Received: 4 November 2021 Revised: 28 January 2022 Accepted: 7 February 2022

DOI: 10.1002/aoc.6645

RESEARCH ARTICLE

Au-NHC complexes with thiocarboxylate ligands: Synthesis,

structure, stability, thiol exchange and in vitro anticancer
activity

Hawraa S. Al-Buthabhak1,2 | Valerio Falasca2 | Yu Yu3,4 |

2 2
Alexandre N. Sobolev | Brian W. Skelton | Stephen A. Moggach2 |
Vito Ferro5 | Hani Al-Salami6,7 | Murray V. Baker2
1
Department of Chemistry, Faculty of Science, University of Kufa, Najaf, Iraq
2
School of Molecular Sciences, The University of Western Australia, Perth, Western Australia, Australia
3
Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
4
Division of Obstetrics and Gynaecology, The University of Western Australia Medical School, Perth, Western Australia, Australia
5
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia
6
Biotechnology and Drug Development Research Laboratory, Curtin Medical School and Curtin Health Innovation Research Institute, Curtin
University, Perth, Western Australia, Australia
7
Hearing Therapeutics, Ear Science Institute Australia, Queen Elizabeth II Medical Centre, Nedlands 6009, Perth, Western Australia, Australia

Correspondence
Murray V. Baker, School of Molecular Novel complexes of form (NHC)Au(SCOR) (NHC = N-heterocyclic carbene,
Sciences M310, The University of Western SCOR
= thiocarboxylate ligand) were synthesised and characterised by spec-
Australia, 35 Stirling Highway, Perth, WA
6009, Australia.
troscopic techniques and X-ray diffraction studies. The results of NMR and X-
Email: murray.baker@uwa.edu.au ray studies indicated that thiocarboxylate ligands are comparable with NHCs
in their electron donor ability. The complexes were stable at room temperature
Funding information
European Union Horizon 2020 research
in the solid state but in solution underwent disproportionation reactions to
project and innovation program under the form equilibria with [Au(NHC)2]+ and [Au(SCOR)2]
. In solution, the
Marie Skłodowska-Curie Grant
thiocarboxylate ligand in (NHC)Au(SCOR) underwent rapid exchange with
Agreement No 872370, Curtin Faculty
ORS-WAHAI Consortium, and the other thiocarboxylate or thiolate ligands. The (NHC)Au(SCOR) complexes
Australian National Health and Medical showed toxicity against cisplatin-resistant ovarian cancer cells (OVCAR-8),
Research Council (NHMRC,
with IC50 < 10 μM, in the range exhibited by cationic [Au(NHC)2]+ complexes
APP9000597); Stephen A. Moggach thanks
the Australian Research Council (ARC) well-known for their promising anticancer activity.
for a Future Fellowship (FT200100243);
The Higher Committee for Education KEYWORDS
Development in Iraq (HCED); Australian anticancer activity, disproportionation, gold, ligand exchange, N-heterocyclic carbene,
Research Council, Grant/Award Number: thiocarboxylate ligands
FT200100243; National Health and
Medical Research Council; Horizon 2020;
European Union; Higher Committee for
Education Development in Iraq;
University of Western Australia

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© 2022 The Authors. Applied Organometallic Chemistry published by John Wiley & Sons Ltd.

Appl Organomet Chem. 2022;e6645. wileyonlinelibrary.com/journal/aoc 1 of 23

https://doi.org/10.1002/aoc.6645

2 of 23
[Correction added on 17 May 2022, after
first online publication: CAUL funding
statement has been added.]
1 | INTRODUCTION
The chemistry of Au-NHC complexes is an exciting and
rapidly growing field, with Au-NHC complexes finding
many potential applications in catalysis,[1,2] medicine[3–9]
and nanochemistry and surface chemistry.[10,11] Amongst
the most easily accessible Au-NHC complexes are the
halido complexes (NHC)AuX (X = Cl, Br, I) which can
be obtained by reaction of Au sources such as (Me2S)AuX
with free NHCs[12,13] or Ag-NHCs[13–16] or with azolium
salts in the presence of base.[17] The halido ligands in
(NHC)AuX can be exchanged by a wide range of ligands
L (e.g., phosphines,[18] other NHCs,[19] acetylides[20]
and thiolates[16,21,22]) to form (NHC)AuL. S-donor
ligands are especially interesting because of the great
variety of S-donor functional groups that are available.
S-donor ligands (L) that have been incorporated into
(NHC)AuL complexes include thiocyanates,[15,23]
dithiocarbamates,[24,25] thiolates[20,22,23,26–30] (including
thiolate derivatives of N-heterocycles,[31–33] carbohy-
drates[16,21,31,34–36]) and a peptide containing a cysteine
residue.[37–39] Furthermore, many Au complexes bearing
S-donor ligands, including Au-NHC complexes, have
shown anticancer and/or antibacterial activity and have
thus received great attention.[24,26,31,34,36,40–43] Despite
this rich chemistry, Au-NHC complexes having
thiocarboxylates as co-ligands have not been explored
previously.
Thiocarboxylates are attractive S-donor ligand candi-
dates. They are very strong σ-donors and, as soft bases,
bind readily to soft metal centres.[44–49] Furthermore, they
are easily obtained by deprotonation of thiocarboxylic
acids, which themselves are easily prepared by reaction of
acid chlorides with potassium hydrosulfide (KSH).[50]
Thus, it should be possible to access a range of complexes
of the form (NHC)Au(SCOR). (NHC)Au(SCOR) com-
plexes should possess anticancer activity, similar to that
of other (NHC)AuX analogues.[3,8,32,41,51] Therefore, in
this work, we explore the synthesis and properties of
complexes of the form (NHC)Au(SCOR). The NHC
ligands include examples of imidazolin-2-ylidene
(Im) and benzimidazolin-2-ylidene (BIm) with various
N substituents. The thiocarboxylate ligands were
thioacetate and thiobenzoate, derived from their
corresponding commercially available thiocarboxylic
acids. The new (NHC)Au(SCOR) complexes were thor-
oughly characterised by elemental analysis, spectroscopic
methods and X-ray diffraction techniques. We also report
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AL-BUTHABHAK ET AL.
preliminary studies of ligand exchange reactions of the
(NHC)Au(SCOR) complexes and activity of (NHC)Au
(SCOR) complexes against a cisplatin-resistant ovarian
cancer cell line (OVCAR-8).
2 | EXPERIMENTAL
2.1 | Materials
The following compounds were used as received:
potassium carbonate (Analar Normapur), potassium
hexafluorophosphate (Aldrich, 98%), imidazole (Fluka),
sodium hydroxide (Chem Supply), thioacetic acid (Fluka)
and thiobenzoic acid (TCI). (Me2S)AuCl[52] and N-Acetyl--
L-cysteine[53] were prepared via literature methods.
Solvents were of analytical or reagent grade and used with-
out further purification. Gold complexes were prepared
under a nitrogen atmosphere in oven dried glassware,
which was wrapped in aluminium foil to exclude light.
2.2 | Characterisation techniques
NMR spectra were recorded using Bruker AV500 III HD
(500.13 MHz for 1H, 125.77 MHz for 13C, 202.45 MHz for
31
P), Bruker AV600 III HD (600.13 MHz for 1H,
150.90 MHz for 13C), Varian 400 (399.86 MHz for 1H,
100.55 MHz for 13C) or Bruker AV NEO (400.15 MHz for
1
H) spectrometers at ambient temperature, unless other-
wise indicated. 1H and 13C NMR chemical shifts are
referenced to the residual signal of the solvent (DMSO-
d6: 1H 2.50 ppm; 13C 39.52 ppm; CDCl3: 1H 7.26 ppm; 13C
77.16 ppm; acetone-6:1H 2.05 ppm; 13C 29.84 ppm).
Assignments of signals were confirmed with the aid of
1
H-13C HSQC (heteronuclear single quantum coherence)
and 1H-13C HMBC (heteronuclear multiple bond correla-
tion) spectra when necessary. NMR spectra of (NHC)Au
(SCOR) complexes are provided in the supporting infor-
mation. Microanalyses were performed by Microanalyti-
cal Service, School of Chemistry and Molecular
Biosciences, The University of Queensland, Australia.
High-resolution mass spectra were measured using
Agilent LCMS 6510 Q-TOF and Waters LCT Premier XE
spectrometers, using the APCI or ESI methods, with 9:1
CH3CN:H2O as solvent. High resolution mass spectra for
several (NHC)Au(SCOR) complexes are provided in the
supporting information. Fourier transform infrared

AL-BUTHABHAK ET AL.
spectra (see supporting information) were measured at
room temperature using a PerkinElmer FT-IR spectrome-
ter with a universal ATR sampling accessory.
2.3 | Synthesis of (NHC)Au(SCOR)
complexes
The following general procedure was used for the
synthesis of all (NHC)Au(SCOR) complexes. Potassium
carbonate was added to a solution of (NHC)AuCl (for syn-
thesis, see supporting information) in dichloromethane,
and the mixture was stirred for 5 min at room tempera-
ture. The thiocarboxylic acid was added, and the mixture
was stirred until examination of an aliquot by 1H NMR
spectroscopy showed that the reaction had gone to
completion. The mixture was filtered through Celite, and
the filtrate was evaporated to dryness. The residue was
dissolved in a minimum amount of dichloromethane,
and hexanes were added. A white precipitate formed
immediately and was washed with hexanes and dried
under vacuum to leave the product as a powder.
2.3.1 | (1,3-Diisopropylimidazolin-2-ylidene)
gold(I) thioacetate (1)
Following the general procedure using potassium carbon-
ate (100 mg, 0.724 mmol), (1,3-diisopropylimidazolin-
2-ylidene)gold(I) chloride (28.3 mg, 0.0735 mmol),
dichloromethane (10 ml) and thioacetic acid (7.0 μl,
0.098 mmol) and stirring overnight gave the product as a
white crystalline powder (20 mg, 62%). 1H NMR
(500 MHz, CDCl3): δ 6.97 (s, 2H, imidazolyl H4/H5), 5.03
(2H, sept., 3JH,H = 6.7 Hz, CH (CH3)2), 2.49 (s, 3H,
COCH3), 1.49 (12H, d, 3JH,H = 6.7 Hz, CH (CH3)2). 13C
NMR (100.5 MHz, CDCl3): δ 206.98 (CO), 179.57
(imidazolyl C2), 116.80 (imidazolyl C4/C5), 53.55 (CH
(CH3)2), 36.56 (COCH3), 23.16 (CH (CH3)2). Microanaly-
sis: Found: C, 31.01; H, 4.88; N, 6.61; S, 7.70%
C11H19AuN2OS requires C 31.14; H, 4.51; N, 6.60; S,
7.56%. HRMS (APCI+): Calcd for C11H20N2OSAu [M
+ H+], m/z 425.0962. Found: m/z 425.0978. Crystals
suitable for X-ray diffraction studies were grown by slow
evaporation of a solution of the compound in dic-
hloromethane/hexanes.
2.3.2 | (1,3-Dibenzylimidazolin-2-ylidene)
gold(I) thioacetate (2)
Following the general procedure using potassium
carbonate (287 mg, 2.08 mmol), (1,3-dibenzylimidazolin-
10990739, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/aoc.6645 by Readcube (Labtiva Inc.), Wiley Online Library on [17/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
3 of 23
2-ylidene)gold(I) chloride (100 mg, 0.208 mmol), dic-
hloromethane (20 ml) and thioacetic acid (20 μl,
0.28 mmol) and stirring for 7 h gave the product as a
white powder (55 mg, 51%). 1H NMR (500 MHz, DMSO-
d6): δ 7.58 (s, 2H, imidazolyl H4/H5), 7.42 (4H, m, ArH
ortho), 7.37 (4H, m, ArH meta), 7.32 (2H, m, ArH para),
5.37 (s, 4H, CH2), 2.27 (s, 3H, COCH3). 13C NMR
(125.7 MHz, DMSO-d6): δ 204.22 (CO), 179.44 (imidazolyl
C2), 136.68 (ArC ipso), 128.75 (ArC meta), 128.12 (ArC
para), 127.76 (ArC ortho), 122.22 (imidazolyl C4/C5),
53.65 (CH2), 37.10 (COCH3). Microanalysis: Found: C,
43.85; H, 3.68; N, 5.38; S, 6.16% C19H19AuN2OS
requires C, 43.62; H, 3.69; N, 5.39; S, 6.19%. Crystals suit-
able for X-ray diffraction studies were grown by diffusion
of vapours between pentane and a solution of the com-
pound in dichloromethane.
2.3.3 | (1,3-Diisopropylimidazolin-2-ylidene)
gold(I) thiobenzoate (3)
Following the general procedure using potassium carbon-
ate (150 mg, 1.08 mmol), (1,3-diisopropylimidazolin-
2-ylidene)gold(I) chloride (43.0 mg, 0.11 mmol), dic-
hloromethane (10 ml) and thiobenzoic acid (18 μl,
0.15 mmol) and stirring overnight gave the product as a
beige powder (39 mg, 72%). 1H NMR (500 MHz, CDCl3):
δ 8.14 (2H, m, SCOPhH ortho), 7.44 (1H, m, SCOPhH
para), 7.36 (2H, m, SCOPhH meta), 6.99 (s, 2H,
imidazolyl H4/H5), 5.07 (2H, sept, 3JH,H = 6.8 Hz, CH
(CH3)2), 1.51 (12H, d, 3JH,H = 6.8 Hz, CH (CH3)2). 13C
NMR (125.7 MHz, CDCl3): δ 201.97 (CO), 179.52
(imidazolyl C2), 142.15 (SCOPh C ipso), 131.60 (SCOPh C
para), 128.45 (SCOPh C meta), 127.88 (SCOPh C ortho),
116.80 (imidazolyl C4/C5), 53.61 CH (CH3)2, 23.69 CH
(CH3)2. Microanalysis: Found: C, 39.40; H, 4.38; N,
5.85; S, 6.49% C16H21AuN2OS requires C 39.51; H,
4.35; N, 5.76; S, 6.59%.
2.3.4 | (1,3-Dicyclohexylimidazolin-
2-ylidene)gold(I) thiobenzoate (4)
Following the general procedure using potassium carbon-
ate (149 mg, 1.07 mmol), (1,3-dicyclohexylimidazolin-
2-ylidene)gold(I) chloride (50.0 mg, 0.107 mmol),
dichloromethane (10 ml) and thiobenzoic acid (15 μl,
0.13 mmol) and stirring for 4 h gave the product as a
white crystalline powder (32 mg, 52%). 1H NMR
(500 MHz, DMSO-d6): δ 7.95 (2H, m, SCOPhH ortho),
7.59 (s, 2H, imidazolyl H4/H5), 7.52 (1H, m, SCOPhH
para), 7.43 (2H, m, SCOPhH meta), 4.48–4.43 (2H, m, Cy
CH), 1.97–1.21 (m, 20H, Cy CH2), 13C NMR (100.5 MHz,

4 of 23
DMSO-d6): δ 199.22(CO), 176.65 (imidazolyl C2), 141.74
(SCOPh C ipso), 131.69 (SCOPh C para), 128.04
(SCOPh C meta), 127.54 (SCOPh C ortho), 118.87
(imidazolyl C4/C5), 60.38 (Cy CH), 33.31 (Cy CH2),
25.10 (Cy CH2). 24.53 (Cy CH2). Microanalysis:
Found: C, 42.51; H, 4.67; N, 4.23; S, 5.04%
C22H29AuN2OS.(CH2Cl2) requires C, 42.41; H, 4.80; N,
4.30; S, 4.92%. HRMS (APCI+): Calcd for C22H30N2OSAu
[M + H+], m/z 567.1744. Found: m/z 567.1763. Crystals
suitable for X-ray diffraction studies were grown by slow
evaporation of a solution of the compound in
dichloromethane.
2.3.5 | (1,3-Dibenzylimidazolin-2-ylidene)
gold(I) thiobenzoate (5)
Following the general procedure using potassium carbon-
ate (287 mg, 2.08 mmol), (1,3-dibenzylimidazolin-
2-ylidene)gold(I) chloride (100 mg, 0.208 mmol), dic-
hloromethane (20 ml) and thiobenzoic acid (30 μl,
0.25 mmol) and stirring for 6 h gave the product as a
white crystalline powder (73 mg, 60%) 1H NMR
(500 MHz, DMSO-d6): δ 7.96 (2H, m, SCOPhH ortho),
7.59 (s, 2H, imidazolyl H4/H5), 7.52 (1H, m, SCOPhH
para), 7.47 (4H, m, ArH ortho), 7.39 (2H, m, ArH para),
7.37 (4H, m, ArH meta), 7.32 (2H, m, SCOPhH meta),
5.40 (s, 4H, CH2). 13C NMR (125.7 MHz, DMSO-d6): δ
199.42 (CO), 179.02 (imidazolyl C2), 141.65 (SCOPh C
ipso), 136.66 (ArC ipso), 131.76 (SCOPhC para), 128.78
(ArC meta), 128.17 (SCOPhC meta), 128.07 (ArC para),
127.94 (ArC ortho), 127.54 (SCOPh C ortho), 122.20
(imidazolyl C4/C5), 53.72 (CH2). Microanalysis:
Found: C, 49.33; H, 3.63; N, 4.81; S, 5.43%.
C24H21AuN2OS requires C, 49.49; H, 3.63; N, 4.81; S,
5.50%. Crystals suitable for X-ray diffraction studies were
grown by diffusion of vapours between pentane and a
solution of the compound in dichloromethane.
2.3.6 | (1,3-Diisopropylbenzimidazolin-
2-ylidene)gold(I) thioacetate (6)
Following the general procedure using potassium carbon-
ate (93.0 mg, 0.67 mmol), (1,3-diisopropybenzlimidazolin-
2-ylidene)gold(I) chloride (29.3 mg, 0.067 mmol),
dichloromethane (10 ml) and thioacetic acid (5.2 μl,
0.073 mmol) and stirring overnight gave the product as a
beige crystalline powder (20 mg, 63%). 1H NMR
(500 MHz, CDCl3): δ 7.64–7.62 (m, 2H, BIm-H, H4/H7 or
H5/H6), 7.38–7.36 (m, 2H, BIm-H, H5/H6 or H4/H7), 5.44
(2H, sept., 3JH,H = 7.0 Hz, CH (CH3)2), 2.50 (s, 3H,
COCH3), 1.77 (12H, d, 3JH,H = 7.0 Hz, CH (CH3)2). 13C
10990739, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/aoc.6645 by Readcube (Labtiva Inc.), Wiley Online Library on [17/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
AL-BUTHABHAK ET AL.
NMR (100.5 MHz, CDCl3): δ 206.61 (CO), 186.51 (BIm
C2), 132.73 BIm(C=C), 123.92 (BIm-C4/C7 or BIm-C5/
C6), 113.06 (BIm-C5/C6 or BIm-C4/C7), 53.83 CH (CH3)2,
36.33 (COCH3), 22.14 (CH (CH3)2. Microanalysis:
Found: C, 36.16; H, 4.50; N, 5.39; S 6.69%. C15H21AuN2OS.
(H2O) requires C, 36.59; H, 4.71; N, 5.69; S 6.51%.
HRMS (ESI+): Calcd for C15H22N2OSAu [M + H+], m/z
475.1118. Found: m/z 475.1117. Crystals suitable for
X-ray diffraction studies were grown by slow evaporation
of a solution of the compound in dichloromethane/
hexanes.
2.3.7 | (1,3-Dibenzylbenzimidazolin-
2-ylidene)gold(I) thioacetate (7)
Following the general procedure using potassium carbon-
ate (208 mg, 1.50 mmol), (1,3-dibenzylbenzimidazolin-
2-ylidene)gold(I) chloride (80.0 mg, 0.15 mmol),
dichloromethane (20 ml) and thioacetic acid (15 μl,
0.20 mmol) and stirring for 5 h gave the product as a
white powder (70 mg, 82%). 1H NMR (500 MHz,
Acetone-d6): δ 7.72–7.71 (2H, m, BIm-H, H4/H7 or
H5/H6), 7.59 (4H, m, ArH ortho),7.42–7.40 (m, 2H,
BIm-H, H5/H6 or H4/H7), 7.37 (4H, m, ArH meta), 7.32
(2H, m, ArH para), 5.90 (s, 4H, (CH2)), 2.31 (s, 3H,
COCH3). 13C NMR (100.5 MHz, Acetone-d6): δ 204.45
(CO), 189.80 (BIm C2), 136.74 (ArC ipso), 134.31
BIm(C=C) 129.71 (C meta), 129.13 (C para), 128.62
(C ortho), 125.48 (BIm-C4/C7 or C5/C6), 113.41 (BIm-
C5/C6 or C4/C7), 52.80 (CH2), 36.88 (COCH3). Micro-
analysis: Found: C, 47.99; H, 3.66; N, 5.00; S, 5.22%
C23H21AuN2OS, requires C, 48.43; H, 3.71; N, 4.91; S,
5.62%. Crystals suitable for X-ray diffraction studies were
grown by diffusion of vapours between pentane and a
solution of the compound in ethyl acetate.
2.3.8 | (1,3-Dimethylbenzimidazolin-
2-ylidene)gold(I) thiobenzoate (8)
Following the general procedure using potassium carbon-
ate (290 mg, 2.1 mmol), (1,3-dimethylbenzimidazolin-
2-ylidene)gold(I) chloride (82.2 mg, 0.21 mmol),
dichloromethane (20 ml) and thiobenzoic acid (30 μl,
0.25) and stirring for 6 h gave the product as a beige pow-
der (91 mg, 90%). 1H NMR (500 MHz, DMSO-d6): δ 7.98
(2H, m, SCOPhH ortho), 7.80–7.78 (m, 2H, BIm H4/H7
or H5/H6), 7.54 (1H, m, SCOPhH para). 7.52–7.50 (2H,
m, BIm H5/H6 or H4/H7), 7.44 (2H, m, SCOPhH meta),
4.06 (s, 6H, CH3). 13C NMR (100.5 MHz, DMSO-d6): δ
199.43 (CO), 186.69 (BIm C2), 141.63 (SCOPh C ipso),
133.42 BIm(C=C), 131.85 (SCOPh C para), 128.12

AL-BUTHABHAK ET AL.
(SCOPh C meta), 127.54 (SCOPh C ortho), 124.35
(BImC4/C7 or C5/C6), 111.97 (BImC5/C6 or C4/C7),
34.69 (CH3). Microanalysis: Found: C, 40.09; H, 3.06; N,
5.71; S, 6.73% C16H15AuN2OS requires C, 40.01; H,
3.15; N, 5.83; S, 6.68%. HRMS (APCI+): Calcd for
C16H16N2OSAu [M + H+], m/z 481.0649. Found: m/z
481.0653. Crystals suitable for X-ray diffraction studies
were grown by slow evaporation of a solution of the com-
pound in dichloromethane.
2.3.9 | (1,3-Diisopropylbenzimidazolin-
2-ylidene)gold(I) thiobenzoate (9)
Following the general procedure using potassium carbon-
ate (300 mg, 2.17 mmol), (1,3-diisopropylbenzimidazolin-
2-ylidene)gold(I) chloride (100 mg, 0.23 mmol),
dichloromethane (20 ml) and thiobenzoic acid (45 μl,
0.38 mmol) and stirring overnight gave the product as a
beige powder (104 mg, 84%) 1H NMR (500 MHz, CDCl3):
δ 8.16 (2H, m, SCOPhH ortho), 7.65–7.63 (m, 2H, BIm-H,
H4/H7 or H5/H6), 7.46 (1H, m, SCOPhH para), 7.39–
7.36 (m, 2H, BIm-H, H5/H6 or H4/H7 and 2H, SCOPhH
meta), 5.49 (2H, sept, 3JH,H = 6.8 Hz, CH (CH3)2). 1.80
(12H, d, 3JH,H = 6.8 Hz, CH (CH3)2). 13C NMR
(125.7 MHz, CDCl3): δ 201.57 (CO), 186.38 (BIm C2),
142.05 (SCOPh C ipso), 132.75 BIm(C=C) 131.69 (SCOPh
C para), 128.49 (SCOPh C ortho), 127.91 (SCOPh C
meta), 123.92 (BIm-C4/C7 or C5/C6), 113.07 (BIm-C5/C6
or C4/C7), 53.87 CH (CH3)2, 22.21 CH (CH3)2. Microanal-
ysis: Found: C, 44.44; H, 4.31; N, 5.20; S, 5.87%
C20H23AuN2OS requires. C, 44.78; H, 4.32; N, 5.22; S,
5.98%. Crystals suitable for X-ray diffraction studies were
grown by slow evaporation of a solution of the compound
in dichloromethane.
2.3.10 | (1,3-Dibenzylbenzimidazolin-
2-ylidene)gold(I) thiobenzoate (10)
Following the general procedure using potassium carbon-
ate (300 mg, 2.17 mmol), (1,3-dibenzylbenzimidazolin-
2-ylidene)gold(I) chloride (114 mg, 0.215 mmol),
dichloromethane (20 ml) and thiobenzoic acid (35 μl,
0.29 mmol) and stirring for 5 h gave the product as a
white powder (91 mg, 67%) 1H NMR (500 MHz, DMSO-
d6): δ 7.96 (2H, m, SCOPhH ortho) 7.72–7.71 (m, 2H,
BIm-H, H4/H7 or H5/H6), 7.55 (4H, m, ArH ortho), 7.52
(1H, m, SCOPhH para), 7.43–7.40 (2H, m, BIm-H, H5/6
or H4/H7 and 2H SCOPH meta), 7.38 (4H, m, ArH meta),
7.32 (2H, m, ArH para), 5.84 (s, 4H, CH2). 13C NMR
(100.5 MHz, DMSO-d6): δ 199.38 (CO), 186.98 (BIm C2),
141.50 (ArC ipso), 135.75 BIm(C=C), 132.84 (SCOPh C
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5 of 23
ipso), 131.91 (SCOPh C para), 128.85 (SCOPh C meta),
128.23 (ArC para), 128.13 (ArC meta), 127.67 (ArC ortho),
127.59 (SCOPh C ortho), 124.68 (BImC4/C7 or C5/C6),
112.71 (BImC 5/6 or C4/C7), 51.45 (CH2). Microanalysis:
Found: C, 53.13; H, 3.57; N, 4.38; S, 5.06% C28H23AuN2OS
requires C, 53.17; H, 3.67; N, 4.43; S, 5.07%. HRMS
(APCI+): Calcd for C28H24N2OSAu [M + H+], m/z
633.1275. Found: m/z 633.1269. Crystals suitable for
X-ray diffraction studies were grown by diffusion of
vapours between pentane and a solution of the com-
pound in dichloromethane.
2.4 | Single crystal X-ray diffraction
Crystallographic data were measured at 100(2) K on an
Oxford Diffraction Gemini, an Oxford Diffraction
Xcalibur or an Rigaku-Oxford Diffraction XtaLAB
Synergy (compounds 2 and 5, at 150(2) K) X-ray diffrac-
tometers using Mo Kα or Cu Kα radiation. Following
analytical absorption corrections and solution by direct
methods, the structures were refined against F2 with full-
matrix least squares using the SHELX programme
suite.[54] Unless stated differently below, all hydrogen
atoms were added at calculated positions and refined by
use of riding models. Crystallographic data for the struc-
tures reported in this paper have been deposited at the
Cambridge Crystallographic Data Centre. CCDC deposit
numbers have been included in Table 1. Copies of data
can be obtained free of charge via https://www.ccdc.cam.
ac.uk/structures/ or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK (fax +441223336033; email deposit@ccdc.cam.
ac.uk).
2.5 | Anticancer activity
2.5.1 | Cell culture reagents
Rosewell Park Memorial Institute (RPMI-1640) medium
(with L-glutamine and sodium bicarbonate), foetal
bovine serum (FBS) and penicillin–streptomycin were
obtained from Sigma Aldrich. Cell culture medium con-
sists of RPMI-1640 medium (with L-glutamine and
sodium bicarbonate) supplemented with 10% v/v FBS
and 1% v/v penicillin–streptomycin.
Cells were dissociated during passaging using trypsin
solution 0.05% in Hanks balanced salt solution
(HBSS) and ethylenediaminetetraacetic acid (EDTA),
without calcium or magnesium (Hyclone GE Healthcare
Life Sciences). MTT (3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide) was obtained from
 TABLE 1 Crystal data for (NHC)Au(SCOR) complexes 1–2, 4.CH2Cl2–10
6 of 23

Compound 1 2 4.CH2Cl2 5 6
Empirical formula C11H19AuN2OS C19H19AuN2OS C45H60Au2Cl2N4O2S2 C24H21AuN2OS C15H21AuN2OS
Mr 424.31 520.39 1217.92 582.45 474.36
Wavelength (Å) 1.54184 1.54184 0.71073 1.54184 0.71073
Crystal system Triclinic Triclinic Orthorhombic Monoclinic Orthorhombic
Space group P1 P1 Pbcn P21/n Pnma
a (Å) 9.4156(5) 10.3299(1) 14.8604(2) 11.6822(1) 14.9509(3)
b (Å) 12.8880(9) 11.3216(1) 11.4101(1) 11.9674(1) 7.6928(2)
c (Å) 24.5761(14) 17.3291(1) 27.6295(4) 15.4530(1) 27.5540(6)

α( ) 79.518(5) 96.111(1) 90 90 90
β ( ) 79.048(4) 93.554(1) 90 99.504(1) 90

γ( ) 89.830(3) 114.201(1) 90 90 90
3
V (Å ) 2877.5(3) 1825.52(3) 4684.82(10) 2130.76(3) 3169.10(12)
Z 8 4 4 4 8
ρcalc (Mg m
3) 1.959 1.893 1.727 1.816 1.988

1
μ (mm ) 20.44 16.269 6.499 14.022 9.413
3
Crystal size (mm ) 0.17  0.09  0.03 0.24  0.12  0.07 0.28  0.14  0.074 0.36  0.14  0.13 0.33  0.17  0.14

θ range for coll. ( ) 1.863 to 67.593 2.582 to 86.759 2.25 to 32.048 4.412 to 75.679 3.07 to 34.40
Refls. collected 23,055 51,940 62,770 41,390 90,238
Indep. reflections 10,157 7475 7886 4332 6913
Rint 0.0636 0.0603 0.0359 0.0733 0.0651
Max/min trans. 0.599/0.088 0.823/0.183 0.656/0.359 0.622/0.050 0.384/0.154
Restraints/params 379/578 0/435 0/271 0/262 0/232
2
GooF. on F 1.043 1.241 1.155 1.086 1.003
R1 (I > 2σ(I)) 0.0665 0.0345 0.0331 0.0282 0.0401
wR2 (I > 2σ(I)) 0.1854 0.0848 0.0595 0.0755 0.0909
R1 (all data) 0.1008 0.0410 0.0475 0.0292 0.0572
wR2 (all data) 0.2214 0.1166 0.0631 0.0763 0.1008

3
Δρmax/min (e Å ) 3.114/
3.037 0.9/
2.4 1.17/
1.992 0.7/
1.6 6.04/
6.00
CCDC number 2078016 2091872 2068717 2091873 2091874
AL-BUTHABHAK ET AL.

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 TABLE 1 (Continued)

Compound 7 8 9 10
Empirical formula C23H21AuN2OS C16H15AuN2OS C20H23AuN2OS C28H23AuN2OS
Mr 570.44 480.33 536.43 632.51
AL-BUTHABHAK ET AL.

Wavelength (Å) 1.54178 0.71073 0.71073 0.71073

Crystal system Monoclinic Monoclinic Monoclinic Monoclinic
Space group Pc C2/c P21/c P21/c
a (Å) 10.0554(1) 14.6974(3) 9.4468(1) 14.2717(5)
b (Å) 5.3561(1) 7.4715(1) 23.0207(3) 10.3303(4)
c (Å) 19.2469(3) 27.3344(5) 9.6203(2) 16.4621(6)

α( ) 90 90 90 90

β( ) 90.701(1) 90.599(2) 97.032(2) 107.165(4)

γ( ) 90 90 90 90
V (Å3) 1036.52(3) 3001.47(9) 2076.41 (6) 2318.92(15)
Z 2 8 4 4

3
ρcalc (Mg m ) 1.828 2.126 1.716 1.812

1
μ (mm ) 14.395 9.941 7.195 6.458
Crystal size (mm3) 0.29  0.05  0.03 0.41  0.31  0.056 0.23  0.21  0.10 0.44  0.40  0.22
θ range for coll. ( ) 4.40 to 67.31 2.77 to 32.00 2.77 to 32.8 2.99 to 32.39
Refls. collected 16,762 17,157 24,034 48,943
Indep. reflections 3704 5017 7097 7913
Rint 0.0515 0.0243 0.0431 0.0673
Max/min trans. 1.0/0.284 0.574/0.094 0.536/0.275 1.0/0.288
Restraints/params 2/254 0/192 0/230 0/298
2
GooF. on F 1.001 1.193 1.002 1.000
R1 (I > 2σ(I)) 0.0357 0.0229 0.0336 0.0344
wR2 (I > 2σ(I)) 0.0900 0.0441 0.0714 0.0819
R1 (all data) 0.0373 0.0263 0.0504 0.0424
wR2 (all data) 0.0917 0.0449 0.0795 0.0883
Δρmax/min (e Å
3) 1.88/
1.45 1.008/
1.105 1.75/
1.45 3.30/
1.03
CCDC number 2091875 2068714 2091876 2091877
7 of 23

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8 of 23
Thermo Fisher. Phosphate buffered saline (PBS) was
obtained from Astral Scientific. Stock solutions (10 mM)
of test compounds were prepared in DMSO (cell culture
grade), obtained from Bio-Strategy. DMSO (to dissolve
the MTT after incubation step in the MTT assay) was
obtained from Sigma Aldrich.
2.5.2 | Cell culture
Human ovarian cancer cells (OVCAR-8, from ATCC)
were cultured in 75 cm2 tissue culture flasks in cell cul-
ture medium (10 ml) at 37 C under air (5% humidity, 5%
CO2). After being incubated for 2 days, the cells had
reached 80% confluency and were then passaged as fol-
lows. The medium was poured off, and the cells were
detached by incubation and agitation with trypsin (3 ml)
for 3–5 min at 37 C. To neutralise the trypsin solution,
cell culture medium (3 ml) was added, and the cell sus-
pensions were transferred to Falcon tubes and cen-
trifuged for 5 min at 1500 rpm. The supernatant was
drawn off by pipette, and the cell pellet was resuspended
in culture medium (10 ml). The cells were replated into
three tissue culture flasks (2 ml cell suspension and 8 ml
culture medium per flask) and incubated for 2 days. The
cell culture medium was replaced after 1 day if the cells
had shown substantial proliferation and confluency.
2.5.3 | Cell viability assays
Stock solutions of Au-NHC compounds (10 mM) were pre-
pared in DMSO and were stored at
20 C until required.
These stock solutions were serially diluted in cell culture
medium. For cell viability assays, OVCAR-8 cells that had
reached 80% confluency in the tissue culture flasks were
used. For cell seeding, the cells were dissociated as
described above, the cell number was counted using a
haemocytometer and the cells were suspended in culture
medium at a final concentration of 2000 cells/100 μl.
SCHEME 1 Synthesis of (NHC)Au(SCOR) complexes
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AL-BUTHABHAK ET AL.
Cell viability was determined using the MTT assay
following the previously published protocol.[55] Briefly,
OVCAR-8 cells were seeded in polystyrene 96-well plates
(Costar; 2000 cells in 100 μl culture medium/well) and
incubated for 24 h. Aliquots of solutions of Au-NHC
compounds in cell culture medium (100 μl) were added
to the wells so that the final concentrations of Au-NHC
complex in wells were 0.39, 0.78, 1.56, 3.125, 6.25, 12.5,
25, 50, or 100 μM. The cells with the Au-NHCs were then
incubated for 72 h. The medium was then carefully and
completely removed by multichannel pipette and rep-
laced by fresh cell culture medium (90 μl/well) and MTT
solution (5 mg/ml MTT dissolved in PBS, 10 μl), and the
plates were agitated to ensure homogeneity of solutions.
The plates were incubated at 37 C for 2 h, then the solu-
tion was removed by multichannel pipette and replaced
by DMSO (200 μl/well) to solubilise the formazan purple
colour from the live cells. The absorbance at 570 nm
(A570) was measured using a plate reader (Ensight
Multimode Plate Reader, PerkinElmer). Relative cell via-
bility (%) was determined by comparison of A570 for wells
that had contained cells treated with Au-NHC complexes
with A570 for wells that contained cells in culture
medium alone. GraphPad Prism 8 software was used to
determine IC50 values from cell viability data and to plot
graphs of cell viability as a function of concentration of
the Au-NHC complexes. Two azolium salts (precursors of
NHC ligands) were used as negative controls for the cyto-
toxicity of the compounds to OVCAR-8 cells.
3 | RESULTS A ND DISCUSSION
3.1 | Synthesis of the (NHC)Au(SCOR)
complexes
The (NHC)Au(SCOR) complexes (R = Me, Ph) were
prepared by reacting (NHC)AuCl with thioacetic or
thiobenzoic acid in the presence of K2CO3, in dic-
hloromethane at room temperature under a nitrogen
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AL-BUTHABHAK ET AL. 9 of 23

atmosphere (Scheme 1). The complexes were purified by
recrystallisation from dichloromethane/hexanes and
were obtained as white or pale beige powders in fair to
excellent yields (50–91%). The (NHC)Au(SCOR) com-
plexes are soluble in polar organic solvents (e.g., DMSO,
CH2Cl2, acetone and CH3CN) but are insoluble in water
and hexanes.
The (NHC)Au(SCOR) complexes, while generally sta-
ble, were susceptible to disproportionation reactions to
form equilibria with complexes of the form [Au(NHC)2]+
and [Au(SCOR)2]
. The [Au(SCOR)2]
complexes are
new, and so they were separately synthesised (as their
potassium salts) by reaction of the appropriate
thiocarboxylic acid with (Me2S)AuCl in DMF in the pres-
ence of K2CO3 (see supporting information).
3.2 | Structural studies
The results of X-ray diffraction studies of the (NHC)Au
(SCOR) complexes 1, 2 and 4.CH2Cl2–10 are summarised
in Tables 1–3 and Figures 1–4 and S1–S8. This study is
the first to structurally characterise (NHC)Au(SCOR)
complexes. All the complexes showed quasilinear coordi-
nation about the Au centre, with the C-Au-S bond angles
in the range 171.7(10)-179.3(2) and C-Au and Au-S bond
lengths in the ranges 1.96(3)-2.059(5) Å and 2.281(3)-
2.3142(8) Å, respectively. The C-S-Au angles were in the
range 99.91(9)–110.5(2) . These bond distances and bond
angles are in the ranges seen for (NHC)AuL complexes
where L = an arylthiolate[22,23,26,27,29] (including thiolate
derivatives of pyrimidine[32] and tetrazole[33]), a
dithiocarbamate,[24,25] tetraacetylglucosethiolate[16,34]
[15,23]
and a thiocyanate.
Despite the broad similarity in the coordination about
Au in the (NHC)Au(SCOR) complexes, their various crys-
tal structures show several interesting features. All the
(NHC)Au(SCOR) complexes showed intramolecular Au…
O distances in the range 3.108–3.447 Å, which is close to
the sum of the van der Waals radii calculated according
to Bondi (3.2 Å),[56] but substantially shorter than the
sum of the van der Waals radii calculated according to
Alvarez (3.8 Å).[57] Since the C-S-Au angles are similar
in (NHC)Au(SCOR) and (NHC)AuSR (thiolate) com-
plexes, however, it seems unlikely that Au…O interac-
tions influence the S-Au-C angle. In all the structures
except 6, the planes defined by the NHC ligand, and the
thiocarboxylate SC(O)C atoms are tilted with respect to
one another, the interplanar angle θ being larger for the
imidazole-based complexes (in the range 24.03–88.44 )
than for the benzimidazole-based complexes (in the
range 0–60 ).
Amongst groups of similar M-NHC complexes, there is
a trend of increasing M-C bond length with increasing
donor ability of the trans ligand.[58,59] Comparison of Au-C
bond lengths amongst [(NHC)Au(SCOR)], [(NHC)AuCl]

TABLE 2 Selected bond distances (Å) and angles ( ) in the structures of (NHC)Au(SCOR) complexes

Compound Au-C Au-S C-Au-S C-S-Au Au…O C-O C-S Au…Aua

1b 1.96(3) 2.291(9) 176.9(9) 104.9(10) 3.23(3) 1.25(4) 1.77(4) c

2.01(3) 2.289(10) 176.3(9) 104.6(11) 3.25(2) 1.21(4) 1.77(3)

1.99(4) 2.295(9) 178.3(10) 103.3(13) 3.24(3) 1.21(4) 1.71(3)
1.99(4) 2.308(9) 177.1(11) 102.2(12) 3.20(3) 1.23(5) 1.73(4)
b c
2 2.017(6) 2.2943(16) 176.83(18) 105.4(2) 3.290(7) 1.209(9) 1.746(8)
2.012(8) 2.296(2) 179.3(2) 104.5(3) 3.258(6) 1.203(9) 1.755(8)
4.CH2Cl2 2.005(3) 2.3142(8) 171.70(10) 102.10(11) 3.205(3) 1.218(4) 1.751(4) 3.1137(2)d
5 2.012(3) 2.2932(9) 172.90(10) 106.01(12) 3.278(3) 1.218(4) 1.746(4) 5.580(4)
b
6 2.042(7) 2.2888(15) 176.01(16) 109.7(2) 3.408(5) 1.212(8) 1.734(6) 4.0377(0)e
2.059(5) 2.2857(18) 172.79(13) 110.5(2) 3.447(6) 1.210(8) 1.741(6)
7 2.003(11) 2.281(3) 176.2(3) 106.9(5) 3.351(9) 1.211(1) 1.756(2) 5.3561(5)e
8 2.009(3) 2.3008(7) 174.21(7) 99.91(9) 3.108(2) 1.216 (3) 1.771(2) 4.3323(6), 5.8977(5)e
9 1.992(4) 2.2927(10) 177.54(12) 104.54(13) 3.272(3) 1.213(5) 1.765(4) 3.5720(3)d
10 2.004(3) 2.2963(9) 179.24(9) 102.57(12) 3.194(3) 1.232(5) 1.760(3) 3.8317(4)d
a
Shortest intermolecular Au…Au distance in the structure.
b
Data shown for the four independent molecules of 1 and the two independent molecules of 2 and 6.
c
Shortest Au…Au distances between Au atoms in the four independent molecules >6 Å.
d
Au…Au within the dimer/pair of molecules.
e
Au…Au distance between Au atoms of adjacent molecules in the columns.
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10 of 23 AL-BUTHABHAK ET AL.

TABLE 3 Selected interplanar distances (Å) and angles ( ) in the structures of (NHC)Au(SCOR) complexes

θa θ0 b θ00 c Dd S-π (C3N2)e S-π (C6)f π–πg π–πh

1i 39, 42, 41, 40 - - - - - - -
2 59.79, 88.32 - 66.75, 88.15,67.66, 83.24 - - - - -
4.CH2Cl2 24.03 35.50 - - - - - -
5 32.07 17.23 70.32, 86.22 - - - - -
i
6 0, 0 - - 3.846 3.934, 3.915 4.386, 4.360 - -
7 13.00 - 71.16, 85.96 3.353 4.104 - - 4.091
8 11.81 13.76 - 3.29, 3.32 4.01, 5.37 3.75, 5.27 5.23, 4.13 -
9 60.10 17.52 - 3.774 3.476 4.298 5.090 -
10 10.27 18.66 73.34, 81.39 3.744 3.630 4.024 4.621 -
a
θ = Interplanar angle between thiocarboxylate group and the heterocyclic ring.
b 0
θ = Interplanar angle between thiocarboxylate group and the phenyl ring in the thiobenzoate ligand.
c 00
θ = Interplanar angle between heterocyclic ring and aryl substituents (benzyl rings) respectively in 2, 5, 7 and 10.
d
D = Distance between BIm planes in adjacent molecules.
e
Distance between S of one molecule and centroid of the C3N2 ring of the BIm ligand in an adjacent molecule.
f
Distance between S of one molecule and the C6 centroid of the BIm ligand in an adjacent molecule.
g
Distance between the centroid of the C6 ring of the BIm ligand of one molecule and centroid of the C6 ring of the thiobenzoate ligand in an adjacent
molecule.
h
Distance between the centroid of the C6 ring of the BIm ligand of one molecule and centroid of the C3N2 ring of the BIm ligand in an adjacent molecule.
i
Data shown for the four independent molecules of 1 and the two independent molecules of 2 and 6.

F I G U R E 1 Structure of 1. Views of
molecule 1 (50% probability level for the
atomic displacement ellipsoids, H atoms
have been omitted for clarity)
(a) perpendicular to the Au coordination
axis and (b) skewed to the Au coordination
axis, highlighting the difference between the
NHC and thiocarboxylate planes.
(c) Hydrogen bonding within the tetramer
formed from two of each of molecules 1 and
2 in the crystal structure of 1. Molecules
3 and 4 form a similar tetramer
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AL-BUTHABHAK ET AL. 11 of 23

and [(NHC)2Au]X complexes (Table 4) shows trends
broadly as expected. Au-C bonds have similar lengths in
[(NHC)Au(SCOR)] and [(NHC)2Au]X, where the trans
F I G U R E 2 The two independent molecules in the crystal
structure of 2, with H atoms omitted for clarity
ligands are a thiocarboxylate and an NHC, respectively
(both strong donors), while the Au-C bond is shorter in
[(NHC)AuCl], where the trans ligand Cl
is a much wea-
ker donor. However, as has been noted previously in an
interesting study of a range of complexes of the form
(iPrBIm)PdBr2L,[58] trends in variation of bond length with
donor ability of the trans ligand are complicated by other
factors, including crystal packing effects, intramolecular ste-
ric interactions, solvation effects, and counter ion effects.
The crystal structure of 1 contains four independent
molecules in the asymmetric unit. In each of these
(e.g., Figure 1a,b), the plane of the thiocarboxylate group
is tilted slightly out of the plane defined by the NHC
ligand (interplanar angle θ–40 , Table 3). In the overall
array, molecules 1, 3 and molecules 2, 4 are pseudo-

F I G U R E 3 A pair of molecules
formed into a dimer in the crystal
structure of 4.CH2Cl2. (a) Molecular
representation (with ellipsoids drawn at
the 50% probability level, H atoms
omitted for clarity), with the
intermolecular aurophilic interaction
(Au…Au 3.1137(2) Å) highlighted.
(b) Space-filling representation, to
highlight possible dispersion interactions
between Cy2Im groups

F I G U R E 4 (a) Crystal packing

of 5, showing key intermolecular
π–π interactions, H atoms omitted
for clarity. (b) A pair of the two
independent molecules in the
structure of 6 (below is molecule
1, above is molecule 2). The
intrapair Au…Au distance (4.038 Å)
and the distance from the centroids
of each C3N2 and C6 ring to the S
atom of the opposing molecule
(3.914 and 3.934 Å, 4.386 and
4.360 Å, respectively) are
highlighted

12 of 23
TABLE 4 Au-C bond length of [(NHC)Au(SCOR)], [(NHC)AuCl] and [(NHC)2Au]X complexes
[(NHC)AuSCOR]
NHC R = Me R = Ph
i
Pr2Ima
1.96(3), 2.01(3),
1.99(4), 1.99(4) (1)a
Bn2Ima 2.017(7), 2.012(9) (2) 2.012(4) (5)
Cy2Im 2.011(11) (4)
Me2BIm 2.009(3) (8)
i
Pr2BIma 2.042(7), 2.059(5) (6)a 1.987(4) (9)
Bn2BIm 2.003(11) (7) 2.004(3) (10)
a
Au-C bond length for four independent molecules (for 1) or two independent molecules (for 2 and 6).
related by a cell translation of c/2. Molecules 1 and 2 form
tetrameric arrangements via four hydrogen bonds
(Figure 1c). In each tetramer, two of molecule 1 are
approximately coplanar, their NHC groups oriented
toward each other, and two of molecule 2, also approxi-
mately coplanar, are oriented with their C=O groups
toward each other. The four hydrogen bonds occur
between the imidazole H4 and H5 protons of each mole-
cule 1 and the O atom of each molecule 2. A similar pat-
tern is seen for molecules 3 and 4.
The structure of 2 contained two independent mole-
cules (Figure 2). In both molecules, the thioacetate group
is tilted out of the plane defined by the NHC ligand
(interplanar angle θ–59 in molecule 1 and 88 in mole-
cule 2, and the benzyl groups of each NHC ligand are
mutually anti about the C3N2 core. In the packed arrange-
ment of 2, molecules 1 and 2 assemble into planes parallel
to a, the overall structure built up from successive bila-
yers of molecule 1 and molecule 2 (Figure S1). The array
is possibly stabilised by π–π interactions between benzylic
groups (centroid to centroid distance between benzyl
groups of pairs of molecule 1 are 5.355 Å and between
benzyl groups of pairs of molecule 2 are 5.011 Å). There
are no Au…Au or intermolecular S…π interactions.
In the structure of 4.CH2Cl2, adjacent molecules form
dimers via an aurophilic interaction (Au…Au 3.1137(2) Å;
Figure 3). The deviation of the Au coordination from line-
arity (C-Au-S 171.70(10) ) appears to be a consequence of
this interaction, the Au atoms in the two molecules being
drawn towards each other. Curiously, aurophilic interac-
tions are also seen in the chlorido analogue (Cy2Im)AuCl
(Au…Au 3.1566(6) Å).[16] This observation is at first
surprising, since, intuitively, one might expect the steric
bulk of the cyclohexyl substituents to disfavour formation
of intermolecular Au…Au interactions. It may be, how-
ever, that for both 4.CH2Cl2 and (Cy2Im)AuCl, dispersion
interactions between the Cy2Im groups within the dimers
reinforce the aurophilic interaction.
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AL-BUTHABHAK ET AL.
[(NHC)AuCl] [(NHC)2Au]X
1.964(6) (Ref. [16]
) 2.027(2), 2.027(2) (X = Cl; Ref.[60])
1.992(3) (Ref.[61]) 2.06(1), 2.04(1) (X = Br. Ref.[62])
1.978(8) (Ref.[16]) 1.97(1), 2.02(1) (X = Cl; Ref.[60])
1.985(11) (Ref. [28]
) 2.02(2), 2.03(2), 2.05(10) (X = PF6)[63,64]
1.973(7) (Ref.[65]) 2.048(9), 2.028(4) (X = BF4; Ref.[65])
1.976(5) (Ref.[64]) 2.03(3) (X = BF4; Ref.[64])
In structure of 5, there is one unique molecule, again
with the plane of the thiocarboxylate group skewed
relative to the NHC plane and with the benzyl groups
mutually anti about the C3N2 core of the NHC
(Figure S2). Packing within the crystal structure appears
to be stabilised by intermolecular π…π interactions
between the adjacent phenyl rings of benzyl groups
(4.648 Å) and between phenyl rings of thiobezoate and
C3N2 rings (4.643 Å; Figure 4a).
In structure 6, there are two independent molecules,
and in both molecules, the NHC and thiocarboxylate
ligands are coplanar (Figure 4b). The molecules are
arranged into columns (Figure S3). Within the columns,
molecules 1 and 2 occur in alternate layers and are anti-
parallel to each other. In this arrangement, the S atom in
molecule 1 is sandwiched between the C3N2 rings of mol-
ecule 2 in the layer below and molecule 2 in the layer
above, and vice versa. The spacing between the molecules
in the column is uniform (3.846 Å). The columnar
arrangement may be stabilised by S–π interactions. The
distances between the S atom of one molecule and the
centroids of the C3N2 and the centroids of the adjacent
molecules are 3.914 and 3.934 Å, and between the S atom
of one molecule and the centroids of the C6 rings of adja-
cent molecules are 4.386 and 4.360 Å (see Figure 4b),
within the range reported for attractive S–π interac-
tions.[66,67] In both molecules 1 and 2, there are close con-
tacts (2.66–2.79 Å) between the H atoms of the iPr groups
of the iPr2BIm ligand and the Au centre (Figure S4), but
these contacts do not appear to be indicative of anagostic
interactions (see supplementary information for further
discussion).
The (R2BIm)Au(SCOR) complexes 7–10 show molecu-
lar structures and crystal packing features similar to those
exemplified by complexes 1, 2 and 4.CH2Cl2–6—further
discussion is included in the supporting information.
Interestingly, amongst 1, 2 and 4.CH2Cl2–10, only 4.
CH2Cl2 shows an aurophilic interaction (Au…Au 3.1137

AL-BUTHABHAK ET AL.
(2) Å). In all other complexes, the Au…Au distances are
substantially larger than the sum of the van der Waals
radii (3.32 Å).[56] Even in complexes 6–10, where the mol-
ecules form pairs or stacks in which the planes of the BIm
moieties are quite close (e.g., 3.29 and 3.32 Å in the case
of 8), the Au…Au distance is larger because the molecules
are offset from one another. The packing of molecules
appears to be dominated by S–π and π–π interactions.
3.3 | NMR studies of (NHC)Au(SCOR)
complexes
The appearance of 1H and 13C NMR spectra of solutions
of the new complexes is consistent with the structures
seen in the X-ray studies. 1H NMR spectra (e.g., Figure 5)
showed signals consistent with the presence of an NHC
ligand and a thiocarboxylate ligand. In the 13C NMR
spectra, the signal due to the carbene carbon for the
imidazole-based complexes 1–5 occurred in the range δ
176.2–179.4 ppm, while that for the benzimidazole-based
complexes 6–10 occurred in the range 184.3–187.4 ppm
(Table 5). The signal due to the carbonyl carbon in
(NHC)Au(SCOR) complexes appeared further downfield,
in the range δ 199–206 ppm (Table 5).
Previous studies have shown that the 13C NMR
chemical shift of the carbene carbon in [(NHC)AuL]
complexes increases as the σ-donating ability of L
increases.[15,58,69] More downfield chemical shifts suggest
lesser Lewis acidity of Au, implying increased σ-donation
from L, and vice versa.[70] The carbene chemical shifts for
the new thiocarboxylate complexes 1–10 are about
1–4 ppm lower than for the corresponding [(NHC)2Au]+
1
FIGURE 5 H NMR spectrum (500 MHz,
DMSO-d6) of 8
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13 of 23
complexes,[60,65] but 8–10 ppm higher than for the
corresponding [(NHC)AuCl] complexes,[16,28,65]
suggesting that the thiocarboxylate ligands are almost as
strong σ-donors as NHCs. These trends were seen for Im
complexes and BIm complexes, even though the chemi-
cal shift of the carbene carbon in the Im complexes was
7–11 ppm less than that for the BIm complexes.
Au-C bond lengths measured by X-ray crystallographic
studies of (NHC)AuL complexes (Table 4) do not show a
strong correlation between donor strength of L and increas-
ing length of the Au-CNHC bond: Au…C (NHC)AuCl,
[(NHC)2Au]+ and (NHC)Au(SCOR) are 1.978(10)Å, 2.028
(25)Å and 2.008(24)Å, respectively. The 13C NMR chemical
shift of the carbene carbon appears to offer better ‘resolu-
tion’ as a probe of the effects of the ancillary ligand L on
Au-C bonding. Hyunh has noted that 13C NMR chemical
shifts of carbene carbons are very sensitive and can detect
subtle variations in the structure of the trans ligand.[59]
Huynh's electronic parameter (HEP)[71] can be used
to rank the donor ability of a ligand L based on the 13C
NMR chemical shift of the carbene carbon in trans-
[(iPr2BIm)PdIIBr2(L)][58] or (iPr2BIm)AuI(L).[19] For a
ligand L in the Au series, HEP = 1.19[Au] - 45.0, where
[Au] is the chemical shift of the carbene carbon in
(iPr2BIm)AuI(L) in CDCl3 solution (where δC CDCl3 is
taken as 77.7 ppm).[19,72] In the present study, 13C NMR
chemical shift of the carbene carbons in CDCl3 solutions
of (iPr2BIm)Au(SCOMe) 6 and (iPr2BIm)Au(SCOPh)
9 was determined to be 187.0 and 186.9 ppm, respectively
(relative to CDCl3 at 77.7 ppm), indicating a HEP of
177.5 for the thiocarboxylate ligands. This HEP value
indicates that the thiocarboxylate ligand is a far stronger
donor than halides, N-donors and even phosphines and
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14 of 23 AL-BUTHABHAK ET AL.

T A B L E 5 Comparison of 13C NMR

[(NHC)AuSCOR]
chemical shifts for carbene carbons of
NHC R = Me R = Ph [(NHC)AuCl] [(NHC)2Au]X [(NHC)Au(SCOR)], [(NHC)AuCl] and
i
Pr2Im 176.6 (1) 176.3 (3) a
168.7 (Ref. [16]
) 180.2 (X = Cl; Ref.[60]) [(NHC)2Au]X complexes

179.6a 179.5a
Bn2Im 179.4 (2) 179.0 (5) 169.1 186.4 (X = Br; Ref.[62])
171.4a
Cy2Im 176.6 (4) 166.1a (Ref.[16]) 180.4 (X = Cl; Ref.[60])
Me2BIm 186.7 (8) 177.2 (Ref.[68]) 190.2 (X = BF4; Ref.[68])
a
179.2 (Ref. [28]
) 190.2 (X = PF6; Ref.[28])
i
Pr2BIm 184.4 (6) 184.0 (9) 175.8a (Ref.[65]) 187.4a (X = BF4; Ref.[65])
186.5a 186.4a
Bn2BIm 187.4 (7) 187.0 (10) 177.8 (Ref.[64]) 190.0 (X = BF4; Ref.[64])

Note: Spectra recorded as part of this work, at ambient temperature in DMSO-d6, unless indicated otherwise.
a
Recorded in CDCl3.

F I G U R E 6 Comparison of Huynh's
electronic parameter (HEP) values for
ligands L in (iPr2BIm)AuL complexes

is similar to NHCs in donor ability. This result is perhaps
not surprising when considered in terms of hard-soft
acid–base theory, S and Au being soft donor and accep-
tor, respectively.[73] Consistent with this suggestion, the
HEP value for thiocarboxylate is the same as that of
another S-donor 2-thiolatopyrimidine (Figure 6).[32]
3.4 | Stability and disproportionation of
(NHC)Au(SCOR) Complexes
The thiocarboxylate complexes 1–10 appeared to be sta-
ble indefinitely (>2 years) in the solid state when stored
at
18 C in stoppered flasks in the dark under the
laboratory atmosphere. At room temperature, however,
the complexes were susceptible to slow disproportion-
ation in the solid state during prolonged storage, to form
mixtures containing the corresponding [Au(SCOR)2]

and [(NHC)2Au]+ complexes in addition to the initial
(NHC)Au(SCOR) complex. In DMSO-d6 solution, all the
(NHC)Au(SCOR) complexes underwent disproportion-
ation slowly at room temperature but established
equilibrium with their disproportionation products
within 1 h at 100 C (Scheme 2). The equilibrium con-
stant for the process 2[(NHC)Au(SCOR)] ⇌ [Au(SCO-
R)2]
+ [(NHC)2Au]+ (estimated by integration of 1H
NMR spectra recorded at 25 C) was in the range 0.006–
0.023 (Table S2), with the equilibrium strongly favouring
the heteroleptic [(NHC)Au(SCOR)] over the two
homoleptic complexes in all cases. There was no clear
relationship between the equilibrium constant and the
structure of the NHC or thiocarboxylate ligand.
A 1H NMR study of the disproportionation of
(Me2BIm)Au(SCOPh) 8 was undertaken to confirm the
structure of the products of disproportionation and explore
the possibility of thermal degradation of the sample at ele-
vated temperatures. A freshly prepared solution of
8 showed no signs of disproportionation at room
temperature. After the solution was heated at 100 C for
1 h, an equilibrium mixture had formed, containing
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AL-BUTHABHAK ET AL. 15 of 23

S C H E M E 2 Equilibration of (NHC)Au
(SCOR) with [(NHC)2Au]+ and [Au
(SCOR)2]
in DMSO-d6 at 100 C

S C H E M E 3 Equilibrium between (Me2BIm)Au(SCOPh) 8 and its disproportionation products [Au(SCOPh)2]
12
and
[(Me2BIm)2Au]+ 13+ and structures of the decomposition products 1,3-dimethylbenzimidazolium ion 14+ and 1,3-dimethyl-2(3H)-
benzimidazolethione 15 that were formed upon heating at 100 C for 24 h

F I G U R E 7 1H NMR spectra (500 MHz, DMSO-d6) of: (a) A freshly prepared solution of K.12 and 13.PF6 in a 2:1 ratio, respectively;
(b) same sample as (a) but after heating at 100 C overnight; (c) sample prepared by heating a freshly prepared solution of 8 at 100 C for 1 h;
and (d) a freshly prepared solution of 8. Spectra (b) and (c) both show signals due to 8, 12
and 13+ in equilibrium, but (b) also shows
signals due to 1,3-dimethylbenzimidazolium 14+ and 1,3-dimethylbenzimidazole-2-thione 15, which formed during prolonged heating. Two
or more diagnostic signals for each compound are labelled in the various spectra

(Me2BIm)Au(SCOPh) 8 and its disproportionation prod- detected, predominantly the 1,3-dimethylbenzimidazolium

ucts [Au(SCOPh)2]
(12
) and [(Me2BIm)2Au]+ (13+)
(Scheme 3). Integration of the 1H NMR spectrum
(Figure S12) showed that complex 8 and its disproportion
products 12
and 13+ were present in a ratio of approxi-
mately 81:10:9, respectively. When the sample was heated
for 24 h, this approximate ratio was maintained and 8, 12

and 13+ accounted for over 90% of the sample. However,
very minor amounts of additional compounds were
ion 14+ and its thione derivative 15 (Scheme 3 and
Figure S12)
In this 1H NMR study, the identity of the complex
+
13 was confirmed by addition of a small amount of 13.
PF6 (prepared separately; see supporting information) to
the NMR sample—when the 1H NMR spectrum was re-
examined after the addition, the signals attributed to 13+
had increased in intensity. When a solution of 13.PF6 in

16 of 23
DMSO-d6 was heated separately overnight at 100 C,
small signals for the 1,3-dimethylbenzimidazolium ion 14
were seen in the 1H NMR spectrum.
To further explore the equilibrium between 8, 12

and 13+, complexes 12
and 13+ were synthesised sepa-
rately, as their K+ and PF6
salts K.12 and 13.PF6, respec-
tively (see supporting information). The salts K.12 and 13.
PF6 were mixed in a ratio of approximately 2:1, respec-
tively, in DMSO-d6, and then the sample was heated at
100 C overnight. Examination of the 1H NMR spectrum
of the sample after heating showed the presence of signals
due to 8, 12
and 13+ (Figure 7b), confirming the exis-
tence of the equilibrium between 8, 12
and 13+. Based
on integration of 1H NMR signals due to 8, 12
and 13+,
the equilibrium constant was estimated to be Keq  0.013,
the same as was measured when the equilibrium was
attained by disproportion of 8 (Table S2).
Curiously, immediately after dissolution of K.12 and
13.PF6 in DMSO-d6, the 1H NMR spectrum of the DMSO-
d6 solution showed that signals for the two complexes
were slightly shifted relative to their appearance in spec-
tra recorded for K.12 or 13.PF6 in separate solutions in
DMSO-d6 (Figure S13). This observation suggested the
possibility of formation of a double salt-type ion
pair (12
)(13+), possibly via an aurophilic interaction
(Figure 8).
A Job Plot analysis[74] was undertaken to explore the
possible interaction between complexes 12
and 13+ in
solution. The analysis was based on 1H NMR chemical
shifts of the signal due to the ortho protons of 12

(7.94 ppm) and the signal due to the benzimidazolium
H4 and H7 protons of 13+ (7.85 ppm), measured from
solutions containing different mole fractions X of K.12
and 13.PF6. The Job Plots (Figure 9) show a maximum
near Χ 12
= Χ 13+ = 0.5, as expected if 12
and 13+ form
a 1:1 complex.[74] The fact that the plot is curved rather
than sharp (like an inverted ‘V’) indicates that the inter-
action between 12
and 13+ is not strong.[74] (For more
detailed discussion, see supporting information.) We
F I G U R E 8 Proposed aurophilic interaction of double salt ion
pair (12
)(13+) in solution
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AL-BUTHABHAK ET AL.
made several attempts to co-crystallise 12
and 13+ from
solutions containing both K.12 and 13.PF6 in DMF, but
we obtained no evidence for formation of (12
)(13+) ion
pairs in the solid state. One of the crystallisation experi-
ments yielded two types of crystals, but both proved to be
polymorphs of 13.PF6.
3.5 | Thiol exchange activity of the
(NHC)AuSCOR complexes
3.5.1 | Reaction of (Me2BIm)Au(SCOPh)
8 with thioacetic acid
The reactivity of Au complexes with thiols and other
ligands in the biological milieu is a significant factor con-
tributing to their biological activity.[8,51] To begin to
explore thiol reactivity of the new thiocarboxylate com-
plexes, the reaction of (Me2BIm)Au(SCOPh) 8 with
thioacetic acid was investigated. Since the (NHC)Au
(SCOR) complexes are insoluble in water, these prelimi-
nary experiments were conducted in DMSO-d6.
A sample of 8 in DMSO-d6 was treated with 4 equiv-
alents of thioacetic acid,* and changes were monitored by
1
H NMR spectroscopy. The spectrum of the sample
immediately broadened (Figure 10). In the aromatic
region, signals due to the aryl protons of the Me2BIm
group broadened but did not change significantly in
chemical shift, while the methyl signal for the Me2BIm
group split into two components, in a ratio of 2:3. The
signals due to the thiobenzoate ligand also broadened,
and new broad signals emerged at chemical shifts close
to those seen for thiobenzoic acid in separate samples.
These results are consistent with addition of thioacetic
acid resulting in formation of a rapid equilibrium
between 8 and its thioacetate analogue 16 (Figure 10). By
integration of the 1H NMR spectrum, the equilibrium
constant for the equilibrium 8 + thioacetic acid ⇌ 16
+ thiobenzoic acid was estimated to be 0.19 (see
supporting information). A broad singlet at 2.38 ppm is
tentatively attributed to the methyl protons of the
thioacetate ligand in 16 and is well removed from the sig-
nal due to the methyl protons of thioacetic acid
(2.56 ppm). Overall, this experiment suggests that under
the reaction conditions, the thiocarboxyate ligand in 8 is
more labile than the NHC ligand.
Interestingly, when the sample was left at room tem-
perature overnight, the 1H NMR signal due to the methyl
group of thioacetic acid (δ 2.56 ppm) almost disappeared.
*The thioacetic acid contained traces of acetic acid. Separate
experiments showed that (Me2BIm)Au(SCOPh) 8 did not react with
acetic acid in DMSO-d6 solution, even when present in 30-fold excess.
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AL-BUTHABHAK ET AL. 17 of 23

F I G U R E 9 Job Plots for mixtures of K.12

and 13.PF6 in DMSO-d6 solution where [12
]
+ [13+] = 5 mM. (a) Plot based on 1H NMR
chemical shift of the ortho protons of 12

(7.935 ppm, marked ▲ in lowest spectrum)
and 1H NMR chemical shift of the more
downfield signal of the benzimidazolium
protons of 13+ (7.856 ppm, marked □ in
uppermost spectrum). (b) Aromatic region of the
1
H NMR spectra (500 MHz, DMSO-d6) of
samples containing [Au(SCOPh)2]
12
and/or
(Me2BIm)2Au+ 13+. NMR samples were
prepared from stock solutions of K[Au
(SCOPh)2] K.12 and [(Me2BIm)2Au]PF6 13.PF6
so that [12
] + [13+] = 5 mM. From top to
bottom, X12
ranges from 0 to 1 in increments of
0.1

F I G U R E 1 0 Aromatic and N-methyl regions of 1H NMR spectra (500 MHz, DMSO-d6) for (a) a fresh sample of 8 and (b) the same
sample immediately after addition of thioacetic acid

This disappearance was accompanied by emergence of a 1.91 ppm due to acetic acid). Additionally, the signals in
new signal at δ 2.21 (tentatively attributed to diacetyl the aromatic region sharpened, so that two overlapping
disulfide and a significant increase in the signal at sets of Me2BIm signals were evident—one set due to the

18 of 23
Me2BIm ligand 8 and the other tentatively assigned to
the Me2BIm ligand in 16. The signals for the
thiobenzoate ligand in 8 were evident, but additional sig-
nals that corresponded to benzoic acid and traces of
1,3-dimethylbenzimidazolium ion 14+ and its thione
derivative 15 were also present. When the sample was
heated at 100 C for 2 h, benzoic acid 17 and the thione
15 became the dominant aromatic products in the mix-
ture (Figure 11); all the diacetyl disulfide was converted
to acetic acid, and crystals of S8 grew in the sample. In
this experiment, the assignments of signals attributed to
benzoic acid and the thione 15 were confirmed by record-
ing of spectra after addition of authentic samples of those
compounds, and the S8 crystals were identified by X-ray
diffraction.
The conversion of thioacetic acid to the
corresponding diacetyl disulfide is not unprecedented.
The analogous conversion for thiobenzoic acid has been
achieved catalytically in the presence of AgI,[75] and non-
catalytic decomposition of cuprous thiobenzoate under
prolonged heating can produce dibenzoyl disulfide and
other products.[76] Formation of benzoic acid seen in the
above experiment could be due to the hydrolysis of
thiobenzoic acid.[77] It may be that DMSO serves as an
oxidising agent (perhaps with catalysis by Au) to oxidise
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AL-BUTHABHAK ET AL.
S-II (from thiobenzoic acid, thioacetic acid, diacetyl disul-
fide or the hydrolysis product H2S) to S0,[78] which in
turn led to formation of S8 and the thione 15.
The above results suggest an explanation for why the
broad signals in the 1H NMR spectrum in Figure 11a
were replaced by sharp signals in the 1H NMR spectrum
in Figure 11b. Broadness was due to rapid exchange of
thiolate for thiobenzoate on the Au centre when excess
thioacetic acid was present in the reaction mixture, but
when the thioacetic acid was consumed by various side
reactions (conversion into diacetyl disulfide, the
benzimidazole-2-thione 15, S8, acetic acid, etc), exchange
reactions could no longer occur.
3.5.2 | Reaction of (Me2BIm)Au(SCOPh)
8 with N-acetylcysteine
The reactivity of (Me2BIm)Au(SCOPh) 8 with N-
acetylcysteine was explored as a model for ligand
exchange activity of (NHC)Au(SCOR) complexes with
cysteine residues that are abundant in biological systems.
When equimolar amounts of N-acetylcysteine and com-
plex 8 were mixed at room temperature in DMSO-d6,
there was little change in the 1H NMR signals for either
F I G U R E 1 1 1H NMR spectra
(500 MHz, DMSO-d6) of (a) the sample
of 8 immediately following mixing with
thioacetic acid, (b) the same sample of
8 and thioacetic acid left overnight and
(c) the same sample after heating at
100 C for 2 h
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AL-BUTHABHAK ET AL. 19 of 23

F I G U R E 1 2 The aromatic
region of the 1H NMR spectra
(500 MHz, DMSO-d6) for a fresh
sample of N-acetylcysteine (top
spectrum), a fresh sample of
8 (bottom spectrum) and a
sample containing 8 and N-
acetylcysteine immediately after
mixing

compound (Figure S17). Upon closer inspection, how- T A B L E 6 IC50 values for (NHC)Au(SCOR) complexes against
ever, signals associated with the thiobenzoate ligand and OVCAR-8 cells
most signals associated with N-acetylcysteine and the Compound IC50 (μM) ± SEM n
Me2BIm ligand appeared to be broadened (Figure 12).
1 3.0 ± 0.3 4
This broadening suggests that there may be rapid
exchange between thiobenzoate and the thiolate form of 2 4.3 ± 0.3 3
N-acetylcysteine, analogous to the exchange seen when 3 3.2 ± 0.3 4
8 was mixed with thioacetic acid. The absence of a signal 4 2.7 ± 0.2 3
(expected near 9.6 ppm) that could be attributed to the 5 3.8 ± 0.5 3
H2 proton of the 1,3-dimethylbenzimidazolium ion 14+, 6 2.9 ± 0.5 5
and the lack of significant change in the chemical shift of
7 3.5 ± 0.1 3
the signals due to benzimidazolium H4-H7, indicates that
8 3.5 ± 0.3 3
the Me2BIm ligand remained attached to the Au centre.
After 3 weeks, however, the sample had become a com- 9 2.9 ± 0.5 4
plex mixture of products and the 1H NMR spectrum 10 5.2 ± 0.4 3
suggested that at least half of the Me2BIm ligands had 18 a
1.0 ± 0.2 4
been converted into 1,3-dimethylbenzimidazolium 14+ 19 b
>100 4
(Figure S18). The mixture of products was not investi-
20b >100 4
gated further.
Note: OVCAR-8 cells were exposed to test compounds during incubation for
72 h, and activity of the compounds on cell viability was evaluated using an
MTT assay. Data are shown as mean ± SEM of at least three independent
3.6 | Activity of (NHC)Au(SCOR) experiments (n), each of which used two to four replicates per concentration
complexes against OVCAR-8 cells for the relevant test compound.
a
[(Pr2Im)2Au]Br 18 used as positive control.
b
Azolium salts 19 and 20 used as negative control.
The OVCAR-8 cell line is an excellent model to test the
activity of the new compounds. OVCAR-8 cancer cells
were used because their genomic profile highly resembles concentrations, as shown by the IC50 values (Table 6)
high-grade serous ovarian carcinoma, which is the most and plots of cell viability versus concentration
common histological subtype of advanced ovarian can- (Figure 13). The (NHC)Au(SCOR) complexes 1–10
cer.[79] OVCAR-8 cells were originally cultured from showed similar inhibitory activity regardless of the NHC
patients treated with intensive chemotherapy and are ligand (R2Im or R2BIm), lipophilicity (large or small R
known to have high resistance to platinum anticancer groups) or thiocarboxylate (thioacetate or thiobenzoate)
agents (cisplatin).[80] with IC50 values ranging between 2.7 and 5.2 μM. As
The new (NHC)Au(SCOR) complexes 1–10 inhibited expected, the imidazolium and benzimidazolium salts 19
the viability of ovarian cancer cell line OVCAR-8 at low and 20 (used as negative controls) did not inhibit the
 10990739, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/aoc.6645 by Readcube (Labtiva Inc.), Wiley Online Library on [17/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
20 of 23 AL-BUTHABHAK ET AL.

F I G U R E 1 3 The inhibition activity of the (NHC)Au (SCOR) complexes against OVCAR-8 cells, measured by an MTT assay after 72 h of
treatment. The azolium salts 19 and 20 were used as negative controls, and [(Pr2Im)2Au]Br 18 was used as a positive control. Data are shown
as mean ± SEM of at least three independent experiments, each of which used two to four replicates per concentration for the relevant test
compound

growth of OVCAR-8, suggesting that the Au has an concentration. The exception here is (Bn2BIm)Au
important role in the inhibition of cancer cells. (SCOPh) 10, which shows a less sharp sigmoidal curve at
Most of the (NHC)Au(SCOR) complexes showed the high end of the concentration range examined, but
sharply sigmoidal curves for cell viability versus this result may be a consequence of low solubility of the

AL-BUTHABHAK ET AL.
complex in the medium—solutions prepared by dilution
of DMSO stock solutions of 10 with cell culture medium
were cloudy. However, (Cy2Im)Au(SCOPh) 4, which also
showed poor solubility and formed cloudy solutions
when diluted, was the most potent compound and had a
sharply sigmoidal curve for cell viability versus
concentration.
The new complexes (NHC)Au(SCOR) showed activity
in OVCAR-8 cells comparable with that previously
reported for [(Pr2Im)2Au]Br 18 and its analogues
in MDA-MB-231 breast cancer cell lines.[8] The
[(Pr2Im)2Au]Br compound 18 (used as positive control)
showed an IC50 value of 1.0 ± 0.2 μM, suggesting that it is
slightly more potent than all of the (NHC)Au(SCOR)
complexes. This result might be due to the cationic char-
acter of 18 that might allow it to target mitochondria[8]
more effectively than the neutral (NHC)Au(SCOR)
complexes. However, the cell viability versus concentra-
tion curve for 18 showed a much broader sigmoidal shape
than the (NHC)Au(SCOR) complexes. The sharp
sigmoidal shape of the curves for the (NHC)Au(SCOR)
complexes suggests that at sufficiently high concentra-
tions, these complexes are more effective at killing a larger
proportion of the cells, leaving minimal residual viable
cells, whereas the broader sigmoidal curve for 18 suggests
that there is some intrinsic heterogeneity within the
OVCAR-8 cell line that causes 18 to be less effective
against some cell clones. For example, at concentrations
slightly above 10 μM, the (NHC)Au(SCOR) compounds
kill almost all the cells, whereas with 18 at the same con-
centration, 10%–20% of the cells are still alive.
The cationic complex 18 showed some activity against
OVCAR-8 cells even at very low concentrations, whereas
the (NHC)Au(SCOR) complexes showed little activity at
concentrations below 1 μM. This difference might be a
consequence of the high lability of the thiocarboxylate
ligand, making the (NHC)Au(SCOR) complexes suscepti-
ble to reactions with metal scavenging molecules such as
glutathione in the cytosol,[81,82] which would impede the
progress of the compounds (or AuI, the likely active
component) to thioredoxin reductase (TrxR) in the mito-
chondria. At higher concentrations of (NHC)Au(SCOR),
the cells' stocks of metal scavenging species such as gluta-
thione would be overwhelmed, allowing (NHC)Au
(SCOR) to find its way to the TrxR target.
4 | C ON C L U S I ON
Thiocarboxylate ligands readily replace the halido ligands
in (NHC)AuCl complexes to form (NHC)Au(SCOR)
complexes. NMR and X-ray studies showed that the
thiocarboxylate ligands have similar donor abilities to
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21 of 23
NHC ligands. The (NHC)Au(SCOR) complexes were sta-
ble in the solid state. In DMSO-d6 solution at room tem-
perature, the thiocarboxylate ligand in (NHC)Au(SCOR)
undergoes rapid exchange with other S-donors
(thiocarboxylate, thiolate), and at 100 C, (NHC)Au
(SCOR) rapidly forms equilibria with the homoleptic
disproportionation products [Au(NHC)2]+ and [Au
(SCOR)2]
. While coordination geometries seen for
(NHC)Au(SCOR) complexes in the solid state were unex-
ceptional, some interesting intramolecular (Au…O) and
intermolecular (Au…Au, S…π, π…π) interactions were
seen. All (NHC)Au(SCOR) complexes were active at low
micromolar concentrations against ovarian cancer cells
(OVCAR-8).
A C KN O WL ED G EME N T S
The authors acknowledge the facilities and the scientific
and technical assistance of the Australian Microscopy
and Microanalysis Research Facility at the Centre for
Microscopy, Characterisation and Analysis, The Univer-
sity of Western Australia. Hawraa S. Al-Buthabhak
thanks The Higher Committee for Education Develop-
ment in Iraq (HCED) for financial support. Al-Salami is
supported by the European Union Horizon 2020 research
project and innovation programme under the Marie
Skłodowska-Curie Grant Agreement no. 872370, Curtin
Faculty ORS-WAHAI Consortium and the Australian
National Health and Medical Research Council
(NHMRC, APP9000597). Stephen A. Moggach thanks the
Australian Research Council (ARC) for a Future
Fellowship (FT200100243). Open access publishing facili-
tated by The University of Western Australia, as part of
the Wiley - The University of Western Australia agree-
ment via the Council of Australian University Librarians.
AUTHOR CONTRIBUTIONS
Hawraa S. Al-Buthabhak: Formal analysis; investiga-
tion; methodology. Valerio Falasca: Investigation. Yu
Yu: Methodology. Alexandre Sobolev: Data curation;
formal analysis; investigation. Brian Skelton: Data
curation; formal analysis; investigation. Stephen
Moggach: Data curation; formal analysis; investigation.
Hani Al-Salami: Resources.
DA TA AVAI LA BI LI TY S T ATE ME NT
The data that support the findings of this study are avail-
able in the supporting information of this article.
ORCID
Hawraa S. Al-Buthabhak https://orcid.org/0000-0003-
1676-9554
Valerio Falasca https://orcid.org/0000-0002-3592-9034
Yu Yu https://orcid.org/0000-0002-0209-0586

22 of 23
Alexandre N. Sobolev https://orcid.org/0000-0003-3290-
2044
Brian W. Skelton https://orcid.org/0000-0002-1515-
6636
Stephen A. Moggach https://orcid.org/0000-0001-5339-
7070
Vito Ferro https://orcid.org/0000-0003-3306-2550
Hani Al-Salami https://orcid.org/0000-0003-0049-6969
Murray V. Baker https://orcid.org/0000-0002-0482-3421
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SU PP O R TI N G I N F O RMA TI O N
Additional supporting information may be found in the
online version of the article at the publisher's website.
How to cite this article: H. S. Al-Buthabhak,
V. Falasca, Y. Yu, A. N. Sobolev, B. W. Skelton, S.
A. Moggach, V. Ferro, H. Al-Salami, M. V. Baker,
Appl Organomet Chem 2022, e6645. https://doi.org/
10.1002/aoc.6645