Benzoxazole and dioxolane substituted benzimidazole–based N–heterocyclic carbene–silver(I) complexes: Synthesis, structural characterization and in vitro antimicrobial activity

Article abstract of DOI:10.1016/j.jorganchem.2018.04.039

A novel series of 1,3–benzoxazole and 1,3–dioxolane substituted benzimidazole–based N–heterocyclic carbene (NHC) precursors (6a–b and 11a–b) and their corresponding NHC–silver(I) acetate (12a–b and 14a–b) and bis–NHC–silver(I) hexafluorophosphate complexe

Full text of DOI:10.1016/j.jorganchem.2018.04.039

Accepted Manuscript
Benzoxazole and dioxolane substituted benzimidazole–based N–heterocyclic
carbene–silver(I) complexes: Synthesis, structural characterization and in vitro
antimicrobial activity
C.R. Shahini, Gautam Achar, Srinivasa Budagumpi, Helge Müller–Bunz, Matthias
Tacke, Siddappa A. Patil
PII:
S0022-328X(18)30292-4
10.1016/j.jorganchem.2018.04.039
JOM 20431
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 4 January 2018
Revised Date: 12 April 2018
Accepted Date: 30 April 2018
Please cite this article as: C.R. Shahini, G. Achar, S. Budagumpi, H. Müller–Bunz, M. Tacke, S.A.
Patil, Benzoxazole and dioxolane substituted benzimidazole–based N–heterocyclic carbene–silver(I)
complexes: Synthesis, structural characterization and in vitro antimicrobial activity, Journal of
Organometallic Chemistry (2018), doi: 10.1016/j.jorganchem.2018.04.039.
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ACCEPTED MANUSCRIPT
Benzoxazole and dioxolane substituted benzimidazole–based N–
heterocyclic
carbene–silver(I)
complexes:
Synthesis,
structural
characterization and in vitro antimicrobial activity
a
a
a
b
Shahini C. R. , Gautam Achar , Srinivasa Budagumpi , Helge Müller–Bunz , Matthias
b
a
Tacke , Siddappa A. Patil *
a
Centre for Nano and Material Sciences, Jain University, Jain Global Campus, Kanakapura,
Ramanagaram, Bangalore 562112, India
b
School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland
*
Corresponding author: Dr. Siddappa A. Patil
Tel: +91 80 27577254
Fax: +91 80 27577211
E–mail: p.siddappa@jainuniversity.ac.in/patilsiddappa@gmail.com
1

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ABSTRACT
A novel series of 1,3–benzoxazole and 1,3–dioxolane substituted benzimidazole–based N–
heterocyclic carbene (NHC) precursors (6a–b and 11a–b) and their corresponding NHC–
silver(I) acetate (12a–b and 14a–b) and bis–NHC–silver(I) hexafluorophosphate complexes
1
13
(
13a–b and 15a–b) were synthesized and characterized by H NMR, C NMR, ATR-IR
spectroscopic methods and elemental analysis techniques. Also, the molecular structure of
benzimidazolium salt (6a) and bis–NHC–silver(I) hexafluorophosphate complex (13b) were
unambiguously established by single crystal X–ray diffraction analysis. Fascinatingly, bis–
NHC–silver(I) hexafluorophosphate complex (13b) was revealed to be dinuclear in nature.
All the azolium salts (6a–b and 11a–b) as well as the corresponding silver(I) complexes
(12a–b, 13a–b, 14a–b and 15a–b) were evaluated for their antimicrobial potentials against
Gram positive (Staphylococcus aureus), and a set of Gram negative (Escherichia coli,
Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa) bacterial
strains and two fungi, Candida albicans and Cryptococcus neoformans. Antimicrobial studies
revealed the comparable antimicrobial activities of benzimidazolium salts (6a–b and 11a–b)
and the silver(I) complexes (12a–b, 13a–b and 15a–b). Whereas, the 1,3–dioxolane
substituted benzimidazole–based silver(I) acetate complexes (14a–b) demonstrated excellent
potentials with both bacterial and fungal growth inhibition above 95%.
Keywords: Antibacterial; Antifungal; Benzoxazole; Dioxolane; NHC–silver(I) complex; X–
ray structure.
2

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1
. Introduction
The introduction of N–heterocyclic carbenes (NHCs) as ligands to organometallic chemistry
in 1968 unlatched a contemporary stream of study, the N–heterocyclic carbene chemistry,
that in the following years was explored and researched to be applied in broad spectrum of
applications such as catalysis, pharmaceutical and materials science [1–5]. Their success can
be attributed to the ability to bind to almost every transition metal via a strong σ–donation
and poor π–back donation from the metal, which renders NHCs an immensely versatile class
of ligands [6, 7]. Amongst the available choice of transition metals, copper, silver, gold,
platinum, palladium, ruthenium and others have been used in union with NHCs over the years
for their ample range of applications [8–11]. Though majority of metal based biological
research involves gold and platinum, employment of silver has an outstanding reputation in
medicinal usage in history [12, 13].
In the ascending instances of multiple drug resistant microbial strains in modern days,
the search for effective antibiotics is unceasing [14]. In the quest for such drug like
candidates, NHC–silver(I) complexes categorically stand out owing to their low toxicity, easy
synthesis, stability and limited possibility of side effects [15–18]. In addition, as an effective
drug candidate is a combination of aptly designed ligand structure to attain a precise
lipophilicity that is biocompatible, ligand design plays a pivotal role in drug design [19–21].
Also, as the competence of the biological potential of NHC–silver(I) complexes is essentially
influenced by the type of ligands bound to the metal centre, the functionalization of the N–
heterocyclic core is noteworthy [22,23]. As our most recent reports suggest incorporation of a
heterocyclic moiety as the N–substituent on the N–heterocyclic core offer appreciable
biological activity [24–27], we were prompted to entail 1,3–benzoxazole and 1,3–dioxolane
as wingtip moieties to access novel series of NHC–precursors and their corresponding
silver(I) complexes. Both 1,3–benzoxazole and 1,3–dioxolane derivatives have been mildly
3

ACCEPTED MANUSCRIPT
studied as antiinflammatory scaffolds, nucleoside analogues and effective modulators to
overcome multidrug resistance [28–32]. Having scarce examples of both the heterocycles
integrated with NHCs as ligands, the 1,3-benzoxazole and 1,4-dioxolane moieties were
chosen as they are less explored toward antimicrobial applications. The current study
investigates their effects on the biological potential of the corresponding benzimidazole–
based NHC–silver(I) complexes. Also, in continuation with our previous studies, a
comparison can be drawn between the structure–activity relationships between mono– and
bis–NHC–silver(I) complexes.
2
. Results and discussion
2
.1. Chemistry
During the last decade, NHCs have received substantial attention as precursors in transition
metal coordination chemistry, which has resulted in the preparation of numerous stable
NHC–metal complexes with wide variety of applications as catalysts and bioactive
compounds. All the reported NHC salts (6a–b and 11a–b) and their corresponding silver(I)
complexes (12a–b, 13a–b, 14a–b and 15a–b) were readily soluble in common organic
solvents such as dichloromethane, chloroform, acetone, dimethylformamide and dimethyl
sulfoxide and were synthesized in excellent yields with high purity from low cost
commercially available starting materials. All the compounds were nonhygroscopic in nature
and can be stored at room temperature for longer periods of time.
2
.2. Syntheses of NHC–precursors and their corresponding silver(I) complexes
The reported 1,3–benzoxazole substituted benzimidazole–based hexafluorophosphate salts
6a–b) were synthesized by successive N–alkylation route followed by salt metathesis
(
reaction as shown in Scheme 1. 1–Benzyl/ethyl benzimidazole (3a–b) was prepared
according to the reported method with minor modification [33]. On the other hand, 2–
Bromomethyl–1,3–benzoxazole (4) was synthesized following the reported procedure with
4

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slight modification [34]. The 1,3–benzoxzole substituted benzimidazolium bromide salts (5a–
b) were obtained by the reaction of 1–benzyl/ethyl benzimidazole with 2–bromomethyl-1,3–
0
benzoxazole in dioxane at 100 C for 24 h, and the corresponding hexafluorophosphate salts
(6a–b) were yielded by the salt metathesis reaction of the benzimidazolium bromide salts
(
5a–b) with KPF in methanol and water mixture (9:1 v/v) at room temperature for 4 h, with
6
good yields of 69 and 71% respectively. 1,3–Dioxolane substituted benzimidazole–based
hexafluorophosphate salts (11a–b) were synthesized in two steps as shown in Scheme 2. In
the first, 2–bromomethyl–1,3–dioxolane was treated with benzimidazole in the presence of
potassium carbonate in acetonitrile in room temperature for 72 h to obtain 1–(2–methyl–1,3–
dioxolan)–benzimidazole (8). Secondly, successive N–alkylation was carried out by treating
0
1
–(2–methyl–1,3–dioxolan)benzimidazole with ethyl/benzyl bromide in dioxane at 100 C
for 24 h to access the corresponding bromide salts (10a–b). The corresponding
hexafluorophosphate salts (11a–b) were yielded by the reaction of the benzimidazolium
bromide salts (10a–b) with KPF in methanol and water mixture (9:1 v/v) at room
6
temperature for 4 h, with good yields of 64 and 67%, respectively.
Scheme 1. Synthesis of 1,3–benzoxazole substituted benzimidazole–based salts.
5

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Scheme 2. Synthesis of 1,3–dioxolane substituted benzimidazole–based salts.
The synthetic route to obtain 1,3–benzoxazole and 1,3–dioxolane substituted
benzimidazole–based NHC–silver(I) acetate (12a–b and 14a–b) and bis–NHC–silver(I)
hexafluorophosphate complexes (13a–b and 15a–b) is shown in Schemes 3 and 4,
respectively. The NHC–silver(I) acetate complexes (12a–b and 14a–b) were synthesized by
treating the benzimidazolium hexafluorophosphate salts (6a–b and 11a–b) with 2 equivalents
of silver(I) acetate at room temperature in methanol for 4 h with appreciable yields ranging
from 62 to 72% and the bis–NHC–silver(I) hexafluorophosphate complexes (13a–b and 15a–
b) were accessed by treating the benzimidazolium hexafluorophosphate salts (6a–b and 11a–
b) with 1.2 equivalent of silver(I) oxide in acetonitrile at room temperature for 4 h with
excellent yields in the range 70 to 75%.
All the synthesized benzimidazolium hexafluorophosphate salts (6a–b and 11a–b)
and their corresponding silver(I) complexes (12a–b, 13a–b, 14a–b and 15a–b) were fully
1
13
characterized by H NMR, C NMR, ATR–IR spectroscopic methods and elemental analysis
techniques. Additionally, the structure of the benzimidazolium salt (6a) and silver(I) complex
(13b) were unambiguously established by single crystal X–ray diffraction method.
6

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R
N
PF6
N
N
N
O
N Ag
N
O
O
O
CH3
O
N
N
1.2 Ag O
2
AgOAc
2
Ag O
PF6
Ag N
N
R
MeOH
rt, 4 h
N
R
MeCN
rt, 4 h
N
R
PF6
1
2a-b
6a-b
13a-b
6
6
a, 12a, 13a, R =
b, 12b, 13b, R =
CH3
Scheme 3. Synthesis of 1,3–benzoxazole substituted benzimidazole–based silver(I)
complexes.
O
O
O
O
O
O
R
N
N
CH3
O
N
N
1.2 Ag O
2
AgOAc
2
Ag O
PF6
Ag
N
R
MeOH
rt, 4 h
N
R
MeCN
rt, 4 h
N
R
N
PF6
O
1
4a-b
11a-b
15a-b
O
1
1
1a, 14a, 15a, R =
1b, 14b, 15b, R=
CH3
Scheme 4. Synthesis of 1,3–dioxolane substituted benzimidazole–based silver(I) complexes.
2
.3. Spectral characterization
1
In the H NMR spectra of the benzimidazolium hexafluorophosphate salts (6a–b and 11a–b),
a downfield resonance was observed in the range δ = 9.96 to 10.05 ppm attributed to the
resonance of NCHN proton. Additionally, peaks in the range δ = 7.25 to 8.13 ppm were
attributed to the resonance of aromatic protons (CHBenzimid + CHBenzox + CHBenzyl). Further,
peaks corresponding to the methylene protons of 1,3–benzoxazole, 1,3–dioxolane, benzyl and
ethyl modules were observed in the range δ = 4.01 to 6.28 ppm. Additionally, the backbone
CH protons of the 1,3–dioxolane substitution resonated at δ = 3.61 to 3.98 ppm, and ethyl
2
7

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1
3
CH protons resonated at δ = 1.51 to 1.56 ppm. The C NMR spectra of the
3
benzimidazolium hexafluorophosphate salts (6a–b and 11a–b) showed a distinct peak in the
range δ = 140.5 to 143.1 ppm attributed to the resonance of C2 carbon atom of the
benzimidazole core. Then, peaks corresponding to the other carbon atoms (CBenzimid + CBenzox
+
CDiox + CBenzyl) were observed between δ = 60.3 and 160.1 ppm. The methylene carbon
atom of the 1,3–benzoxazole, 1,3–dioxolane, benzyl and ethyl module was observed between
δ = 32.4 and 50.6 ppm. Further, peaks corresponding to the CH carbon of the ethyl chain was
3
found in the range δ = 14.4 to 15.2 ppm.
The successful formation of the desired silver(I) complexes (12a–b, 13a–b 14a–b and
1
5a–b) was recognised by the disappearance of the downfield peak at δ = 9.96 to 10.05 ppm
1
in comparison with the H NMR spectra of the corresponding salts (6a–b and 11a–b). In case
of the silver(I)–acetate complexes (12a–b and 14a–b), new peak at δ = 1.39 to 2.04 ppm
1
3
corresponding to the protons of the acetate (OCOCH ) group was observed. The C NMR
3
spectra of the silver(I) complexes (12a–b, 13a–b 14a–b and 15a–b) exhibited a downfield
signal of the carbene carbon atom in the range δ = 190.1 to 191.7 ppm. Additionally, the
spectra of the NHC–silver(I) acetate complexes witnessed the appearance of new signals at δ
=
174.8 for 12b and 21.7 to 33.9 ppm corresponding to carbonyl and methyl carbon atoms of
1
3
the acetate group. The C NMR spectra of bis–NHC–silver(I)–hexafluorophosphate
complexes (13a–b and 15 a–b) exhibited a downfield signal of the carbene carbon atom in
the range δ = 143.9 to 191.8 ppm. These observations collectively confirm the formation of
the desired compounds (12a–b, 13a–b 14a–b and 15a–b).
In the ATR–IR spectra of benzimidazolium hexafluorophosphate salts (6a–b and
–
1
1
1a–b) the aromatic ν(C–H) stretching vibrations were evidenced at 2923–2941 cm , and
stretching vibrational bands for ν(C–N/O) of the N–substitutions were observed at 1130 –
–
1
.
1
593 cm Further, ν(C=N) stretching vibrations corresponding to the benzoxazole
8

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–1
substituent of the salts 6a and 6b were observed at 1593 and 1562 cm . For the NHC–
–
1
silver(I) acetate complexes (12a–b and 14a–b), strong bands in the region 1701–1713 cm ,
attributed to the acetate ν(C=O) stretching vibrations, along with medium intensity stretching
–1
vibrational bands in the region 2949–2953 and 1128–1523 cm corresponding to ν(C–H)
and ν(C–N/O) stretching vibrations respectively. Additionally, comparable with that of the
salts, ν(C=N) stretching vibrations of the benzoxazole substituent of the complexes 12a and
–
1
1
2b were observed at 1581 and 1573 cm . Similarly, the spectra of the bis–NHC–silver(I)
hexafluorophosphate complexes (13a–b and 15a–b), exhibit medium intensity stretching
–
1
vibrational bands in the region 1119–1592 and 2936–2953 cm attributed to ν(C–N/O) and
aromatic ν(C–H) stretching vibrations and ν(C=N) stretching vibrations for the benzoxazole
–
1
substituent of the complexes 13a and 13b at 1591 and 1592 cm were observed. In addition
to the spectral characterization, the elemental analysis of the benzimidazolium
hexafluorophosphate salts (6a–b and 11a–b) and the corresponding silver(I) complexes (12a–
b, 13a–b 14a–b and 15a–b) indicated the successful formation and purity of the compounds.
2
.4. Single crystal X–ray diffraction analysis
Suitable single crystals for X–ray diffraction analysis of the benzimidazolium
hexafluorophosphate salt (6a) were grown by slow diffusion of hexane into saturated
dichloromethane solution at room temperature. A perspective view of (6a) is depicted in Fig.
1
. Benzimidazolium hexafluorophosphate salt (6a) crystallized in the monoclinic space group
P21/c with sixteen motifs in a unit cell. An asymmetric unit of (6a) consists of four
crystallographically different units of benzimidazolium cations and four hexafluorophosphate
anions. The internal ring angle of benzimidazole at the C2 carbon center N1–C1–N3 is
1
10.64(15), at N4–C18–N6 is 110.66(15), at N7–C35–N9 is 110.37(16), and at N10–C52–
N12 is 110.80(16). The bond angles and distances are in well agreement with those observed
in the related benzimidazolium salts and benzoxazole derivative [27, 35]. A considerable π–π
9

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interaction is noted with a centroid to centroid distance of 3.631 Å between the benzyl
backbones of the 1,3-benzoxazole substitutions of adjacent benzimidazolium cations. Also,
the molecular arrangement in a linear fashion is shown in Fig. 2.
On the other hand, suitable single crystals for X–ray diffraction analysis of the
silver(I) complex (13b) were grown by slow evaporation of saturated acetonitrile solution in
room temperature. Silver(I) complex (13b) crystallized in the triclinic space group P–1 with
eight motifs in a unit cell. An asymmetric unit of (13b) consists of a benzimidazolium ligand
bonded to a silver(I) centre and one hexafluorophosphate anion. In addition, an unresolved
moiety was observed which could not be accounted to a solvent molecule. Interestingly, the
molecular structure reveals an unexpected bonding pattern between two benzimidazolium
ligand molecules and the silver(I) centre of the type CCarbene – Ag(I) – NBenzoxazole to give a
dinuclear structure as shown in Fig. 3. The benzoxazole moiety coordinates to the hetero
silver(I) atoms at right angle to the parent NHC. This type of coordination geometry allows a
cavity in the structure of (13b) bridged by two silver(I) atoms. Similar structures have been
reported by Li et al. where bond formation was observed between N atom of the
benzimidazole N-substitutent, an analogue of benzoxazole and the metal centre to reveal an
intriguing complex structure [36,37]. However, there are no reports of a benzoxazole moiety
being involved in the reported fashion. The internal ring angle of benzimidazole at the
carbene carbon center (N1–C1–N2) is 105.95(16) that is in well agreement along with the
bond distances with those observed in similar silver(I) complexes [38]. Further, C1–Ag–N3
o
bond angle was found to be distorted than usual at 171.58(7) owing to the bonding pattern
and ligand design. Furthermore, like that of the benzimidazolium salt (6a), a π–π interaction
is noted between two benzimidazole rings with a centroid to centroid distance of 3.955 Å.
Also, molecular arrangement of silver(I) complex (13b) is depicted in Fig. 4.
1
0

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C16
C17
N3
C6
C4
C11
C7
C1
C12
C13
C5
O1
C10
N1
C2
C9
C8
C3
C15
C14
N2
Fig. 1. Molecular structure of benzimidazolium hexafluorophosphate salt (6a). Thermal
ellipsoids are drawn on the 50% level and hexafluorophosphate anion is omitted for clarity.
Fig. 2. Molecular arrangement in benzimidazolium hexafluorophosphate salt (6a).
1
1

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C19
C12
C18
O1
C17
C20
C11
C13
C14
C10
C21
C22
C16
C9
C15
N3
N2
C1
N1
Ag
I
C8
C2
C7
C3
Ag
C1
I
C6
C4
N3I
C5
Fig. 3. Molecular structure of bis–NHC–silver(I) complex (13b). Thermal ellipsoids are
drawn on the 50% level and hexafluorophosphate anions are omitted for clarity.
Fig. 4. Molecular arrangement in bis–NHC–silver(I) complex (13b).
2
.5. Antimicrobial studies
All the synthesized benzimidazolium hexafluorophosphate salts (6a–b and 11a–b) and their
corresponding silver(I) complexes (12a–b, 13a–b 14a–b and 15a–b) were investigated for
antibacterial and antifungal potentials against Gram positive (Staphylococcus aureus) and
Gram negative (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and
1
2

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Pseudomonas aeruginosa) bacterial strains and two fungi Candida albicans and
Cryptococcus neoformans, respectively (Fig. 5–11). The tests were carried out at a
concentration of 32 µg/mL of the test sample with standards Colistin and Vancomycin as
positive antibacterial standards and fluconazole as antifungal standard and the activities are
summarized in Table 1. As reported earlier, DMSO did not exhibit any antimicrobial activity
[
39–41].
Generally, all the test compounds exhibited antibacterial activity against the Gram
positive bacterial strain Staphylococcus aureus. While the benzimidazolium
hexafluorophosphate salts (6a–b and 11a–b) performed poorly by percentage inhibition of
1
5.80–21.95%, the 1,3–benzoxazole substituted benzimidazole–based NHC–silver(I)
complexes (12a–b and 13a–b) exhibited similar results with percentage inhibition of 11.40–
6.90%. Similarly, the 1,3–dioxolane substituted benzimidazole–based bis–NHC–silver(I)
2
complexes (15a–b) displayed percentage inhibition of 6.80–21.40%. There was seldom any
difference in the antibacterial activity against Staphylococcus aureus between the
benzimidazolium hexafluorophosphate salts (6a–b and 11a–b) and the silver(I) complexes
(12a–b, 13a–b and 15a–b). Whereas, 1,3–dioxolane substituted benzimidazole–based NHC–
silver(I) acetate complexes (14a–b) orchestrated excellent antibacterial potential against
Staphylococcus aureus by inhibiting 95.70–97.90% of bacterial growth.
In the investigation of antibacterial potential against Gram negative bacterial strains
(Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter
baumannii), the benzimidazolium hexafluorophosphate salts (6a–b and 11a–b), the 1,3–
benzoxazole substituted benzimidazole–based NHC–silver(I) complexes (12a–b and 13a–b)
and 1,3–dioxolane substituted benzimidazole–based bis–NHC–silver(I) complexes (15a–b)
exhibited poor to average percentage inhibition of 0 – 21.90%, –0.2 – 22.50% and 6.80 –
2
2.65% respectively. Like that of the Gram positive strain, the antibacterial potentials of the
1
3

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benzimidazolium hexafluorophosphate salts (6a–b and 11a–b) and the silver(I) complexes
(12a–b, 13a–b and 15a–b) against the test Gram negative strains were comparable. Also,
1
,3–dioxolane substituted benzimidazole–based NHC–silver(I) acetate complexes (14a–b)
demonstrated excellent antibacterial potential against the test Gram negative strains by
inhibiting 96.00 – 98.15% of bacterial growth.
Unlike the antibacterial activity, the benzimidazolium hexafluorophosphate salts (6a–
b and 11a–b) were inactive against the tested fungal strains (Candida albicans and
Cryptococcus neoformans) evidenced by the percentage inhibition in the range –92.70 –
2
.75%. The 1,3–benzoxazole substituted benzimidazole–based NHC–silver(I) complexes
12a and 13a) exhibited moderate activity by inhibiting 49.70 and 36.40% of the growth of
Candida albicans, whereas the bis–NHC–silver(I) analogues were almost inactive at 0.40 and
2.10%, respectively. Further, 1,3–benzoxazole substituted benzimidazole–based NHC–
(
–
silver(I) complexes (12a–b and 13a–b) demonstrated very poor antifungal potential in the
percentage growth inhibition range –126.30 – 4.50 %.
The
1,3–dioxolane
substituted
benzimidazole–based
bis–NHC–silver(I)
hexafluorophosphate complexes (15a–b) showed negligible activity against both the tested
fungal strains in the range –99.00 – 7.40% inhibition which is comparable with the 1,3–
benzoxazole counterparts. On the contrary, 1,3–dioxolane substituted benzimidazole–based
NHC–silver(I) acetate complexes (14a–b) showed the highest activity against both the fungal
strains. Complexes (14a) and (14b) exhibited excellent activity with percentage growth
inhibition of 97.60 and 98.90% against Candida albicans and 110.25 and 106.95 % against
Cryptococcus neoformans.
As opposed to the observations in our previous studies [38, 39], the biological activity
of the benzimidazolium hexafluorophosphate salts were not amplified on complexing them
with silver(I) centre. However, as 1,3–dioxolane substituted benzimidazole–based NHC–
1
4

ACCEPTED MANUSCRIPT
silver(I) acetate complexes (14a–b) performed excellently against all the test strains, it cannot
be concluded that the silver(I) centre does not play a role in the antimicrobial activity of the
complexes.
Table 1.
Antimicrobial activity of compounds at concentration of 32 µg/mL in DMSO
[a]
Percentage growth inhibition of bacteria and fungi
Antibacterial activity
Antifungal activity
Candida Cryptococcus
Code Gram–positive
Gram–negative
Staphylococcus Escherichia Klebsiella
aureus
Pseudomonas
aeruginosa
Acinetobacter
baumannii
coli
pneumoniae
albicans
neoformans
6
6
1
1
1
1
1
1
1
1
1
1
a
b
19.95±7.70
21.20±5.37
21.95±5.16
15.80±8.06
19.85±1.34
23.00±3.95
26.90±2.12
11.40±5.65
95.70±3.67
97.90±7.21
21.40±6.92
2.15±0.49
4.30±1.27
4.45±1.34
3.40±1.55
21.45±3.18
6.75±1.34
16.10±1.27
–0.20±0.14
96.95±0.49
97.35±0.21
10.00±2.40
6.80±0.84
9.25±3.74
9.60±7.77
0.00±6.50
13.75±0.21
17.55±14.63
19.70±1.41
19.15±2.47
6.85±6.29
9.00±9.47
–4.15±5.02
9.60±5.79
96.00±0.56
96.00±0.56
16.50±0.70
17.65±9.82
1.85±2.05
2.75±2.33
–0.70±3.11
0.55±2.61
49.70±71.27 4.50±141.70
0.40±1.55 –73.00±3.67
36.40±29.69 126.30±58.97
–2.10±1.69
97.60±0.42
98.90±0.84
1.35±2.33
7.40±1.69
–54.75±4.17
–89.00±32.10
–68.05±12.79
–92.70±17.39
13.50±12.44
10.60±8.48
7.95±5.02
19.75±8.13
13.90±3.53
22.50±9.47
1.70±1.41
98.15±0.07
97.65±0.21
9.50±10.74
15.85±4.31
1a
1b
2a
2b
3a
3b
4a
4b
5a
5b
21.90±4.80
11.70±1.69
17.55±5.72
14.55±4.87
16.50±10.18
16.65±1.06
96.55±0.21
97.2±1.13
–58.10±3.67
110.25±0.49
106.95±2.19
–99.00±22.76
–21.85±1.90
22.65±10.53
21.85±5.58
6.80±4.80
a
Highest percentile of antibacterial/antifungal growth inhibition are highlighted in bold. Data are expressed as the mean±SD
.
Fig. 5. Percentage growth inhibition of Staphylococcus aureus.
1
5

ACCEPTED MANUSCRIPT
Fig. 6. Percentage growth inhibition of Escherichia coli.
Fig. 7. Percentage growth inhibition of Klebsiella pneumoniae.
1
6

ACCEPTED MANUSCRIPT
Fig. 8. Percentage growth inhibition of Pseudomonas aeruginosa.
Fig. 9. Percentage growth inhibition of Acinetobacter baumannii.
1
7

ACCEPTED MANUSCRIPT
Fig. 10. Percentage growth inhibition of Candida albicans.
Fig. 11. Percentage growth inhibition of Cryptococcus neoformans.
3
. Conclusions
Novel NHC–silver(I) complexes possessing heterocyclic N–substituents such as 1,3–
benzoxazole and 1,3–dioxolane are reported. The benzimidazolium bromide salts (5a–b and
1
0a–b) were synthesized by successive N–alkylation and then subjected to salt metathesis
reactions to obtain the hexafluorophosphate counterparts. The benzimidazolium
hexafluorophosphate salts (6a–b and 11a–b) were treated with silver(I) acetate and silver(I)
1
8

ACCEPTED MANUSCRIPT
oxide to yield the corresponding NHC–silver(I) acetate (12a–b and 14a–b) and bis–NHC–
silver(I) hexafluorophosphate complexes (13a–b and 15a–b) respectively. The
benzimidazolium hexafluorophosphate salts as well as the silver(I) complexes were
1
13
characterized by H NMR, CNMR, ATR–IR spectroscopic methods and elemental analysis
techniques. The molecular structure of (6a) and (13b) was solved by single crystal X–ray
diffraction analysis. Interestingly, (13b) was revealed to be dinuclear in nature. As all the
compounds were evaluated for their antibacterial and antifungal potential against
Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii,
Pseudomonas aeruginosa bacterial strains and fungi Candida albicans and Cryptococcus
neoformans, it was revealed that unlike the observations in our previous study, complexation
of the NHC–precursors with silver(I) did not result in enhanced activity. The
benzimidazolium hexafluorophosphate salts (6a–b and 11a–b) and the silver(I) complexes
(12a–b, 13a–b and 15a–b) exhibited comparable antibacterial activity in the range –0.2 to
2
4
6.90% of bacterial growth inhibition and fungal growth inhibition in the range –126.30 to
9.70% at a concentration of 32 µg/mL. But, silver(I) acetate complexes (14a–b)
demonstrated commendable calibre with bacterial growth inhibition of 95.70 to 98.15% and
fungal growth inhibition in the range 97.60 to 110.25%. This excellent potential paves way
for an intense study to explore further into their pharmacological properties.
4
. Experimental
4
.1. General considerations
All experiments were conducted in aerobic conditions using oven dried glassware without
Schlenk technique and dry box. Benzimidazole, benzyl bromide, ethyl bromide, 2–
aminophenol, bromoacetic acid, polyphosphoric acid, 1,4– dioxolane, potassium hydroxide,
potassium hexafluorophosphate, silver(I) acetate, silver(I) oxide and all solvents were
procured from commercial sources and used without further purification. 1–Ethyl
1
9

ACCEPTED MANUSCRIPT
benzimidazole and 1–benzyl benzimidazole were synthesized following literature procedures
with slight modifications [33]. Also, 1–(2–methyl–1,3–dioxalan)benzimidazole was prepared
following similar synthetic route. Further, 2–bromomethyl–1,3–benzoxazole was synthesized
according to the reported method [34]. Reactions were monitored using thin– layer
chromatography (TLC) performed on 0.25 mm Merck TLC silica gel plates and UV light was
used as a visualizing agent. Volatile solvents were removed using rotary evaporator equipped
with a dry diaphragm pump (10–15 mm Hg) followed by pumping to a constant weight with
1
an oil pump (<300 mTorr). H NMR spectra were recorded on Bruker AVANCE III 400 MHz
spectrometer and are reported relative to DMSO–d (δ 2.50 ppm) or CDCl (δ 7.24 ppm).
6
3
1
Coupling constants (J) in H NMR are reported in Hertz (Hz) and multiplicities are
1
3
designated as singlet (s), doublet (d), triplet (t) and multiplet (m). Proton–decoupled
C
NMR spectra were recorded at 100 MHz and reported relative to DMSO–d (δ 39.5 ppm)
6
CDCl (δ 77 ppm). ATR–IR spectra were obtained using a Bruker ECO–ATR
3
–
1
spectrophotometer in the range 600–4000 cm and Elemental analyses were accomplished
using a PerkinElmer 2400 Series II CHN/S microanalyzer.
4
.2. Single crystal X–ray analysis
Crystal data of (6a) and (13b) were collected using an Agilent (formerly Oxford Diffraction)
SuperNova A diffractometer fitted with an Atlas detector using monochromated Mo Kα
radiation (0.71073 Å). A complete data set was collected assuming the Friedel pairs were
non–equivalent. An analytical absorption correction based on the shape of the crystal was
performed [42]. The structures were solved by direct methods using SHELXS – 2014 and
refined by full–matrix least squares on F2 for all data using SHELXL – 2014 [43]. Hydrogen
atoms were added at calculated positions and refined using a riding model. Anisotropic
thermal displacement parameters were used for all non disordered non–hydrogen atoms. The
crystallographic data of structural analysis have been deposited in the Cambridge
2
0

ACCEPTED MANUSCRIPT
Crystallographic Data Center, CCDC 1814461 and 1814462 contain the supplementary
crystallographic data for the present work. These data can be obtained free of charge from
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. The
crystal data and structure refinement details are provided in Table 2.
Table 2
Crystallographic data and the structure refinement details for the benzimidazolium salt (6a)
and NHC–silver(I) complex (13b)
Identification code
Empirical formula
Molecular formula
6a
13b
C H N OF P
C44.37H35.48N O F P Ag
[C H N O Ag ] {[F P] } x0.37
44 34 6 2 2 6 2
17
16
3
6
6
2.37 12
2
2
+
–
2+
–
[C H N O] [F P]
1
7
16
3
6
(
CH O)
4
Formula weight
Temperature
423.30
100(2) K
1196.29
100(2) K
Wavelength
Crystal system
Space group
1.54184 Å
Monoclinic
P21/c (#14)
1.54184 Å
Triclinic
P–1 (#2)
Unit cell dimensions
a = 8.34867(6) Å
b = 24.1067(2) Å
c = 35.0649(3) Å
α= 90°
a = 10.3238(2) Å
b = 11.4084(2) Å
c = 11.6654(2) Å
α= 113.175(2)°
β= 90.124(2)°
β= 91.7016(7)°
γ= 90°
γ = 114.999(23)°
3
Volume
7054.01(10) Å
1
1
121.08(4) Å
Z
16
3
3
Density (calculated)
1.594 Mg/m
1
.771 Mg/m
–1
Absorption coefficient
2.094 mm
3456
–1
8
.554 mm
F(000)
Crystal size
594
3
3
0.265x0.245x0.204 mm
0
.283x0.241x0.172 mm
Theta
range
for
data 3.667 to 76.929°.
4.750 to 76.943°.
collection
Index ranges
–10<=h<=8
–12<=h<=13
–14<=k<=14
–14<=l<=14
26567
–
–
30<=k<=30
44<=l<=43
Reflections collected
83314
Independent reflections
14831 [R(int) = 0.0256]
4685 [R(int) = 0.0237]
100.0 %
Completeness to theta = 100.0 %
7.684°
6
Absorption correction
Max. and min. transmission
Refinement method
Gaussian
0.750 and 0.660
Gaussian
0.396 and 0.193
2
Full–matrix least–squares
Full–matrix least–squares on F
2
on F
Data / restraints / parameters 14831 / 0 / 1013
4685 / 0 / 320
2
1

ACCEPTED MANUSCRIPT
2
1.027
1.062
R =0.0221, wR =0.0557
Goodness–of–fit on F
Final R indices [I>2sigma(I)] R =0.0450, wR =0.1225
1
2
1
2
R indices (all data)
R =0.0493, wR =0.1265
R =0.0226, wR =0.0559
1
2
1
2
Extinction coefficient
Largest diff. peak and hole
n/a
0.00149(11)
–
3
–3
0.610 and –0.477 e.Å
0
.402 and –0.585 e.Å
4
4
.3. Syntheses
.3.1. General procedure for the synthesis of 1–alkyl benzimidazoles (3a–b)
The synthesis of 1–alkyl benzimidazoles was carried out according to procedure reported in
the literature with minor modification [33]. A mixture of benzimidazole (0.11 g, 1.0 mmol)
and potassium hydroxide (0.06 g, 1.5 mmol) in minimum amount of DMSO was stirred at
o
1
00 C for 2 h. The temperature of the reaction mixture was reduced to room temperature and
alkyl bromide (1.0 mmol) was added and stirring was continued for further 2 h. Then the
reaction mixture was plunged into ice–cold water. The oily substance obtained was separated
by decantation and washed with water (3 x 10 mL) to eliminate unreacted starting materials
and DMSO. The product was then extracted using chloroform and reduced under high
vacuum to access pure (3a–b).
4
.3.2. Synthesis of 2–bromomethyl–1,3–benzoxazole (4)
Compound (4) was synthesized following the reported synthetic procedure with slight
modification [34]. A mixture of 2–aminophenol (0.1 g, 1.0 mmol), bromoacetic acid (0.16 g,
0
1
.2 mmol) and polyphosphoric acid (1.46 g, 15 mmol) were stirred at 130 C for 4 h. The
reaction mixture was then poured into water and the precipitate obtained was washed with
water (3 x 10 mL) and dried under vacuum to access pure (4).
4
.3.3. General experimental procedure for synthesis of 1–alkyl–3–(2–methyl–1,3–
benzoxazol)benzimidazolium bromide salts (5a–b)
A mixture of 1–alkyl benzimidazole (1.0 mmol) and 2–bromomethyl–1,3–benzoxazole (0.21
0
g, 1.0 mmol) was stirred at 100 C for 24 h in dioxane. The light brown precipitate yielded
2
2

ACCEPTED MANUSCRIPT
was separated by filtration and washed with fresh dioxane (3 x 10 mL) to obtain the
corresponding bromide salt (5a–b).
4
.3.3.1. Synthesis of 1–ethyl–3–(2–methyl–1,3–benzoxazol)benzimidazolium bromide (5a)
Compound (5a) was prepared using 1–ethyl benzimidazole (0.15 g, 1.0 mmol) according to
the general procedure. Light brown solid. Yield: 69%.
4
.3.3.2. Synthesis of 1–benzyl–3–(2–methyl–1,3–benzoxazol)benzimidazolium bromide (5b)
Compound (5b) was prepared using 1–benzyl benzimidazole (0.21 g, 1.0 mmol) according to
the general procedure. Light brown solid. Yield: 71%.
4
.3.4. General experimental procedure for synthesis of 1–alkyl–3–(2–methyl–1,3–
benzoxazol)benzimidazolium hexafluorophosphate salts (6a–b)
The benzimidazolium bromide salts (5a–b) were converted to the hexafluorophosphate
counterpart by treating the methanolic solution of (5a–b) with potassium
hexafluorophosphate (0.22 g, 1.2 mmol) in methanol:water mixture (9:1) for 4 h. The
reaction mixture was then plunged into water and the precipitate obtained was filtered,
washed with water followed by methanol and dried under vacuum to obtain pure
benzimidazolium hexafluorophosphate salts (6a–b).
4
.3.4.1.
Synthesis
of
1–ethyl–3–(2–methyl–1,3–benzoxazol)benzimidazolium
hexafluorophosphate (6a)
Compound (6a) was prepared from the benzimidazolium bromide salt (5a) (0.36 g, 1.0
1
mmol) according to the general procedure. White solid. Yield: 83%. H NMR (δ ppm,
DMSO–d , 400 MHz): 9.96 (s, 1H, NCHN), 8.13–8.11 (m, 2H, CHBenzimid), 7.74–7.69 (m,
6
4
H, CHBenzimid + CHBenzox), 7.44–7.37 (m, 2H, CHBenzox), 6.26 (s, 2H, CH2Benzox), 4.60 (q, J =
1
3
8
Hz, 2H, CH2Ethyl), 1.56 (t, J = 7.2 Hz, 3H, CH3Ethyl). C NMR (δ ppm DMSO–d , 100
6
MHz, proton decoupled): 160.1, 150.9, 143.4, 131.9, 131.2, 127.5, 127.2, 126.3, 125.4,
20.4, 114.3, 114.2, 111.5 (CBenzimid+ CBenzox), 140.5 (NCN), 44.0 (CH2Benzox), 42.9 (CH2Ethyl),
1
2
3

ACCEPTED MANUSCRIPT
–
1
1
4.4 (CH3Ethyl). ATR–IR (cm ): 2912.1 (w), 2941.7 (s), 1130.3 (m), 1593.2 (m), 1162.8 (m).
Micro Analysis: C H N OPF , Calculated: C, 48.2; H, 3.8; N, 9.9%. Found: C, 48.4; H, 3.6;
17
16
3
6
N, 9.8%.
.3.4.2.
hexafluorophosphate (6b)
4
Synthesis
of
1–benzyl–3–(2–methyl–1,3–benzoxazol)–benzimidazolium
Compound (6b) was prepared from the benzimidazolium bromide salt (5b) (0.42 g, 1.0
1
mmol) according to the general procedure. White solid. Yield: 85%. H NMR (δ ppm,
DMSO–d , 400 MHz): 10.05 (s, 1H, NCHN), 8.12–8.10 (m, 1H, CHBenzimid), 8.01 (d, J = 8.4
6
Hz, 1H, CHBenzimid), 7.76–7.74 (m, 2H, CHBenzimid), 7.70–7.68 (m, 2H, CHBenzox), 7.53–7.51
(m, 2H, CHBenzox), 7.44–7.37 (m, 5H, CHBenzyl), 6.28 (s, 2H, CH2Benzox), 5.85 (s, 2H,
1
3
CH2Benzyl), C NMR (δ ppm DMSO–d , 100 MHz, proton decoupled): 160.1, 151.0, 144.1,
6
1
34.1, 132.0, 131.2, 129.5, 129.3, 128.8, 127.6, 127.4, 126.3, 125.4, 120.4, 114.6, 114.5,
11.5 (CBenzimid + CBenzox + CBenzyl), 140.5 (NCN), 50.6 (CH2Benzox), 44.2 (CH2Benzyl). ATR–IR
1
–
1
(
cm ): 2930.1 (w), 1119.2 (m), 1562.2 (m), 1173.9 (m). Micro Analysis: C H N OPF ,
22 18 3 6
Calculated: C, 54.4; H, 3.7; N, 8.6%; Found: C, 54.5; H, 3.8; N, 8.7%.
4
.3.5. Synthesis of 1–(2–methyl–1,3–dioxolan)benzimidazole (8)
The synthesis of compound (8) was carried out according to procedure reported in the
literature with minor modification [33]. A mixture of benzimidazole (0.11 g, 1.0 mmol), 2–
methyl–1,3–dioxalane (0.17 g, 1.0 mmol) and potassium carbonate (0.21 g, 1.5 mmol) in
acetonitrile was stirred in room temperature for 72 h. Then the reaction mixture was washed
with fresh acetonitrile (3 x 10 mL) and dried under vacuum to access pure (8).
4
.3.6. General experimental procedure for synthesis of 1–(2–methyl–1,3–dioxalan)–3–alkyl–
benzimidazolium bromide (10a–b)
1
–(2–Methyl–1,3–dioxolan)benzimidazole (0.21 g, 1.0 mmol) was treated with excess alkyl
o
bromide (5.0 mmol) in dioxane at 100 C for 24 h. The white precipitate yielded was
2
4

ACCEPTED MANUSCRIPT
separated by filtration and washed with fresh dioxane (3 x 10 mL) to obtain pure
corresponding bromide salts (10a–b).
4
.3.6.1. Synthesis of 1–(2–methyl–1,3–dioxolan)–3–ethyl–benzimidazolium bromide (10a)
Compound (10a) was prepared according to the general procedure using excess ethyl
bromide (0.73 g. 5.0 mmol). White solid. Yield: 64%.
4
.3.6.2. Synthesis of 1–(2– methyl–1,3–dioxalan)–3–benzyl–benzimidazolium bromide (10b)
Compound (10b) was prepared according to the general procedure using excess benzyl
bromide (1.04 g. 5.0 mmol). White solid. Yield: 67 %.
4
.3.7. General experimental procedure for synthesis of 1–(2–methyl–1,3–dioxalan)–3–alkyl–
benzimidazolium hexafluorophosphate salts (11a–b)
The benzimidazolium bromide salts (10a–b) were converted to the hexafluorophosphate
counterpart by treated the methanolic solution of (10a–b) with potassium
hexafluorophosphate (0.22 g, 1.2 mmol) in methanol:water mixture (9:1) for 4 h. The
reaction mixture was then plunged into water and the precipitate obtained was filtered,
washed with methanol followed by water and dried under vacuum to obtain pure
benzimidazolium hexafluorophosphate salts (11a–b).
4
.3.7.1.
Synthesis
of
1–(2–methyl–1,3–dioxolan)–3–ethyl–benzimidazolium
hexafluorophosphate (11a)
Compound (11a) was prepared from the benzimidazolium bromide salt (10a) (0.31 g, 1.0
1
mmol) according to the general procedure. White solid. Yield: 83.1 %. H NMR (δ ppm,
CDCl , 400 MHz): 7.93 (s, 1H, NCHN), 7.84–7.76 (m, 1H, CHBenzimid), 7.39–7.37 (m, 1H,
3
CHBenzimid), 7.28–7.25 (m, 2H, CHBenzimid), 5.12–5.10 (m, 2H, CH2Diox), 4.23–4.17 (m, 1H,
CHDiox), 4.04–4.01 (m, 2H, CH2Ethyl), 3.98–3.90 (m, 4H, CH2Diox), 1.51 (t, J = 7.2 Hz, 3H,
1
3
CH3Ethyl) C NMR (δ ppm CDCl , 100 MHz, proton decoupled): 122.7, 122.0, 120.1, 109.5,
3
1
01.9, 65.6, 60.3 (CBenzimid + CDiox), 142.2 (NCN), 39.8 (CH2Diox), 32.4 (CH2Ethyl), 15.2
2
5

ACCEPTED MANUSCRIPT
–
1
(
CH3Ethyl). ATR–IR (cm ): 2959.8 (w), 2938.5 (m), 1147.2 (m), 1178.8 (m). Micro Analysis:
C H N O PF , Calculated: C, 41.2; H, 4.5; N, 7.4%; Found: C, 40.9; H, 4.6; N, 7.5%.
13
17
2
2
6
4
.3.7.2.
Synthesis
of
1–(2–methyl–1,3–dioxolan)–3–benzyl–benzimidazolium
hexafluorophosphate (11b)
Compound (11b) was prepared from the benzimidazolium bromide salt (10b) (0.37 g, 1.0
1
mmol) according to the general procedure. White solid. Yield: 85 %. H NMR (δ ppm,
DMSO–d , 400 MHz): 9.87 (s, 1H, NCHN), 8.07–8.05 (m, 1H, CHBenzimid), 7.94–7.92 (m,
6
1
2
H, CHBenzimid), 7.65–7.61 (m, 2H, CHBenzimid), 7.51–7.33 (m, 5H, CHBenzyl), 5.80–5.77 (m,
H, CH2Diox), 5.34–5.33 (m, 1H, CHDiox), 4.82 (s, 2H, CH2Benzyl), 3.79–3.61 (m, 4H, CH2Diox).
1
3
C NMR (δ ppm DMSO–d , 100 MHz, proton decoupled): 134.4, 132.6, 129.4, 129.2, 128.7,
6
1
28.5, 127.2, 127.1, 114.9, 114.4, 114.0, 100.2, 65.3 (CBenzimid+ CDiox), 143.1 (NCN), 50.3
–
1
(
CH2Diox), 48.2 (CH2Benzyl), ATR–IR (cm ): 2945.4 (w), 2923.0 (m), 1136.4 (m), 1458.8 (m),
1
4
4
164.9 (m). Micro Analysis: C H N O PF , Calculated: C, 49.1; H, 4.3; N, 6.3%; Found: C,
18 19 2 2 6
8.8; H, 4.4; N, 6.2%.
.3.8. General experimental procedure for synthesis of 1–alkyl–3–(2–methyl–1,3–
benzoxazol)benzimidazol–silver(I) acetate (12a–b)
A mixture of the benzimidazolium hexafluorophosphate salt (6a–b) (1.0 mmol) and silver(I)
acetate (0.33 g, 2.0 mmol) in methanol (20 mL) was stirred at room temperature for 4 h. The
reaction vessel was wrapped in aluminium foil to eliminate light. Then, the reaction mixture
was filtered through a Celite bed and the filtrate was reduced under vacuum to afford a light
brown solid. The solid was washed with excess diethyl ether and dried under vacuum to
obtain pure NHC–silver(I) acetate complexes (12a–b).
4
.3.8.1. Synthesis of 1–ethyl–3–(2–methyl–1,3–benzoxazol)benzimidazol–silver(I) acetate
(12a)
2
6

ACCEPTED MANUSCRIPT
Compound (12a) was prepared using the benzimidazolium hexafluorophosphate salt (6a)
1
(
0.42 g, 1.0 mmol) according to the general procedure. White solid. Yield: 62 %. H NMR (δ
ppm, DMSO–d , 400 MHz): 8.12–8.09 (m, 2H, CHBenzimid), 7.86–7.84 (m, 2H, CHBenzimid),
6
7
.75–7.64 (m, 2H, CHBenzox), 7.47–7.30 (m, 2H, CHBenzox), 6.23 (s, 2H, CH2Benzox), 4.61–4.53
13
(
m, 2H, CH2Ethyl), 1.55 (t, J = 7.2 Hz, 3H, CH3Ethyl), 1.42–1.39 (m, 3H, CHCOCH3). C NMR
(
δ ppm DMSO–d , 100 MHz, proton decoupled): 190.7(NCN), 160.1, 150.9, 143.4, 134.1,
6
1
33.2, 131.9, 127.5, 125.3, 124.8, 120.4, 114.3, 112.6, 111.4 (CBenzimid+ CBenzox), 46.0
–
1
(
CH2Benzox), 44.4 (CH2Ethyl), 21.7 (COCH ), 14.4 (CH3Ethyl). ATR–IR (cm ): 2931.6 (w),
3
2
952.3 (m), 1128.2 (s), 1581.8 (m), 1159.7 (m), 1701.6 (s). Micro Analysis: C H N O Ag,
19 18 3 3
Calculated: C, 51.3; H, 4.0; N, 9.4%; Found: C, 50.9; H, 4.1; N, 9.7%.
4
.3.8.2. Synthesis of 1–benzyl–3–(2–methyl–1,3–benzoxazol)benzimidazol–silver(I) acetate
(12b)
Compound (12b) was prepared using the benzimidazolium hexafluorophosphate salt (6b)
1
(
0.48 g, 1.0 mmol) according to the general procedure. White solid. Yield: 68 %. H NMR (δ
ppm, DMSO–d , 400 MHz): 7.81–7.73 (m, 2H, CHBenzimid), 7.62–7.58 (m, 2H, CHBenzimid),
6
7
2
.41–7.29 (m, 5H, CHBenzyl), 7.23–7.22 (m, 4H, CHBenzox), 6.24 (s, 2H, CH2Benzox), 5.78 (s,
13
H, CH2Benzyl), 1.72 (s, 3H, CHCOCH3), C NMR (δ ppm DMSO–d , 100 MHz, proton
6
decoupled): 174.8 (C=O), 161.7, 150.8, 140.6, 136.5, 134.3, 133.6, 129.1, 128.4, 127.9,
26.0, 125.2, 124.8, 124.7, 120.3, 112.9, 112.8, 111.3 (CBenzimid + CBenzox + CBenzyl), 52.5
1
–
1
(
CH2Benzox), 46.3 (CH2Benzyl) 24.0 (COCH ). ATR–IR (cm ): 2949.9 (w), 1129.4 (m), 1573.2
3
(
s), 1168.3 (m), 1713.9 (m). Micro Analysis: C H N O Ag, Calculated: C, 56.9; H, 3.9; N,
2
4
20
3
3
8
4
.3%; Found: C, 56.7; H, 3.9; N, 8.1%.
.3.9. General experimental procedure for synthesis of bis–[1–alkyl–3–(2–methyl–1,3–
benzoxazol)benzimidazol]–silver(I) hexafluorophosphate (13a–b)
2
7

ACCEPTED MANUSCRIPT
A mixture of the benzimidazolium hexafluorophosphate salt (6a–b) (1.0 mmol) and silver(I)
oxide (0.27 g, 1.2 mmol) was stirred at room temperature for 4 h in acetonitrile (20 mL). The
reaction vessel was wrapped in aluminium foil to eliminate light. Then, the reaction mixture
was filtered through a Celite bed and the filtrate was reduced under vacuum to afford a light
brown solid. The solid was washed with excess diethyl ether and dried under vacuum to
obtain pure bis–NHC–silver(I) complexes (13a–b).
4
.3.9.1. Synthesis of bis–[1–ethyl–3–(2–methyl–1,3–benzoxazol)benzimidazol]–silver(I)
hexafluorophosphate (13a)
Compound (13a) was prepared using the benzimidazolium hexafluorophosphate salt (6a)
1
(
0.42 g, 1.0 mmol) according to the general procedure. Light brown solid. Yield: 70.1 %. H
NMR (δ ppm, DMSO–d , 400 MHz): 7.86–7.84 (m, 2H, CHBenzimid), 7.67–7.64 (m, 2H,
6
CHBenzimid), 7.47–7.45 (m, 2H, CHBenzox), 7.36–7.32 (m, 2H, CHBenzox), 6.23 (s, 2H,
1
3
CH2Benzox), 4.56 (m, 2H, CH2Ethyl), 1.43–1.39 (m, 3H, CH3Ethyl). C NMR (δ ppm DMSO–d ,
6
1
1
1
00 MHz, proton decoupled): 190.6 (NCN), 162.1, 150.8, 140.4, 134.1, 133.2, 126.2, 125.3,
24.8, 124.7, 120.3 112.6, 112.5, 111.4 (CBenzimid + CBenzox), 46.1 (CH2Benzox), 44.4 (CH2Ethyl),
–
1
6.2 (CH3Ethyl). ATR–IR (cm ): 2923.8 (w), 2948.3 (m), 1119.7 (m), 1591.5 (m), 1158.3 (s).
Micro Analysis: C H N O P F Ag , Calculated: C, 38.4; H, 2.9; N, 7.9 %; Found: C, 38.9;
3
4
31
6
2
2
12
2
H, 3.3; N, 8.2 %.
.3.9.2. Synthesis of bis–[1–benzyl–3–(2–methyl–1,3–benzoxazol)benzimidazol]–silver(I)
4
hexafluorophosphate (13b)
Compound (13b) was prepared using the benzimidazolium hexafluorophosphate salt (6b)
1
(
0.48 g, 1.0 mmol) according to the general procedure. Light brown solid. Yield: 72.4 %. H
NMR (δ ppm, DMSO–d , 400 MHz): 7.85–7.83 (m, 1H, CHBenzimid), 7.74–7.72 (m, 1H,
6
CHBenzimid), 7.62–7.44 (m, 2H, CHBenzimid), 7.43–7.28 (m, 4H, CHBenzox), 7.25–7.21 (m, 5H,
1
3
CHBenzyl), 6.25 (s, 2H, CH2Benzox), 5.78 (s, 2H, CH2Benzyl), C NMR (δ ppm DMSO–d , 100
6
2
8

ACCEPTED MANUSCRIPT
MHz, proton decoupled): 191.8 (NCN), 161.9, 150.8, 140.5, 136.5, 134.3, 133.6, 129.1,
1
28.4, 127.8, 126.1, 125.2, 124.9, 124.8, 120.2, 112.9, 112.8, 111.3 (CBenzimid + CBenzox +
–
1
CBenzyl), 56.4 (CH2Benzox), 52.4 (CH2Benzyl). ATR–IR (cm ): 2953.2 (w), 1131.6 (m), 1592.2
(
s), 1164.7 (m). Micro Analysis: C H N O P F Ag , Calculated: C, 44.5; H, 2.9; N, 7.0%;
44 35 6 2 2 12 2
Found: C, 44.2; H, 2.7; N, 8.3 %.
4
.3.10. General experimental procedure for synthesis of 1–(2–methyl–1,3–dioxalan)–3–
alkyl– benzimidazol–silver(I) acetate (14a–b)
,3–Dioxalane substituted benzimidazole based NHC–silver(I) complexes (14a–b) were
synthesized following a similar procedure as the 1,3–benzoxazole substituted counterparts.
.3.10.1. Synthesis of 1–(2–methyl–1,3–dioxalan)–3–ethyl–benzimidazol– silver(I) acetate
14a)
1
4
(
Compound (14a) was prepared using the benzimidazolium hexafluorophosphate salt (11a)
1
(
0.38 g, 1.0 mmol) according to the general procedure. White solid. Yield: 68%. H NMR (δ
ppm, CDCl , 400 MHz): 7.63–7.56 (m, 2H, CHBenzimid), 7.23–7.15 (m, 2H, CHBenzimid), 5.06–
3
5
.04 (m, 2H, CH2Diox), 4.27–4.20 (m, 1H, CHDiox), 3.95–3.80 (m, 2H, CH2Ethyl), 3.49–3.48
13
(
m, 4H, CH2Diox), 1.88 (s, 3H, CHCOCH3), 1.38 (t, J = 7.2 Hz, 3H, CH3Ethyl) C NMR (δ ppm
CDCl , 100 MHz, proton decoupled): 133.9, 122.5, 121.8, 119.8, 110.7, 101.5, 65.3 (C
3
Benzimid
–
1
+
CDiox), 33.9 (COCH ), 15.6 (CH
). ATR–IR (cm ): 2951.5 (w), 2948.9 (w), 1139.3 (m),
3
3Ethyl
1
181.8 (s), 1709.7 (m). Micro Analysis: C H N O Ag, Calculated: C, 45.1; H, 4.8; N, 7.0%;
15 19 2 4
Found: C, 45.1; H, 5.0; N, 7.1%.
4
.3.10.2. Synthesis of 1–(2–methyl–1,3–dioxalan)–3–benzyl–benzimidazol–silver(I) acetate
(14b)
Compound (14b) was prepared using the benzimidazolium hexafluorophosphate salt (11b)
1
(
0.44 g) according to the general procedure. White solid. Yield: 72%. H NMR (δ ppm,
DMSO–d , 400 MHz): 7.81–7.79 (d, J = 8 Hz, 1H, CHBenzimid), 7.68–7.66 (d, J = 8 Hz, 1H,
6
2
9