1H, 13C NMR and UV spectroscopy studies of gold(III)-tetracyanide complex with l-cysteine, glutathione, captopril, l-methionine and dl-seleno-methionine in aqueous solution

Article abstract of DOI:10.1016/j.ica.2010.06.001

Auricyanide [Au(CN)₄]^- interaction with biologically important thiols, thioether and selenoether were carried out and monitored using ¹H, ¹³C NMR and UV spectroscopy. These ligands include l-cysteine, glutathion

Full text of DOI:10.1016/j.ica.2010.06.001

Inorganica Chimica Acta 363 (2010) 3244–3253
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Inorganica Chimica Acta
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1H, 13C NMR and UV spectroscopy studies of gold(III)-tetracyanide complex
with L-cysteine, glutathione, captopril, L-methionine and DL-seleno-methionine
in aqueous solution
*
Bassem A. Al-Maythalony, Mohamed I.M. Wazeer, Anvarhusein A. Isab
Department of Chemistry, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Auricyanide [Au(CN)4]ꢀ interaction with biologically important thiols, thioether and selenoether were
Article history:
carried out and monitored using 1H, 13C NMR and UV spectroscopy. These ligands include
L
-cysteine, glu-
-methionine and DL-seleno-methionine. Thiols show very strong affinity to be oxi-
dized into the disulfide by auricyanide, which gets reduced to aurocyanide [Au(CN)2]ꢀ.
-cysteine
reaction mechanism with [Au(CN)4]ꢀ was found to be dependent on reactants mole ratio. While
-methi-
Received 4 April 2010
Accepted 4 June 2010
Available online 17 June 2010
tathione, captopril,
L
L
L
Keywords:
Au(III)-tetracyanide complexes
Thiols
onine was completely inert toward auricyanide, DL-Se-methionine showed some reactivity with
[Au(CN)4]ꢀ after raising solution pH to 12 that facilitated cyanide exchange.
Ó 2010 Elsevier B.V. All rights reserved.
L-methionine
DL-seleno-methionine
UV–Vis
1H and 13C NMR
1. Introduction
red blood cells uptake of gold from gold(I)-thiomalate by 21.1%
after incubation for 24 h [14,15].
Gold is a pharmaceutically important metal, because of its use
in anti-arthritic drug such as auranofin and myocrisin [1–4].
Anti-rheumatic gold complexes are activated by their conversion
into aurocyanide [Au(CN)2]ꢀ [5], this stimulates investigation of
aurocyanide complexes interaction with various bioligands, espe-
cially that contain sulfur because of the known gold-sulfur affinity
[6,7]. While auricyanide [Au(CN)4]ꢀ was considered previously as
metabolic product of anti-arthritic gold(I) in-vivo [8], however,
low stability of gold(III) complexes limited their medical
importance. Tiekink have reported that gold complexes are
resilient in-vivo by inflamed tissues experiencing oxidative bursts
that can oxidize gold(I) into gold(III) [9]. Heavier chalcogens-gold
chemistry is still an unexplored field of modern inorganic chemis-
try [10]; this could be attributed to their lower stability.
In order to determine the mechanism of action of the anti-ar-
thritic gold complexes, it is necessary to understand the physio-
chemical properties of these complexes and their reactivity
under physiological conditions.
In a study of [Au(CN)4]ꢀ reaction with GSH three potential
mechanisms were suggested for auricyanide reduction into auro-
cyanide [8,16]; (i) Reductive elimination of cyanogen, followed
by nucleophilic attack of GSH on cyanogen leading to its reduction
to cyanide [17]; (ii) Formation of hexacyanodiaurate(II), [(NC)3Au–
Au(CN)3]2ꢀ, probably by 2 one-electron transfers, followed by re-
dox disproportionation [19,20] and (iii) cyanide ligand exchange
by GSH followed by reductive elimination of GSSG.
This work presents a study of the interaction of auricyanide
with CySH, GSH, Cap, Met and Se–Met at different ratios, in order
to throw some light on the reaction mechanism. 1H, 13C NMR
and UV spectroscopy techniques were utilized.
Inhalation of HCN from tobacco smoke raises [Au(CN)2]ꢀ con-
centration in smokers blood who takes gold(I) anti-arthritic drug
[11]. Large formation constant is believed to be responsible for
generating [Au(CN)2]ꢀ, (log b = 37–39) [12–14]. Graham et al. have
reported aurothiomalate (Autm) activation go through its interac-
tion with cyanide ion [15], this interaction was found to increase
2. Experimental
2.1. Chemicals
Abbreviations: CySH, L-cysteine; CyS–SCy, L-cystine; Met, methionine; Se–Met,
DL-seleno-methionine; Cap, captopril; GSH, glutathione.
* Corresponding author.
HAuCl4ꢁ3H2O were obtained from Strem Chemicals Co., D2O was
obtained from Fluka Chemicals Co., ligands e.g. GSH, CySH, were
obtained from Sigma–Aldrich, K13C15N, CySH–13C3, Met–13C5,
E-mail address: aisab@kfupm.edu.sa (A.A. Isab).
0020-1693/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2010.06.001

B.A. Al-Maythalony et al. / Inorganica Chimica Acta 363 (2010) 3244–3253
3245
SeMet–13C5 were obtained from Isotech, USA. The synthesized
compounds were identified by melting point, elemental analysis,
IR and NMR spectroscopy techniques.
at pH 7.4 at 25 °C were measured on GBC Cintra 303 spectro-
photometer.
3. Results and discussion
2.2. KAu(CN)4 complex preparation
[Au(CN)4]ꢀ interaction with different thiols and thioethers were
carried out by mixing reactants at different ratios, and reactions
monitored by NMR and UV techniques. Selected data that show
reaction progress are presented here. Signals assignments were
carried out based on literature [8,18].
Gold(III)-tetracyanide were prepared according to literature [8],
two solutions were prepared separately; solution 1 consist of
2.00 g (5.33 mmol) auric acid dissolved in 5 mL distilled water,
and solution 2, 1.73 g KCN (8% K13C15N enriched) (26.62 mmol)
dissolved in 5 mL distilled water, solutions 1 and 2 were mixed
while stirring (this reaction must be done in fume hood, that
HCN gas will evolve from reaction vessel), white precipitate was
formed immediately and allowed to grow for 3 h, produced solid
was separated by decantation andꢀdried in open air area, 95% yield
was obtained. IR data showed t(CN ) band at 2189 cmꢀ1 correspond
to [Au(CN)4]ꢀ that agree with literature [8].
3.1. L
-Cysteine interaction with [Au(CN)4]ꢀ
The reaction of CySH with [Au(CN)4]ꢀ was carried out at 1:1 ra-
tio and monitored by 1H NMR. 1H NMR chemical shifts for CySH
reaction with [Au(CN)4]ꢀ are given in Table 1. Downfield shift of
signals corresponding to H2 and H3 were observed after reaction,
H3 signal showed more downfield shift indicating binding through
sulfur atom, but 1H NMR is not much informative about gold ion
oxidation state and cyanide ligand binding mode.
2.3. NMR measurements
Fig.
1
shows 13C NMR spectra for CySH reaction with
All NMR measurements were carried out on a JEOL JNM-LA 500
NMR spectrophotometer at 297 K using 140 mM concentrations of
reactants in D2O, reactants pD were adjusted to 7.4 before and after
mixing. 13C NMR spectra were obtained at 125.65 MHz with 1H
broadband decoupling. The spectral conditions were: 32 k data
points, 0.967 s acquisition time, 1.00 s pulse delay, 45° pulse angle
and 135° pulse angle for 13C DEPT NMR experiments.
[Au(CN)4]ꢀ. Signal corresponding to CySH–13C3 shifted downfield
(from d = 25 ppm to d = 38 ppm) indication of oxidation into
L
-cystine, while Au(III) were reduced to Au(I) i.e. [Au(CN)2]ꢀ
(d = 156 ppm) [16,18]. Triplet signal at 112 ppm (Fig. 1c) was
assigned to cyanogen that may be reductively eliminated from
auricyanide as was suggested by Ettorre and Martelli [17] for the
reductive elimination of Br2 from [Au(CN)2Br2]ꢀ.
It is observed here that the signal corresponding to cyanogen
(d = 112 ppm) appears as a deceptive triplet due to fully labeled
cyanogen which has a spin system of AA‘XX’. The large one bond
13C–13C coupling in the spin system provides a deceptive triplet
[19–21].
2.4. UV measurements
UV spectra in the range 200–320 nm (2 nm step size) for com-
ponents of 0.1 mM concentration in phosphate buffer (100 mM)
No intermediates were detected from reaction, so it is not pos-
sible to shed light on the reaction mechanism. So further experi-
ments where CySH–13C3 were reacted with [Au(CN)4]ꢀ at 0.5:1
equivalents, 1:1 equivalents; and at 2:1 equivalents, respectively,
CySH–13C3 were used for better monitoring of reaction in the
NMR time scale, UV spectrophotometry was also employed for
reaction monitoring in this work.
Table 1
1H NMR chemical shifts of [Au(CN)4]ꢀ complex with CySH ligands at 1:1 ratio in D2O
at 25 °C, pD = 7.4.
H2
H3
CySH
3.922
4.045
2.980, 2.904
3.295, 3.268
[Au(CN)4]ꢀ + CySH
Fig. 1. 13C NMR of spectra for (a) [Au(CN)4]ꢀ, (b) CySH and (c) 30 h after reaction with [Au(CN)4]ꢀ at 2:1 ratio in D2O at 25 °C, pD = 7.4.

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Fig. 2. 13C NMR spectra for [Au(CN)4]ꢀ reaction with CySH-13C3 at 1:0.5, (a) for CySH–13C3 before reaction, (b) 16 hour after reaction and (c) 36 h after reaction, in D2O and
25 °C, pD = 7.4.
Fig. 2 presents 13C NMR spectra for [Au(CN)4]ꢀ reaction CySH at
1:0.5 ratio in D2O at pD 7.4. A complete shift of C3 corresponding
signal was observed right after mixing, which split into four
new signals that corresponding to mono-substituted complex
[(CyS)Au(CN)3]ꢀ (33.0 ppm), signal at 38.5 ppm attributed to sulfe-
nic acid [22], these two signals are converted gradually to CyS–SCy
(38.2 ppm) and L-cysteic acid (CySO3H) (35 ppm). L-Cysteic acid
chemical shift was found almost the same as reported by Shaw
et al. after referencing to dioxin [23]. After 4 days all species were
corresponding signal is shown as CyS–Au(III) UV absorption at
228 nm. Bands at 250 and 289 nm were not intense this indicate
that CyS–SCy could be formed by reductive elimination from two
adjacent [(CyS)Au(CN)3]ꢀ species resulting in the formation of
CyS–SCy and hexacyano-diaurate (Scheme 1), which undergoes
disproportionation reaction into [Au(CN)4]ꢀ and [Au(CN)2]ꢀ in
solution. The corresponding 13C NMR signals appear at 104.6 and
156 ppm, respectively (Fig. 2c). The increase of cyanide signal
intensity at 104.6 ppm (corresponding to [Au(CN)4]ꢀ) is an indica-
tion of the disproportionation mechanism occurrence, that could
regenerate the [Au(CN)4]ꢀ in solution after its consumption during
the initial step.
converted into L-cysteic acid (35 ppm).
Fig. 3 shows CySH reaction with [Au(CN)4]ꢀ at 1:1 ratio.
CySH–C3 signal shifted downfield from 25 ppm (Fig. 3b) to
33 ppm (Fig. 3c), this is a result of fast cyanide exchange by CySH.
Three signals correspond to cyanide were found in the spectrum
(Fig. 3c), i.e. [Au(CN)4]ꢀ (d = 104 ppm), [Au(CN)2]ꢀ (d = 156 ppm)
and [(CyS)Au(CN)3]ꢀ (d = 115 ppm). In these spectra, we observe
a decrease and then an increase of [Au(CN)4]ꢀ signal (Fig. 3c).
Fig. 4 shows the UV absorption spectra for [Au(CN)4]ꢀ reaction
with CySH at 1:0.5 mole ratio (pH 7.4). Absorption band at 228 nm
(band I) corresponding to [(CyS)Au(CN)3]ꢀ increased to its maxima
in 3 min and then started converting gradually into set III bands
after 8 days, indicating that the reaction is mainly progressing
through one cyanide ligand exchange that is followed by
[Au(CN)2]ꢀ formation with very low formation of the second cya-
nide exchange procedure.
Fig. 5 shows UV absorption spectra for [Au(CN)4]ꢀ reaction with
CySH at 1:1 ratio pH 7.4. A faster reaction occurs compared to 1:0.5
ratio (Fig. 4), bands from 204 to 240 nm were distinct after 4 h,
while mono- and di-substitution corresponding bands are concur-
rently present in solution. So it can be concluded that the reaction
proceeds through two subsequent cyanide exchange steps by CySH
followed by reductive elimination when relatively higher CySH ra-
tio is present in solution.
Fig. 6 shows representative 13C NMR spectra for [Au(CN)4]ꢀ
reaction with CySH at 1:2 ratio. It is noted that CyS–SCy formation
was much faster when CySH mole ratio increased. Five signals in
the cyanide region were found in Fig. 3b that represent five differ-
ent species in solution; [Au(CN)4]ꢀ (d = 104 ppm), [(CyS)Au(CN)3]ꢀ
(d = 115 ppm), [(CyS)2Au(CN)2]ꢀ (d = 124 ppm), NCCN (d = 112
ppm) and [Au(CN)2]ꢀ (d = 156 ppm). The spectra shows the
Based on earlier discussion, the mechanism in Scheme 1 can be
suggested. The reaction starts with cyanide exchange by CySH, the

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3247
Fig. 3. 13C NMR spectra for [Au(CN)4]ꢀ reaction with CySH–13C3 at 1:1, (a) for CySH–13C3 before reaction, (b) 2 h after reaction and (c) 24 h after reaction, in D2O and 25 °C,
pD = 7.4.
Fig. 5. UV absorbance for [Au(CN)4]ꢀ (0.1 mM) and CySH (0.2 mM) before and after
reaction at 1:1 mole ratio, at 25 °C and pH 7.4 (0.1 M phosphate buffer).
Fig. 4. UV absorbance for [Au(CN)4]ꢀ (0.1 mM) and CySH (0.2 mM) before and after
reaction at 1:0.5 mole ratio in the range 200–320 nm at 25 °C and pH 7.4 (0.1 M
phosphate buffer).
ter, after 30 min into bands from 204 to 240 nm corresponding to
formation of cyanogen (d = 112 ppm), [Au(CN)4]ꢀ reduction into
[Au(CN)2]ꢀ, CySH oxidation into CyS–SCy and formation of
[(CyS)2Au(CN)2]ꢀ in solution (Fig. 6b).
reduced [Au(CN)2]ꢀ resulting from fast reduction reaction when in-
creased CySH mole ratio found in solution.
UV absorption study reveals that the reaction proceeds through
two consecutive cyanide ligand exchanges that take place very fast.
However, some stability is found for [(CyS)2Au(CN)2]ꢀ because of
cis/trans isomerization, the complex ion in the cis form will go very
fast into reductive elimination reaction of CyS–SCy, while gold(III)
reduced to gold(I) in the form of [Au(CN)2]ꢀ. Suggested mechanism
is shown in Scheme 2.
[Au(CN)4]ꢀ reaction with CySH was also carried out at 1:2 ratio
and monitored by UV spectrophotometry, as shown in Fig. 7. The
first exchange of cyanide takes place very fast so the band at
228 nm appears at the first minute of reaction time and then it is
converted into bands at 250 and 289 nm in less than 3 min indica-
tion of very fast consecutive exchange reaction, that converted la-

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Au(CN)3]-
Scheme 1. Suggested mechanism for [Au(CN)4]ꢀ reaction with CySH at 1:0.5 and 1:1 mole ratio.
Fig. 6. 13C NMR spectra (a) for CySH–13C3, (b) after 14 h of reaction with [Au(CN)4]ꢀ at 1:2 ratio, in D2O and 25 °C, pD = 7.4 and (c) after 32 h of reaction.
It can be concluded that higher CySH mole ratio in reaction lead
3.2. Glutathione (GSH) interaction with [Au(CN)4]ꢀ
to fast exchange of two cyanide ligands that is followed by reduc-
tive elimination of CyS–SCy from cis-[(CyS)2Au(CN)2]ꢀ and forma-
tion of [Au(CN)2]ꢀ.
GSH interaction with [Au(CN)4]ꢀ has been studied in aqueous
solution at pH 7.4 by Shaw and co-workers [8]. They reported that

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3249
the formation of [(SG)Au(CN)3]ꢀ, and [(SG)2Au(CN)2]ꢀ species were
detected by mass spectrometry. In this work, interaction of GSH
with auricyanide was studied using 1H and 13C NMR to compare
the mode of interaction with other thiols.
Fig. 8 shows 13C NMR spectra of GSH before and after reaction
with [Au(CN)4]ꢀ. The C3 signal shifted down-field from 27 to
39 ppm, while C2 signal shifted up-field, indicating the formation
of GSSG, the corresponding signals are C20 and C30, respectively.
C200 and C300 could be assigned for GSH in [(GS)Au(CN)3]ꢀ complex
[8]. Cyanide signals appeared at 156 ppm corresponding to
[Au(CN)2]ꢀ and at 112 ppm and 115 ppm corresponding to
NC–CN and [(GS)Au(CN)3]ꢀ, respectively.
Scheme 3 shows a suggested mechanism that may account for
GSH reaction with [Au(CN)4]ꢀ. The reaction starts with two cya-
nide exchange by GSH, cis/trans isomerization takes place next,
and the cis-isomer will go further into disulfide dimer by reductive
elimination.
Fig. 7. UV absorbance for [Au(CN)4]ꢀ (0.1 mM) and CySH (0.2 mM) before and after
reaction at 1:2 mole ratio, at 25 °C and pH 7.4 (0.1 M phosphate buffer).
Scheme 2. Suggested mechanism for [Au(CN)4]ꢀ reaction with CySH at 1:2 equivalents.
Fig. 8. 13C NMR of GSH (a) before and (b) after reaction with [Au(CN)4]ꢀ oxidation at 2:1 ratio in D2O at 25 °C, pD 7.4.
[Au(CN)2]-
Scheme 3. Suggested mechanism for [Au(CN)4]ꢀ interaction with GSH in D2O and 25 °C.

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Fig. 9. 13C NMR spectra for (a) cap, (b) cap DEPT spectrum and (c) DEPT spectrum after reaction with H2O2 in D2O at 25 °C and pD 7.4.
Fig. 10. 13C NMR (0–75 ppm) spectra (a) for 100 mM cap before reaction, (b) after reaction [Au(CN)4]ꢀ at 1:1 ratio and (c) after reaction with [Au(CN)4]ꢀ at 0.5: 1 ratio, in D2O
at 25 °C and pD 7.4.

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3251
Fig. 11. 13C NMR (0–190 ppm) spectra for 100 mM cap before reaction (a), after reaction [Au(CN)4]ꢀ at 1:1 ratio (b) after reaction with [Au(CN)4]ꢀ at 0.5:1 ratio (c), in D2O at
25 °C and pD 7.4.
3.3. Captopril (Cap) interaction with [Au(CN)4]ꢀ
sponding to [Au(CN)2]ꢀ (d = 156 ppm), cyanogen (d = 112 ppm)
and cis/trans-[(cap)Au(CN)3]ꢀ (d = 115 and 120 ppm, respectively).
These results indicate similar reaction intermediates to other thiols
described earlier. The reaction proceeds through two cyanide sub-
stitution by cap at higher cap/Au(III) ratio, while mono-substitu-
tion reaction takes place followed by disproportionation at lower
ratio of cap was employed as shown earlier for CySH reaction with
[Au(CN)4]ꢀ.
The observation of similar intermediates produced during CySH,
cap and GSH reactions with [Au(CN)4]ꢀ at the similar mole ratio
leads to the conclusion that similar reaction mechanisms may be
found for all these reactions, with high dependence on species
ratio.
Cap isomerizes in solution into cis and trans isomers. The ratio
of these isomers depends mainly on solution pH [24–26], however,
at pH 7.4 both isomers exist with a higher concentration of trans
isomer (ꢂ60%) as reported by Rabenstein and Isab [27]. Oxidation
of cap by H2O2 was carried out, and the products were analyzed
using 13C NMR.
Fig. 9 shows 13C NMR spectra for cap oxidation by H2O2. C2 was
found to be shifted up-field upon dimerization into disulfide while
C3 and Ca show down-field shift after oxidation.
13C NMR spectra for cap reaction with [Au(CN)4]ꢀ in the range
(0–75 ppm) are given in Fig. 10. The C3 signal was found to shift
according to the earlier mentioned mechanism and it was also
dependent on the thiol ligand ratio in solution (Fig. 10b). It was
shifted down-field to 41.6 ppm corresponding to Cap-S–S-Cap
(Fig. 10c). Three distinct cap species were found in solution accord-
ing to spectrum (Fig. 10c). They correspond to un-reacted cap
(referred as C3), cap disulfide (referred as C30) and [(cap)Au(CN)3]ꢀ
species (referred as C300). Other signals corresponding to cis/trans
cap isomers were also found.
3.4. L
-methionine and DL-Se–methionine interactions with [Au(CN)4]ꢀ
Met and Se–Met interactions with auricyanide were studied by
mixing the components at different ratios. No change was ob-
served at all ratios by both 1H and 13C NMR at pDs 7 and 12. The
monitoring by NMR was continued for more than three days but
no reaction was found. However, when Se-Met was mixed with
auricyanide at 2:1 ratio and pD adjusted to 12 and stirred for three
days, a little [Au(CN)4]ꢀ was reduced to [Au(CN)2]ꢀ while Se-Met
Fig. 11 shows 13C NMR for cap reaction with [Au(CN)4]ꢀ at 1:0.5
mole ratio. Four cyanide signals were found in spectrum corre-

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Fig. 12. 13C NMR for Se–Met–13C5 before (a) and after reaction with [Au(CN)4]ꢀ, in D2O at 25 °C and pD 12.0.
was oxidized into Met–SeO–CH3 [28–30] (Fig. 12). Signals were as-
signed by comparison with Se–Met oxidation experiment with
hydrogen peroxide [31–33]. Se–Met binding to gold metal center
is expected to be through selenium or amine group as reported
from computational work for methyl-seleno-cysteine by Shoeib
et al. [7].
Met was reported to be highly reactive with Au(III) ion [34], but
it showed no reactivity toward auricyanide even after stirring for
five days. So it can be concluded that cyanide ligand causes stabil-
ization for Au(III) against reaction with Met and Se–Met [35]. Lack
of reactivity of Met and Se–Met with [Au(CN)4]ꢀ complex could be
rationalized in terms of the strong Au(III)–CN bond at pH 7.4, how-
ever, basic solution at high pH (ꢂ12), which facilitates hydrolysis
that proceeds with ligand exchange reaction as shown by El-Kha-
teeb et al. [36]. They studied the interaction of Met with cis-platin
(cis-[(NH3)2PtCl2]) and reported that Met binding to cis-platin com-
plexes proceeds first by hydrolysis step of the complexes followed
by Met-S ligation. The carboxylate and amine groups enhanced the
reaction by electrostatic stabilization of the metal ligand complex
[37,38].
Acknowledgment
The authors would like to acknowledge the support by the
Deanship of Scientific Research at King Fahd University of
Petroleum and Minerals for funding this work through project
No. (IN080421). We also thank the Squibb Institute for Medical
Research, Princeton, NJ, USA for their generous gift of captopril.
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[Au(CN)4]ꢀ shows high reactivity toward thiols. At low thiol ra-
tio, the reaction proceeds through exchange of one cyanide ligands
followed by reductive elimination of the disulfide from two mono-
substituted intermediates produce in formation of disulfide and
hexa-cyano-diaurate that disproportionates into auocyanide and
auricyanide. At higher thiol ratio, reaction proceeds through two
cyanide exchange followed by reductive elimination of the disul-
fide from cis-[(RS)2Au(CN)2]ꢀ intermediates along with Au(III)
reduction to Au(I) in the form of [Au(CN)2]ꢀ. Similar intermediates
were found for cap and GSH reactions with [Au(CN)4]ꢀ, indicating
similar reaction mechanism for these thiols, that depend on thiol
ratio in solution. Met and Se–Met were inert toward auricyanide
at pH 7.4 while some reactivity was observed for Se–Met at pH 12.
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