Novel derivatives of the antibiotic NHC–Ag(I) drug candidate SBC3: Synthesis, biological evaluation and 109Ag NMR studies

Article abstract of DOI:10.1016/j.poly.2018.04.017

The synthesis of six novel N-heterocyclic carbene silver(I) acetate complexes, three symmetrical and three non-symmetrical, were achieved using 4,5-diphenylimidazole to produce intermediate imidazolium salts and then obtain the corresponding silver(I) com

Full text of DOI:10.1016/j.poly.2018.04.017

Accepted Manuscript
Novel derivatives of the antibiotic NHC-Ag(I) drug candidate SBC3: Synthesis,
biological evaluation and 109Ag NMR studies
Cillian O'Beirne, Hessah T. Althani, Oyinlola Dada, Jennifer Cassidy, Kevin
Kavanagh, Helge Müller-Bunz, Yannick Ortin, Xiangming Zhu, Matthias Tacke
PII:
S0277-5387(18)30185-2
https://doi.org/10.1016/j.poly.2018.04.017
POLY 13119
DOI:
Reference:
Polyhedron
To appear in:
Received Date:
Accepted Date:
20 February 2018
12 April 2018
Please cite this article as: C. O'Beirne, H.T. Althani, O. Dada, J. Cassidy, K. Kavanagh, H. Müller-Bunz, Y. Ortin,
X. Zhu, M. Tacke, Novel derivatives of the antibiotic NHC-Ag(I) drug candidate SBC3: Synthesis, biological
evaluation and 109Ag NMR studies, Polyhedron (2018), doi: https://doi.org/10.1016/j.poly.2018.04.017
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Novel derivatives of the antibiotic NHC-Ag(I) drug candidate SBC3:
Synthesis, biological evaluation and 109Ag NMR studies
Cillian O’Beirne1, Hessah T. Althani1, Oyinlola Dada1, Jennifer Cassidy1, Kevin Kavanagh2,
Helge Müller-Bunz1, Yannick Ortin1, Xiangming Zhu1, and Matthias Tacke1*
1School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland
2Department of Biology, NUI Maynooth, Ireland
*Correspondence to: matthias.tacke@ucd.ie
___
The synthesis of six novel N-heterocyclic carbene silver(I) acetate complexes, three symmetrical and
three non-symmetrical, were achieved using 4,5-diphenylimidazole to produce intermediate
imidazolium salts and then obtain the corresponding silver(I) complexes through complexation with
silver acetate via the Youngs’ method. In vitro biological testing, using the Kirby-Bauer disk diffusion
method, was conducted against Methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia
coli, with a NHC-silver(I) acetate compound, SBC3, and Tetracycline as standards. Silver(I) acetate
complex 7 resulted in a 4 mm clearance against MRSA, showing the highest antibiotic activity of the
novel derivatives. Crystallographic data revealed similar bond lengths and angles to previously
reported NHC-silver(I) acetate complexes, with complex 8 showing interesting η2-coordination
between the silver atom and acetate oxygens. 109Ag NMR studies were conducted, highlighting the
effects of the substituents of the imidazole ring on the silver atom shown by the corresponding shifts
in the 109Ag NMR spectra. The incorporation of isopropyl groups to several of the novel complexes
resulted in larger upfield 109Ag NMR shift values compared to all other substituents.
________
___
___
Keywords: NHC-silver(I) acetate complexes; MRSA; antibiotic resistance; 109Ag NMR; XRD structures.
Introduction:
Antimicrobial resistance has become a global phenomenon1,2 and with cornerstone antibiotic classes
becoming less effective3,4 there is increasing need for new resistance breaking antibiotic compounds.
In order to overcome developing resistance, future generation of antibiotics will have to employ
multiple mechanisms of action to decrease the chance of such resistance developing, as well as
break current resistant strains.5
For this purpose, silver is a reliable choice for incorporation into a new antibiotic class. With recent
research highlighting that its combination with frontline antibiotics can increase their potency.6 The
decades of clinical use as burn wound creams have resulted in infrequent reports of sustained silver
resistance, which could be contributed to silver’s multiple mechanisms of bactericidal action,
including transport protein disruption and redox enzyme inhibition.7,8
To utilise and enhance silver’s proven antibiotic ability, N-heterocyclic carbenes (NHCs) can be
incorporated as supplementary biomolecules. Since the isolation of a stable, singlet carbene by
Arduengo,9 N-heterocyclic carbene research has dramatically increased in areas of catalysis and
medicinal chemistry.12 The work of Youngs in the mid-2000’s then highlighted the usage of NHC-
silver(I) acetate compounds derived from xanthine against bacterial pathogens in the lungs.10 Since

this work, the knowledge base of NHC-Ag(I) complexes has been greatly expanded and reviewed
extensively.11,12,22
In order to increase antibacterial ability, the transport of NHC-silver(I) complexes into bacterial cells
24-28
is an important factor. The large derivability of imidazole-based NHCs15,
allows for the
incorporation of substituent groups that can bestow improved bioavailability and electronically
influence the slow release of silver cations in the intracellular environment through the strong σ-
bonding of the NHC.13
Lipophilic character of the stabilising NHC ligand has been shown to be a key characteristic in NHC-
Au(I) anticancer compounds.14,21 Previous research by our group has led to the hypothesis that
lipophilic substituents are a large factor by which the antibiotic compound SBC3, a silver(I) complex
containing four lipophilic phenyl rings (Fig. 1)15, is so effective against gram-positive bacteria such as
Staphylococcus aureus and its widespread resistant strain, Methicillin-resistant Staphylococcus
aureus (MRSA).16,17
In an attempt to increase the antibacterial activity of this NHC-silver(I) acetate compound class, the
molecular weight was decreased in six new NHC-silver(I) acetate compound. The incorporation of
lower molecular weight alkyl chains will improve the drug-like character of the new complexes,18
whilst retaining some lipophilic character that is hypothesized to make the previous SBC3 complex
so effective.15 To assess this hypothesis, all complexes were tested for antibacterial activity using the
Kirby-Bauer disk diffusion method against MRSA and Escherichia coli.19
Fig. 1; 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene silver(I) acetate (SBC3)15
In addition to the synthesis and testing of these novel NHC-silver(I) complexes, 109Ag NMR studies
were conducted. Silver has two isotopes, 107Ag and 109Ag, each with a spin of ½ and although 107Ag
has a slightly higher natural abundance compared to 109Ag (51.8% versus 48.2%, respectively), the
NMR studies are usually done using the 109Ag isotope as it has a higher gyromagnetic ratio. Even if
the largest problems remain the low sensitivity and long relaxation times of the silver isotopes,23 the
use of 109Ag NMR studies could determine interesting analytical information for this class of NHC-
silver(I) compounds.
Crystal structures were obtained for all complexes 3 – 8 and structural information will be reviewed
for any influence on the characteristic bonds observed in these types of NHC-silver(I) complexes. The
η2-coordination between the silver(I) moiety and acetate oxygens are two and the possible
argentophilic interactions are two notable phenomena that have previously been reported and were
surveyed for in this work.15,24-28

Experimental
General Considerations
Unless otherwise stated in the synthesis procedures, all chemicals and solvents were used as
supplied from commercial sources without further purification or drying. The melting points of the
corresponding compounds were measured using a Stuart™ melting point apparatus SMP10, AC input
1
230V and were uncorrected. H and 13C NMR spectra were obtained at room temperature on a
Varian VnmrS 400 MHz spectrometer and 109Ag NMR spectra were obtained on an Agilent DD2 500
MHz spectrometer. All NMR data was collected using CDCl3 as deuterated solvent which contains
0.03% (v/v) TMS. 1H NMR chemical shifts were referenced to TMS. All other spectra were referenced
using absolute referencing from a referenced proton spectrum. For obtaining 109Ag NMR spectra, a
1H NMR measurement was simultaneously obtained using CDCl3 as the deuterated solvent and
Tetramethylsilane (TMS) as internal references. Total elemental analysis was undertaken using an
Exeter Analytical CE-440 elemental analyser. Infrared spectra were obtained using a Bruker ALPHA
Platinum ATR spectrometer.
Synthesis
All synthesis procedures carried out at over 100oC were undertaken in sealed, pressurised
containers. All silver complex synthesises were carried out under nitrogen and in lightproof flasks.
Several silver complexes were purified using Davisil® 40-63 micron silica using pencil columns
fashioned from Pasteur pipettes, with dichloromethane used as the eluent.
Synthesis of 1-methyl-3-benzyl-4,5-diphenylimidazolium bromide (1)
1-Methyl-4,5-diphenyl Imidazole (0.234 g, 1.00 mmol) and benzyl bromide (0.12 ml, 1.00 mmol)
were placed in 30 ml acetonitrile and stirred under reflux at 85oC for 24 h. The solution was filtered
and washed with 10 ml acetonitrile. The filtrate was concentrated down to 3 ml and then 50 ml
diethyl ether was added. The product was then filtered and dried in vacuo for 2 h to produce an off-
white solid. (0.367 g, 90% yield).
1H NMR (399.899 MHz, CDCl3, ppm): 11.00 (1H, NCHN, s), 7.48 – 7.36 (6H, CHArom, m), 7.28 – 7.27 (3H, CHArom
m), 7.22 (2H, CHArom, dd, 8, 1.5 Hz), 7.16 – 7.12 (4H, CHArom, m), 5.48 (2H, CH2, s), 3.96 (3H, CH3, s)
,
13C NMR (100.553 MHz, CDCl3, ppm): 137.8, 133.2, 132.5, 131.7, 130.8, 130.5, 130.4, 130.2, 129.3, 129.2,
129.1, 128.6, 124.8, 124.4 (CArom), 51.2 (CH2), 35.1 (CH3)
Elemental Analysis calculated for C23H21N2Br: Calculated: C, 68.15; H, 5.22; N, 6.91; Found: C, 67.80; H, 5.15;
N, 6.63
IR (KBr, cm-1): 3117 (w), 2998 (w,v), 1560 (w), 1441 (w), 766 (m), 736 (m), 700 (s), 517 (w), 463 (w)
Melting point: 239 – 240 oC
Synthesis of 1-isopropyl-3-benzyl-4,5-diphenylimidazolium bromide (2)
1-Isopropyl-4,5-diphenyl Imidazole (0.262 g, 1.00 mmol) and benzyl bromide (0.14 ml, 1.2 mmol)
were placed in 20 ml acetonitrile and stirred for 3 d. The solution was filtered and washed with 10 ml
acetonitrile. The filtrate was concentrated down to 3 ml and 80 ml diethyl ether was added. The
resulting precipitate was allowed to settle for 10 min before being filtered in vacuo for 2 h to
retrieve an off-white solid. (0.230 g, 54% yield).

1H NMR (399.899 MHz, CDCl3, ppm): 11.25 (1H, NCHN, s), 7.46 – 7.31 (6H, CHArom, m), 7.25 – 7.20 (5H, CHArom
,
m), 7.15 – 7.10 (4H, CHArom, m), 5.67 (2H, CH2, s), 4.45 (1H, CHIsopropyl, Hept, 7 Hz), 1.70 (6H, CH3Isopropyl, d, 1.5
Hz)
13C NMR (100.553 MHz, CDCl3, ppm): 136.0, 133.8, 131.8, 131.5, 130.8, 130.5, 130.4, 130.4, 129.2, 129.1,
128.9, 128.8, 125.0, 124.4 (CArom), 51.6 (CH Isopropyl), 51.1 (CH2 Benzyl), 23.5 (CH3 Isopropyl
)
Elemental Analysis calculated for C25H25N2Br: Calculated: C, 69.28; H, 5.81; N, 6.46; Found: C, 68.35; H, 5.71;
N, 6.43
IR (KBr, cm-1): 3095 (w), 2973 (w,v), 1547 (m), 1452 (w), 1183 (w), 769 (m), 737 (s), 706 (m,v), 521 (w), 459
(w)
Melting point: 217 – 218 oC
General procedure for silver(I) complexes 3 – 8
1.00 mmol of precursor imidazolium salt was stirred with 2.00 mmol of silver acetate (0.333 g) in 50
ml of dry dichloromethane for 3 d. The reaction mixture was filtered, concentrated to 3 ml and 50 ml
o
diethyl ether was added. The resulting solution was placed in a freezer at -4 C for 12 h and the
resulting solid filtered and dried in vacuo for 4 h to yield complexes 3 – 8.
Synthesis of 1,3-dimethyl-4,5-diphenylimidazol-2-ylidene silver(I) acetate (3)
Silver(I) complex 3 was prepared as an off white solid. (0.227 g, mmol, 55% yield).
1H NMR (399.899 MHz, CDCl3, ppm): 7.36 – 7.34 (6H, CHArom, dd, 5, 2 Hz), 7.19 – 7.16 (4H, CHArom, m), 3.73
(6H, CH3Methyl, s), 2.11 (3H, CH3 AgOAc, s)
13C NMR (100.553 MHz, CDCl3, ppm): 179.2 (NCN), 132.2, 130.3, 129.1, 128.8, 127.9 (CArom), 37.5 (CMethyl), 22.9
(CAgOAc
)
109Ag NMR (23.278 MHz, CDCl3, ppm): 476
Elemental Analysis calculated for C19H19N2AgO2: Calculated: C, 54.96; H, 4.61; N, 6.75; Found: C, 54.00; H,
4.46; N, 6.55
IR (KBr, cm-1): 3535 (w,v), 3053 (w,v), 2951 (w,v), 1567 (s), 1374 (s), 1328 (s), 1012 (w), 765 (s), 698(s), 664 (s),
625 (s), 515 (m,v)
Melting point: 198 – 201 oC
Synthesis of 1,3-diethyl-4,5-diphenylimidazol-2-ylidene silver(I) acetate (4)
Silver(I) complex 4, was prepared as a light brown solid. (0.156 g, 36% yield).
1H NMR (399.899 MHz, CDCl3, ppm): 7.35 – 7.33 (6H, CHArom, dd, 5, 2 Hz), 7.20 – 7.18 (4H, CHArom, m), 4.13
(4H, CH2 Ethyl, q, 7 Hz), 2.12 (3H, CH3 AgOAc, s), 1.23 (6H, CH3 Ethyl, t, 7 Hz)
13C NMR (100.553 MHz, CDCl3, ppm): 179.2 (NCN), 131.6, 130.4, 129.1, 128.7, 128.2 (CArom), 44.9 (CH2 Ethyl),
22.9 (CH3 AgOAc), 17.3 (CH3 Ethyl
)
109Ag NMR (23.278 MHz, CDCl3, ppm): 480
Elemental Analysis calculated for C21H23N2AgO2: Calculated: C, 56.89; H, 5.22; N, 6.31; Found: C, 57.35; H,
5.31; N, 6.12
IR (KBr, cm-1): 3052 (w,v), 2925 (w,v), 1578 (m,v), 1400 (m), 1340 (m,v), 767 (w,v), 699 (s), 666(m)
Melting point: 212 – 215 oC

Synthesis of 1,3-diisopropyl-4,5-diphenylimidazol-2-ylidene silver(I) acetate (5)
Silver(I) complex 5, was prepared as a light brown solid. (0.120 g, 26% yield).
1H NMR (399.899 MHz, CDCl3, ppm): 7.34-7.31 (CHArom, 6H, m), 7.17-7.14 (CHArom, 4H, m), 4.40 (CHIsopropyl, 2H,
7 Hz, hept), 2.13 (CH3AgOAc, 3H, s), 1.66 (CH3 Isopropyl, 12H, 7 Hz, d)
13C NMR (100.553 MHz, CDCl3, ppm): 178.8 (NCN); 130.8, 128.9, 128.6, 128.4 (CArom), 50.2 (CHIsopropyl), 24.7
(CH3 Isopropyl), 22.8 (CH3 AgOAc
)
109Ag NMR (23.278 MHz, CDCl3, ppm): 533
Elemental Analysis calculated for C23H27N2AgO2: Calculated: C, 58.60; H, 5.77; N, 5.94; Found: C, 58.83; H,
5.85; N, 5.87
IR (KBr, cm-1): 3055 (w,v), 2973 (w,v), 1715 (w), 1368 (m), 1329 (m), 1113 (w), 760 (m), 699 (s), 616 (m), 523
(w)
Melting point: 178 oC
Synthesis of 1-isopropyl-3-methyl-4,5-diphenylimidazol-2-ylidene silver(I) acetate (6)
Silver(I) complex 6, was prepared as a light brown solid. (0.110 g, 24% yield).
1H NMR (399.899 MHz, CDCl3, ppm): 7.37 – 7.31 (6H, CHArom, m), 7.18 – 7.15 (4H, CHArom, m), 4.34 (1H,
CHIsopropyl, Pent, 7 Hz), 3.78 (3H, CH3 Methyl, s), 2.12 (3H, CH3 AgOAc), 1.65 (6H, CH3 Isopropyl, d, 7 Hz)
13C NMR (100.553 MHz, CDCl3, ppm): 179.1 (NCN), 130.8, 130.2, 129.2, 128.9, 128.8, 128.6, 128.0 (CArom), 49.9
(CH2 Benzyl), 24.8 (CH3 Isopropyl), 22.9 (CH3 AgOAc
)
109Ag NMR (23.278 MHz, CDCl3, ppm): 499
Elemental Analysis calculated for C21H23N2AgO2: Calculated: C, 56.88; H, 5.23; N, 6.32; Found: C, 56.55; H,
5.19; N, 6.40
IR (KBr, cm-1): 3655 (w), 3056 (w,v), 2975 (w,v), 1568 (m), 1378 (m,v), 1328 (m,v), 765 (m), 699 (s), 665 (m),
526 (w)
Melting point: 195 – 200 oC
Synthesis of 1-methyl-3-benzyl-4,5-diphenylimidazol-2-ylidene silver(I) acetate (7)
Silver(I) complex 7, was prepared as a light brown solid. (0.130 g, 26% yield).
1H NMR (399.899 MHz, CDCl3, ppm): 7.34 – 7.30 (4H, CHArom, m), 7.27 – 7.21 (5H, CHArom, m), 7.18 – 7.15 (2H,
CHArom, m), 7.02 – 6.97 (2H, CHArom, m), 5.27 (2H, CH2 Benzyl, s), 3.78 (3H, CH3 Methyl, s), 2.09 (3H, CH3 AgOAc, s)
13C NMR (100.553 MHz, CDCl3, ppm): 178.8 (NCN), 136.2, 132.7, 132.1, 130.77, 130.3, 129.2, 129.1, 128.7,
128.6, 127.9, 127.9, 127.7, 127.5 (CArom), 53.4 (CBenzyl), 37.8 (CMethyl), 22.5 (CAgOac
)
109Ag NMR (23.278 MHz, CDCl3, ppm): 476
Elemental Analysis calculated for C27H27N2AgO2: Calculated: C, 61.77; H, 4.71; N, 5.70; Found: C, 60.82; H,
4.71; N, 5.50
IR (KBr, cm-1): 3054 (w,v), 2920 (w,v) 1704 (w), 1573 (m,v), 1379 (m), 1257 (m), 735 (s,v), 696 (s), 617 (m), 514
(w)
Melting point: 118 – 120 oC
Synthesis of 1-isopropyl-3-benzyl-4,5-diphenylimidazol-2-ylidene silver(I) acetate (8)
Silver(I) complex 8, was prepared as a light brown solid. (0.060 g, 12% yield).
1H NMR (399.899 MHz, CDCl3, ppm): 7.35 – 7.29 (4H, CHArom, m), 7.24 – 7.20 (5H, CHArom, m), 7.17 – 7.15 (2H,
CHArom, m), 7.00 – 6.94 (4H, CHArom, ddd, 12, 7.5, 2.5 Hz), 5.33 (2H, CHBenzyl, s), 4.39 (1H, CHIsopropyl, hept, 7 Hz),
2.10 (3H, CH3 AgOAc, s), 1.70 (6H, CH3 Isopropyl, d, 7 Hz)

13C NMR (100.553 MHz, CDCl3, ppm): 179.0 (NCN), 136.3, 130.8, 130.7, 129.2, 128.9, 128.7, 128.6, 128.5,
128.0, 127.9, 127.9, 127.3 (CArom), 54.5 (CBenzyl), 50.1 (CHisopropyl), 24.8 (CH3 isopropyl), 22.8 (CAgOAc
)
109Ag NMR (23.278 MHz, CDCl3, ppm): 506
Elemental Analysis calculated for C27H27N2AgO2: Calculated: C, 62.43; H, 5.23; N, 5.39; Found: C, 62.05; H,
5.08; N, 5.16
IR (KBr, cm-1): 3056 (w,v), 2972 (w,v), 1716 (w), 1570 (m), 1375 (m), 1329 (m), 700 (s), 666 (s), 617 (m), 576
(m)
Melting point: 176 – 178 oC
Antibacterial Studies
Preliminary in vitro biological studies were carried out to assess the antibacterial effect of the newly
synthesised symmetrical and non-symmetrical derivatives of SBC3 against two pathogenic bacterial
strains. Methicillin-Resistant Staphylococcus aureus (ATCC 43300) was chosen as the Gram-positive
bacterial test strain and Escherichia coli (ATCC 25922) chosen as the Gram-negative bacterial test
strain.
To test the biological activity of the novel complexes, 3–8, the Kirby-Bauer disk diffusion method was
used.19 Both bacterial strains were cultured in 2 ml LB medium from single colonies at 37oC for 24
hours whilst shaking. All antibacterial work was carried out under sterile conditions.
For both bacterial strains, 50 µL of culture was spread over agar-LB medium in a petri plate. To each
plate, 5.5 mm Whatman paper disks were evenly placed into four marked quadrants. Stock solutions
of 1 mg/ml of each silver complex in DMSO were made, with two volumes of 5 µL and 10 µL tested
for each complex against both bacterial strains.
DMSO, without the addition of a silver complex, was used with each round of testing as a control in
5 µL and 10 µL volumes. Plates were covered and incubated at 37oC for 24 hours. The area of
clearance is defined as the distance between the beginning of bacterial growth and the edge of the
Whatman disk; the area of inhibition was measured in millimetres (mm).
Results and Discussion:
Synthesis
With the objective of understanding the influence of changing non-polar substituents at the 1 and 3
position of the SBC3 silver(I) complex (Fig. 1), a series of NHC imidazolium salts were synthesized and
their corresponding silver(I) complexes were produced. With the incorporation of the silver acetate
moiety as the primary antimicrobial agent, the derivatisation of the NHC imidazole backbone was a
logical step to try and increase the biological efficacy.
By incorporating alkyl chains at the 1 and 3 positions of the imidazole ring, lower molecular weight
silver(I) complexes were synthesized to increase the ‘drug-like’ character of this class. Six novel lower
weight derivatives of the SBC3 molecule have been synthesized (Scheme 1) and tested for antibiotic
activity. All silver complexes were characterised by spectroscopic and analytical methods, with
elemental analysis of C, H, N, and crystal structure data obtained for certainty of structure and
purity.

Dichloromethane
2 eq. AgOAc
Acetonitrile
1 - 3 d
-AgX(s)
-HOAc
3. R / R1 = CH3
R = CH3/ CH2CH3/ CH(CH3)2
R
= H / CH3 / CH(CH3)2
4. R / R1 = CH2CH3
R1 = CH3/ CH2CH3/ CH(CH3)2/ CH2(C6H5)
X = I / Br
R1 = CH3 / CH2CH3 / CH(CH3)2 /
CH2(C6H5)
5. R / R1 = CH(CH3)2
6. R = CH(CH3)2, R1 = CH3
7. R = CH3, R1 = CH2(C6H5)
8. R = CH(CH3)2, R1 = CH2(C6H5)
X = Br / I
1. R = CH3, R1 = CH2(C6H5); X = Br
2. R = CH(CH3)2, R1 = CH2(C6H5); X = Br
Scheme 1; Synthesis of symmetrical and non-symmetrical imidazolium salt precursors, and their
corresponding NHC-silver(I) complexes 3 – 8
Using 4,5-diphenyl imidazole as the starting material, the mono-alkylated imidazoles of 1-methyl and
1-isopropyl-4,5-diphenyl imidazole were synthesized by adjusted literature methods20; both were
confirmed by NMR spectroscopy and elemental analysis.
The symmetrical imidazolium salt precursors of complexes 3, 4 & 5 were synthesized under high
pressure and high temperature conditions with 4,5-diphenyl imidazole and potassium carbonate
added to a teflon container with a small amount of acetonitrile. The corresponding ligand
(iodomethane; bromoethane; 2-bromopropane) was then injected before the container was sealed
in a stainless steel casing and heated at 120oC for 3 days. All reactions were filtered, concentrated
and precipitated from solution using diethyl ether in yields of 81%, 89% and 85% for the precursors
of silver(I) complexes 3, 4 and 5, respectively. All imidazolium salts were confirmed through NMR
spectroscopy and elemental analysis and compared to literature values.20,29,30
The non-symmetrical imidazolium salt precursors of complexes 6, 7 & 8 were synthesized from the
previously mentioned mono-alkylated imidazoles. The precursor imidazolium salt to complex 6 was
synthesized using the same high pressure and high temperature conditions and the same workup
procedure as for the salt precursors of 3, 4 & 5; the imidazolium salt was confirmed by NMR
spectroscopy, elemental analysis and compared to literature values.20 The precursor imidazolium
salt for silver(I) complex 7 was synthesized by refluxing 1-methyl-4,5-diphenyl imidazole and benzyl
bromide for 24 hours, and worked up as the other precursor salts to obtain the desired product in
90% yield. The precursor imidazolium salt for silver(I) complex 8 was synthesized by stirring 1-
isopropyl-4,5-diphenyl imidazole and benzyl bromide for 3 days at room temperature. The reaction
was worked up as the other precursor salts to obtain the desired imidazolium salt in 54% yield.
The corresponding silver(I) acetate complexes, 3 - 8, were all synthesized by stirring the respective
precursor imidazolium salt with two equivalents of silver acetate in dry dichloromethane, under
nitrogen, in a lightproof flask for 3 days. All products were filtered, washed with dry
dichloromethane, concentrated and precipitated with diethyl ether. All complexes were placed in a -
4oC freezer for 12 hours to allow greater precipitation to achieve yields between 12% - 54%. Several
of the imidazolium salts proved less reactive than others with silver acetate under these conditions,
and the corresponding silver(I) complexes (4, 6, 7, 8) required post-precipitation purification using a
pencil column, made from a cotton wool bud and one inch of Davisil® 40- 63 micron silica inside a
Pasteur pipette.

The precursor imidazolium salt to the SBC3 molecule was synthesized in an improved yield of 98%
using a modified literature method.15 4,5-Diphenyl imidazole and 2.2 equivalents of benzyl bromide
o
were reacted under reflux at 85 C for 24 hours in 50 ml acetonitrile and worked up as previous
precursor salts. The SBC3 molecule was synthesized by literature method in a yield of 59% by
reacting silver acetate with the precursor imidazolium salt in dry dichloromethane for 3 days at room
temperature, in darkness. The complex was worked up as the other silver(I) complexes.
NMR spectroscopy
1
All of the imidazolium salt intermediates and silver(I) complexes were fully characterised by H, 13C
NMR spectroscopy, along with further analysis by 109Ag NMR spectroscopy for the silver(I)
complexes. All previously published imidazoles and imidazolium salts were confirmed by
comparison with literature values.15,20,27,28
In the case of the imidazolium salts, a singlet peak can be clearly seen on the 1H spectra in the range
of δ = 10.38 – 11.39 ppm. This corresponds to literature values for imidazolium salts with halogen
anions (Br-, I-)15,19,24-28, as the proton attached to the carbene carbon of the imidazole ring becomes
deshielded due to the positive nature of the imidazolium and presence of the anionic halide counter
ion.10
For all silver(I) complexes, there is the distinctive loss of the carbene proton signal in the range δ =
10.38 – 11.39 ppm, and there is the presence of the new silver acetate CH3 singlet peak in the range
δ = 2.09 – 2.13 ppm.
For complexes 3 to 8, the 13C resonances for the carbene carbon fall within the region of δ = 177.0 –
179.2 ppm, as seen in previous publication.15 Along with the shifted carbene signals, the silver
acetate CH3 group is the other characteristic peak that is present in the 13C NMR spectrum after
complexation, falling in the range of δ = 22.5 – 22.9 ppm.
109Ag NMR was conducted on all silver complexes and the corresponding broad resonance peaks (δ
ppm) were found, as shown in Table 1. The NMR resonances of the silver complexes were
determined on a w/v concentration basis, with 100 mg of silver(I) complex to 0.6 ml deuterated
chloroform as the solvent.
The different substituent patterns at the 1 and 3 positions of the imidazole ring will directly affect
the electronic properties of the carbene carbon. These electronic effects result in differentiations in
NMR shifts, as is the case for the carbene hydrogen in the imidazolium salt precursors and now in
the shifts of the silver moiety in the complexes.
These values were found within a similar region to a previously reported imidazole NHC-silver(I)
chloride complex that resolves a 109Ag NMR signal at δ = 597 ppm, in deuterated acetonitrile,31 and a
previously reported dinuclear silver OTf complex resolving a 109Ag NMR signal at δ = 541 ppm, in
deuterated chloroform.32 No literature values could be found for NHC-silver(I) acetate complexes for
direct comparison.
Each 109Ag signal was resolved as a broad signal, despite the relative low sensitivity experiment. The
signal for the SBC3 molecule resolved at δ = 488 ppm; with two benzyl groups on the 1 and 3
positions, this was used as the standard comparison against the six novel complexes.
The signals of the three symmetrical silver(I) complexes steadily shift further upfield with the
increase in atoms on the carbon chain, with a larger up-field shift when isopropyl groups are

incorporated in complex 5. For the non-symmetrical compounds we again see the influence of the
isopropyl group compared to the methyl substituent. Comparing the shift of complex 3 (δ = 476
ppm) to that of complex 7 (δ = 476 ppm), there does not seem to be a large influence from the
benzyl substituent.
The largest downfield shifts seen in this series are associated with the complexes containing
isopropyl groups. The jump of 12 ppm in the silver chemical shift for complex 8 compared to SBC3
seems to result from a single substitution of the benzyl group by an isopropyl one. This jump is even
more pronounced with a 55 ppm shift for the complex 5 after the outright replacement of benzyl
groups with isopropyl substituents. This isopropyl effect seems to indicate a large downfield field
shift even with a single replacement of the methyl, ethyl or benzyl substituents with an isopropyl
group.
Table 1
Recorded 109Ag NMR resonance shifts for novel silver(I) complexes
______ Complex
109Ag shift (δ ppm)_____
SBC3
3
488
476
4
5
480
533
6
7
8
499
476
506
_______
____________________
IR spectroscopy
In the IR spectra of all silver complexes there are consistent absorptions in the region of 1560 – 1580
cm-1 corresponding to the C=O stretching vibration of the 1-bonded acetate group, which is
consistent with previously reported complexes.15,19,24-28 All complexes also show low-intensity
absorptions just above and under the 3000 cm-1 region, which are corresponding to aromatic and
aliphatic C-H stretching vibrations, and strong absorptions in the 695 – 750 cm-1 region that
correspond to the phenyl C–H bending vibrations.
Crystal Structure Data
Crystal data of 3 - 8 were collected using an Rigaku Oxford Diffraction (former Agilent Technologies,
former Oxford Diffraction) SuperNova A diffractometer fitted with an Atlas detector. 4 was
measured with Mo-Kα (0.71073 Å), all others with Cu-Kα (1.54184 Å). A complete dataset was
collected, assuming that the Friedel pairs are not equivalent. An analytical absorption correction
based on the shape of the crystal was performed.33 The structures were solved by direct methods
using SHELXS 34 and refined by full matrix least-squares on F2 for all data using SHELXL.34 Refinement
data can be seen in Table 2.
The hydrogen atoms of the water molecules in 3 were located in the difference Fourier map. In
subsequent refinements the water molecules were restrained to have the ideal shape using DFIX.
After convergence the water molecules were refined as rigid groups. All other hydrogen atoms were
added at calculated positions and refined using a riding model. Their isotropic temperature factors
were fixed to 1.2 times (1.5 times for methyl groups and water hydrogens) the equivalent isotropic
displacement parameters of the parent atom. Anisotropic thermal displacement parameters were
used for all non-hydrogen atoms.

Table 2
Crystal data and structural refinement information for complexes 3-8.
Identification
code
3
4
5
6
7
8
Empirical formula
C19 H23 N2 O4 C21 H23 N2 O2 C24 H29 N2 O2 C43 H48 N4 O4 C25.64 H24.28 N2 C27 H27 N2 O2
Ag
Ag
Cl2 Ag
Cl2 Ag2
O2 Cl1.28 Ag
Ag
Molecular
formula
C19 H19 N2 O2
Ag x 2 (H2 O)
C23 H27 N2 O2 (C21 H23 N2 O2 C25 H23 N2 O2
Ag x C H2 Cl2
Ag)2 x C H2 Cl2
Ag x 0.64 (C H2
Cl2)
Formula weight
Crystal system
Space group
451.26
443.28
556.26
971.49
545.78
519.37
Triclinic
P–1 (#2)
Triclinic
P–1 (#2)
Orthorhombic
P212121 (#19)
Triclinic
P–1 (#2)
Orthorhombic
Triclinic
P–1 (#2)
Pna21 (#33)
Unit
cell
a
=
8.5705(2)
a
=
b
a = 8.89667(7)
b = 9.20695(7)
a
=
8.9450(2) a = 15.1362(2)
a
=
dimensions/ Å (o)
b = 9.1007(2)
14.60488(6)
= 16.07477(7)
c
b = 9.5119(2)
b
=
10.09486(8)
b = 10.9479(1)
11.37991(9)
c = 13.2387(3)
=
c = 29.3893(3) c = 13.5607(2) c = 28.5638(2) c = 12.1433(1)
Å
α
=
18.86008(9)
= 70.2548(4)
α
α = 90°
α = 71.653(2)°
α = 90°
α = 96.2856(7)°
99.037(2)°
β = 105.107(2)° β = 70.2548(4)
β
=
90° β = 83.779(2)°
γ = 73.152(2)°
β
=
90°
β
=
=
γ = 93.185(2)°
γ = 75.3434(3)
γ = 90°
γ = 90°
111.1459(7)°
γ
105.4602(8)°
Volume/Å3
Z
979.47(4)
2
3915.50(3)
8
2407.31(4)
4
1047.96(4)
1
4920.07(8)
8
1174.395(19)
2
Density
(calculated)
1.530 Mg/m3
1.504 Mg/m3
1.535 Mg/m3
8.941 mm–1
1136
1.539 Mg/m3
9.035 mm–1
494
1.474 Mg/m3
8.045 mm–1
2215.4
1.469 Mg/m3
Absorption
coefficient
8.471 mm–1
460
1.046 mm–1
1808
7.084 mm–1
532
F(000)
Crystal size
0.241 x 0.174 x 0.325 x 0.240 x 0.2152
x
x
0.202 x 0.154 x 0.197 x 0.138 x 0.194 x 0.122 x
0.039 mm3
0.169 mm3
0.1344
0.093 mm3
0.125 mm3
0.086 mm3
0.1165 mm3
Theta range for 3.514
to 2.85 to 33.02°.
3.01 to 76.72°.
3.434
76.849°.
to 4.182
77.060°
to 4.010
76.989°.
to
data collection
76.848°.
Index ranges
–10 ≤ h ≤ 10 –21 ≤ h ≤ 21 –7 ≤ h ≤ 11, –11 ≤ h ≤ 11, –16 ≤ h ≤ 18 –12 ≤ h ≤ 12,
–11 ≤ k ≤ 11 –24 ≤ k ≤ 24 –11 ≤ k ≤ 11, –11 ≤ k ≤ 11, –14 ≤ k ≤ 14 –11 ≤ k ≤ 13,
–16 ≤ l ≤ 16
–28 ≤ l ≤ 28
–36 ≤ l ≤ 33
–17 ≤ l ≤ 17
–35 ≤ l ≤ 35
–15 ≤ l ≤ 15
Reflections
collected
21048
241717
17276
20542
115490
46914
Independent
reflections
4081 [R(int) = 28036 [R(int) = 5001 [R(int) = 4351 [R(int) = 10325 [R(int) = 4920 [R(int) =
0.0283]
0.0397]
0.0354]
0.0665]
0.0454]
0.0288]
Completeness to 100.00%
99.40%
99.20%
99.80%
99.80%
100.00%
θ = 67.684°
Absorption
correction
Gaussian
Gaussian
Analytical
Gaussian
Gaussian
Gaussian
Max. and min. 0.736
transmission 0.227
and 0.877
0.774
28036 / 0 / 949 5001 / 0 / 285
and 0.503
and 0.643
and 0.496
0.291
10325 / 1 / 601 4920 / 0 / 330
and 0.666
and
0.306
0.375
0.422
Data / restraints / 4081 / 0 / 245
parameters
4351 / 0 / 294
Goodness–of–fit
1.041
1.088
1.019
1.117
1.059
1.084
on F2
Final
R
indices R1
=
0.0206, R1
=
0.0306, R1
=
0.0217, R1
=
0.0481, R1
=
0.0482, R1
=
0.0350,
[I>2sigma(I)]
wR2 = 0.0527
wR2 = 0.0714
wR2 = 0.0540
wR2 = 0.1194
wR2 = 0.1413
wR2 = 0.0814
R indices (all data)
R1
=
0.0224, R1
=
0.0420, R1
=
0.0228, R1
=
0.0568, R1
=
0.0496, R1
=
0.0398,
wR2 = 0.0537
wR2 = 0.0789
wR2 = 0.0546
wR2 = 0.1470
wR2 = 0.1434
wR2 = 0.0857
Largest diff. peak 0.442 and
and hole
0.507 e.Å–3
–
3.186 and
1.328 e.Å–3
–
0.650 and
0.502 e.Å–3
–
1.924 and
1.869 e.Å–3
–
1.404 and
0.855 e.Å–3
-
0.905 and –
1.589 e.Å–3

Appropriate crystals of complexes 3 to 8 were obtained for x-ray crystallography by the slow
diffusion of pentane into a small volume of a saturated solution of dichloromethane at 2oC, Fig. 2 &
Fig. 3.
Selected bond lengths and angles are listed in Table 3. Both the shapes of the imidazole rings and
the Ag-C bond length agree very well with previously reported values. 15, 19, 24-28
In all complexes reported here the Ag-O bond length is even shorter than the one in the SBC3
molecule15, with the possible exception of the minor disorder part in 8. All C-Ag-O bond angles are
close to 180°, again with the possible exception of 8. There the acetate group is disordered in such a
way that both monodentate and bidentate binding to the silver atom seem to be present.
However, the displacement ellipsoid of the silver atom indicates that it may also be disordered. An
attempt to refine this led to unreasonably high correlations due to the close proximity of the
disorder positions, but the result suggests that in both disorder parts the acetate coordinates to the
silver in the same way, with the Ag-O1 distance about 2.1 Å, the Ag-O2 distance about 2.8 Å and the
C-Ag-O angle about 175°. In conclusion, the binding mode of the acetate to the silver in 8 cannot be
determined with certainty. In all other complexes reported here there is no hint of a bidentate
coordination of the acetate to the silver. No argentophilic interactions were observed in any of the
complexes reported here.
Table 3
Selected bond lengths and angles for silver(I) complexes 3-8
Bond
length/Å
C(1)-N(1)
C(1)-N(2)
N(1)-C(2)
C(2)-C(3)
C(3)-N(2)
Ag-C(1)
3
4 a)
5
6
7 a)
8
1.352(2)
1.349(3)
1.393(2)
1.362(3)
1.393(2)
1.352(2)
1.353(2)
1.3928(19)
1.365(2)
1.395(2)
1.360(3)
1.355(3)
1.398(3)
1.353(3)
1.398(3)
2.080(2)
2.1119(18)
1.378(7)
1.361(6)
1.391(6)
1.365(7)
1.388(6)
2.065(5)
2.138(4)
1.346(9)
1.333(8)
1.406(8)
1.358(9)
1.393(8)
2.080(7)
2.109(6)
1.349(3)
1.344(4)
1.400(4)
1.359(5)
1.397(3)
2.073(3)
2.133(4) b)
2.0705(19) 2.0667(16)
2.0986(14) 2.1336(13)
Ag-O(1)
Bond angle/°
C(1)-Ag-O(1)
172.74(6)
173.36(6)
176.50(8)
104.64(19)
167.23(16)
103.6(4)
170.6(3)
105.6(6)
165.7(3) b)
105.4(2)
N(1)-C(1)-N(2) 104.99(16) 104.84(13)
a) First molecule in the asymmetric unit; all others have very similar values b) Affected by disorder,
see text

3
4
C7
C6
C9
C8
C8
O2
C7
C5
C4
C10
C5
N1
C19
C11
C4
C1
C18
C6
C9
C10
C1
C2
N1
C2
Ag
O1
O2
N2
C12
C3
C20
C3
C13
Ag1
C17
C11
C21
O1
C17
C12
N2
C16
C18
C14
C13
C16
C15
C14
C19
C15
5
C12
C6
C5
C13
C11
C4
C23
C14
C22
O2
N1
C10
C2
C15
O1
C1
Ag
C21
C3
N2
C7
C20
C16
C17
C8
C19
C9
C18
6
7
O2
C20
C21
C23
C10A
C22
C9
C24
C8
C6
C25
N2
C19
C3
C4
O2
C18
C17
C12
C5
O1
Ag1
C7
C1
C11A
C20
C2
N1
C12A
Ag
C21
C2
C11
C16
N1
C4
C3
C18
C1
C13
C13
O1
C5
C17
N2
C6
C14
C10
C14
C19
C15
C9
C16
C7
C15
C8
Fig. 2; Crystal structures of symmetrical and non-symmetrical complexes 3 – 7; X-ray diffraction of
all complexes thermal ellipsoids are drawn on the 50% probability level; disorder neglected for
structure of complex 6**

C24
C23
C22
C25
C16
C17
C20
C19
C15
C18
C21
C14
C3
C13
N2
O1A
Ag
C1
C5
C26A
C2
C8
N1
C9
C7
C27A
O2A
C4
C10
C12
C11
C6
Fig. 3; Crystal structure of complex 8; thermal ellipsoids are drawn on the 50% probability level,
disorder neglected
Antibacterial Testing
In vitro antibacterial studies were carried out for the six novel silver(I) complexes using the
qualitative Kirby-Bauer disk diffusion method of testing. The corresponding antibacterial results are
outlined in Table 4. Antibacterial activity was determined against the drug-resistant, gram-positive
bacteria Methicillin-resistant Staphylococcus aureus (MRSA) and the gram-negative bacteria
Escherichia coli.
Along with the new complexes, the SBC3 molecule and Tetracycline were used as standards for
antibacterial activity. SBC3 is the premier antibiotic that has been found for this class of NHC-silver(I)
compounds and tetracycline is the base compound for an entire family of clinical level antibacterial
medicines. Each represents a standard required for firstly providing good antibacterial effect, and
then the requirement of further activity for a clinic level antibiotic.
From Table 4 we can see that the most effective complex with the largest area of clearances is that
with the incorporated benzyl group, complex 7, with 4 mm of clearance against MRSA at a volume of
10 µl. It is followed by the other benzyl containing complex, 8, and two of the symmetrical
complexes 3 and 4 with 3 mm of clearance at a 10 µl volume.
Despite the lower molecular weight of the newly synthesized complexes, they did not achieve the
antibacterial efficacy of SBC3 or Tetracycline. These results would suggest that the incorporation of
lower molecular weight substituents in place of the lipophilic benzyl groups highlight the importance
of chemical structures that incorporate biologically important effects over lower molecular weight.
Despite these results, this work has concluded that the 1,3-dibenzy-4,5-diphenyl imidazole is an
optimised NHC-backbone for coinage metals to utilise in future antibacterial work.

Table 4
Kirby-Bauer areas of clearance for complexes 3-8, SBC3 and Tetracycline (TC) against selected
bacterial strains
______Silver(I) Complex
MRSA
E. coli
Volumes [µl]
5
10
5
10
Area of clearance
SBC3
3
4
5
6
7
8
TC
9 mm
3 mm
2 mm
2 mm
1 mm
3 mm
1 mm
14 mm
10 mm
3 mm
3 mm
2 mm
2 mm
4 mm
3 mm
15 mm
2 mm
1 mm
1 mm
1 mm
1 mm
1 mm
2 mm
11 mm
2 mm
2 mm
2 mm
1 mm
2 mm
1 mm
1 mm
13 mm
Conclusion
The synthesis and subsequent characterisation of these three symmetrical and three non-
symmetrical novel N-heterocyclic carbene silver(I) complexes have been synthesized and full
characterised, showing several interesting chemical behaviours highlighted by their crystallographic
and 109Ag NMR spectroscopic data.
The 109Ag NMR data of these molecules shows the effect of the substitution pattern on the chemical
shift of the silver atom with the incorporation of isopropyl groups inducing large downfield chemical
shifts. The crystallographic data from the six complexes shows similar linearity in their bonding from
the NHC carbene carbon to the silver atom, with no argentophilic interactions found. However, with
complex 8 we see the definite interaction of both the acetate oxygen and carbonyl oxygen with the
silver atom in η2-coordination, with the bond lengths found as 2.133(4) Å for the bond with the
acetate oxygen (O–1A) and 2.634(8) Å for the bond with the carbonyl oxygen (O–2A).
Biological data shows that the most effective of these compounds against MRSA was complex 7,
with clearances of 4 mm clearance in the Kirby-Bauer disk diffusion test, though unfortunately this
activity was not as pronounced as SBC3 complex or Tetracycline. These derivatisations have shown
that the 1,3-dibenzy-4,5-diphenyl imidazole is the most optimised imidazole NHC backbone for this
complex category, and should be incorporated for future NHC-silver antibiotic compounds.
Appendix A. Supplementary data
(CCDC 1818518), (CCDC 1818516), (CCDC1818515), (CCDC1818519), (CCDC1818517) and
(CCDC1818520) contain the supplementary crystallographic data for 3-8. These data can be obtained
free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-
mail: deposit@ccdc.cam.ac.uk.

Acknowledgements
We like to thank the College of Science and School of Chemistry, University College Dublin for the
funding opportunity to conduct this work.
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C24
C23
C22
C25
C16
C17
C20
C19
C15
C18
C21
C14
C3
C13
N2
O1A
Ag
C1
C5
C26A
C2
C8
N1
C9
C7
C27A
O2A
C4
C10
C12
C11
C6
Synthesis, characterisation and biological testing of six novel N-heterocyclic carbene silver(I)
acetate complexes that are specifically targeting Methicillin-Resistant Staphylococcus aureus
(MRSA). XRD and 109Ag NMR studies investigate substituent effects inducing changes on the
interactions between the NHC-ligands and silver acetate.