3): dH 2.35 (s, 3H); 4.38 (s, 2H); 4.60
(s, 4H); 4.69 (s, 2H); 5.57 (s, 4H); 7.01 (d, 2H, J ¼ 7.8 Hz); 7.32 (s, 2H); 7.34–7.46 (m,
11H); 7.75 (t, 7H, J ¼ 8.4 Hz); 13C NMR: (75 MHz, CDCl3) dc 2 1.6, 54.2, 64.1, 71.9,
122.6, 127.6, 127.8, 128.5, 128.9, 129.6, 130.5, 130.7, 135.5, 136.9, 137.7, 138.9, 140.3,
144.2, 195.3. MS (ESI): m/z ¼ 778 [M þ 1]. Anal. Calcd. For C43H38N8O5S: C, 66.31; H,
4.92; N, 14.39. Found: C, 66.55; H, 5.08; N, 14.55.

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Triazolophane 4
Following the general procedure A, the triazolophane 4 was obtained as yellow solid
from the precyclophane 12 (0.3 g, 0.65 mmol) and the bisazide 11 (0.16 g, 0.65 mmol).
1
1
Yield: 65%, mp: 104 ꢀC. H NMR: (300 MHz, CDCl3): dH: H NMR, CDCl3: 2.42 (s,
6H); 4.60 (s, 4H); 4.65 (s, 4H); 5.50 (s, 2H); 5.63 (s, 2H); 7.09–7.19 (m, 6H); 7.31 (s,
1H); 7.33 (s, 1H); 7.45 (t, 14H, J ¼ 8.4 Hz); 7.63 (s, 1H); 7.83 (d, 4H, J ¼ 7.2 Hz); 13C
NMR: (75 MHz, CDCl3) dc 21.6, 54.4, 63.4, 71.7, 127.4, 127.7, 128.5, 128.7, 129.1, 129.7,
129.8, 130.9, 135.4 MS (ESI): m/z ¼ 946[M þ 1]. Anal. Calcd. For C50 H46 N10 O6S2: C,
63.41; H,4.90; N, 14.90. Found: C, 63.62; H,5.25; N, 15.02.
Triazolophane 5
Following the general procedure A, the triazolophane 5 was obtained as yellow solid
from the precyclophane 14 (0.3 g, 0.65 mmol) and the bisazide
9
(0.16 g,
1
0.65 mmol).Yield: 62%, mp: 104 ꢀC. H NMR: (300 MHz, CDCl3): dH: 5.16 (s, 2H); 5.20
(s, 2H); 5.30 (s, 4H); 7.14 (t, 9H, J ¼ 8.1 Hz); 7.43 (t, 3H, J ¼ 8.7 Hz); 7.70–7.75 (m, 5H);
7.80 (d, 3H, J ¼ 8.1 Hz); 7.86–7.89 (m, 2H); 13C NMR: (75 MHz, CDCl3) dc 29.7, 53.3,
63.9, 116.0, 120.7, 122.8, 124.0, 125.4, 126.5, 126.7, 127.7, 128.0, 129.1, 129.5, 130.4,
130.6, 133.9, 137.2, 138.2, 153.6. MS (ESI): m/z ¼ 654 [M þ 1]. Anal. Calcd. For C41 H30
N6 O3: C, 75.21; H,4.62; N, 12.84. Found: C, 75.39; H,4.86; N, 12.95.
Triazolophane 6
Following the general procedure A, the triazolophane 6 was obtained as yellow solid
from the precyclophane 14 (0.3 g, 0.65 mmol) and the bisazide 11 (0.16 g, 0.65 mmol).
1
Yield: 30%, mp: 104 ꢀC. H NMR, CDCl3: 2.31 (s, 3H); 4.94 (t, 8H, J ¼ 7.2 Hz); 6.44 (t,
2H, J ¼ 6 Hz); 6.71 (s, 3H); 6.94 (d, 14H, J ¼ 21.9 Hz); 7.79 (s, 8H); 13C NMR, CDCl3:
21.6, 57.0, 71.8, 114.1, 115.4, 115.9, 120, 2, 122.6, 124.0, 125.4, 126.4, 127.3, 127.9, 128.9,
129.7, 130.9, 132.4, 133.9, 135.4, 139.3, 144.3, 152.6, 153.5. MS (ESI): m/z ¼ 822 [M þ 1].
Anal. Calcd. For C48 H38 N8 O4 S: C, 70.06; H,4.65; N, 13.62. Found: C, 70.31; H,4.82;
N, 13.76.
Conclusions
In conclusion, S(-)-BINOL and benzophenone based triazolophanes 1–6 were obtained
in moderate to excellent yield by click chemistry. All the triazolophanes show excellent
inhibitory activity against both Gram-positive and Gram-negative bacteria viz. S. aureus,
B. Subtilis, S. typhimurium, and E. Coli The triazolophane 5 shows a better antibacterial
activity against all the four tested pathogens than that of the triazolophanes 1, 2, 3, 4,
and 6. However, with respect to E. coli bacteria triazolophane 4 also shows better anti-
bacterial activity comparable to that of the triazolophane 5. The antibacterial activity of
all the synthesized cyclophanes is dose-dependent against aureus, subtilis, typhi bacteria
but with respect to E. coli the antibacterial activity of the synthesized cyclophane is
dose-independent.

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V. SARAVANAN AND P. RAJAKUMAR
Acknowledgments
The authors thank DST-FIST for providing an NMR facility to the Department of organic chem-
istry, University of Madras, and A. Sathiyaseelan, and Professor P. T. Kalaichelvan CAS—
Department of botany, University of Madras, for carrying out the antibacterial activity. VS thanks
the University of Madras for the infrastructure facility and for providing Kalaignar endow-
ment fellowship.
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