Synthetic strategies of gold(I)-selenolates from ortho-substituted diaryl diselenides via selenol and selenenyl sulfide intermediates

Article abstract of DOI:10.1016/j.ica.2016.06.022

In the present study we describe the synthetic strategies to gold(I)-selenolate complexes by the reaction of ortho-substituted diaryl diselenides and electrophilic anti-arthritic gold(I)-compounds in the presence of thiol such as PhSH. Diselenides react with thiol to generate a mixture of selenol and selenenyl sulfide. While selenols react with electrophilic Au(I) compounds to form gold(I)-selenolate complexes, the selenenyl sulfides do not react and therefore, a prior conversion of selenenyl sulfide to selenol is necessary for an effective formation of gold(I)-selenolate from diselenide. However, this process is associated with the ligand exchange reaction in selenenyl sulfide in the presence of PhSH that hampers the regeneration of selenol. The structural aspects as well as the mode of reactivities of selenenyl sulfides and the products (gold(I)-selenolates) were analyzed using experimental as well as computational methods. These studies indicated that the presence of ortho-coordinating donor groups and oxidation state of Se-center play crucial roles towards their reactivities. Density functional theory calculations were undertaken to determine the natural charges on heteroatoms and to find the site for nucleophilic attack related to ligand exchange reactions.

Full text of DOI:10.1016/j.ica.2016.06.022

Inorganica Chimica Acta 450 (2016) 337–345
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Research paper
Synthetic strategies of gold(I)-selenolates from ortho-substituted diaryl
diselenides via selenol and selenenyl sulfide intermediates
Krishna P. Bhabak a,b, , Debasish Bhowmick c
⇑
a
Department of Chemistry, Indian Institute of Technology, Guwahati, Guwahati 781039, India
Department of Chemistry, Presidency University, Kolkata 700073, India
Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012, India
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
In the present study we describe the synthetic strategies to gold(I)-selenolate complexes by the reaction
of ortho-substituted diaryl diselenides and electrophilic anti-arthritic gold(I)-compounds in the presence
of thiol such as PhSH. Diselenides react with thiol to generate a mixture of selenol and selenenyl sulfide.
While selenols react with electrophilic Au(I) compounds to form gold(I)-selenolate complexes, the
selenenyl sulfides do not react and therefore, a prior conversion of selenenyl sulfide to selenol is neces-
sary for an effective formation of gold(I)-selenolate from diselenide. However, this process is associated
with the ligand exchange reaction in selenenyl sulfide in the presence of PhSH that hampers the regen-
eration of selenol. The structural aspects as well as the mode of reactivities of selenenyl sulfides and the
products (gold(I)-selenolates) were analyzed using experimental as well as computational methods.
These studies indicated that the presence of ortho-coordinating donor groups and oxidation state of
Se-center play crucial roles towards their reactivities. Density functional theory calculations were under-
taken to determine the natural charges on heteroatoms and to find the site for nucleophilic attack related
to ligand exchange reactions.
Received 24 March 2016
Received in revised form 17 May 2016
Accepted 10 June 2016
Available online 11 June 2016
Keywords:
Glutathione peroxidase mimics
Anti-arthritic gold(I) compounds
Selenenyl sulfide
Gold(I)-selenolate
Ligand exchange
DFT calculation
HOMO-LUMO
Ó 2016 Published by Elsevier B.V.
1
. Introduction
Gold(I)-based compounds have been used for the treatment of
complexes with cysteine (Cys)-containing proteins has been exten-
sively studied. For example, serum albumin (Alb-SH) [4], human
glutathione reductase (hGR) [5] and protein tyrosine phosphatases
(PTPs) [6] are shown to bind rapidly with gold(I) drugs to produce
the corresponding protein-gold-thiolate complexes. Furthermore,
recent studies speculate that gold drugs effectively inhibit several
selenoenzymes such as glutathione peroxidase (GPx) [7], type-I
iodothyronine deiodinase (ID-1) [8] and thioredoxin reductase
(TrxR) [9], probably by reacting with the protein active site
selenocysteine (Sec) residues leading to the formation of protein-
gold(I)-selenolate complexes.
While X-ray crystal structure of several protein-gold-thiolate
complexes is reported [2], the structure of protein-gold-selenolate
complex is not known. However, the structural aspects of
gold(I)-selenolate complexes are evidenced by the design, synthe-
sis and single crystal X-ray structures of small-molecule gold(I)-
selenolate complexes [10]. The gold(I)-selenolate complexes could
be synthesized by the reduction of diselenides either by using
sodium borohydride or by using suitable thiols to generate selenol
intermediates followed by the reaction with trialkyl/arylphosphine
gold(I) chlorides, auranofin (AUR) or any other electrophilic
Au(I)-based anti-arthritic compound [10,11]. While the first
method of reduction might not be compatible in the cellular
many diseases such as tuberculosis, endocarditis, syphilis and
rheumatoid arthritis (RA) for quite long time [1]. Particularly,
gold(I) complexes such as gold thiomalate (myochrisine, GTM),
gold thioglucose (solganol, GTG) and auranofin (AUR) are
employed for the treatment of RA (chrysotherapy) for many years
and this has attracted considerable research attention as these
compounds have been shown to effectively slow down or even
stop the progress of RA (Fig. 1) [2]. While GTM and GTG are poly-
meric in nature, AUR, which is considered as 2nd generation gold(I)
3
drug, is monomeric containing linear -S-Au-PEt moiety [3]. A con-
siderable number of experimental evidences suggest that these
compounds exert their therapeutic effects by inhibiting certain
enzyme activities or affecting the functions of inflammatory cells.
This is mostly due to the presence of electrophilic Au(I)-center that
allows the nucleophilic reactivity in the presence of reactive
groups in proteins/small molecules. The interaction of gold(I)
⇑
Corresponding author at: Department of Chemistry, Indian Institute of Tech-
nology, Guwahati, Guwahati 781039, India.
E-mail address: kbhabak@iitg.ernet.in (K.P. Bhabak).
http://dx.doi.org/10.1016/j.ica.2016.06.022
0
020-1693/Ó 2016 Published by Elsevier B.V.

3
38
K.P. Bhabak, D. Bhowmick / Inorganica Chimica Acta 450 (2016) 337–345
OH
OAc
H
H
R
NaO C
2
H O
OH
H
R
P
Au Cl
O
HO
HO
AcO
AcO
R
H
H
NaO C
S
Au
H
H
H
2
n
OAc
H
S
S
AuPEt3
R = Me, Et, Ph
Au
n
GTM
GTG
AUR
Fig. 1. Chemical structures of some representative gold(I) compounds.
environment, the later method is justified as such reductive cleav-
age of diselenide/disulfide bonds often takes place by cellular and
activated thiols during many enzymatic processes. This is further
supported by the recent reports on inhibition of the thiol-mediated
antioxidant activity of native GPx as well as some functional mim-
ics by anti-arthritic gold(I) compounds [11]. Considering the cat-
alytic cycle, it is observed that only the selenol intermediate
reacts with conventional gold(I) compounds during the inhibition
leading to the formation of gold-selenolate complexes (Scheme 1)
O
N
H
Se )2
N
Se )2
N
Se )2
N
1
Se )2
O
2
4
3
O
O
N
Se )
N
H
N
H
N
Se )
Se )
Se )
2
2
2
2
[
11]. Therefore, the overall formation of gold-selenolate from dise-
5
6
7
8
lenide is dependent on the feasibility of in situ generation of selenol
from corresponding diselenides in the presence of thiol. It should
be noted that the presence of N/O-containing coordinating groups
are necessary for an efficient cleavage of Se–Se bonds in dise-
lenides but such groups interferes on the generation of selenols
from selenenyl sulfide intermediates due to the ligand exchange
Fig. 2. Chemical structures of some representative diaryl diselenides 1–8 as
synthetic GPx mimics.
functional mimics of GPx [12,14]. As shown in Fig. 2, a series of
symmetrical diaryl diselenides 1–8 are chosen as representative
synthetic mimics of GPx in the present study and the chemical
structures of selenenyl sulfides and gold(I)-selenolate complexes
are shown in Fig. 3. While diselenides 3–8 contain a coordinating
group with N/O heteroatom at the ortho-position to the Se-center,
diselenides 1 and 2 do not have such a coordinating group. It has
been shown previously that the Se–Se bond in most diselenides
can be cleaved by thiols such as glutathione (GSH) or aryl/benzyl
thiols in the presence/absence of peroxide and the cleavage is fur-
ther assisted by the presence of ortho-coordinating groups [12,14].
As depicted in Scheme 1, nucleophilic attack of one equivalent of
PhSH to Se–Se bond of diselenide 5 having ortho-coordinating N,
N-dimethylamino group produces a mixture of selenol 25 and sele-
nenyl sulfide 17. While the produced selenenyl sulfide 17 is unre-
(
thiol) reactions at Se-centers [12,13]. Therefore, any condition
that prevents the ligand exchange (thiol) reaction and effectively
generate selenol intermediate from diselenide, would lead to the
formation of gold(I)-selenolate complexes. In the present report,
we have considered a series of diaryl diselenides 1–8, with/without
ortho-coordinating amine/amide groups (Fig. 2). The structural
aspects of selenenyl sulfides and gold(I)-selenolates are investi-
gated both experimentally and theoretically to understand the role
of intramolecular interactions, oxidation state on Se-center and
geometrical features towards the feasibility of ligand exchange
reactions and overall stabilities. Finally a number of special condi-
tions are proposed for minimizing the unwanted thiol exchange
reactions in selenenyl sulfide stage for an exclusive synthesis of
gold(I)-selenolates from diaryl diselenides.
3
active towards gold(I) compound (Me PAuCl), the generated
selenol 25 promote nucleophilic attack at the Au(I)-center leading
to the formation of gold(I)-selenolate complex 18 (Scheme 1).
Although, the produced selenenyl sulfide 17 can further be con-
verted to the corresponding selenol in the presence of an addi-
tional amount of PhSH, the process is hampered by unwanted
thiol exchange reaction at the Se-center of selenenyl sulfide
2
. Results and discussion
2.1. Formation of gold-selenolates from diselenides 1–8
Considering the presence of selenocysteine (Sec) residue at the
[
12,13]. A similar scenario also arises in the presence of other
active site of native GPx enzyme, a number of organoselenium
compounds have been developed since last few decades as
amine/amide-based coordinating groups. However, a nucleophilic
N
Se )2
5
PhSH
Me PAuCl
Me PAuCl
3
N
3
N
PhSH
N
N
.
.
.
.
.
Se-AuPMe3
SeH
Se
Se-AuPMe
3
1
8
25
+
PhSSPh
S
18
PhSH
Ph
1
7
Thiol
Exchange
Scheme 1. Schematic representation to the formation of gold(I)-selenolate complex 18 upon the thiophenol-mediated cleavage of diselenide 5. Similar scenario also prevails
in the presence of other ortho-coordinating groups.

K.P. Bhabak, D. Bhowmick / Inorganica Chimica Acta 450 (2016) 337–345
339
O
following the method as reported earlier (Scheme S1, Supporting
Information) [16]. The crude compound 21 was obtained as white
solid, which was recrystallized from dichloromethane to afford
needle-shaped crystals. The pure compound was thoroughly char-
acterized by NMR spectroscopic and Mass spectrometric analyses
along with single crystal X-ray diffraction studies. On the other
hand, although the X-ray crystal structure of protein-gold(I)-
selenolate was not reported, the single crystal X-ray structures of
several small-molecule gold(I)-selenolates such as compounds
10, 28 and 29 were reported in the literature (Fig. 4) [10].
N
H
Se R
N
N
Se
N
Se
R
R
Se
R
9
1
, R = SPh
0, R = AuPMe3 12, R = AuPMe3 14, R = AuPMe3
11, R = SPh
13, R = SPh
15, R = SPh
16, R = AuPMe3
O
O
O
N
N
H
Se
N
H
N
Se
R
R
Se
R
Se R
The ORTEP diagram of compound 21 as shown in Fig. 5 exhibits
certain structural features. The carbonyl oxygen atom of amide
group is found to interact with the electron deficient Se-center
1
7, R = SPh
19, R = SPh
21, R = SPh
23, R = SPh
24, R = AuPMe3
1
8, R = AuPMe3 20, R = AuPMe3 22, R = AuPMe3
(
dSeÁ Á ÁO = 2.639 Å) and owing to this interaction, the OÁ Á ÁSe–S
Fig. 3. Chemical structures of selenenyl sulfides and gold(I)-selenolates corre-
sponding to diselenides 1–8.
moiety in the selenenyl sulfide aligns itself almost in a linear fash-
ion with an angle of 175.6° (near 180°). This is in well agreement
with the already reported imine-based selenenyl sulfides as shown
in Table 1 [15]. Indeed such donor-acceptor non-bonded interac-
tions in selenenyl sulfides are quite expected as the Se-center is
electron deficient in nature (oxidation state of Se-center: -1). Apart
from this intramolecular non-bonded SeÁ Á ÁO interactions, the sele-
nenyl sulfide 21 exhibits intermolecular H-bonding interactions.
The free N–H group of sec-amide functionality of one molecule
interacts with the carbonyl oxygen of amide group of another
molecule with the formation of N–HÁ Á ÁO linkages. Extrapolation
of this intermolecular H-bonding led to the formation of
attack of thiol at the S-center of Se-S bond in selenenyl sulfide is
rather necessary for the generation of selenol. Thus, although the
presence of SeÁÁÁN/O non-bonded interactions are beneficial for
the cleavage of Se–Se bond in diselenides, this has negative
influence for the generation of selenol from the corresponding
selenenyl sulfide intermediate.
2.2. Important structural features of selenenyl sulfides and gold(I)-
selenolate complexes
network-like
structural
pattern
(dN–HÁ Á ÁO = 2.105 Å;
hN–HÁ Á ÁO = 160.7°) as shown in Fig. 6. The presence of similar
SeÁÁÁN/O non-bonded interaction is also observed in amine- and
amide-based diselenides as reported earlier in their X-ray crystal
structures [12,14].
Upon the development of different series of synthetic mimics of
GPx, a number of selenenyl sulfides were synthesized and charac-
terized by spectroscopic methods as reported earlier [14b] To the
best of our knowledge, crystallographic data on selenenyl sulfides
was not available except three imine-based selenenyl sulfides
Similar to selenenyl sulfides, single crystal X-ray structures of
several gold(I)-selenolate complexes were reported in the litera-
ture [10]. To understand the importance and alignments of coordi-
nating groups near Se-center (electron rich) on the structure and
overall stability of gold-selenolate complexes, X-ray structures of
three already reported gold-selenolate complexes such as 10, 28
and 29 are considered in the present study (Fig. 7). Some important
structural features of compounds 10, 28 and 29 are presented in
Table 1. While compound 10 does not contain any coordinating
group, compounds 28 and 29 possess N,N-dimethylaminomethyl
group at the ortho-position of Se-center. As expected, irrespective
of the presence of any coordinating group, the Se–Au–P moiety
in gold(I)-selenolates adopt almost linear geometries with bond
angles ranging from 171° to 178°, which is the characteristic
pattern of gold(I) complexes (Table 1). Owing to the selenolate
character (electron rich center, oxidation state of Se-center: -2)
(
compounds 13, 26 and 27) having intramolecular SeÁÁÁN interac-
tions (Fig. 4) [15]. Non-bonded interactions in other selenenyl sul-
fides having different ortho-substitutions were mainly speculated
based on the energy optimized geometries as calculated using den-
sity functional theory (DFT) [12–14]. In the present study, for the
first time, we describe the single crystal X-ray structure of a
sec-amide-based selenenyl sulfide 21 having strong SeÁ Á ÁO non-
bonded interaction (Fig. 4). The non-bonded donor-acceptor inter-
actions in selenenyl sulfides are expected due to the presence of
electron donating heteroatoms at the ortho-position of elec-
trophilic Se-center (oxidation state of Se-center: -1). The selenenyl
sulfide 21 was synthesized almost in a quantitative yield from the
corresponding cyclic selenenylamide by the reaction with PhSH
O
O
O
H
N
N
N
N
O
Se
Se
Se
S
S
Se
S
Ph
Ph
Ph
S
Ph
13
21
Ph
26
27
H
N
N Me
2
P
PPh
2
Ph
2
Au
Se
Au
Se
Se
Au
P
P
Au Se
Me
Me N
Cl-
Me
N
2
Fe
2
Me
NMe2 Me2N
Me
P
Au Se
Ph
2
1
0
28
29
Fig. 4. Chemical structures of some selenenyl sulfides (13 [15b], 21, 26 [15c] & 27
15a]) and gold(I)-selenolate complexes (10, 28 & 29) [10], whose X-ray structures
are known in the literature. X-ray data of compound 21 is described in the present
[
Fig. 5. X-ray crystal structure of selenenyl sulfide 21. Displacement ellipsoids are
drawn at 50% probability level and hydrogen atoms are shown as small spheres of
arbitrary radii.
study and is not reported earlier.

3
40
K.P. Bhabak, D. Bhowmick / Inorganica Chimica Acta 450 (2016) 337–345
Table 1
Some of the representative structural parameters of selenenyl sulfides (13, 21, 26 &
7) and gold(I)-selenolate complexes (10, 28 & 29) as obtained from their single
method has been reported earlier [16a]. The crude compound
was purified by column chromatography and characterized by
spectroscopic methods.
2
crystal X-ray structures.
In contrast to selenenyl sulfides, the Se-centers in
gold(I)-selenolates do not favor the nucleophilic attack of thiols
for a ligand exchange reaction. This is mainly due to relatively
higher electron density of Se-center in gold(I)-selenolates even as
compared to the adjacent Au-center. However, ligand exchange
reactions were observed in gold(I)-selenolate complexes in the
presence of trialkyl/arylphosphine or selenol compounds as
detected by P, Se NMR spectroscopic and ESI-MS spectrometric
methods [10a,11]. For example, as reported earlier, treatment of N,
N-dimethylbenzylamine-based gold(I)-selenolate 18 with an
excess amount of triphenylphosphine led to the phosphine
exchanged gold-selenolate 31 via intermediate formation of
mixed phosphine-gold(I) complexes. This observation indicates
that the incoming phosphine attacks at Au(I)-center rather than
Se-center to generate new gold(I)-selenolate complex 31 with
the elimination of trimethylphosphine that undergone aerial
oxidation to the corresponding phosphine oxide (Scheme 3) [11].
Similarly, when the same gold-selenolate 18 was treated with
selenol 25, the bis-selenolato gold(I) complex 32 was detected as
predominant species with the release of phosphine unit. These
observations indicate that Au(I)-center in gold(I)-selenolates is
the electrophilic center for possible ligand exchange reactions in
the presence of nucleophiles.
Compound dSeÁÁÁN/O
d
(Å)
Se-S/Au
d
(Å)
Au-P
h
N/OÁ Á ÁSe-S/Au (°)
hSe-Au-P (°) Refs.
(Å)
Selenenyl sulfides
1
2
2
2
3
1
6
7
2.617
2.639
2.636
2.458
2.218
2.197
2.213
2.249
–
–
–
–
176.6
175.5
178.4
176.4
–
–
–
–
[15b]
Present
[15c]
[15a]
3
1
77
Gold(I)-selenolate complexes
1
2
2
0
8
9
–
2.440
2.404
2.425
2.266
2.262
2.268,
2.273
–
176.0
173.1
170.6,
177.9
[10b]
[10a]
[10a]
4.600
4.579,
102.9
150.9,
169.6
3.265
of the Se-center in compounds 28 and 29, the electron donating
ortho-coordinating groups align themselves away from Se–Au–P
moieties. This is in contrast to the alignment of sec-amide group
in selenenyl sulfide 21 and imino groups in selenenyl sulfides 13,
2
6
and 27 that exhibit significant intramolecular SeÁ Á ÁO/N
interactions. The absence of any SeÁÁÁN non-bonded interaction in
gold(I)-selenolates 28 and 29 is also reflected in the values of bond
distances and angles as shown in Table 1. These observations indi-
cate that the relative oxidation state of Se-center in diselenides
(
oxidation state of Se-center: -1) [16b], selenenyl sulfides (oxida-
To understand the reactivity of gold selenolate 18 with thiols
such as DTT or PhSH, we have studied, the interactions of complex
tion state of Se-center: -1) [15], and gold(I)-selenolates (oxidation
state of Se-center: -2) [10a] play crucial roles for the non-bonded
donor-acceptor interactions with the ortho-coordinating groups.
31
77
1
8 with thiols. As indicated by P and Se NMR spectroscopic
experiments some ligand displacement reactions take place in
the presence of thiols. When the reaction of selenol 25 as produced
in situ by the treatment of diselenide 5 with DTT followed by
2
.3. Ligand exchange reactions
3 3
Ph PAuCl, the formation of triphenylphosphine selenide (Ph PSe)
It is now well established that ligand exchange reactions take
place at the Se-center in selenenyl sulfides in the presence of thiols
12,13]. The extent of this exchange is amplified further in the
presence of ortho-coordinating groups to the Se-center. The similar
observation was also noticed for the sec-amide based selenenyl
sulfide 21 as shown in Scheme 2. When the pure crystals of 21
was treated with another thiol such as 4-methylthiophenol, forma-
tion of a new selenenyl sulfide 30 was detected as monitored by
was detected and the intensity of this compound was found to
increase with increasing concentration of DTT in the reaction mix-
ture. However, the ligand exchange by PhSH was found ti be very
negligible [11]. At this point, it is worth mentioning that, although
the ligand exchange reaction (thiol exchange) in selenenyl sulfide
intermediate has negative influence for both of the GPx-like
antioxidant activity of diselenide or selenenylamides and towards
the formation of gold(I)-selenolate complexes, the ligand exchange
reaction at Au(I)-center of gold(I)-selenolate has positive/neutral
impact regarding the interaction of therapeutic gold(I) compounds
[
7
7
Se NMR spectroscopic method (Scheme 2). The process of thiol
77
exchange with compound 21 using
Se NMR spectroscopic
Fig. 6. Intermolecular H-bonding network in selenenyl sulfide 21 consisting of N–HÁ Á ÁO moieties of amide functionality.

K.P. Bhabak, D. Bhowmick / Inorganica Chimica Acta 450 (2016) 337–345
341
1
0
28
29
Fig. 7. X-ray crystal structures of gold(I)-selenolates 10 [10b], 28 [10a] and 29 [10a]. The heteroatoms are represented with ball and stick model. All these structures are taken
from the reported crystal structural data (CIF) [10].
Table 2
H
O
H
O
Some representative structural parameters on the energy optimized geometries of
selenenyl sulfides and gold(I)-selenolates corresponding to diselenides 1–8. The DFT
calculation was performed at B3LYP/LANL2DZ level of theory.
N
N
SH
Me
SH
+
+
Compounds dSeÁÁÁN/O (Å) hN/OÁ Á ÁSe-S/Au (°) hSe-Au-P (°) qSe
qS/Au
Se
Se
9
1
11
1
1
1
1
1
1
1
19
20
2
2
2
2
–
–
–
–
–
–
–
–
–
0.260
0.006
S
S
0
178.2
–
179.1
–
175.5
–
178.3
–
178.1
–
177.5
–
177.7
–
178.3
À0.215 0.252
0.236
À0.005
À0.222 0.185
0.388
À0.109
À0.088 0.149
0.304
À0.095
À0.185 0.167
0.326
À0.017
À0.179 0.167
0.410
À0.088
À0.185 0.183
0.402
À0.080
À0.186 0.180
0.394
À0.074
À0.189 0.180
21
30
Me
2
3
4
5
6
7
8
2.515
3.010
2.539
3.393
2.529
3.400
2.453
4.053
2.476
4.033
2.500
4.003
175.7
175.6
174.5
156.4
175.7
155.2
173.9
155.3
173.0
149.1
172.7
146.5
Scheme 2. Reaction of selenenyl sulfide 21 with a new thiol (4-methylthiophenol)
with the formation of new selenenyl sulfide 30 by thiol exchange reaction (present
work).
with cysteine- or selenocysteine-containing proteins. This is
because such exchange with any other reactive thiol or selenol
group would lead to produce bis-thiolato gold(I), bis-selenolato
gold(I) or mixed gold(I) complexes without freeing the previous
selenol/thiol.
1
2
3
4
2.4. Theoretical studies
in agreement with our expectations, such interactions are almost
absent or very weak in the corresponding gold(I)-selenolates. For
example, while dSeÁÁÁN distance in selenenyl sulfide 17 was
2.529 Å, the distance was significantly increased in the correspond-
ing gold-selenolate 18 (3.400 Å). Reduction in strength of non-
bonded SeÁÁÁN interaction is also associated with the significant
deviation from linearity of NÁÁÁSe–S/Au angles on going from
selenenyl sulfides to gold-selenolates (compound 17: hNÁÁÁSe–
S = 175.7°; compound 18: hNÁÁÁSe–Au = 155.2°). A quite similar
scenario is also observed when the amino group was replaced with
the corresponding amide counterpart. A significantly high increase
in SeÁ Á ÁO distance was observed on going from amide-based sele-
nenyl sulfides to amide-based gold-selenolate complexes. Devia-
tion from the linear arrangement of amide moiety with Se-Au-P
unit of the molecule is also evident from much lower values of
OÁ Á ÁSe–Au angles of amide-based gold(I)-selenolate complexes.
Interestingly, similar to the results obtained from single crystal
To gather more generalized views and also to further support
the experimental observations about the effect of SeÁÁÁN/O non-
bonded interactions on selenenyl sulfides and gold-selenolates,
we have carried out detailed density functional theory (DFT)
calculations on all the selenenyl sulfides and corresponding gold
(
I)-selenolate complexes of diselenides 1–8. The calculations were
performed using Gaussian03 package at B3LYP level of theory and
the LANL2DZ basis set was chosen due to the presence of heavier
Au-atom. All the geometries were optimized in gas phase and
non-bonded interactions were determined by carrying out natural
bond orbital (NBO) theory analysis on the energy optimized
geometries. Some important structural parameters of these com-
pounds are shown in Table 2 and the optimized geometries of
some selected compounds are shown in Fig. 8. As observed from
Fig. 8 and/or Table 2, significant SeÁÁÁN/O non-bonded interactions
are present in imine/amine/amide-based selenenyl sulfides and
H
N
N
PPh3
N
25
O=PMe +
+ O=PMe
3
3
Se Au PPh3
Se Au PMe3
Se Au Se
N
3
1
18
32
Scheme 3. Schematic representations for ligand exchange reactions in gold-selenolate 18 in the presence of phosphine and selenol compounds (our own previously reported
work) [11].

3
42
K.P. Bhabak, D. Bhowmick / Inorganica Chimica Acta 450 (2016) 337–345
9
10
17
18
21
22
Fig. 8. Energy optimized geometries of some representative selenenyl sulfides and corresponding gold-selenolate complexes.
X-ray structures of gold(I)-selenolate complexes 10, 28 and 29,
theoretical studies on all gold-selenolates reveal that Se–Au–P
moiety adopt almost linear arrangement, which is the characteris-
tics of Au(I) complexes. Unlike in selenenyl sulfides, very weak or
the absence of non-bonded SeÁÁÁN/O interaction in gold-selenolate
complexes can be ascribed to the presence of a relatively electron
rich Se-center (selenolate character) linked with Au(I)-center that
prevents the electronic contribution from the ortho-substituted
coordinating groups. To validate this assumption, natural charges
on the heteroatoms were calculated using NBO analysis. Interest-
ingly, both Se- and S-centers in selenenyl sulfides 9 and 11 were
positively charged (Table 2) and the positive charge density (elec-
tron deficiency) on Se-center was found to be higher than that on
S-centers in those selenenyl sulfides, indicating the feasibility of
nucleophilic attack at Se-center. In contrast, the Se-centers in the
corresponding gold-selenolates 10 and 12 are negatively charged
principle. As expected a significant increase in positive charge den-
sity or the electron deficiency at Se-center in selenenyl sulfides is
observed in the presence of amine- or amide-based coordinating
groups, indicating the transfer of electron density from coordinat-
ing groups to the anti-bonding molecular orbital of Se–S bond
(Table 2) [12,13]. These observations clearly indicate that, the
nucleophilic attack of thiols at Se-centers in selenenyl sulfides
becomes more feasible in the presence of ortho-substituted coordi-
nating groups, which is not a desired pathway for the generation of
gold(I)-selenolates. Assumptions from these theoretical calcula-
tions are in well agreement with the experimentally observed
(X-ray crystal structures) results on representative selenenyl sul-
fides 13, 21, 26, 27 and gold-selenolate complexes 10, 28 and 29
as discussed above.
The feasibility of ligand exchange reactions and the extent of
intramolecular donor-acceptor interactions in selenenyl sulfides
and gold(I)-selenolates can be well investigated by understanding
the frontier molecular orbitals (FMOs) of these compounds. An
(Table 2) and Au(I)-centers rather have positive charge. These
observations support the lack of any intramolecular donor-accep-
tor interactions of the ortho coordinating groups with the Se-cen-
ters in gold(I)-selenolates. Furthermore, such interactions with
the relatively positively charged Au(I)-centers are very less likely
due to discrepancies with hard-hard and soft-soft interaction
electronic interaction/transition is basically
a transition of
electrons from ground state to first excited state. It is generally
described as a transition of electron from highest occupied
molecular orbital (HOMO) to lowest unoccupied orbital (LUMO).

K.P. Bhabak, D. Bhowmick / Inorganica Chimica Acta 450 (2016) 337–345
343
Therefore, the HOMOs are the orbitals that have the ability to
donate an electron and LUMOs are the ones that can accept an elec-
tron. They are often referred to as frontier molecular orbitals
HOMO-LUMO energy gap. The positive and negative phases are
represented in red and green colors, respectively. In the present
context, the mode as well as the site of ligand exchanges in the
presence of external nucleophiles can be satisfactorily justified
using the 3D HOMO-LUMO surfaces of selenenyl sulfides and
gold(I)-selenolates (Fig. 9). As seen in the surface views of HOMOs
of selenenyl sulfides, major charge density is localized on thiophe-
nol component (S-center and phenyl ring) and relatively smaller
density on Se-centers, indicating that the electrons in HOMO are
mainly delocalized over the -SPh moiety of selenenyl sulfides. A
part of charge density is also localized on the coordinating heteroa-
tom in case of ortho-coordinated derivatives. Whereas, in LUMOs,
the charge density is distributed over Se–S units. Unlike in HOMOs
of selenenyl sulfides, the electronic distribution in LUMOs is more
diffused on Se-center than that on S-centers, indicating that the
molecular orbital has more of Se-character. These observations
further implies that the Se-center has relatively higher tendency
of accepting electron density from an external nucleophile as well
as coordinating donor groups, which is in well agreement with the
experimental mode of ligand exchange in selenenyl sulfides in the
presence of nucleophile such as thiophenol [12,13].
(
FMOs). According to the Koopmans theorem, the energy of the
HOMO is related to the ionization potential, while the energy of
LUMO is related to the electron affinity [17] and therefore, these
molecular orbitals mainly determine the stability or the reactivity
of a molecule. The energy gap between HOMOs and LUMOs is
related to the biological activity of the molecule [18,19] and a large
HOMO–LUMO energy gap represents the high kinetic stability. The
high energy gap indicates that the transfer of an electron from
higher occupied molecular orbitals (HOMO) to lower unoccupied
molecular orbitals (LUMO) is energetically unfavorable. Generally,
the atom or fragment occupied by more densities of HOMOs
should have stronger ability to detach an electron whereas; the
atom with more occupation of LUMOs should have ability to gain
an electron. In the present study, we have calculated the energetics
of frontier orbitals of some representative selenenyl sulfides (9 and
1
7) and their corresponding gold(I)-selenolates (10 and 18). The 3D
surfaces of HOMOs and LUMOs of these compounds are
represented in Fig. 9 along with their corresponding energies and
HOMO
ΔEHOMO-LUMO
LUMO
(eV)
9
(E = -6.229 eV)
3.591
4.406
9 (E = -2.638 eV)
10 (E = -0.245 eV)
10 (E = -4.651 eV)
17 (E = -5.467 eV)
18 (E = -4.787 eV)
4.025
17 (E = -1.442 eV)
4.297
18 (E = -0.490 eV)
Fig. 9. 3D surfaces of Frontier Molecular Orbitals (FMOs) of some representative selenenyl sulfides and their corresponding gold(I)-selenolates. Values in the parentheses
represent energies of HOMOs and LUMOs. An isovalue of 0.03 was used for visualizing the molecular orbital surfaces in Gaussview.

3
44
K.P. Bhabak, D. Bhowmick / Inorganica Chimica Acta 450 (2016) 337–345
A similar and rather a better picture is reflected in the HOMOs
of selenol from diselenide is crucial for an effective formation of
gold(I)-selenolate. As observed from experimental as well as
computational methods that moderate to strong intramolecular
SeÁÁÁN/O interactions are present in most diselenides and selenenyl
sulfides but such interactions are absent in gold(I)-selenolates. This
absence is mainly due to different nature and oxidation state of
Se-centers (electron rich) as well as typical characteristics of Au
(I)-centers in gold(I)-selenolates. Furthermore, the observed ligand
exchange reactions at Au(I)-center instead of electron rich Se-cen-
ter in gold(I)-selenolates as supported by NBO charges and FMO
surface views, would be beneficial for an stability of Se–Au bond
and probably for an effective inhibition of selenoproteins by elec-
trophilic anti-arthritic gold(I) compounds with possible formation
of protein-gold(I)-selenolate complexes in the presence of high cel-
lular concentration of thiols.
and LUMOs of gold(I)-selenolates (Fig. 9). While the electron den-
sity of HOMOs are localized mainly on Se-center, a localized elec-
tron density diffused over Au(I)-center is observed in the
corresponding LUMOs, supporting that Au(I)-center as the site for
nucleophilic attack (ligand exchange). A very high electron density
on Se-center in HOMOs of gold(I)-selenolates represents that
Se-center is electron rich. The energies of HOMO and LUMO and
HOMO–LUMO energy gap for these compounds as shown in
Fig. 9 are also important for their overall reactivity/stability. In
general, the calculated HOMO-LUMO energy gap of selenenyl sul-
fides and gold(I)-selenolates are small indicating their general
reactivity. However, relatively lower energy gap for selenenyl sul-
fides as compared to the corresponding gold(I)-selenolates reveals
the higher reactivity of selenenyl sulfides.
Although thiol exchange reactions were found to be relatively
dominant in selenenyl sulfides than the generation of selenols as
shown in Schemes 1, the unwanted thiol exchange could be over-
come using few logical strategies that were established and evi-
denced earlier for the enhancement of antioxidant activities of
synthetic GPx mimics [12,14a]. Therefore, selenols can effectively
be synthesized from selenenyl sulfides under certain conditions
such as (a) by using very high concentration of thiol [13a]; b) by
weakening of SeÁÁÁN/O non-bonded interactions [16b]; c) by
introducing suitable substituent at 6-position of aromatic ring
4. Experimental
4.1. General procedure
Thin layer chromatographic (TLC) analyses were carried out on
pre-coated silica gel on aluminum sheets. The product was purified
by Flash chromatographic system (Biotage) using pre-loaded silica
1
13
31
gel cartridges. H (400 MHz), C (100.5 MHz), P (161.9 MHz) and
7
7
Se (76.3 MHz) NMR spectra were obtained on a Bruker 400 MHz
NMR spectrometer. Chemical shifts are cited with respect to Me Si
[
16b]; d) by using a dithiol such as DTT or Lipoic acid [13b] or e)
by introducing some strong coordinating group near to S-center
13a]. Under these conditions treatment of trialkyl/arylphosphine
4
1
13
31
77
3 4 2
( H and C) as internal standard and H PO ( P) and Me Se ( Se)
[
as external standards. Mass spectral studies were carried out on a
Bruker Daltonics Esquire 6000plus mass spectrometer with ESI-MS
mode analysis. Crystal structures of selenenyl sulfides 13 [15b], 26
[15c] and 27 [15a] are taken from earlier reports for a comparative
study with compound 21 (present work). Similarly, the crystal
structures of gold(I)-selenolates 10 [10b], 28 [10a] and 29 [10a]
gold(I) chlorides in the reaction mixture would lead to an
exclusive formation of phosphine gold(I)-selenolate complex
from the corresponding selenenyl sulfide. Indeed the
minimization of thiol exchange reaction in the presence of a
dithiol was observed and this was utilized for the synthesis of
gold(I)-selenolates in our earlier report [11]. While a treatment
of two equivalents of PhSH to diselenide 5 led to a mixture selenol
were taken from previously reported literatures for
comparative study.
a
2
5 and selenenyl sulfide 17 as evidenced by 77Se NMR spectro-
scopic method, an exclusive formation of selenol 25 was detected
when diselenide 5 was treated with two equivalents of dithiothre-
itol (DTT). Therefore, later method was followed for the prepara-
4.2. Synthesis of selenenyl sulfide 30
2 2
Method 1: To a CH Cl (5 mL) solution of selenenyl sulfide 21
tion of gold-selenolates from diselenide
5
using different
(30 mg, 0.12 mmol), 4-methylthiophenol (15.5 mg, 0.12 mmol)
was added at room temperature and the reaction mixture was
stirred for 30 min. The solvent was evaporated and the solid
obtained was washed with petroleum ether (4 Â 20 mL) to remove
the unreacted 4-methylthiophenol and the eliminated PhSH. The
residue was then dried in vacuo to obtain the corresponding
selenenyl sulfide 30 in almost quantitative yield.
phosphine gold(I) chlorides [11]. These observations indicate that,
although the treatment of thiol to diselenide produces a mixture of
selenol and selenenyl sulfide, the produced selenenyl sulfide could
efficiently be converted to the corresponding selenol under certain
conditions for an effective generation of gold(I)-selenolate even in
the presence of SeÁÁÁN/O non-bonded interactions. Furthermore,
some of the above conditions might fit under cellular environment
for the formation of protein gold(I)-selenolate complexes. For
example, the reactive multiple cysteine residues in proteins may
serve the functions of dithiols with the formation of internal pro-
tein disulfide linkages. The thiol concentration can be supple-
mented by the significantly high intracellular concentration of
glutathione and the coordinating groups to S-center in selenenyl
sulfide stage might be possible by some proximal amino acid resi-
dues under special circumstances. Therefore, it is unsurprising to
assume the formation of protein-gold(I)-selenolate complexes
but warrants the crystallographic evidences for a solid proof.
Method 2: 4-Methylthiophenol (15.5 mg, 0.125 mmol) was
added to a CH Cl (5 mL) solution of cyclic selenenylamide deriva-
2 2
tive [16a] (30 mg, 0.125 mmol, Mol wt: 240), at room temperature
and the reaction mixture was stirred for 30 min. The solvent was
evaporated and the solid obtained was washed with petroleum
ether (4 Â 20 mL) to remove the unreacted thiol and the
corresponding disulfide impurities. The residue was then dried in
vacuum to obtain the selenenyl sulfide 30 in quantitative yield.
1
3
H NMR (CDCl ) d (ppm): 1.27-1.28 (d, 6H, J = 4.0 Hz), 2.28
(s, 3H), 4.25-4.33 (m, 1H), 6.10 (br, 1H), 7.02–7.04 (d, 2H,
J = 8.0 Hz), 7.22-7.25 (t, 1H, J = 8.0 Hz), 7.39-7.51 (m, 4H), 8.19-
1
3
8
.21 (d, 1H, J = 8.0 Hz). C NMR (CDCl
3
) d (ppm): 20.9, 22.8, 42.3,
3
. Conclusion
125.8, 126.2, 128.5, 129.2, 129.6, 130.8, 131.8, 133.3, 136.4 and
7
7
1
37.2. Se NMR (CDCl
3
) d (ppm): 599. ESI-MS m/z calcd. for
+
In summary, in the present study we describe the synthetic
17
C H19NOSSe [M+Na] 388.0250; found: 388.0248.
methodology to gold(I)-selenolate complexes using ortho-
substituted diaryl diselenides and electrophilic anti-arthritic gold
4.3. Synthesis of gold-selenolate 18
(
I)-compounds in the presence of thiol such as PhSH or DTT. As
selenenyl sulfides do not directly produce gold(I)-selenolates and
leads to unwanted thiol exchange reaction, an exclusive generation
The synthesis was done following our previously reported
method [11]. To the solution of diselenide 5 in CDCl3, DTT was

K.P. Bhabak, D. Bhowmick / Inorganica Chimica Acta 450 (2016) 337–345
Biochem. 30 (1987) 177;
345
added (2 equiv) and the formation of selenol 25 was confirmed by
7
7
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stoichiometric amount of Ph PAuCl in CDCl in an NMR tube. The
3
3
(
yellow solution of selenol turned almost colorless immediately
upon the addition of gold(I) chloride. The formation of triph-
enylphosphinegold(I) selenolate species 18 was characterized by
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P and Se NMR spectroscopy and mass spectrometric tech-
3
1
77
niques. P NMR (CDCl
3
, ppm): d 37.50. Se NMR (CDCl
3
, ppm):
+
d 74. ESI-MS. Calcd [(M+H) ]: m/z 674.0790. Found: m/z 673.9761.
[
(
(
1997) 703;
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1
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Acknowledgments
Chem. 18 (2007) 127.
[
16] (a) K.P. Bhabak, G. Mugesh, Chem. Asian J. 4 (2009) 974;
(
(
b) K.P. Bhabak, G. Mugesh, Chem. Eur. J. 14 (2008) 8640;
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The project is supported by Science and Engineering Research
Board (SERB), India. KPB acknowledges SERB for the award of
DST-INSPIRE (Ref: IFA12-CH-68) and DST Start-Up research grant
[
17] T. Koopmans, Physica 1 (1934) 104.
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SB/FT/CS-022/2014). We thank Presidency University and IIT
[
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004.
21] G.M. Sheldrick, SADABS, University of Göttingen, Germany, 1996.
Guwahati for providing infrastructural facilities. We sincerely thank
Prof. G. Mugesh for allowing us to access some of his laboratory
research facilities. DB thanks Indian Institute of Science, Bangalore
for a Research Associate fellowship and infrastructural facilities.
2
[
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paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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Appendix A. Supplementary data
[
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.ica.2016.06.022.
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