The importance of Au ... π(aryl) interactions in the formation of spherical aggregates in binuclear phosphane gold(I) complexes of a bipodal thiocarbamate dianion: A combined crystallographic and computational study, and anti-microbial activity

Article abstract of DOI:10.1039/c5ra05604g

Binuclear phosphanegold(i) complexes of a bipodal thiocarbamate dianion, (R₃PAu)₂L, R = Et (1), Ph (2) and Cy (3), where LH₂ is {1,4-[MeOC(S)N(H)]₂C₆H₄}, have been synthesised, and characterised spectroscopically (NMR and IR) and by X-ray crystallography. The gold atoms are linearly coordinated within a P-,S-donor set, and are oriented toward the central ring to form intramolecular Au ...π(aryl) interactions, rather than the intramolecular Au ...O interactions normally observed in mononuclear analogues. This phenomenon has been investigated by theory (LC-ωPBE-XDM) for 1 which revealed that the geometry optimised species with two Au ...π(aryl) interactions is more stable by at least 12 kcal mol^-1 compared to conformations having one or more Au ...O interactions instead. The disk diffusion, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) methods were used to observe the inhibitory effect of complexes 1-3. The disk diffusion results demonstrated that 1 exhibited a broad spectrum of anti-bacterial activity toward 24 strains of Gram-positive and Gram-negative bacteria. By contrast, the anti-bacterial activity of 2 and 3 was limited to Gram-positive bacteria. Further evaluation showed that 1 exhibited marked bactericidal activity against B. cereus, B. subtilis, E. faecalis, L. monocytogenes, S. aureus, S. saprophyticus and methicillin resistant S. aureus cf. standard antibiotics tetracycline and chloramphenicol.

Full text of DOI:10.1039/c5ra05604g

RSC Advances
View Article Online
View Journal | View Issue
PAPER
The importance of Au/p(aryl) interactions in the
formation of spherical aggregates in binuclear
phosphane gold(I) complexes of a bipodal
thiocarbamate dianion: a combined
Cite this: RSC Adv., 2015, 5, 41401
crystallographic and computational study, and
anti-microbial activity†
Chien Ing Yeo,a Chai-Hoon Khoo,b Wern-Cui Chu,b Bao-Jing Chen,b Pek-Lim Chu,b
b
b
Jiun-Horng Sim, Yoke-Kqueen Cheah, Jimmy Ahmad,a Siti Nadiah Abdul Halim,a
*
c
a
d
a
*
*
Hoi-Ling Seng, Soon Ng, A. Otero-de-la-Roza and Edward R. T. Tiekink
Binuclear phosphanegold(I) complexes of a bipodal thiocarbamate dianion, (R3PAu)2L, R ¼ Et (1), Ph (2) and
Cy (3), where LH2 is {1,4-[MeOC(]S)N(H)]2C6H4}, have been synthesised, and characterised
spectroscopically (NMR and IR) and by X-ray crystallography. The gold atoms are linearly coordinated
within a P-,S-donor set, and are oriented toward the central ring to form intramolecular Au/p(aryl)
interactions, rather than the intramolecular Au/O interactions normally observed in mononuclear
analogues. This phenomenon has been investigated by theory (LC-uPBE-XDM) for 1 which revealed that
the geometry optimised species with two Au/p(aryl) interactions is more stable by at least 12 kcal molꢀ1
compared to conformations having one or more Au/O interactions instead. The disk diffusion,
minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) methods were
used to observe the inhibitory effect of complexes 1–3. The disk diffusion results demonstrated that 1
exhibited a broad spectrum of anti-bacterial activity toward 24 strains of Gram-positive and Gram-
negative bacteria. By contrast, the anti-bacterial activity of 2 and 3 was limited to Gram-positive bacteria.
Further evaluation showed that 1 exhibited marked bactericidal activity against B. cereus, B. subtilis,
E. faecalis, L. monocytogenes, S. aureus, S. saprophyticus and methicillin resistant S. aureus cf. standard
antibiotics tetracycline and chloramphenicol.
Received 30th March 2015
Accepted 21st April 2015
DOI: 10.1039/c5ra05604g
www.rsc.org/advances
heavy elements.2 Over and above aesthetics, interest in gold
compounds/aurophilic interactions stems from their lumines-
cence properties, in both the solid-state and in solution.3 By
Introduction
The structural diversity and the fascinating architectures they
sustain have ensured that aurophilic (Au/Au) interactions have
garnered the attention of chemists for decades.1 The aggrega-
tion of gold compounds in this fashion arises from relativistic
effects which are at a maximum for gold compared to other
contrast to aurophilic interactions, the recognition of supra-
molecular association based on Au/p(aryl) interactions is still
in its infancy,4a despite them being oen crucial in the reaction
mechanisms related to the burgeoning eld of gold-based
catalysis.5 It is only in recent years that bibliographic surveys
have shown that Au/p(aryl) interactions provide readily iden-
tiable points of contact between molecules in their crystal
structures, operating in isolation of other supramolecular
synthons.4
The themes of aurophilic and Au/p(aryl) interactions as
well as luminescence feature prominently in the chemistry of
phosphanegold(I) thiocarbamates, where the thiolate anion is
derived from thiocarbamide molecules of the general formula
RN(H)C(]S)OR0, R,R0 ¼ alkyl and/or aryl.6 In the overwhelming
majority of crystal structures of phosphanegold(I) thio-
carbamates, the thiolate ligand is oriented so that the oxygen
aDepartment of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia.
E-mail: Edward.Tiekink@gmail.com
bDepartment of Biomedical Science, Faculty of Medicine and Health Sciences,
University Putra Malaysia, 43400 Serdang, Selangor Darul Ehsan, Malaysia. E-mail:
ykcheah@medic.upm.edu.my
cDepartment of Biological Sciences, Faculty of Science and Technology, Sunway
University, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia
dNational Institute for Nanotechnology, National Research Council of Canada, 11421
Saskatchewan Drive, Edmonton, Alberta, Canada T6G 2M9. E-mail: alberto.
oterodelaroza@nrc-cnrc.gc.ca
† Electronic supplementary information (ESI) available. CCDC 1041500–1041502.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c5ra05604g
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 41401–41411 | 41401

View Article Online
RSC Advances
Paper
atom is located in close proximity to the gold atom. However, by up to 1.5T1. Subsequently, a nal measurement was made to
careful choice of R and R0 substituents of the thiolate anion and conrm the value T1 ¼ 0.69 s at 20 ꢁC. Then, the NOE
by using isomeric tolylphosphane ligands, it proved possible to measurements were made in two consecutive experiments: one
orient the thiolate so that the aryl ring was proximate to the gold with complete proton decoupling with a relaxation delay of 6.0 s
atom instead.6c Crystal engineering considerations notwith- and an acquisition time of 1.04 s, and the other experiment with
standing, phosphanegold(I) thiocarbamates also exhibit prom- gated-decoupling in which the NOE was suppressed but with
ising biological activity.
the remaining conditions the same as in the rst experiment.
Gold(I) compounds are used clinically in the treatment of The pulse angle was 90ꢁ. Good signal intensity was obtained
severe forms of rheumatoid arthritis, being a member of the with 1024 scans. The total integrated intensity of the signal was
disease modifying anti-rheumatic drugs (DMARDS) class of anti- obtained with the spectrometer's data processing soware. The
arthritic agents.7a–c Spurred by the observation that patients ratio of the signal intensities in the two experiments gives the
undergoing chrysotherapy, appeared to suffer reduced rates of NOE value, usually given as NOE ¼ 1 + h, where h is the NOE
malignant disease,7d both gold(I) and gold(III) compounds are enhancement factor. IR spectra were measured on a Perkin
under intense investigation as potential anti-tumour drugs.8 In Elmer Spectrum 400 FT Mid-IR/Far-IR spectrophotometer from
the context of the present study, phosphanegold(I) thiocarbamates 4000 to 400 cmꢀ1; abbreviations: vs, very strong; s, strong; m,
of the general formula Ph3PAu[SC(OR)]NPh], R ¼ Me, Et and iPr, medium; br, broad. Thermogravimetric analyses were per-
exhibit signicant cytotoxicity toward HT-29 colon cancer cells, formed on a Perkin Elmer TGA 4000 Thermogravimetꢀri1c
ꢁ
ꢁ
have been shown to function through both intrinsic and extrinsic Analyzer in the range of 35–850 C at the rate of 10 C min
.
apoptotic pathways, and to be topoisomerase I inhibitors.9 Gold Powder X-ray diffraction (PXRD) data were recorded with a
compounds are also under active evaluation as anti-microbial PANalytical Empyrean XRD system with Cu-Ka1 radiation
agents.10 Recently, another series of phosphanegold(I) thio- (l ¼ 1.54056 A) in the 2q range 5 to 50 . The comparison
carbamates, namely Ph3PAu[SC(OR)]N(p-tol)], R ¼ Me, Et and between experimental and calculated (from CIF's) PXRD
iPr, have proven to be very effective against a panel of Gram- patterns were performed with X'Pert HighScore Plus.13
ꢁ
˚
positive bacteria.11
Synthesis of LH2. LH2 was prepared in similar manner as
It was primarily the biological context that led to the described in the literature for mono-functional analogues14
synthesis of the title binuclear compounds, (R3PAu)2L, R ¼ Et whereby p-phenylene diisothiocyanate (2.50 mmol, 0.48 g;
(1), Ph (2) and Cy (3), where LH2 is the bipodal molecule {1,4- Sigma-Aldrich) was reacted in MeOH (100 ml) in the presence of
[MeOC(]S)N(H)]2C6H4}. Herein, their characterization, two mole equivalents of NaOH, yielding a pale-yellow powder.
including by X-ray crystallography and Density Functional Yield: 0.596 g (93%). mp 209.0–210.0 ꢁC. Anal. calc. for
Theory (DFT) calculations is described along with an evaluation
of their potential anti-microbial activity.
C10H12N2O2S2: C, 46.85; H, 4.72; N, 10.93. Found: C, 46.71; H,
4.64; N, 10.94%. IR (n, cmꢀ1): 3219 (br) n(N–H), 1454 (s) n(C–N),
1140 (s) n(C–O), 1046 (s) n (C]S). 1H NMR (DMSO-d6): d 11.10 [s,
br, 2H, NH], 7.59 [s, br, 2H, aryl-H], 7.30 [s, br, 2H, aryl-H], 3.99
[s, 6H, OCH3] ppm. 1H NMR (CDCl3): d 8.32 [s, br, 2H, NH], 7.56
[s, br, 2H, aryl-H], 7.22 [s, br, 2H, aryl-H], 4.12 [s, 6H, OCH3]
Experimental section
Materials, methods and Instruments
All chemicals and solvents were used as purchased without ppm. 13C{1H} NMR (DMSO-d6): d 189.1, 188.4 [Cq], 135.8, 134.8
purication. All reactions were carried out under ambient [Cipso], 123.7 and 122.6 [Cortho], 58.3, 56.8 [OCH3] ppm.
conditions. Elemental analyses were performed on a Perkin
Synthesis of (R3PAu)2L, R ¼ Et (1), Ph (2) and Cy (3). The
Elmer PE 2400 CHN Elemental Analyser. Melting points were methods employed for the preparation and recrystallization of
1
determined on a Kruss KSP1N melting point meter. H and 13C 1–3 were similar, so the preparation of the Et3P derivative (1) is
¨
{1H} NMR spectra were recorded in both DMSO-d6 and CDCl3 described in detail as a representative example. The R3PAuCl, R
solutions for LH2, and CDCl3 solutions for 1–3 on a Bruker ¼ Et, Ph and Cy, precursors employed in the synthesis were
Avance 400 MHz NMR spectrometer with chemical shis rela- prepared following standard procedures by reducing KAuCl4
tive to tetramethylsilane. 31P{1H} NMR spectra were recorded in (Sigma-Aldrich) using one mole excess sodium sulte (Merck),
CDCl3 solution on the same instrument but with the chemical and then further reacted with one mole equivalent of either Et3P
shis recorded relative to 85% aqueous H3PO4 as the external (Merck), Ph3P (Merck) or Cy3P (Sigma-Aldrich), to yield the
reference; abbreviations for NMR assignments: s, singlet; d, respective precursor.
doublet; m, multiplet; dq, doublet of quartets; dt, doublet of
(Et3PAu)2L (1). NaOH (0.50 mmol) in water (5 ml) was added
triplets. For the relaxation experiments on 1, a solution of the to a suspension of Et3PAuCl (0.50 mmol) in acetonitrile (20 ml)
compound (20 mg) was prepared in CDCl3 (4.5 cm) in a 5 mm followed by addition of LH2 (0.25 mmol) in acetonitrile (20 ml).
NMR tube (Wilmad). The solution was degassed through ve The resulting mixture was stirred for 3 h at 50 ꢁC. Extraction
freeze–pump–thaw cycles and sealed under vacuum. The NMR followed with dichloromethane (100 ml) and an equivalent
measurements were carried out on a JEOL ECX500 NMR spec- volume of acetonitrile added. The solution was le for slow
trometer. The 13C spin–lattice relaxation time (T1) was obtained evaporation at room temperature, giving colourless crystals
by using the two-pulse inversion–recovery (IR) method.12 aer 2 weeks. Yield: 0.206 g (93%). mp 174.0–176.0 ꢁC. Anal.
Initially, an approximate T1 value was obtained before a more calc. for C22H40Au2N2O2P2S2: C, 29.87; H, 4.56; N, 3.17. Found:
precise measurement was made using 10 IR intervals in a range C, 29.92; H, 4.53; N, 3.04%. IR (cmꢀ1): 1421 (m) n(C]N),
41402 | RSC Adv., 2015, 5, 41401–41411
This journal is © The Royal Society of Chemistry 2015

View Article Online
Paper
RSC Advances
1123 (vs) n(C–O), 1094 (s) n(C–S). 1H NMR (CDCl3): d 6.72 [s, 4H,
aryl-H], 3.81 [s, 6H, OCH3], 1.70 [dq, 12H, CH2P, 3JHH ¼ 7.75, 2JPH
¼ 9.82 Hz], 1.06 [dt, 18H, CH3CH2P, 3JHH ¼ 7.62, 3JPH ¼ 18.32 Hz]
ppm. 13C{1H} NMR (CDCl3): d 165.3 [Cq], 145.7 [aryl, Cipso], 122.8
Computational study
The calculations were run using Gaussian09 (ref. 16) and the
LC-uPBE17 functional combined with the exchange-hole dipole
moment (XDM) model dispersion correction,18–20 implemented
in the postg program.21 In a previous contribution, it was shown
that LC-uPBE-XDM gives excellent performance in the treat-
ment of aurophilicity,22 so it is a reasonable choice to study
interactions involving gold. Three conformations were examined
for 1: (i) the same conformation as in the crystal structure, with
two Au/p(aryl) contacts, (ii) a mixed conformation with one
Au/p(aryl) and one Au/O contact, i.e. where one Au/p(aryl)
interaction of the experimental structure was replaced by a
contact between gold and a thiocarbamate-O atom, and (iii) the
fully extended, rod-like conformations with two Au/O interac-
tions. The geometry of each conformer was relaxed using the 6-
31+G* basis set for all s- and p-block elements and aug-cc-pVDZ-
PP scalar relativistic pseudo-potential and basis set combination
for Au.23 Despite the modest size of this basis set, it has been
shown in previous work that just one set of diffuse and polari-
zation functions is sufficient to model non-covalent interactions
with an accuracy relatively close to the basis-set limit.24
1
[aryl, Cortho], 55.2 [OCH3], 17.6 [d, CH2P JCP ¼ 33.3 Hz], 8.8 [s,
CH3CH2P] ppm. 31P{1H} NMR (CDCl3): d 35.6 ppm.
(Ph3PAu)2L (2). A similar synthetic procedure as employed for
1 was used for the synthesis of 2 except that the gold precursor
was replaced by Ph3PAuCl. Colourless crystals. Yield: 0.255 g
(87%). mp 181.5–183.0 ꢁC. Anal. calc. for C46H40Au2N2O2P2S2: C,
47.11; H, 3.44; N, 2.39. Found: C, 47.25; H, 3.31; N, 2.41%. IR
1
(cmꢀ1): 1434 (s) n(C]N), 1143 (s) n(C–O), 1101 (s) n(C–S). H
NMR (CDCl3): d 7.49–7.41 [m, 30H, Ph3P], 6.41 [s, 4H, aryl-H],
3.73 [s, 6H, OCH3] ppm. 13C{1H} NMR (CDCl3): d 163.2 [Cq],
2
145.7 [aryl, Cipso], 134.4 [d, o-Ph3P, JCP ¼ 13.9 Hz], 131.4 [d,
p-Ph3P, 4JCP ¼ 2.2 Hz], 129.6 [d, i-Ph3P, JCP ¼ 57.0 Hz], 128.9 [d,
m-Ph3P, 3JCP ¼ 11.5 Hz], 122.4 [aryl, Cortho], 55.0 [OCH3] ppm. 31
P
{1H}NMR (CDCl3): d 38.1 ppm.
(Cy3PAu)2L (3). The synthesis was as for 1 but using Cy3PAuCl.
Colourless crystals. Yield: 0.275 g (91%). mp 180.0–181.0 ꢁC.
Anal. calc. for C46H76Au2N2O2P2S2: C, 45.69; H, 6.34; N, 2.32.
Found: C, 45.57; H, 6.40; N, 2.24%. IR (cmꢀ1): 1444 (s) n(C]N),
1130 (s) n(C–O), 1093 (m) n(C–S). 1H NMR (CDCl3): d 6.84 [s, 4H,
aryl-H], 3.82 [s, 6H, OCH3], 1.98–1.20 [m, 66H, Cy3P] ppm. 13C
{1H} NMR (CDCl3): d 163.9 [Cq], 145.4 [aryl, Cipso], 122.4 [aryl,
Anti-microbial assay
Bacterial strains. The standard reference strains of bacteria
Cortho], 54.8 [OCH3], 33.3 [d, 1-Cy3P, JCP ¼ 27.8 Hz], 30.7 [s, used in the present study were Aeromonas hydrophila (A. hydro-
3-Cy3P], 27.0 [d, 2-Cy3P, 3JCP ¼ 11.9 Hz], 25.9 [s, 4-Cy3P] ppm. 31
{1H}NMR (CDCl3): d 56.5 ppm.
P
phila) ATCC 35654, Acinetobacter baumannii (A. baumannii)
ATCC 19606, Bacillus cereus (B. cereus) ATCC 10876, Bacillus
subtilis (B. subtilis) ATCC 6633, Citrobacter freundii (C. reundii)
ATCC 8090, Enterobacter cloacae (E. cloacae) ATCC 35030,
Enterobacter aerogenes (E. aerogenes) ATCC 13048, Enterococcus
faecalis (E. faecalis) ATCC 29212, Enterococcus faecium (E. fae-
cium) ATCC 19434, Escherichia coli (E. coli) ATCC 25922, Klebsi-
ella pneumoniae (K. pneumoniae) ATCC 700603, Listeria
monocytogenes (L. monocytogenes) ATCC 19117, Proteus mirabilis
(P. mirabilis) ATCC 25933, Proteus vulgaris (P. vulgaris) ATCC
13315, Pseudomonas aeruginosa (P. aeruginosa) ATCC 27853,
Salmonella paratyphi A (S. paratyphi A) ATCC 9150, Salmonella
typhimurium (S. typhimurium) ATCC 14028, Shigella exneri (S.
exneri) ATCC 12022, Shigella sonnei (S. sonnei) ATCC 9290,
Staphylococcus aureus (S. aureus) ATCC 25923, methicillin
resistant Staphylococcus aureus (MRSA) ATCC 43300, Staphylo-
coccus saprophyticus (S. saprophyticus) ATCC 15305, Steno-
trophomonas maltophilia (S. maltophilia) ATCC 13637 and Vibrio
parahaemolyticus (V. parahaemolyticus) ATCC 17802. All bacte-
rial strains were purchased from the American Type Culture
Collection (ATCC, Manassas, VA, USA).
X-ray data collection and structure determination
Intensity data were measured at 100 K on an Agilent Technol-
ogies SuperNova Dual CCD with an Atlas detector tted with Mo
˚
Ka radiation (l ¼ 0.71073 A). Data processing and absorption
correction were accomplished with CrysAlis PRO.15a With the
use of SHELX programs15b integrated into WinGX,15c the struc-
tures were solved by direct methods and rened on F2 by full-
matrix least-squares with anisotropic displacement parame-
ters for all non-hydrogen atoms. The C-bound H atoms were
placed on stereochemical grounds and rened in the riding
model approximation with Uiso ¼ 1.2–1.5Ueq(carrier atom). A
weighting scheme of the form w ¼ 1/[s2(Fo2) + (aP)2 + bP] where
2
P ¼ (Fo2 + 2Fc )/3 was introduced in each case. For 1, the residual
electron density peaks were located 0.95 and 0.96 from the Au
atom, and for 2, the peaks were 0.90 and 0.86 from the Au atom.
Details of cell data, X-ray data collection and structure rene-
ment are given in Table 1. The programs ORTEP-3 for Win-
dows,15c PLATON,15d DIAMOND15e and QMol15f were also used in
the analysis.
Anti-bacterial activity. The anti-bacterial activity of 1–3 was
evaluated using the Kirby–Bauer disc diffusion method in
accordance with the National Committee for Clinical Labora-
tory Standards (NCCLS) guidelines. The bacterial cultures were
Powder X-ray diffraction
Powder X-ray patterns (PXRD) measured on the bulk material adjusted to 0.5 McFarland standard turbidity (which corre-
for each of 1–3 were compared with the simulated patterns sponds to approximately 108 CFU mlꢀ1) by adding Mueller-
calculated based on the CIF's obtained for the experimental Hinton broth (Difco, USA). This suspension was then swabbed
crystal structures.13 There is a high agreement between the onto the surface of Mueller-Hinton agar (Difco, USA) plates. The
patterns, ESI Fig. S1,† suggesting the single crystal results are tested compounds were dissolved in DMSO to a test concen-
representative of the bulk materials.
tration of 2 mg mlꢀ1. Sterile 6 mm lter paper discs were
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 41401–41411 | 41403

View Article Online
RSC Advances
Paper
Table 1 Crystal data, data collection and refinement parameters for compounds 1–3
1
2
3
Formula
C
22H40Au2N2O2P2S2
C46H40Au2N2O2P2S2
1172.79
C46H76Au2N2O2P2S2
1209.08
0.20 ꢂ 0.30 ꢂ 0.30
Monoclinic
P21/n
9.7522(3)
12.2227(3)
19.9917(5)
90
93.683(3)
90
2378.05(11)
2
1.689
6.355
2.8–27.5
26 714
5408; 0.032
4894
Formula weight
Crystal size (mm)
Crystal system
Space group
884.56
0.10 ꢂ 0.20 ꢂ 0.25
Monoclinic
P21/c
6.8843(6)
11.6056(7)
17.7118(10)
90
94.244(6)
90
1411.23(17)
2
2.082
10.667
2.9–27.5
15 284
3218; 0.030
2955
0.20 ꢂ 0.20 ꢂ 0.30
Triclinic
ꢀ
P1
˚
a/A
8.9980(4)
9.0501(4)
14.2542(6)
107.851(4)
100.439(4)
100.556(4)
1050.66(8)
1
1.854
7.190
3.0–27.5
12 872
4751; 0.054
4433
˚
b A
˚
c/A
a/ꢁ
b/ꢁ
g/ꢁ
3
˚
V/A
Z
Dx/g cmꢀ3
m/mmꢀ1
q range/ꢁ
Reections measured
Independent reections; Rint
Reections with I > 2s(I)
Number of parameters
R(F) [I > 2s(I) reections]
a, b in weight scheme
wR(F2) (all data)
GOF(F2)
149
0.025
0.031, 3.103
0.064
1.08
254
0.024
0.008, 0
0.044
0.97
254
0.021
0.010, 1.698
0.041
1.05
ꢀ3
˚
Drmax,min (e A
)
1.71, ꢀ1.46
1.12, ꢀ1.31
0.59, ꢀ0.61
aseptically placed on Mueller-Hinton agar surfaces and 5 ml of compound, an aliquot of 100 ml from each well which showed
ꢁ
the dissolved compounds were immediately added to discs. no visible growth was spread onto MHA at 37 C for 24 h. The
DMSO was used as a negative control whereas standard anti- MBC is dened as the lowest concentration of the tested
biotic paper disc was used as the positive control. All plates compound at which bacteria are killed.
were incubated at 37 ꢁC for 24 h. The anti-bacterial activity was
evaluated by measuring the diameter of the inhibition zone
against the test bacterial strains. Each trial was performed in
triplicate.
Results and discussion
Syntheses and spectroscopy
The reaction of p-phenylene di-isothiocyanate with MeOH in the
presence of base yielded bipodal LH2 in high yield. The 1H and,
especially, 13C NMR of LH2 showed unexpected features in that
chemically equivalent sites gave multiple resonances. Accord-
ingly, a variable temperature 1H NMR study in DMSO-d6 solution
(to attain a wider temperature range) was conducted with the
results summarised in Table 2. Two resonances were observed
for the ring protons when equivalence might have been expec-
ted. The splitting is ascribed to the formation of intramolecular
methyl-C–H/p(aryl) interactions rendering the protons
Minimum inhibitory concentration (MIC) and minimum
bactericidal concentration (MBC) determination. The MIC was
determined by the broth micro-dilution method according to
the NCCLS guidelines. An inoculum suspension with a density
105 CFU mlꢀ1 of exponentially growing bacterial cells was added
into each well. The test compounds were serially two-fold
diluted in DMSO and then added to each well of a 96-well
microplate. The 96-well microplates were incubated at 37 ꢁC for
24 h. All tests were performed in triplicate. Four controls
comprising medium with standard anti-biotic (positive control),
medium with DMSO (solvent control), medium with inoculum
bacterial cells (negative control) and medium with broth only
(negative growth control) were included in each test. The
bacterial growth was detected by adding 50 ml of a 0.2 mg mlꢀ1
p-iodonitrotetrazolium violet (INT) indicator solution into each
of the microplate wells and incubated at 37 ꢁC for 30 min. under
aerobic agitation. The INT changed from clear to red in the
presence of bacterial activity. Where bacterial growth was
inhibited, the suspension in the well remained clear aer
incubation with INT. The lowest concentration of the tested
compound which completely inhibited bacterial growth was
taken as the MIC. Aer MIC determination of each tested
Table 2 Variable temperature 1H NMR data (d, ppm; W1/2, band width
at half-height) for LH2 recorded in DMSO-d6 solution
Temp. (ꢁC)
NH
aryl-H
Ome
W1/2 (Hz)
28
38
48
58
68
78
11.08
11.04
10.99
10.95
10.90
10.86
7.59, 7.29
7.57, 7.31
7.41
7.44
7.44
3.98
3.98
3.98
3.99
3.99 (sh, 3.98)
4.00 (sh, 3.98)
29.32
12.40
6.52
4.95
3.17
2.29
7.44
41404 | RSC Adv., 2015, 5, 41401–41411
This journal is © The Royal Society of Chemistry 2015

View Article Online
Paper
RSC Advances
inequivalent. Upon heating the solution, the two signals coa- selected geometric parameters are collated in Table 3. The
lesced into a single resonance, most likely due to rapid exchange, molecule in 1, Fig. 1a, is located about a centre of inversion and
ESI Fig. S2a.† While no splitting was observed for the resonance features a linear gold atom geometry dened by the phosphane-
due to the methyl protons, marked sharpening of the signal was P and thiolate-S atoms. As usual for this type of structure,6 the
evident as manifested in the W1/2 values of 29.32 Hz at 28 ꢁC cf. Au–S bond length is longer than that of Au–P. As the crystal
2.29 Hz at 78 ꢁC, indicative of a rapid exchange process, ESI
Fig. S2b.† This was accompanied by a small downeld shi. The
N-bound proton shied upeld with increasing temperature
consistent with reduced hydrogen bonding with the solvent.
Evidence that the reduction in hydrogen bonding was a two-step
process was found in the appearance of a shoulder for the
methyl-proton at 68 ꢁC consistent with the appearance of a
minor, new species. The two environments arise at high
temperature as one N-bound proton is involved in hydrogen
bonding with the solvent and the other is not, cf. both partici-
pating in hydrogen bonding at low temperature.
1
Upon deprotonation and coordination of LH2, the H NMR
resonance at 8.32 (CDCl3) ascribed to N–H no longer persists in
the spectra of 1–3. By contrast to the spectrum recorded for LH2,
all chemically equivalent nuclei resonated at the same eld
strength. Also noteworthy are the signicant upeld shis in the
resonances due to aryl-H of the central ring, i.e. to 6.72, 6.41 and
6.84 for 1–3, respectively cf. 7.56 and 7.22 observed for LH2. This
observation is correlated with the presence of intramolecular
Au/p(aryl) interactions as delineated by X-ray crystallography
(see below). The key nding of the 13C{1H} NMR spectra was that
the four phenyl hydrogen-bearing nuclei, ortho and meta, are
equivalent and appear as a single resonance in CDCl3 solution.
Similarly, the quaternary ipso carbons are also equivalent. In the
31P NMR, a single resonance was observed for 1–3 at 35.6, 38.1
and 56.5, respectively, which are deshielded with respect to the
uncoordinated Et3P (ꢀ20.0), Ph3P (ꢀ5.2) and Cy3P (9.2) molecules
measured under the same conditions. The relaxation attributes of
1, being representative of the series, were also investigated.
In the 13C{1H} NMR spectrum of 1, the ortho and meta
carbons of the central ring resonated at d ¼ 122.84 ppm. At
20 ꢁC in CDCl3 solution, the observed 13C spin-lattice relaxation
time (T1) for this resonance was 0.69 s, and the NOE ¼ 2.88; the
NOE enhancement factor, h, was 1.88. As this h value is very
near the maximum value of 1.988 for a 13C nucleus, the domi-
nant relaxation mechanism is the dipole–dipole relaxation
mechanism (Td1d), for which the rate of this dipolar relaxation (1/
Td1d), is proportional to the correlation time.12,25 The observed T1
is very low for phenyl nuclei in solution and is consistent with
very low mobility of the phenyl group in the molecule. Hence,
the observed 13C relaxation data are consistent with severe
hindrance in the internal rotation of the phenyl group.
The IR spectra of compounds 1–3 conrmed the absence of
broad absorption at 3219 cmꢀ1, due to n(N–H) in LH2. Further,
the red shis of the n(C–N) absorption to ꢃ1400 cmꢀ1, and blue
shis of n(C]S) to ꢃ1100 cmꢀ1 in 1–3 when compared to LH2
provide further evidence for complexation.
Fig. 1 Perspective views of the molecules of (a) 1, (b) 2 and (c) 3.
Displacement ellipsoids are drawn at the 70% probability level and
hydrogen atoms are shown as small spheres of arbitrary radii. The
Crystallography
The crystal structures of 1–3 were established by X-ray crystal-
unlabelled atoms in (a) are related by the symmetry operation 1 ꢀ x,
lography: the molecular structures are shown in Fig. 1 and 2 ꢀ y, ꢀz, and in (b) and (c) by 1 ꢀ x, 1 ꢀ y, ꢀz.
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 41401–41411 | 41405

View Article Online
RSC Advances
Paper
Table 3 Selected bond lengths (A˚) and angles (ꢁ) for 1–3
precedents for binuclear structures based on bipodal thio-
carbamates or analogues of higher denticity.
1
2
3
The crystal packing of 1 is devoid of directional intermolec-
ular interactions and may be described as comprising columns of
molecules parallel to the a-axis, ESI Fig. S3a.† Weak C–H/p(aryl)
interactions are noted in the crystal packing of 2, and methylene-
C–H/O contacts are seen in 3. Despite these and the disparity in
space groups, Table 1, the packing for each of 2 and 3 is as
described for 1, i.e. comprising columns of molecules aligned
along the a-axis, ESI Fig. S3b and c.†
The linear coordination geometries for gold deviate by up to
12ꢁ from the ideal, deviations that are ascribed to the presence
of intramolecular Au/p(aryl) interactions, Table 3. Such
deviations are usually observed in related mononuclear
structures of [MeOC(S) ]NR]ꢀ but more oen than not due to
intramolecular Au/O interactions. Indeed, of the 31 struc-
tures available in the CSD27 with the general formula, R3PAu
[SC(OMe)]NR0], and diphosphane analogues,6a,28 27 feature
Au–S1
Au–P1
C1–S1
C1–O1
2.3152(10)
2.2663(10)
1.762(4)
1.372(5)
1.258(5)
172.13(4)
107.07(14)
123.5(4)
108.5(3)
132.8(3)
118.7(4)
3.26
2.3058(9)
2.2593(9)
1.761(3)
1.356(4)
1.268(4)
167.79(3)
107.37(12)
122.3(3)
108.1(2)
131.3(3)
120.6(3)
3.32
2.3019(6)
2.2695(6)
1.756(3)
1.362(3)
1.263(3)
168.63(2)
111.77(9)
124.8(2)
106.82(17)
134.3(2)
118.8(2)
3.55
C1–N1
S1–Au–P1
Au–S1–C1
C1–N1–C3
S1–C1–O1
S1–C1–N1
O1–C1–N1
Au/Cg(aryl)a
aa
22.7
21.6
30.7
a
a is the angle between the normal to the plane through the central ring
and the vector passing through the centroid (Cg) of the aryl ring to the
Au atom.
˚
Au/O interactions in the range 2.862(3) A for R ¼ Ph &
R0 ¼ p-tol,6c to 3.172(8) A for R ¼ Cy & R ¼ p-NO2Ph. The
remaining structures, each with isomeric tol3P ligands, were
reported to form intramolecular Au/p(aryl) interactions in
the absence of steric hindrance and by judicious combinations
of R and R0 groups.6c Given that in no circumstances were
intramolecular Au/p(aryl) interactions formed for R3P
ligands with R ¼ Et, Ph or Cy, the observation of these inter-
actions in 1–3 was unexpected. The ckle nature of the
formation of Au/p(aryl) interactions is probably best illus-
trated in the polymorphs of dppm(AuCl)2 where in one form, an
intramolecular Au/Au interaction is formed within an A-frame
arrangement,29a whereas in the other polymorph, an intra-
molecular Au/p(aryl) interaction was observed instead.29b In
order to probe further the nature of the Au/p(aryl) interactions
formed in 1–3, 1 was subjected to a computational study.
0
6a
˚
structure of the precursor thiocarbamide, LH2, is not available,
the comparison between the geometric parameters dening the
thiolate ligand in 1 will be made with PhN(H)C(]S)OMe.26 The
most notable observations is the elongation of the C1–S1 and
contraction of the C1–N1 bond lengths in 1, Table 1, compared
˚
with 1.6708(11) and 1.3288(15) A, respectively in the uncoordi-
nated molecule.26 These changes are consistent with L2ꢀ coor-
dinating each gold atom as
a
thiolate ligand. The
rearrangement of electron density in the anion also results in
signicant differences in bond angles whereby the S1–C1–O1
angle has contracted by about 16ꢁ, and the S1–C1–N1 and
O1–C1–N1 angles have expanded by about 10 and 6ꢁ, respec-
tively, observations readily correlated with the increased elec-
tron density in the C1–N1 bond. The molecular structures of 2
and 3 have essentially the same features as described for 1, as
highlighted in the overlay diagram shown in Fig. 2 that shows
only small conformational variations. According to a search of
the Cambridge Structural Database (CSD),27 there are no
Optimised molecular structures
Phosphanegold(I) thiolates sometimes present unexpected
structures.30 For example, in structures of the type R3PAu
[SC(]S)OR0], R,R0 ¼ alkyl/aryl, intramolecular Au/O interac-
tions are usually formed giving rise to compact structures,
rather than the intramolecular Au/S contacts expected from
hard acid/so base considerations. The latter interactions lead
to open, rod-like molecular structures.30a–c In a similar vein, in a
related species, i.e. Cy3PAu[SC6H4-2-CO2H], in one polymorph
the anticipated eight-membered {.HOCO}2 synthon is formed,
linking molecules in the crystal structure to form rod-type
conformations. However, in each of the three other poly-
morphs, intramolecular O–H/S(thiolate) hydrogen bonds are
formed instead, leading to spherical molecules.30d,e The unex-
pected structures were rationalised in terms of global crystal
packing considerations,31 in that the packing of spherical
aggregates is more efficient that the packing of “rods”.30
Geometry optimisation calculations were performed on 1 with
the energy minimised structure having a conformation very
similar to the experimentally observed structure. As highlighted
in Fig. 3, there has been a attening in the N]C–S–Au part of the
Fig. 2 Overlay diagram of 1 (red image), 2 (green) and 3 (blue). No
hydrogen atoms are shown and only the a-carbon atoms of the
phosphane ligands are included. The molecules have been overlapped
so that the central rings are coincident.
41406 | RSC Adv., 2015, 5, 41401–41411
This journal is © The Royal Society of Chemistry 2015

View Article Online
Paper
RSC Advances
geometry optimised molecule as manifested in the N1–C1–S1–Au
dihedral angle of ꢀ0.9ꢁ, cf. 14.8(5)ꢁ in the experimental structure.
Conformational differences are also noted in the phosphane-
bound ethyl groups. Further, the calculations show that the
conformation presenting two intramolecular Au/p(aryl)
contacts, as is experimentally observed in the crystal structure of
1, is more stable by 12.2 kcal molꢀ1 with respect to the confor-
mation featuring one Au/p(aryl) contact and one Au/O contact,
and by 23.6 kcal molꢀ1 than the rod-like conformer with two Au/
O interactions, Fig. 4. These results shown the Au/p(aryl)
interaction is much stronger than Au/O, and roughly additive.
The Bader delocalization indices (DI's)32 were calculated at
the LC-uPBE-XDM level between gold and the rest of the atoms
in the three studied conformations. Intermolecular DI's are an
excellent tool to evaluate the degree of electron delocalization
(charge transfer) between interacting fragments.33 For the
conformations featuring Au/p(aryl) interactions, there is a
signicant amount of electron sharing between the gold atoms
and the central ring, indicating the existence of orbital inter-
actions between the gold atom and the p-system, and justifying
the high stability of this contact, Fig. 4. The DI between the two
gold atoms and the aryl ring is 0.56 in the compact conformer
and 0.29 in the mixed Au/p(aryl)/Au/O conformer. The
degree of electron delocalization between Au and the
thiocarbamate-O atom in the Au/O contact is relatively small
in comparison (0.10), although larger than the DI with the
atoms adjacent to the oxygen, which indicates an interaction
weaker than Au/p(aryl), in agreement with the energies. In
addition, the S–Au–P angle is linear for the Au/O contact but
bends slightly (170ꢁ) when a Au/p(aryl) contact is present,
indicating a steric clash between the P-bound ethyl groups and
the central ring. Despite this steric clash, the large stabilization
caused by electron delocalization across the intramolecular
Au/p(aryl) contact is clearly responsible for the conformation
adopted in the crystal structure.
Fig.
4
Calculated structures for 1: (a) the compact, spherical,
conformation with two intramolecular Au/p(aryl) interactions, (b)
intermediate structure with one Au/p(aryl) and one Au/O contact,
and (c) the open, rod-like, conformation with two Au/O interactions.
Bader0s delocalization indices between gold (in orange) and all other
individual atoms are given as a colour scale ranging from zero (white)
to 0.30 (red).
Thermogravimetric analysis
Traces for the thermogravimetric analysis for 1–3 are given in
ESI Fig. S4.† The decomposition pathways are quite similar for
1–3 and the following sequence is proposed. For 1, three
discernible steps were resolved: step 1 – onset temperature
181.9 ꢁC to end 226.9 ꢁC resulted in a weight loss of 73.3%
cf. 70.7% corresponding to the loss of 2Et3P. The second step
(226.9–441.8 ꢁC) saw a weight loss of 18.0% cf. 21.5%, correlated
with loss of (2L–2S) leaving 2AuS (obs., calcd weight remaining
52.7% cf. 51.8%). The nal step (441.8–806.1 ꢁC) correlated with
a weight loss of 7.2% cf. 7.3% expected for the loss of 2S with
2Au remaining (obs., calcd weight remaining 45.4% cf. 44.5%).
The difference between the decomposition pathway for 1 and
those for 2 and 3 is that there is no clear distinction between the
rst two steps for 2 and 3. Thus, for 2, step 1, between 163.5 and
346.7 ꢁC, is accompanied by a weight loss of 55.2% cf. with
60.9% for the concomitant loss calculated for 2Ph3P and (2L–2S)
(obs., calcd weight remaining for 2AuS 44.7% cf. 39.1%), and
step 2, between 346.7 and 815.2 ꢁC, having a weight loss of 9.8%
cf. with the theoretical value of 5.5% expected for the loss of 2S
leaving Au (obs., calcd weight remaining for 2Au 35.0%
Fig. 3 Overlay diagram of the experimental molecular structure of 1
(red image) and the energy minimised structure (black). The molecules
have been overlapped so that the central rings are coincident.
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 41401–41411 | 41407

View Article Online
RSC Advances
Paper
cf. 33.6%). The values for step 1 in the decomposition of 3 are observed for 2 and 3, with clear zones of inhibition ranging
ꢁ
onset-end temperatures 160.7 and 422.6 C with 62.7% weight from 7 to 10 mm. Compound 2 was active against all the tested
loss cf. with calculated 62.1% for the loss 2Cy3P and (2L–2S) Gram-positive bacteria except B. cereus. By contrast, 3 exhibi-
(obs., calcd weight remaining for 2AuS 37.2% cf. 37.8%), and for ted the lowest activity of the series, being potent in only ve of
ꢁ
step 2, 422.6 to 815.2 C with 3.6% weight loss cf. with calcu- eight strains of Gram-positive bacteria, i.e. B. subtilis, E. fae-
lated 5.3% for the loss 2S (obs., calcd weight remaining for 2Au cium, L. monocytogenes, MRSA and S. saprophyticus. Clearly, in
33.6% cf. 32.6%).
this preliminary anti-bacterial assay, the tested Gram-positive
bacteria are more susceptible than Gram-negative bacteria.
This nding is also supported by studies which reported that
Gram-negative bacteria are less susceptible to anti-microbial
agents34 and is consistent with results obtained recently for
mononcuclear phosphanegold(I) analogues.11 The presence of
the outer lipopolysaccharide layer in Gram-negative bacteria
inhibits the access of most drugs to intracellular targets in
bacteria and renders Gram-negative bacteria less susceptible
to drugs than Gram-positive bacteria, which lack an outer
membrane.35
Using the broth micro-dilution method, the anti-bacterial
sensitivity of 1–3 was quantitatively assessed by determining
the minimum inhibitory concentration (MIC), dened as the
highest dilution at which no bacterial growth was detected,
Table 5. A lower MIC value indicates a better anti-microbial
agent as a smaller amount of trial compound is required to
inhibit bacterial growth. Compound 1 exhibited excellent
inhibitory activity toward all susceptible Gram-positive
bacteria compared with 2 and 3, and standard anti-biotics
Evaluation of anti-bacterial activity
A total of 24 strains of pathogen were screened in the present
study, and the results of the disk diffusion assay are presented
in the Table 4. Compounds 1–3 exhibited variable degrees of
anti-bacterial activity against the clinically important patho-
gens tested; LH2 showed no inhibitory activity toward the
tested bacteria. Of the series, 1 was the most active compound
with complete inhibitory activity against all tested Gram-
positive and Gram-negative pathogens, except P. aeruginosa,
which is only partially inhibited by 1. A partial zone of inhi-
bition is dened as incomplete inhibition of bacterial growth
and the formation of a lm of bacteria on the surface agar. The
Gram-positive bacteria were most susceptible toward 1, with
greater inhibition zones, ranging from 18 to 30 mm,
compared with Gram-negative bacteria, with reduced inhibi-
tion zones, ranging from 7 to 23 mm. Mild anti-bacterial
activities against several Gram-positive bacteria were
Table 4 Anti-bacterial activity measured by zone of inhibition (mm) of 1–3, LH2 and standard anti-bioticsc
Microorganism
1
2
3
LH2
Standard anti-biotics
Gram-positive bacteria
B. cereus ATCC10876
B. subtilis ATCC6633
E. faecalis ATCC29212
E. faecium ATCC19434
L. monocytogenes ATCC19117
S. aureus (MRSA) ATCC43300
S. aureus ATCC25923
22
27
20
18
20
23
30
30
—
10
9
9
9
9
9
9
—
8
—
8
8
7
—
8
—
—
—
—
—
—
—
—
11a
24a
11a
16b
27a
14b
18b
29a
S. saprophyticus ATCC15305
Gram-negative bacteria
A. baumannii ATCC19606
A. hydrophilla ATCC35654
C. freundii ATCC8090
E. aerogenes ATCC13048
E. cloacae ATCC35030
E. coli ATCC25922
K. pneumonia ATCC700603
P. aeruginosa ATCC27853
P. mirabilis ATCC25933
P. vulgaris ATCC13315
S. typhimurium ATCC14028
S. paratyphiA ATCC9150
S. exneri ATCC12022
S. sonnei ATCC9290
13
8
8
7
8
10
8
14 (T)
8
14
9
9
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
16a
22a
26a
20a
20a
18a
13a
14a
14b
19b
24a
22a
18a
19a
23b
30a
12
10
9
S. maltophilia ATCC13637
V. parahaemolyticus ATCC17802
23
Tetracycline. b Chloramphenicol. c The diameter of inhibition zones in millimetres (mm) were measured in the disc aer 24 h incubation;—, no
zone of inhibition; (T), partial zone of inhibition.
a
41408 | RSC Adv., 2015, 5, 41401–41411
This journal is © The Royal Society of Chemistry 2015

View Article Online
Paper
RSC Advances
Table 5 MIC and MBC of 1–3, LH2 and standard anti-biotics against selected Gram-positive and Gram-negative bacteriac
1
2
3
Standard anti-biotics
Microorganism
MIC
MBC/MIC
MIC
MBC/MIC
MIC
MBC/MIC
MIC
MBC/MIC
Gram-positive bacteria
B. cereus ATCC10876
B. subtilis ATCC6633
E. faecalis ATCC29212
E. faecium ATCC19434
L. monocytogenes ATCC19117
S. aureus (MRSA) ATCC43300
S. aureus ATCC25923
0.10
0.20
0.39
0.20
0.10
0.10
0.10
0.10
1
1
1
32
1
2
—
—
1
1
4
1
1
1
1
—
25.00
—
6.25
6.25
50.00
—
—
1
—
4
1
1
—
2
6.25a
1
1
1
ND
1
1
0.78
6.25
3.13
1.56
1.56
3.13
1.56
0.20a
12.50a
12.50b
12.50a
12.50b
12.50b
0.39a
2
2
1
ND
S. saprophyticus ATCC15305
6.25
Gram-negative bacteria
A. baumannii ATCC19606
A. hydrophilla ATCC35654
C. freundii ATCC8090
E. aerogenes ATCC13048
E. cloacae ATCC35030
6.25
6.25
1
2
4
4
1
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
0.39a
0.39a
0.78a
1.56a
1.56a
0.39a
12.50a
6.25a
12.50b
12.50b
1.56a
1.56a
0.78a
0.78a
3.13b
0.10a
32
1
25.00
25.00
25.00
12.50
50.00
—
12.50
3.13
12.50
12.50
6.25
32
32
ND
ND
ND
ND
8
E. coli ATCC25922
1
K. pneumoniae ATCC700603
P. aeruginosa ATCC27853
P. mirabilis ATCC25933
P. vulgaris ATCC13315
S. typhimurium ATCC14028
S. paratyphi a ATCC9150
S. exneri ATCC12022
S. sonnei ATCC9290
S. maltophilia ATCC13637
V. parahaemolyticus ATCC17802
ND
—
2
4
1
1
1
2
4
4
32
32
32
32
ND
1
6.25
3.13
1.56
1
a
Tetracycline. b Chloramphenicol. c MIC – minimum inhibitory concentration (mg mlꢀ1); MBC/MIC ratio for bacteriostatic or bactericidal activity; –
not applicable; ND – not determined as the bacterium had grown across all tested dilution (MBC > 100 mg mlꢀ1).
(tetracycline and chloramphenicol), with lowest MIC values in microbial agent is bacteriostatic if the MBC is more than four-
the range 0.10–0.39 mg mlꢀ1. The most susceptible Gram- fold greater than the MIC, i.e. MBC/MIC # 4.36 Compounds 2
positive bacteria strains toward 1 were B. cereus, L. mono- and 3 were shown to be bactericidal (MBC/MIC # 4) toward the
cytogenes, MRSA, S. aureus and S. saprophyticus (MIC's ¼ 0.10 susceptible Gram-positive bacteria strains. For 1, bactericidal
mg mlꢀ1) follow by B. subtilis and E. faecium (MIC's ¼ 0.20 mg activity was observed against all susceptible Gram-positive and
mlꢀ1) and E. faecalis (MIC ¼ 0.39 mg mlꢀ1). However, tetracy- Gram-negative bacteria with the exception of E. faecium
cline and chloramphenicol showed equal or, normally, greater (MBC/MIC ¼ 32) and K. pneumoniae (MBC/MIC ¼ ND). These
anti-bacterial activity toward Gram-negative bacteria results suggest that 1–3 are considered bactericidal agents but
compared to 1, with lower MIC values in the range 0.10–12.5 the activity of 1 is dependent on the specic bacterial strain.
mg mlꢀ1. Compound 2 exhibited more promising MIC values
The broad spectrum of activity exhibited by 1 (R ¼ Et) against
(0.78–6.25 mg mlꢀ1) than 3 (6.25–50.00 mg mlꢀ1) toward Gram-positive and Gram-negative bacteria, and the specic
susceptible Gram-positive bacteria. In addition, 2 displayed activity against Gram-positive bacteria exhibited by 2 and 3
greater activity compared with tetracycline and chloram- suggests a key role for the phosphane ligand. This is vindication
phenicol against E. faecalis, E. faecium, L. monocytogenes, of an earlier study against the same panel of 24 pathogens but
MRSA and S. aureus, with lower MIC values in the range 1.56– where the thiolate was a dithiocarbamate ligand, i.e. R3PAu
6.25 mg mlꢀ1
.
[S2CN(iPr)CH2CH2OH], for R ¼ Et, Ph and Cy.37 In this study a
The zone of inhibition and MIC tests may reect temporary similar observation was made in that the R ¼ Et derivative had
inhibition of bacterial growth (bacteriostatic) or bacterial killing broad range activity against both Gram-positive and Gram-
(bactericidal) by a test compound. The bactericidal properties of negative bacteria, and the activity of the R ¼ Ph and Cy
1–3 against susceptible strains were further analyzed by the species was limited to Gram-positive bacteria.37 Perhaps once
minimum bactericidal concentration (MBC) assay and thought as being too expensive for development as anti-
summarized as MBC/MIC ratios in Table 5. An anti-microbial microbial agents, the emerging resistance to conventional
agent is bactericidal if the MBC is not more than fourfold therapies suggest that gold compounds may play a clinical role,
higher than the MIC, i.e. MBC/MIC # 4. By contrast, the anti- especially against virulent strains of bacteria such as MRSA.
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 41401–41411 | 41409

View Article Online
RSC Advances
Paper
M. Haruta, Adv. Catal., 2012, 55, 1; (c) M. Pan, J. L. Gong,
G. B. Dong and C. B. Mullins, Acc. Chem. Res., 2014, 47, 750.
6 (a) S. Y. Ho, E. C.-C. Cheng, E. R. T. Tiekink and
V. W.-W. Yam, Inorg. Chem., 2006, 45, 8165; (b) S. Y. Ho
and E. R. T. Tiekink, CrystEngComm, 2007, 9, 368; (c)
F. S. Kuan, S. Y. Ho, P. P. Tadbuppa and E. R. T. Tiekink,
CrystEngComm, 2008, 10, 548.
7 (a) S. J. Berners-Price and A. Filipovska, Metallomics, 2011, 3,
863; (b) W. F. Kean and I. R. L. Kean, Inammopharmacology,
2008, 16, 112; (c) E. R. T. Tiekink, Gold Bull., 2003, 36, 117; (d)
J. F. Fries, D. Bloch, P. Spitz and D. M. Mitchell, Am. J. Med.,
1985, 78, 56.
8 E. R. T. Tiekink, Critical Reviews in Oncology/Hematology,
2002, 42, 225; I. Ott, Coord. Chem. Rev., 2009, 253, 1670;
C. Gabbiani, M. A. Cinellu, L. Maiore, L. Massai, F. Scaletti
and L. Messori, Inorg. Chim. Acta, 2012, 393, 115;
N. Cutillas, G. S. Yellol, C. de Haro, C. Vicente,
V. Rodriguez and J. Ruiz, Coord. Chem. Rev., 2013, 257,
2784; C. Nardon, S. M. Schmitt, H. J. Yang, J. Zuo,
D. Fregona and Q. P. Dou, PLoS One, 2014, 9, e84248;
B. Bertrand and A. Casini, Dalton Trans., 2014, 4209.
9 C. I. Yeo, K. K. Ooi, A. Md Akim, K. P. Ang, Z. A. Fairuz,
S. N. B. A. Halim, S. W. Ng, H.-L. Seng and
E. R. T. Tiekink, J. Inorg. Biochem., 2013, 127, 24.
Conclusions
Three new binuclear phospanegold(I) compounds of a bipodal
ligand have been characterised. Crystallography shows the
uniform adoption of a spherical aggregate featuring unexpected
intramolecular Au/p(aryl) interactions. Theory shows these
interactions to be attractive, providing energies of stabilization
to the molecular structure of 1 greater than 12 kcal molꢀ1
compared to putative Au/O interactions. Compounds 1–3
exhibited, predominantly, a bactericidal effect on Gram-positive
(1–3) and Gram-negative (only 1) pathogens, with 1 perhaps
having potential clinical benets over standard anti-biotics in
bacteriostatic therapy for immune-compromised patients, i.e.
with cancer and neutropenia, by prompt elimination of the
pathogen to therefore reduce the likelihood of the spread of
infection.
Acknowledgements
Support from the Ministry of Higher Education, Malaysia, and
the University of Malaya, for High Impact Research grant
(UM.C/HIR-MOHE/SC/12) is gratefully acknowledged. AOR
acknowledges support from the Spanish Malta/Consolider
initiative (no. CSD2007-00045) and the Alberta Innovates
Technology Futures (AITF) for funding.
ˇ ´
10 B. Đ. Glisic and M. I. Djuran, Dalton Trans., 2014, 5950.
11 C. I. Yeo, J.-H. Sim, C.-H. Khoo, Z.-J. Goh, K.-P. Ang,
Y.-K. Cheah, Z. A. Fairuz, S. N. B. A. Halim, S. W. Ng,
H.-L. Seng and E. R. T. Tiekink, Gold Bull., 2013, 46, 145.
12 R. K. Harris, Nuclear Magnetic Resonance Spectroscopy,
Longman, Harlow, 1986.
References
1 e.g. S. S. Pathaneni and G. R. Desiraju, J. Chem. Soc., Dalton
Trans., 1993, 319; M. J. Katz, K. Sakai and D. B. Leznoff, 13 X'Pert HighScore Plus, ed. B. V. Almelo, PANalytical, The
Chem. Soc. Rev., 2008, 37, 1884; H. Schmidbaur and Netherlands, 2009.
A. Schier, Chem. Soc. Rev., 2008, 37, 1931; H. E. Abdou, 14 (a) V. J. Hall, G. Siasios and E. R. T. Tiekink, Aust. J. Chem.,
A. A. Mohamed, J. P. Fackler, A. Burini, R. Galassi,
J. M. Lopez-de-Luzuriaga and M. E. Olmos, Coord. Chem.
Rev., 2009, 253, 1661; H. Schmidbaur and A. Schier, Chem.
Soc. Rev., 2012, 41, 370; E. R. T. Tiekink, Coord. Chem. Rev.,
2014, 275, 130.
1993, 46, 561; (b) S. Y. Ho, R. P. A. Bettens, D. Dakternieks,
A. Duthie and E. R. T. Tiekink, CrystEngComm, 2005, 7,
682; (c) F. S. Kuan, F. Mohr, P. P. Tadbuppa and
E. R. T. Tiekink, CrystEngComm, 2007, 9, 574.
15 (a) CrysAlisPro, Agilent Technologies, Santa Clara, CA, USA,
2014; (b) G. M. Sheldrick, Acta Crystallogr., Sect. A: Found.
Crystallogr., 2008, 64, 112; (c) L. J. Farrugia, J. Appl.
Crystallogr., 2012, 45, 849; (d) A. L. Spek, Acta Crystallogr.,
Sect. D: Biol. Crystallogr., 2009, 65, 148; (e) DIAMOND,
Visual Crystal Structure Information System, Version 3.1,
CRYSTAL IMPACT, Postfach 1251, D-53002 Bonn, Germany,
2006; (f) J. Gans and D. Shalloway, J. Mol. Graphics Modell.,
2001, 19, 557.
¨
2 P. Pyykko and Y.-F. Zhao, Angew. Chem., Int. Ed. Engl., 1991,
¨
30, 604; P. Pyykko, Inorg. Chim. Acta, 2005, 358, 4113;
H. Schmidbaur and A. Schier, Chem. Soc. Rev., 2008, 37,
1931; S. Sculforta and P. Braunstein, Chem. Soc. Rev., 2011,
40, 2741.
3 e.g. A. L. Balch, Struct. Bonding, 2007, 123, 1; V. W.-W. Yam
and E. C.-C. Cheng, Top. Curr. Chem., 2007, 281, 269;
E. R. T. Tiekink and J.-G. Kang, Coord. Chem. Rev., 2009,
253, 1627; X. He and V. W.-W. Yam, Coord. Chem. Rev., 16 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
2011, 255, 2111; E. E. Langdon-Jones and S. J. A. Pope,
Chem. Commun., 2014, 50, 10343.
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato,
X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,
J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota,
R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery Jr,
J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd,
E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi,
J. Normand, K. Raghavachari, A. Rendell, J. C. Burant,
S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam,
4 (a) I. Caracelli, J. Zukerman-Schpector and E. R. T. Tiekink,
Gold Bull., 2013, 46, 81; (b) J. Zukerman-Schpector and
E. R. T. Tiekink, CrystEngComm, 2009, 11, 1176; (c)
E. R. T. Tiekink and J. Zukerman-Schpector,
CrystEngComm, 2009, 11, 2701.
5 e.g. (a) B. K. Min and C. M. Friend, Chem. Rev., 2007, 107,
2709; (b) T. Takei, T. Akita, I. Nakamura, T. Fujitani,
M. Okumura, K. Okazaki, J. H. Huang, T. Ishida and
41410 | RSC Adv., 2015, 5, 41401–41411
This journal is © The Royal Society of Chemistry 2015

View Article Online
Paper
M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo,
RSC Advances
E. R. T. Tiekink, Acta Crystallogr., Sect. E: Struct. Rep.
Online, 2009, 65, m1646; P. P. Tadbuppa and
E. R. T. Tiekink, Acta Crystallogr., Sect. E: Struct. Rep.
Online, 2009, 65, m1700; P. P. Tadbuppa and
E. R. T. Tiekink, Acta Crystallogr., Sect. E: Struct. Rep.
Online, 2010, 66, m450; P. P. Tadbuppa and
E. R. T. Tiekink, Acta Crystallogr., Sect. E: Struct. Rep.
Online, 2010, 66, m664.
J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski,
R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth,
P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels,
¨
O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski and
D. J. Fox, Gaussian 09, Revision A.1, Gaussian, Inc.,
Wallingford CT, 2009.
17 O. A. Vydrov and G. E. Scuseria, J. Chem. Phys., 2006, 125, 29 (a) H. Schmidbaur, A. Wohlleben, F. Wagner, O. Orama and
234109; O. A. Vydrov, J. Heyd, A. V. Krukau and
G. E. Scuseria, J. Chem. Phys., 2006, 125, 074106.
G. Huttner, Chem. Ber., 1977, 110, 1748; (b) P. C. Healy, Acta
Crystallogr., Sect. E: Struct. Rep. Online, 2003, 59, m1112.
18 A. D. Becke and E. R. Johnson, J. Chem. Phys., 2007, 127, 30 (a) G. Siasios and E. R. T. Tiekink, Z. Kristallogr., 1993, 204,
154108.
95; (b) G. Siasios and E. R. T. Tiekink, Z. Kristallogr., 1993,
205, 261; (c) E. R. T. Tiekink and I. Haiduc, Prog. Inorg.
Chem., 2005, 54, 127; (d) P. D. Cookson and
E. R. T. Tiekink, J. Coord. Chem., 1992, 26, 313; (e)
D. R. Smyth, B. R. Vincent and E. R. T. Tiekink, Cryst.
Growth Des., 2001, 1, 113.
19 E. R. Johnson and A. D. Becke, J. Chem. Phys., 2006, 124,
174104.
20 A. Otero-de-la-Roza and E. R. Johnson, J. Chem. Phys., 2013,
138, 204109.
21 http://gatsby.ucmerced.edu/.
22 A. Otero-de-la-Roza, J. D. Mallory and E. R. Johnson, J. Chem. 31 J. D. Dunitz and A. Gavezzotti, Acc. Chem. Res., 1999, 32, 677;
Phys., 2014, 140, 18A504.
23 K. A. Peterson and C. Puzzarini, Theor. Chem. Acc., 2005, 114,
J. D. Dunitz and A. Gavezzotti, Chem. Soc. Rev., 2009, 38,
2622; J. D. Dunitz and A. Gavezzotti, Cryst. Growth Des.,
2012, 12, 5873.
283.
24 E. R. Johnson, A. Otero-de-la-Roza, S. G. Dale and 32 R. F. W. Bader and M. E. Stephens, J. Am. Chem. Soc., 1975,
G. A. DiLabio, J. Chem. Phys., 2013, 139, 214109.
25 S. Ng, F. M. Salleh, Y. Xie and H. F. Schaefer III, J. Phys. Org.
Chem., 2012, 25, 1374.
26 S. Y. Ho, C. S. Lai and E. R. T. Tiekink, Acta Crystallogr., Sect.
E: Struct. Rep. Online, 2003, 59, o1155.
97, 7391; R. F. W. Bader, A. Streitwieser, A. Neuhaus,
K. E. Laidig and P. Speers, J. Am. Chem. Soc., 1996, 118, 4959.
33 A. Otero de la Roza, E. R. Johnson and G. A. DiLabio, J. Chem.
Theory Comput., 2014, 10, 5436.
34 K. S. O. Ferraz, N. F. Saliva, J. G. D. Silva, L. F. D. Miranda,
C. F. D. Romeiro, E. M. Souza-Fagundes, I. C. Mendes and
H. Beraldo, Eur. J. Med. Chem., 2012, 53, 98.
27 C. R. Groom and F. H. Allen, Angew. Chem., Int. Ed., 2014, 53,
662.
28 P. P. Tadbuppa and E. R. T. Tiekink, Acta Crystallogr., Sect. E: 35 P. Burn, Trends Biochem. Sci., 1998, 13, 79.
Struct. Rep. Online, 2007, 63, m1101; P. P. Tadbuppa and 36 M. E. Levison, Infect. Dis. Clin., 2004, 18, 451.
E. R. T. Tiekink, Acta Crystallogr., Sect. E: Struct. Rep. 37 J.-H. Sim, N. S. Jamaludin, C.-H. Khoo, Y.-K. Cheah,
Online, 2009, 65, m1557; P. P. Tadbuppa and
E. R. T. Tiekink, Acta Crystallogr., Sect. E: Struct. Rep.
Online, 2009, 65, m1558; P. P. Tadbuppa and
S. N. B. A. Halim, H.-L. Seng and E. R. T. Tiekink, Gold
Bull., 2014, 47, 225.
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 41401–41411 | 41411