Diverse and unexpected outcomes from oxidation of the platinum(II) anticancer agent [Pt{(p-BrC6F4)NCH2CH2NEt2}Cl(py)] by hydrogen peroxide

Article abstract of DOI:10.1016/j.jinorgbio.2021.111360

Oxidation of the anti-tumour agent [Pt{(p-BrC₆F₄)NCH₂CH₂NEt₂}Cl(py)], 1 (py = pyridine) with hydrogen peroxide under a variety of conditions yields a range of organoenamineamidoplatinum(II) compounds [Pt{(p-BrC₆F₄)NCH=C(X)NEt₂}Cl(py)] (X = H, Cl, Br) as well as species with shared occupancy involving H, Cl and Br. Thus, oxidation of the –CH₂–CH₂– backbone (dehydrogenation) occurs, often accompanied by substitution. Oxidation of 1 with H₂O₂ in acetone yielded 1:1 co-crystallized [Pt{(p-BrC₆F₄)NCH=CHNEt₂}Cl(py)], 1H and [Pt{(p-BrC₆F₄)NCH=C(Cl)NEt₂}Cl(py)], 1Cl. The former was obtained pure in low yield from the oxidation of 1 with (NH₄)₂[Ce(NO₃)₆] in acetone, and the latter was obtained from 1 and H₂O₂ in CH₂Cl₂ at near reflux. From the latter reaction under vigorous refluxing [Pt{(p-BrC₆F₄)NCH=C(Br)NEt₂}Cl(py)], 1Br was isolated. In refluxing acetonitrile, oxidation of 1 with H₂O₂ yielded [Pt{(p-BrC₆F₄)NCH=C(H₀.₂₅Br_0.75)NEt₂}Cl(py)], 1H_0.25Br_0.75, in which the alkene is mainly substituted by Br in a dual occupancy. Treatment of 1 with H₂O₂ and tetrabutylammonium hydroxide in acetone at room temperature formed [Pt{(p-HC₆F₄)NCH₂CH₂NEt₂}Cl(py)], 2. Oxidation of [Pt{(p-HC₆F₄)NCH₂CH₂NEt₂}Br(py)], 3 with H₂O₂ in boiling acetonitrile gave the ligand oxidation product [Pt{(p-HC₆F₄)NCH=C(Br)NEt₂}Br(py)], 3Br. All major products were identified by X-ray crystallography as well as by ¹H and ¹⁹F NMR spectra. In cases of mixed crystals or dual occupancy compounds, the ¹⁹F and ¹H NMR spectra showed dissociation into the components in the solution in the same proportions as in isolated crystalline material.

Full text of DOI:10.1016/j.jinorgbio.2021.111360

Journal of Inorganic Biochemistry 218 (2021) 111360
Contents lists available at ScienceDirect
Journal of Inorganic Biochemistry
journal homepage: www.elsevier.com/locate/jinorgbio
Diverse and unexpected outcomes from oxidation of the platinum(II)
anticancer agent [Pt{(p-BrC6F4)NCH2CH2NEt2}Cl(py)] by
hydrogen peroxide
,
,
Ruchika Ojhaa, Dayna Masona, Craig M. Forsytha, Glen B. Deacona *, Peter C. Junkb *, Alan
,
*
M. Bonda
a School of Chemistry, Monash University, Clayton 3800, VIC, Australia
b College of Science & Engineering, James Cook University, Townsville, Qld 4811, Australia
A R T I C L E I N F O
A B S T R A C T
Keywords:
Oxidation of the anti-tumour agent [Pt{(p-BrC6F4)NCH2CH2NEt2}Cl(py)], 1 (py = pyridine) with hydrogen
peroxide under a variety of conditions yields a range of organoenamineamidoplatinum(II) compounds [Pt{(p-
BrC6F4)NCH=C(X)NEt2}Cl(py)] (X = H, Cl, Br) as well as species with shared occupancy involving H, Cl and Br.
Thus, oxidation of the –CH2–CH2– backbone (dehydrogenation) occurs, often accompanied by substitution.
Oxidation of 1 with H2O2 in acetone yielded 1:1 co-crystallized [Pt{(p-BrC6F4)NCH=CHNEt2}Cl(py)], 1H and [Pt
{(p-BrC6F4)NCH=C(Cl)NEt2}Cl(py)], 1Cl. The former was obtained pure in low yield from the oxidation of 1
with (NH4)2[Ce(NO3)6] in acetone, and the latter was obtained from 1 and H2O2 in CH2Cl2 at near reflux. From
the latter reaction under vigorous refluxing [Pt{(p-BrC6F4)NCH=C(Br)NEt2}Cl(py)], 1Br was isolated. In
Platinum anti-tumour agents
Oxidation
Hydrogen peroxide
Oxidation of the ligand
Br liberation
Olefinic substitution
refluxing acetonitrile, oxidation of
1 with H2O2 yielded [Pt{(p-BrC6F4)NCH=C(H0.25Br0.75)NEt2}Cl(py)],
1H0.25Br0.75, in which the alkene is mainly substituted by Br in a dual occupancy. Treatment of 1 with H2O2 and
tetrabutylammonium hydroxide in acetone at room temperature formed [Pt{(p-HC6F4)NCH2CH2NEt2}Cl(py)], 2.
Oxidation of [Pt{(p-HC6F4)NCH2CH2NEt2}Br(py)], 3 with H2O2 in boiling acetonitrile gave the ligand oxidation
product [Pt{(p-HC6F4)NCH=C(Br)NEt2}Br(py)], 3Br. All major products were identified by X-ray crystallog-
raphy as well as by 1H and 19F NMR spectra. In cases of mixed crystals or dual occupancy compounds, the 19F and
1H NMR spectra showed dissociation into the components in the solution in the same proportions as in isolated
crystalline material.
1. Introduction
effects and to expand their usage against a wider range of tumours
elaborated the area of research beyond structure-activity rules (SAR)
Today almost 50% of the cancer patients who receive chemotherapy
are treated with platinum anticancer drugs [1]. Despite the success
[2–7], clinically used Pt anticancer drugs exhibit intrinsic or acquired
resistance [8,9] and side effects such as nephrotoxicity, neurotoxicity
and myelosuppression [8–15]. Besides, only 1% of cisplatin forms ad-
ducts with DNA after its intravenous administration, while most react
with other biomolecules [16]. Eventually, these metal-based anticancer
drugs can disturb the cellular redox homeostasis [17,18] and this
perturbation is related to side effects like nephrotoxicity and resistance
of cisplatin [19,20]. Several reports have investigated the effect of
platinum(II) drugs on redox homeostasis of cancer cells [21–25].
Eventually, after intensive research [26–28], the need to reduce side
[29]. This broader platform introduced “rule breaker” [30] or “non-
traditional” drugs [31] which violate the previously established
structure-activity rules [29]. The polynuclear platinum compound
BBR3464 is one such compound [32–34]. Amongst the “rule breakers”
are two classes of organoamidoplatinum(II) compounds, namely Class 1,
[Pt{N(R)CH2}2(py)2] (R = polyfluoroaryl) with no H atoms on the N-
donor atoms and Class 2, trans-[Pt{N(R)CH2CH2NR’2}X(py)] (R = pol-
yfluoroaryl; R’ = Et, Me; and X = Cl, Br, I) with trans amine ligands and
trans anionic ligands, and no H atoms on the N-donor atoms (see Fig. 1).
Both classes have shown anticancer activity in vitro and in vivo [35,36].
To this stage, Class 1 has the greater activity, and is more developed.
Recently, the leading compound [Pt{((p-HC6F4)NCH2)2}(py)2], (Pt103)
* Corresponding authors.
E-mail addresses: glen.deacon@monash.edu (G.B. Deacon), peter.junk@jcu.edu.au (P.C. Junk), alan.bond@monash.edu (A.M. Bond).
https://doi.org/10.1016/j.jinorgbio.2021.111360
Received 16 August 2020; Received in revised form 17 January 2021; Accepted 17 January 2021
Available online 5 February 2021
0162-0134/© 2021 Elsevier Inc. All rights reserved.

R. Ojha et al.
Journal of Inorganic Biochemistry 218 (2021) 111360
have turned to chemical oxidation to further illuminate the redox
properties of the Class 2 compounds.
Here we report the chemical oxidation of the Class 2 complexes trans-
[Pt{(p-BrC6F4)NCH2CH2NEt2}Cl(py)] [53], 1 (including the formation
of trans-[Pt{(p-HC6F4)NCH2CH2NEt2}Cl(py)], 2) and trans-[Pt{(p-
HC6F4)NCH2CH2NEt2}Br(py)], 3 [55]. These reactions lead to oxidation
of the ligand giving organoenamineamidoplatinum(II) compounds
including complexes with substitution of the olefinic moiety, by Cl or Br
(Scheme 1) rather than PtIV derivatives. The antiproliferative activity of
1 in two cell lines was compared with that of trans-[Pt{p-BrC6F4)
NCH2CH2NEt2}I(py)] 4.
2. Results and discussion
To determine if isolable compounds could be obtained by chemical
oxidation of Class 2 compounds, reactions of the organoamidoplatinum
(II) complex trans-[Pt{(p-BrC6F4)NCH2CH2NEt2}(Cl)(py)] 1, were un-
dertaken with hydrogen peroxide at various temperatures and in
different solvents. In this case, rather than PtIV derivatives, organo-
enamineamidoplatinum(II) complexes with oxidised ligand e.g., 1H,
1Cl, and 1Br were obtained as shown in Table 1 and Scheme 1 for
compound 1.
Fig. 1. Class 1 and Class 2 organoamidoplatinum(II) compounds.
been shown by atomic telemetry and multiscale molecular dynamics to
initially bind to adenine rather than guanine, thus explaining some of its
unique properties [37]. Binding of the compound to DNA has been
detected through attenuated total reflection Fourier transform infrared
(ATR-FTIR) spectroscopy [38] and it has been located in a metaphase
chromosome by atomic force microscopy-based infrared (AFM-IR)
spectroscopy coupled with principal component analysis (PCA) [39].
The leading compound has been converted by photochemical substitu-
tion into [Pt{(p-HC6F4)NCH2CH2NH(p-HC6F4)}(py)(O2CR)], (R = C6F5
or 2,4,6-Me3C6H2) which can be viewed as intermediate between Class 1
and Class 2. These compounds have shown activity against A2780 and
A2780/R ovarian cancer cells with the change being detected by ATR-
FTIR spectroscopy [40] and the interactions with DNA have also been
detected by ATR-FTIR spectroscopy combined with principal component
analysis [41].
The products are PtII complexes following oxidation of the
–CH2–CH2– backbone to –CH=CH– and also with halogenation to
–CH=CX– (X = Cl or Br). Oxidation involves double (sp3) C–H bond
activation causing dehydrogenation, which then leads to concomitant
C=C formation on the backbone of the coordinated ligand. All organo-
enamineamidoplatinum(II) complexes discussed have trans geometry
with the two neutral amine ligands trans to each other as are also the two
anionic ligands, amide and chloride, as shown in Scheme 1.
The outcome of these oxidation reactions depends on the experi-
mental conditions chosen, as summarized in Scheme 2 and discussed
below.
Most reactions gave mixtures of products requiring detailed frac-
tional crystallisation to obtain pure products. In Table 1 are listed the
outcomes of oxidation of 1 under a variety of conditions in different
solvents. The outcomes were further complicated by co-crystallisation of
products and by isolation of products with two substituents disordered
at position Z (Scheme 1) on the –CH=C(Z)– backbone. In the cases of
mixed occupancies, the ratio of the substituents was established by X-ray
crystallography, and dissociation occurred into the individual compo-
nents in solution in the same ratio as determined by X-ray analysis. Thus
1H0.25Br0.75 in solution gave 1H and 1Br in a 1:3 ratio.
The redox chemistry of PtII anticancer compounds is important to
comprehend their reactivity in terms of generating PtIV compounds
[42,43]. These are also of biological interest because they are more inert
than PtII species and thus more likely to reach targets without side re-
actions [49,50] and may be more lipophilic. The chemical oxidation
oxidation of the Class 1 leading compound [Pt{((p-HC6F4)NCH2)2}
(py)2], (Pt103) gave biologically active PtIV complexes [Pt{((p-HC6F4)
NCH2)2}(py)2Cl2], (Pt103Cl2) [Pt{((p-HC6F4)NCH2)2}(py)2(Cl)OH],
(Pt103(Cl)OH) and [Pt{((p-HC6F4)NCH2)2}(py)2(OH)2], (Pt103(OH)2),
all active in vitro. The last two were more active in vivo than the PtII
precursor, Pt103, when delivered in peanut oil [44,45]. The most
exciting biological results were obtained for Pt103(OH)2 which was
prepared by oxidation of Pt103 with hydrogen peroxide, thus raising our
interest in what might be obtained by oxidation of Class 2 complexes
with the same oxidant. Even though hydrogen peroxide is a strong
oxidant, it has been extensively used for the oxidation of platinum(II)
anticancer agents to less toxic platinum(IV) derivatives [42,44,46–50].
Redox understanding may be relevant to their mode of intracellular
action, as in the presence of ROS including H2O2 in the cell, intracellular
oxidation of PtII compounds may occur [51,52].
A more detailed schematic representation of the oxidation pathways
is given in Scheme S1. Prolonged oxidation of 1 with an excess of H2O2
in warm acetone yields co-crystallized trans-[Pt{(p-BrC6F4)
NCH=CHNEt2}Cl(py)], 1H and trans-[Pt{(p-BrC6F4)NCH=C(Cl)NEt2}Cl
(py)], 1Cl (1:1 ratio) in moderate yields on crystallisation from the re-
action mixture and also from the crystallisation of additional oily
product from acetone/hexane (see experimental). Attempted separation
of 1H and 1Cl from the oil by chromatography resulted in a few crystals
of [Pt{(p-BrC6F4)NCH=CH0.25Br0.75NEt2}Cl(py)], 1H0.25Br0.75. A pure
sample of 1H was obtained in low yield from the oxidation of 1 with
(NH4)2[Ce(NO3)6] in acetone. The chlorine substituent of 1Cl (Z = Cl) at
least in acetone, has to be derived from the Pt–Cl bond. Consumption of
the complex in supplying Cl or Br limits the possible yields of 1Cl and
1Br to ≤50%. From oxidation of 1 with H2O2 in CH2Cl2, pure 1Cl was
obtained in reasonable yield. In the synthesis of 1Cl, there is a possible
alternative source of Cl besides PtCl, namely the solvent. However, a
higher H2O2 to 1 ratio (see entry 2 vs entry 4 in Table 1) with vigorous
conditions and longer reaction time did not increase the yield of 1Cl and
instead gave 1Br in moderate yield (see Scheme 2), hence the solvent is
unlikely to be the chloride source. There was the concomitant formation
of a trace of [Pt{(p-BrC6F4)NCH=CCl0.5Br0.5NEt2}Cl(py)], 1Cl0.5Br0.5
when a higher H2O2 to 1 ratio was used with moderate heating. The use
of acetonitrile gave a low yield of 1H0.25Br0.75 with some free pro-ligand
We have already examined the electrochemical oxidation of the Class
2 compounds trans-[Pt{(p-BrC6F4)NCH2CH2NEt2}(Cl)(py)], 1 [53] and
trans-[Pt{(p-HC6F4)NCH2CH2NEt2}(Cl)(py)],
2 [54] and generated
moderately stable formally PtIII monomeric species (formal reversible
potentials: 180 ± 10 mV and 125 ± 5 mV vs Fc0/+ (Fc = Ferrocene)
respectively for PtII/III process), although substantial delocalisation of
spin density onto the ligand system is observed [53,54]. Interestingly, no
PtIV species were formed by electrochemical oxidation of this Class in
inert dichloromethane media. Because of this and as we were unable to
isolate or identify the product of the decay of the formal PtIII species, we
2

R. Ojha et al.
Journal of Inorganic Biochemistry 218 (2021) 111360
Scheme 1. Oxidation of 1 and 3 with hydrogen peroxide or CeIV give organoenamineamidoplatinum(II) compounds.
Table 1
Quantities of reagents and product yields (crystalline) for the oxidation of 1 and 3 with 30% hydrogen peroxide.
Entry No.
Compound
H2O2 (mmol)
Solvent
Temp and reaction time
Products and yields
a
1
1 (0.20 mmol)
5.00
CH3COCH3
9 h Δ at 50 ◦C over 2 d
(1H þ 1Cl)b = 33%;
1H0.25Br0.75 = 3%
1Cl = 39%
a
2
3
4
1 (0.34 mmol)
1 (0.20 mmol)
1 (0.20 mmol)
8.00
10.0
10.0
CH2Cl2
CH2Cl2
CH2Cl2
14 h Δ at 25–30 ◦C over 4 d
a
10 h Δ at 35–40 ◦
C
c over 3 d
1Br = 31%
a
10 h Δ at 30–35 ◦C over 2 d
1Cl = 34%;
b, d
(1Cl0.5Br0.5
)
a
5
6
1 (0.20 mmol)
1 (0.50 mmol)
3 (0.66 mmol)
10.0
CH3CN
10 h Δ at 75–82 ◦
C
c over 2 d
1H0.25Br0.75 = 7%;
free pro-ligand d
2 = 10%
1.00
CH3COCH3
CH3CN
4 h a at 40–50 ◦
C
c over 4 d
+ 40% NBu4OH (1.0 mmol)
7
a
b
c
10.0
7 h a at 60 ◦
C
c over 1 d
3Br = 22%
during the rest of the reaction time (shown in days) the solution was stirred at RT (23 ◦C).
co-crystallized in 1:1 ratio.
reflux.
d
yields could not be calculated due to the presence of oily material.
{(p-BrC6F4)NHCH2CH2NEt2}(see experimental). The crystallisation of
C–H bond activation (dehydrogenation) and concomitant C=C forma-
tion on the backbone of the coordinated ligand. The oxidation of the
–CH2–CH2– backbone to –CH=CH– by H2O2 is likely to be a radical
reaction under the conditions used. Formation of Cl2 or Br2 from the
oxidation of –Pt–Cl (in 1) or –Pt–Br (in 3) bonds and oxidative removal
of bromine from the p-BrC6F4 group (i.e., Br liberation from 1) are
considered to be followed by radical halogenation of –CH=CH– to give
–CHZ–CHZ– (Z = Cl or Br), which undergoes dehydrohalogenation to
the observed –CH=CZ– species. The direction of the elimination sug-
gests a radical process, as a polar dehydrohalogenation might be ex-
pected to give an isomer with the halogen adjacent to the fluorocarbon
group (cf 1Cl and 1Br) owing to the greater acidity of p-BrC6F4N–CHZ
than –CHZNEt2.
the mixed occupancy product is clearly favoured as it has been obtained
from two different reactions as shown in Table 1.
The compounds obtained with Z = Br substituents require Br liber-
ation from the substrate during chemical oxidation with hydrogen
peroxide. Evidently, the Br substituent is replaced by an H substituent at
the para position of the polyfluoroaryl ring, giving trans-[Pt{(p-HC6F4)
NCH2CH2NEt2}Cl(py)] 2. The (p-HC6F4) resonance can be seen between
5.8 and 6.0 ppm as a multiplet in the 1H NMR spectrum of crude
products when 1Br, 1H0.25Br0.75 and 1Cl0.5Br0.5 are obtained in various
reactions (Fig. S21). Occasionally, a broad resonance at 5.5 ppm was
observed in the 1H NMR spectrum of reaction mixtures after Br libera-
tion, the origin of which could be the presence of an –OH group on the Pt
metal center as a replacement for the liberated Cl ligand in [Pt{(p-
BrC6F4)NCH2CH2NEt2}(OH)(py)] (see Scheme 3 and Fig. S22). Pure
trans-[Pt{(p-HC6F4)NCH2CH2NEt2}Cl(py)] (2) with the p-H substituent
(Y = H) was isolated from the hydrogen peroxide oxidation of 1 in the
presence of the base, tetrabutylammonium hydroxide, confirming the
lability of the Y = Br substituent.
Unusual transformations of coordinated ligands at transition metal
centres have attracted attention in organometallic chemistry due to their
use in metal-directed organic synthesis [56,57]. Organozinc-enamines
and organoaluminium-enamines with similar oxidised ligands have
been reported in the early 1980s where organozinc-enamines were
synthesised by the reaction of 1,4-diaza-1,3-butadiene with Et2Zn and
organoaluminum-enamines were the products of the subsequent trans-
metallation with Et3Al [57,58]. The transformation of the saturated
ethylenediamine to dianionic unsaturated diazaethene by dehydroge-
nation, that is a –CH2–CH2– backbone to –CH=CH–, has been reported in
the reaction of N,N′-diisopropylethylenediamine with a reaction
Oxidation of trans- [Pt{(p-HC6F4)NCH2CH2NEt2}Br(py)], 3 [55] with
a 15 fold excess of 30% H2O2 in acetonitrile with heating at 60 ◦C gave
trans- [Pt{(p-HC6F4)NCH=C(Br)NEt2}Br(py)], 3Br (Table 1) with the Br
substituent derived from Pt bound bromo substituent (see Scheme 3).
The formation of ligand-oxidised PtII species involves double (sp3)
3

R. Ojha et al.
Journal of Inorganic Biochemistry 218 (2021) 111360
Scheme 2. Oxidation of 1 with H2O2 and (NH4)2[Ce(NO3)6] under designated conditions. (For interpretation of the references to colour in this figure legend, the
reader is referred to the web version of this article.)
mixture containing nBuLi and tBu2Zn (or Me2Zn) [59]. Analogous
chelated diamido ligands coordinated to transition metals or lanthanoid
metals are also known as catalysts and were obtained from the 1,4-diaza-
1,3-diene (DAD) ligand system. For example Veith has reported a dia-
nionic enediamido complex 1,3-diaza-2-silacyclopentene which can
only be formed by using a high concentration of nBuLi in a reaction with
tBuN(H)CH2CH2N(H)tBu and Cl2Si(Me)N(H)tBu [60], whereas a lower
concentration of nBuLi gives [Si{tBuNCH2CH2NtBu}(CH3)(N(H)tBu)],
the saturated analogue (see Scheme 4) [61].
2.1. Characterization
The molecular structures of the products 1H, 1Cl and 3Br isolated
from the chemical oxidation reactions of 1 and 3 are shown in Fig. 2 and
the crystal structures in Fig. S1. Bond lengths and bond angles of all the
oxidised complexes are given in Table 2 and Table S1 respectively.
Crystal and refinement data are presented in Table 5. The crystallisation
of the organoenamineamidoplatinum complex, trans-[Pt{(p-BrC6F4)
NCH=CHNEt2}Cl(py)], 1H is challenging as 1H can co-crystallise with
4

R. Ojha et al.
Journal of Inorganic Biochemistry 218 (2021) 111360
Scheme 3. Oxidation of 1 and 3 with an excess of 30% hydrogen peroxide.
Scheme 4. Veith’s reaction of tBuN(H)CH2CH2N(H)tBu with nBuLi and trapping with a dichlorosilane [60,61].
Fig. 2. Molecular structures of 1H, 1Cl, and 3Br showing 50% thermal ellipsoids. (For interpretation of the references to colour in this figure legend, the reader is
referred to the web version of this article.)
5

R. Ojha et al.
Journal of Inorganic Biochemistry 218 (2021) 111360
Table 2
Selected bond lengths for compounds 1H, 1Cl, 1H0.25Br0.75, 1Cl0.5Br0.5, and 3Br.
Bond
Pt-X
1H (Å)
17H17BrClF4N3Pt
1Cl (Å)
1H0.25Br0.75 (Å)
17H16.25Br1.75ClF4N3Pt
1Cl0.5Br0.5 (Å)
17H16Br1.5Cl1.5F4N3Pt
3Br*(Å)
C
C17H16BrCl2F4N3Pt
C
C
C17H17Br2F4N3Pt
2.325 (5), (X = Cl)
2.3236 (11), (X = Cl)
2.3172 (11), (X = Cl)
2.3107(14), (X = Cl)
2.4404 (10) - 2.4458 (10),
(X = Br)
Pt-N1(amide)
Pt-N2(amine)
Pt-N3(py)
2.021 (16)
2.074 (15)
2.019 (15)
1.40 (2)
2.028 (4)
2.022 (4)
2.033 (5)
2.012 (7) - 2.020 (7)
2.085 (8) - 2.110 (7)
2.003 (7) - 2.023 (8)
1.383 (11) - 1.395 (10)
1.321(13) - 1.352 (14)
(X = Br), 1.895 (9) - 1.916 (9)
1.348 (13) - 1.390 (12)
1.441(12) - 1.448 (12)
1.505 (13) - 1.519 (11)
1.441 (12) - 1.535 (11)
2.084 (4)
2.085 (4)
2.092 (5)
2.013 (4)
2.013 (4)
2.017 (5)
N1(amide)-C6F4
C7-C8
1.386 (6)
1.384 (5)
1.376 (7)
1.32 (3)
1.337 (7)
1.328 (6)
1.347 (8)
C8-X
(X = H), 0.950
1.35 (3)
(X = Cl), 1.764 (5)
1.387 (6)
(X = Br), 1.854 (4)
1.383 (5)
(X = Br), 1.871 (6)
1.379 (7)
N1(amide)-C7
N2(amine)-C8
N2(amine)-C9(Et)
N2(amine)-C11(Et)
1.48 (3)
1.457 (6)
1.454 (6)
1.452 (7)
1.51 (3)
1.511 (6)
1.508 (6)
1.509 (7)
1.47 (3)
1.518 (6)
1.515 (5)
1.517 (7)
*
The asymmetric unit of 3Br contains 4 molecules, hence the range of the bond lengths for each bond is provided here.
trans-[Pt{(p-BrC6F4)NCH=C(Cl)NEt2}Cl(py)], 1Cl to give 1H þ 1Cl or
have shared occupancy with Br as in 1H0.25Br0.75 (Fig. S1). However,
crystals of pure 1H were isolated in low yield from the oxidation of 1
(NH4)2[Ce(NO3)6] (Fig. 2).
The distinct feature of the organoenamineamide complexes is the
presence of a double bond which is unsubstituted in 1H but is
substituted by a halogen in 1Cl, 1Cl0.5Br0.5, 1H0.25Br0.75 and 3Br, in the
NCCN ligand backbone. In all cases, the halogen is located on C8,
adjacent to –NEt2 (Fig. 2 and Fig. S1). In other aspects, these structures
are similar to those of the parent reactants 1 [53], and 3 [55]. The C=C
bond lengths in the oxidation products are in the range 1.32(3) to 1.347
(8) Å (Table 2). This corresponds to a typical ethene bond length of 1.34
Å [62] and much longer than the C–C backbone in 1 1.5177(3) Å [53]. In
addition the relevant angles around backbone carbons 7 and 8 are ca.
120◦ (Table S1). Like Class 2 organoamidoplatinum(II) compounds 1–3
[53–55], the organoenamineamidoplatinum(II) complexes have square-
planar stereochemistry with a trans orientation of the donor atoms of
like charges e.g., pyridine is trans to –NEt2 and the amido nitrogen is
trans to the chlorido ligand. The Pt–N2(amine) and Pt-N3(py) bond
lengths are similar to those for the parent compounds when 3 esds are
taken into account. However, a slight lengthening of the Pt-N1(amide)
bond in some cases and a slight shortening of the Pt–Cl bond were
observed (see Table 2). The bond angles around the Pt metal are almost
90◦ and the smallest ≈ 84.08◦ is affected by the bite angle of the
chelating ligand. These bond angles are comparable to those of the
parent compound 1 [53] and with 3 [55]. The bond angle sum around
the amide N in 1H (357◦), 1Cl (355.3◦) and in 1H0.25Br0.75 (355.4◦),
∑
diverge considerably from tetrahedral ( 328.5◦) towards triangular
∑
(120◦ 360◦). The polyfluoroaryl ring is inclined at an angle of 53.60◦
(1H), 55.06◦ (1Cl), 55.49◦ (1H0.25Br0.75) and 61.14◦ (3Br) to the co-
ordination plane PtN(1)N(2)N(3)Cl, in order to reduce steric hindrance
(see Fig. 3), similar to that found with the parent compounds 1 [53] and
3 [55]. This inclined arrangement restricts the delocalisation of the lone
pair of the amide N into the polyfluoroaryl ring by resonance, although,
considerable inductive delocalisation of electron density is possible due
to the presence of electron-withdrawing F atoms in the ring. In almost all
the complexes (Fig. 2), the effect of inductive delocalisation is reflected
in the bond length of N(amide)-C(C6F4) ≈ 1.376(7) -1.40(2) Å (Table 2),
which is close to an aromatic bond length [63].
Fig. 3. Twisting of the pyridine and polyfluoroaryl ring planes from the coor-
dination plane in 1Cl. (For interpretation of the references to colour in this
figure legend, the reader is referred to the web version of this article.)
agostic interactions for selected compounds are presented in Table S2.
The distances are generally within the sum of the Pt and H or C van der
Waals radii (2.92 and 3.42 Å, respectively) [64,65].
As observed in Class 2 complexes, a range of supramolecular in-
teractions has been observed in the solid-state of organo-
enamineamidoplatinum(II) complexes. Intermolecular H-bonding forms
In comparison with Class 2 organoamidoplatinum(II) complexes
[53–55], the bond length of N1(amide)-C7, 1.387(6) Å is shorter than a
typical C–N bond 1.47 Å (in the parent compound 1 N1-C7 = 1.463 (4)
Å) [53] and closer to that of an aromatic bond length. These features
imply that a delocalisation across C6N1C7C8 is present in these oxidised
a 2D sheet and π-π interactions between the aromatic rings of these 2D
sheets altogether create a 3D network. For example, in 1H, both m-Fs of
the polyfluoroaryl ring make H-bonds with (F2⋯o-H(py) and F3⋯H
(CH2) (2.398(14) Å and 2.448(11) Å respectively) with two other mol-
ecules. In addition, o-F exhibits H-bonding (F4⋯o-H(py) and F4⋯m-H
(py) at 2.654(11) Å and 2.662(12) Å respectively with one pyridine of
another molecule creating a 2D sheet as shown in the Figs. S2-S6.
Additional H-bonding such as Br⋯H(C=C) (3.053(2) Å) and Cl⋯H(CH3)
(2.998(5) Å) further supports the structure. Intramolecular H-bonding
PtII complexes. In the case of complexes 1H0.25Br0.75 and 1Cl0.5Br0.5
,
there is a shared occupancy of substituents attached to C8.
As in the case with parent Class 2 complexes [54], enamineamido-
platinum(II) complexes have a ‘W’ arrangement of the ethyl groups on
the chelating ligand due to agostic interactions. Distances and angles for
6

R. Ojha et al.
Journal of Inorganic Biochemistry 218 (2021) 111360
between F1⋯H(CH3) with a bond distance of 3.446(12) Å is also
observed.
observations confirm that oxidation of the organoamide ligand has
occurred. As pyridine has a greater trans-influence than the halide li-
gands [67,68], the smaller coupling (34 Hz) is expected to be shown by
the H attached on the carbon trans to pyridine, namely HCNEt2, whereas
the resonance with a platinum-proton coupling constant of 50 Hz is
assigned to HCN(p-BrC6F4) that is trans to chlorine. Also, HCN(p-BrC6F4)
is at a higher frequency than HCNEt2, owing to deshielding of the C–H
bond of HCN(p-BrC6F4) by the electron-withdrawing polyfluoroaryl
group and the multiplicity of these resonances (see above) also supports
these assignments.
In contrast to 1 [53,66], oxidation and dehydrogenation of the
backbone of the coordinated ligand allowed π-π interactions for both
pyridine and the polyfluoroaryl rings in 1H in spite of the presence of
bulky Br in polyfluoroaryl ring (Fig. S3 and Table S3). Interactions
π-π
between the planes of polyfluoroaryl rings (with inter-planar angle:
0.00◦; inter-planar distance: 3.334 Å; inter-centroid distance: 3.809 Å)
and between the planes of pyridines (with inter-planar angle: 0.00◦;
inter-planar distance: 3.278 Å; inter-centroid distance: 3.653 Å) exist
which are offset by 1.61 Å for pyridine rings and 1.77 Å for poly-
In 1Cl, with a chloro substituted backbone, no HCNEt2 resonance is
observed but the 1H resonance of HCN(p-BrC6F4) appears near 6.6 ppm
which is at a higher frequency than in 1H owing to the presence of the
adjacent chlorido substituent. This signal at 6.6 ppm appears as two
separate triplets with combined integration of one proton and each
shows platinum satellites with a platinum-proton coupling constant of
40 Hz (see Fig. 4). The presence of two triplets is unexpected. A two
dimensional NMR spectrum showed that these two triplets are associ-
ated with two different C atoms in similar environments, hence overall
ruling out an assignment as a doublet of triplets. A possible explanation,
suggested by a referee, is that the two triplets, of total integration 1H,
may arise from the presence of two isomers (termed I1 and I2 in the
experimental section) owing to interchange of py and Cl ligands in so-
lution. The 1:1 ratio of these is temperature independent (as observed in
variable temperature 1H NMR studies (Fig. S14-S16); the details are
provided in the supporting information). Two barely resolved reso-
nances in the 195Pt NMR spectrum of 1Cl are consistent with the pres-
ence of two similar isomers in solution (Fig. S13).
fluoroaryl rings (Fig. S3 and Table S3). These
π-π interactions are
further supported by (py) m-H⋯Cl(Pt), 2.871(5) Å for pyridine rings and
by various F⋯H and Br┄H interactions for polyfluoroaryl rings as shown
in Fig. S3. A discussion of supramolecular interactions in other products
is given in the Supporting information.
We have also determined the crystal structure of [Pt{(p-BrC6F4)
NCH2CH2NEt2}I(py)], 4, which is isostructural with 1. The crystal
structure is shown in Fig. S23 with accompanying bond distances and
angles in Table S5. These are as expected with Pt–I bond length 2.6287
(7) Å suitably greater than Pt–Cl 2.3441(10) Å of 1. However, the crystal
packing of 4 is not the same as in 1 and only one of the two ethyl groups
shows agostic interaction. A detailed discussion is provided in sup-
porting information (Section 5) and illustrated in Fig. S23.
Satisfactory microanalyses were obtained for all complexes, except
for 1H where the low yield limited identification to NMR spectra and a
high-resolution mass spectrum.
All oxidised complexes were characterised by accurate mass pro-
tonated molecular ions (M + H)+. Interestingly, the protonated molec-
ular ion (M + H)+ of the starting material (1) was detected under low-
resolution mass spectral conditions even though 1 was not detected in
1H and 19F NMR spectra. This behaviour suggests that 1 forms under the
conditions of obtaining low-resolution mass spectra. However, 1 was not
detected in the accurate mass spectra. The difference is attributed to
different conditions when determining the different mass spectra (see
experimental section).
Notably, the molecular structure of 1Cl has a delocalised C8C7N1C6
system (Fig. 2 and Table 2) with potential double bond character of the
N1 C6 bond. In the parent compound 1, (p-BrC6F4)NCH2 coupling with F
of the polyfluoroaryl ring is unresolved but in 1Cl, due to the presence of
a delocalised C8C7N1C6 system, (p-BrC6F4)NCH, F coupling is resolved.
The methylene groups of the –NCH2Me in 1H and 1Cl give two signals as
observed for the parent compound 1 [53] owing to the diastereotopic
nature of the methylene protons.
The most characteristic IR band for enamineamidoplatinum(II)
complexes is the stretching (aliphatic) C=C vibration, which is evident
in the 1645–1670 cmꢀ 1 region. 1H shows this C=C stretching band at
1660 cmꢀ 1, whereas for the halogenated organoenamineamide com-
plexes, it appears at 1644–1654 cmꢀ 1. A comparison of IR data for the
PtII precursor 1 and 1H is provided in Fig. S7. Table 3 summarises C=C
stretching data for the complexes with a different substituent at C8, H in
2.2. Biological testing
The low yields and difficult syntheses of 1H, 1Cl and 1Br make them
unattractive to pursue for biological testing and large scale syntheses
would generate considerable toxic waste. However, although a consid-
erable number of Class 2 compounds have been tested for anti-tumour
activity in vitro and some in vivo [36], 1 was not examined. We have
now tested this compound together with the iodidoplatinum(II)
analogue, [Pt{(p-BrC6F4)NCH2CH2NEt2}I(py)] 4 against HT-29 colon
carcinoma cells and the MCF-7 breast adenocarcinoma cells. The IC50
values (concentration that causes 50% inhibition of the cell prolifera-
tion) for 1 and 4 are summarized in Table 4.
1H, Cl in 1Cl, Br in 1Br and H0.5/Cl0.5 in 1H þ 1Cl. Strong ν(C–F) ab-
sorption bands appear at comparatively higher wavenumber of 972
cmꢀ 1 (1H), 969 cmꢀ 1 (1Cl) and 972 cmꢀ 1 (1H þ 1Cl) than in the
platinum(II) precursor 1 at 956 cmꢀ 1
.
The 19F NMR resonances of the enamineamidoplatinum(II) com-
plexes (1H–1H0.25Br0.75) appear at a higher frequency, (approximately
3 ppm) relative to the parent compound 1.
The activity of 1 was comparable with that of cisplatin in both cell
lines. However 4 is 7–20 times more active than cisplatin and warrants
further examination. The increase in activity is in line with complex
stability wherein iodidoplatinum compounds are more stable than
chlorido complexes. This trend was noted with other Class 2 complexes
previously though in a different testing regime (L1210 and L1210DDP
mouse leukaemia cells) [36]. Thus while the oxidation products are
unlikely to be explored further, the parent Class 2 organoamides still are
of interest.
Comparison of the 1H NMR spectrum of 1H with that of 1 shows two
new resonances attributable to HC=CH at around 6.07 (multiplet owing
to coupling with ring fluorines in addition to H, H coupling, see Fig. 4)
and 3.75 ppm (doublet from coupling with the other alkenyl proton)
with large platinum‑hydrogen coupling constants, 50Hz and 34Hz
respectively, and the backbone CH2 resonances of 1 are absent. These
Table 3
Comparison of C=C stretching (aliphatic) IR vibration data for 1H, 1Cl, 1Br and
3. Conclusion
1H þ 1Cl.
C-X bond
C=C str (aliphatic) cmꢀ 1
Compound
The generation of organoenamineamidoplatinum(II) compounds by
chemical oxidation of trans-[Pt{(p-BrC6F4)NCH2CH2NEt2}Cl(py)], 1 and
trans-[Pt{(p-HC6F4)NCH2CH2NEt2}Br(py)], 3 with hydrogen peroxide is
reported. Trans-[Pt{(p-BrC6F4)NCH=CHNEt2}Cl(py)], 1H was obtained
in pure form by oxidation of 1 with ceric ammonium nitrate (CAN,
HC=C(H)
1660
1654
1645
1646
1H
HC=C(Cl)
1Cl
HC=C(Br)
1Br
HC=C(H0.5Cl0.5
)
1H þ 1Cl
7

R. Ojha et al.
Journal of Inorganic Biochemistry 218 (2021) 111360
Fig. 4. 1H spectra of 1H (
) and 1Cl (
) showing resonances due to (p-BrC6F4)NCH. (For interpretation of the references to colour in this figure legend, the
reader is referred to the web version of this article.)
BrC6F4)NCH=C(Br)NEt2}Cl(py)], 1Br was generated. Overall, this study
expands the scope of oxidation of PtII anticancer agents by introducing
oxidation of the coordinated ligand. It may provide a tool to modify
other platinum(II) anticancer agents to alter their biological activity. It
is possible that ligand oxidation is the route by which the formally PtIII
.species generated via electrochemical oxidation of 1 and 2, decompose.
In vitro activity of 1 and 4 against two cell lines shows the former to be
comparable with cisplatin, whilst the latter is much more active.
Table 4
IC50 values obtained from in vitro biological testing of Class 2 organo-
amidoplatinum(II) complexes 1 and 4.
Compound
HT-29*
IC50 M]
MCF-7#
[
μ
IC50[μM]
[Pt{(p-BrC6F4)NCH2CH2NEt2}Cl(py)] 1
5.57 (±0.45)
0.35 (±0.12)
3.07 (±0.55)
0.30 (±0.03)
[Pt{(p-BrC6F4)NCH2CH2NEt2}I(py)] [69]
4
Cisplatin
7.0
2.0
*
4. Experimental
HT-29: Human Colon Carcinoma Cells, (not cisplatin-resistant).
MCF-7: Human Breast Adenocarcinoma Cells (not cisplatin-resistant).
#
4.1. Materials
(NH4)2[Ce(NO3)6]) but it co-crystallized with trans- [Pt{(p-BrC6F4)
NCH=C(Cl)NEt2}Cl(py)], 1Cl in 1:1 ratio when oxidation of 1 was un-
dertaken with H2O2 in acetone. Pure 1Cl was obtained from 1 and H2O2
in CH2Cl2 at near reflux, whereas vigorous refluxing led to the liberation
of the Br substituent from the polyfluoroaryl ring and trans-[Pt{(p-
The following compounds were used as received: acetone (BDH),
dichloromethane, acetonitrile (Aldrich), ethyl acetate and n-hexane
(HPLC grade); hydrogen peroxide (30% solution in water) (Merck) was
stored at ꢀ 4 ◦C; MnO2, NBu4Cl, LiCl and (NH4)2[Ce(NO3)6] (Sigma
Aldrich); NBu4OH (40% in water) (Fluka).
Table 5
Crystallographic data for the molecular structures of 1H, 1Cl, 1H0.25Br0.75, co-crystallized 1H þ 1Cl, 1Cl0.5Br0.5 and 3Br.
1H
1Cl
1H0.25Br0.75
1H þ 1Cl
1Cl0.5Br0.5
3Br
Empirical formula
C17H17BrF4N3PtCl
649.78
C17H16BrF4N3PtCl2
684.22
C17H16.25Br1.75ClF4N3Pt
684.23
C34H33Br2Cl3F8N6Pt2
1334.01
Monoclinic
P21
C17H16Br1.5Cl1.5F4N3Pt
706.44
C17H17Br2F4N3Pt
694.24
Formula weight
Crystal system
Triclinic
P1
Monoclinic
P21/n
Monoclinic
P21/n
Monoclinic
P21/n
Triclinic
Space group
P-1
a (Å)
b (Å)
c (Å)
α◦
8.5390 (17)
10.613 (2)
10.846 (2)
82.03 (3)
85.47 (3)
87.28 (3)
969.7 (3)
2
6.9140 (14)
13.607 (3)
21.480 (4)
90
6.9450 (14)
13.617 (3)
21.552 (4)
90
8.5861 (3)
21.9443 (9)
10.5178 (4)
90
6.9200 (14)
13.609 (3)
21.496 (4)
90
7.45952 (16)
22.3980 (2)
24.4897 (2)
84.3586 (8)
86.3173 (13)
86.0205 (12)
4055.25 (10)
4
β◦
94.79 (3)
90
94.59 (3)◦
90
91.856 (2)
90
94.19 (3)
90
γ◦
Vol (Å3)
Z
2013.7 (7)
4
2031.6 (7)
4
1980.68 (13)
2
2019.0 (7)
4
ρ
μ
(calcd) (g/cm3)
2.225
2.2567
2.318
2.237
2.3240
2.274
(mmꢀ 1
)
9.477
9.260
10.523
9.348
10.159
17.962
F(000)
612.0
1282.6
1326.0
1256.0
1317.9
2592.0
Reflections collected/ unique
Rint
6,194/3,132
0.0466
18,512 /5,491
0.0467
18,811/5,599
0.0598
11,004/7,239
0.439
133,827/4,802
0.0508
82,783/16,825
0.1748
2θmax (◦)
50
61.4
63.372
52
55.84
153.942
Goodness-of-fit on F2
1.176
1.024
1.070
1.080
1.042
1.014
R1 indices [I ≥2
σ
(I)]
(I)]
0.0639
0.0383
0.0333
0.0577
0.0358
0.0674
wR2 indices [I ≥2
σ
0.1822
0.0985
0.0840
0.1219
0.0855
0.1671
8

R. Ojha et al.
Journal of Inorganic Biochemistry 218 (2021) 111360
4.2. Preparation of platinum reagents
such, the model suffers from pseudo symmetry effects which impact
upon the anisotropic displacement parameters and the bond distances.
Specifically, in the current model, the C–C, C–N and C–F distances of
pairs of atoms related by the pseudo-inversion centre have been
restrained to be the same. This essentially averages the two unrestrained
bond distances and hence improves the standard uncertainties of the
values. In particular, the unrestrained C(7)-C(8) and C(27)-C(28) dis-
tances were 1.29(3) Å and 1.34(3) Å, respectively. Notably, the four
atoms of the ethene backbone are all coplanar (max. Deviation 0.04(1) Å
at C(8)), indicative of the presence of a C=C (or a delocalised N-C-C-N)
system. The structure also was modelled in the centrosymmetric space
group P21/n as a single molecule with a partially occupied Cl position on
the ethene backbone. However, this resulted in a high R-value (>0.15)
and very poor refinement characteristics. The bond lengths and angles of
co-crystallized 1H þ 1Cl are similar to those for pure 1H and 1Cl given
in Tables 2 and S2. In the case of 3Br, the asymmetric unit contains 4
symmetric non-equivalent molecules with a slight difference in the bond
lengths. The crystals of 3Br were twinned and that could not be resolved.
The crystal data and the crystal structure of 4 are provided in the
Supporting information (Fig. S23).
Class 2 organoamidoplatinum(II) complexes, trans-[Pt{(p-BrC6F4)
NCH2CH2NEt2}Cl(py)] [53] (1), trans-[Pt{(p-HC6F4)NCH2CH2NEt2}Br
(py)] (3) [55] and trans-[Pt{(p-BrC6F4)NCH2CH2NEt2}I(py)] (4) [69]
were synthesised by using literature methods.
4.3. Instrumentation/analytical procedures
Nuclear magnetic resonance (NMR) spectra were recorded from
solutions of deuterated solvents at 27.8 ◦C (unless otherwise stated) with
a Bruker DPX a 400 spectrometer supported by Top Spin NMR software
on a Windows NT workstation with reference to internal CFCl3 and
tetramethylsilane for 19F NMR and H NMR spectra respectively. The
1
195Pt NMR spectrum was recorded with an Avance Neo 500 NMR
spectrometer in (CD3)2CO at 25 ◦C with reference to external Na2PtCl6.
2D NMR spectra (Nuclear Overhauser Effect (NOESY), COrrelation
Spectroscopy (COSY), and Heteroatom Single Quantum Coherence
Spectroscopy (HSQC)) and variable temperature 1H NMR spectra were
recorded with a Bruker 400 spectrometer. Infrared spectra were recor-
ded on a Perkin-Elmer 1600 FT-IR spectrophotometer as Nujol and
hexachlorobutadiene (HCB) mulls between NaCl plates or recorded on
an Agilent Cary 630 attenuated total reflectance (ATR) spectrometer in
the range 4000–600 cmꢀ 1. Low-resolution electrospray mass spectra
were recorded on a Waters micromass ZQ QMS instrument connected to
an Agilent 1200 series HPLC system. High-resolution accurate mass
measurements were performed on a TOF (Agilent) instrument with a
multimode source by using dual method, electrospray ionisation and
atmospheric pressure chemical ionisation. Cited m/z values for ions of
elements with two or more isotopes are the most intense peak of a cluster
with the expected isotope pattern. CHN elemental analyses were carried
out by the Science Centre, London Metropolitan University Elemental
Analyses Service. An electrothermal IA6304 apparatus was used to
measure the melting points of the compounds.
Crystallographic data for the structures reported in this paper have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary number CCDC 2012970 for 1H, 2012971 for 1Cl,
2004209 for co-crystallized 1H þ 1Cl, 2012972 for 1H0.251Br0.75
,
2012974 for 1Cl0.5Br0.5, 2,021,205 for 3Br, 2021208 for {(p-BrC6F4)
NHCH2CH2NþHEt2}Cl¡, and 2040956 for 4. Copies of the data can be
obtained free of charge at www.ccdc.cam.ac.uk/data_request/cif.
4.5. Oxidation of 1 by diammonium hexanitratocerate (CAN) -
generation of 1H
A solution of CAN (0.109 g, 0.20 mmol) in 6 ml of acetone was added
dropwise to a solution of 0.139 g (0.20 mmol) of 1 in 12 ml of acetone.
The reaction mixture was stirred at room temperature for 22 h and was
diluted by adding 20 ml of distilled water. No solid was obtained. Hence,
the product was extracted with ethyl acetate. All the ethyl acetate ex-
tracts were collected and concentrated to 7–9 ml by evaporation and
hexane (10 ml) was added until the solution became cloudy. The
solution was filtered and then concentrated to 5 ml. Acetone (5 ml) was
added and the solution was stored at ꢀ 10 ◦C. Yellow crystals were ob-
tained and characterised as 1H by X-ray crystallography and NMR, IR
and mass spectroscopy.
4.4. X-ray crystallography
X-ray diffraction data for single crystals of 1H, 1Cl, 1H0.25Br0.75, and
1Cl0.5Br0.5 were collected at a wavelength of λ = 0.71073 Å using the
MX1 beamline at the Australian Synchrotron, Victoria, Australia with
Blue Ice [70] graphical user interface (GUI) by using the same method as
in the Experimental section of a previous report [53]. A single crystal of
co-crystallized 1H þ 1Cl was loaded on to a fine glass fibre or cryoloop
using hydrocarbon oil with the temperature kept at 123 K using an open-
flow N2 Oxford Cryosystem. A Bruker Apex II diffractometer was used to
collect the data, which was processed using the SAINT [71] program. X-
ray diffraction data for the crystals of 3Br were collected on a Rigaku
Synergy S diffractometer with a Cu microsource (CuKa 1.54184 Å) and
Hipix 6000HE direct photon counting detector and processed using
CrysAlisPro v1.171.39.46 (Rigaku OD, Yarnton UK, 2018). Data were
processed with the XDS [72] software program. All the structures were
solved by using direct methods with SHELXS-97 [73] and refined using
conventional alternating least-squares methods with SHELXL-2018
[74]. The program OLEX2 [75] was used as the graphical interface.
All non‑hydrogen atoms in the structures were refined anisotropically,
and hydrogen atoms attached to carbon were placed in calculated po-
sitions and allowed to ride on the atom to which they were attached. The
low measured diffraction completeness in 1H is presumably due to
hardware constraints (single fixed rotation axis, minimum detector
distance) at the MX1 beamline at the Australian Synchrotron. The data
for 1H were twinned and partially modelled as a pseudo merohedral
twin in SHELX. In the crystal structure of 1Cl, the calculated negative
residual electron density on Pt01 is presumably an “unresolved ab-
sorption artefact”. The X-ray diffraction data for single crystals con-
taining co-crystallized 1H þ 1Cl have been modelled as a mixture of the
two species 1H and 1Cl in the non-centrosymmetric space group P21. As
[Pt{(p-BrC6F4)NCH¼CHNEt2}Cl(py)], 1H
Metallic yellow coloured blocks. (0.012 g, 12% yield) 19F NMR
1
((CD3)2CO): ꢀ 148.2 [m, 2 F, F 2,6], ꢀ 138.2 [m, 2 F, F 3,5]. H NMR
3
((CD3)2CO): 1.56 [t, 6H, JH,H 7 Hz, NCH2CH3,], 2.30 [m, 2H,
NCHAHBCH3,], 3.43 [m, 2H, NCHBHACH3,], 3.75 [d, 3JH,H 3.45 Hz, 3JH,Pt
34 Hz, 1H, CHNEt2], 6.07 [m with 195Pt satellites, 3JH,Pt 50 Hz, 1H, CHN
(p-BrC6F4)], 7.19 [m, 2H, H 3, 5 (py)], 7.74 [tt, 3JH,H 7.8 Hz, 4JH,H 1Hz, 1
H, H 4 (py)], 8.42 [d with 195Pt satellites, 3JH,H 5.6 Hz, 3JH,Pt 30 Hz, 2H,
H 2, 6 (py)]. IR: 3058w, 2962w, 2926w, 2868w, 2165w, 2080w, 1660s,
1619s, 1468s, 1451w, 1372 m, 1355 m, 1286w, 1263w, 1224 m, 1190s,
1160w, 1111 m, 1142s, 1087w, 1026 m, 998 m, 972 s, 956 m, 846w,
818 s, 762 s, 741 s, 694 s, 639w, 607 s cmꢀ 1. ESI m/z (+ve): 652.2 (20%
(1 + H)+) i.e., (C17H19BrClF4N3Pt + H+); acc. Mass MS/ESI calcd for
((1H) + H)+ i.e., (C17H17BrClF4N3Pt{310(BrClPt)} + H+): 649.9929,
found: 649.9930.
4.6. General method used for oxidation of 1 with hydrogen peroxide
1 dissolved in the designated solvent was placed in a three-necked
round bottom flask fitted with a reflux condenser. Excess 30%
hydrogen peroxide was added dropwise and the reaction mixture was
stirred at room temperature or occasionally heated in an oil-bath under a
light flow of nitrogen gas behind a safety screen as concentrated
hydrogen peroxide in the acetone in the presence of acid catalyst can
9

R. Ojha et al.
Journal of Inorganic Biochemistry 218 (2021) 111360
form the shock and friction sensitive explosive triacetone triperoxide
(TATP) [76]. Since the determination of completion of the reaction by
TLC was ineffective due to the similarity in retention factors of the
products and the starting material, observation of colour-change was
used as a method to determine the reaction completion. To catalytically
degrade residual hydrogen peroxide, MnO2 (2–3 g) was added in the
cold reaction solution which was stirred for 0.5 h. After filtration
through Celite, the reaction solution was concentrated by evaporating
carefully to 5–6 ml followed by the addition of water or hexane until the
solution turned cloudy. In most cases, a cloudy solution with some oil
was obtained which was separated by decanting the cloudy solution. The
separated oil was dissolved again in the designated solvent and crystals
were then obtained by cooling at ꢀ 10 ◦C for 5–6 days. The cloudy so-
lution was concentrated by evaporation and stored at ꢀ 10 ◦C. Usually,
this fraction gave powder or amorphous flakes which were collected and
then recrystallised from appropriate solvent mixtures to obtain crystals
suitable for X-ray structural determination. The crystals of all the com-
plexes were washed with hexane.
from the initial yellow to a deep red colour in the first hour and then to
bright yellow. MnO2 (2 g) was then added. Following filtration and
evaporation of the solution to 3–4 ml, 5 ml hexane were added. The
solution was concentrated by evaporation and stored at ꢀ 10 ◦C and
bright yellow crystals of 1Cl were obtained in 34% yield. After collection
of these crystals, further evaporation of the mother liquor gave a second
crop of 1Cl and green oil. The green oil was dissolved again in
dichloromethane, crystallisation from dichloromethane/hexane pro-
duced two crystals of [Pt{(p-BrC6F4)NCH=C(Cl0.5/Br0.5)NEt2}Cl(py)],
1Cl0.5Br0.5 in 1:1 in a single unit cell (identified by single-crystal X-ray
diffraction).
Method 3
1 (0.134 g, 0.2 mmol) was dissolved in 20 ml dichloromethane and a
30% solution of H2O2 (1 ml, 10.0 mmol, 50 fold excess) was added
dropwise. Occasionally, the solution was vigorously refluxed for 10 h
over 3 days, under nitrogen. The solution changed colour from initial
yellow to red in an hour of initial heating and then to very light yellow
colour at the end of 3 days when MnO2 was added. After filtration and
evaporation to 3–4 ml, 5 ml hexane was added and the solution was
stored at ꢀ 10 ◦C for crystallisation. Light yellow crystals of [Pt{(p-
BrC6F4)NCH=C(Br)NEt2}Cl(py)], 1Br (along with some unidentified
brown oil) were collected and characterised by 1H and 19F NMR spec-
troscopy, mass spectrometry and elemental analysis.
Variations in the procedures are mentioned below as different sol-
vents, concentration of Class 2 organoamidoplatinum(II) complex,
temperature and concentrations of hydrogen peroxide used to optimise
the reaction conditions for a specific synthesis. When a mixture of the
products was obtained after fractional crystallisation, their ratio as
determined by 1H and 19F NMR spectroscopy is given in the case of
already characterised species. For unidentified products, 1H and 19F
NMR resonances are given.
[Pt{(p-BrC6F4)NCH¼C(Br)NEt2}Cl(py)] (1Br): Metallic light yel-
low coloured blocks. (0.05 g, 31% crystalline yield) 19F NMR
((CD3)2CO): ꢀ 148.01 [m, 2 F, F 2, 6], ꢀ 137.63 [m, 2 F, F 3,5]. 1H NMR
((CD3)2CO): 1.55 [overlapping triplets, 6H, 3JH,H 7 Hz, NCH2CH3 (I1 +
I2)], 2.65 [m, 2H, NCHAHBCH3,], 3.36 [m, 2H, NCHBHACH3,], 6.57 [t
with 195Pt satellites, 5JH,F 2 Hz, 3JH,Pt 40 Hz, 0.5H, CHN(p-BrC6F4), I1],
4.7. Details of specific conditions used for oxidation of (1) with different
amounts of 30% hydrogen peroxide in different solvents
5
3
6.61 [t with 195Pt satellites, JH,F 2 Hz, JH,Pt 40 Hz, 0.5H, CHN(p-
BrC6F4), I2], 7.21 [m, 2H, H3,5 (py)], 7.76 [tt,3JH,H 7.7 Hz, 4JH,H 1Hz, 1
H, H4 (py)], 8.43 [d with 195Pt satellites, 3JH,H 5.6 Hz, 3JH,Pt 35 Hz, 2H,
H2,6 (py)]. IR: 2959w, 2924w, 2874w, 2058w, 1917w, 1738 m, 1719w,
1702 m, 1645s, 1613s, 1463s, 1451w, 1376 m, 1312s, 1278w, 1261w,
1211 m, 1139s, 1103s, 1079w, 1053s, 1017w, 991 s, 968 s, 906 m, 872
m, 829 s, 763 s, 738 s, 717 s, 688 s, 618 s cmꢀ 1. acc. Mass MS/ESI calcd
for (1Br) + H)+ i.e., (C17H16Br2ClF4N3Pt + H+): 729.9025, found:
729.9020. Elemental analysis Calcd for C17H16Br2Cl1F4N3Pt1.0.5 CH2Cl2
(M = 771.18): C, 27.26%; H, 2.22%; N, 5.45%. Found: C, 27.05%; H,
2.09%; N, 5.66%.
4.7.1. Dichloromethane
Method 1
To a solution of 1 (0.224 g, 0.34 mmol) in 20 ml dichloromethane, a
30% solution of H2O2 (0.8 ml, 8.0 mmol, 23 fold excess) was added
dropwise and the reaction solution was stirred at room temperature for
1 h under nitrogen. The solution was then heated intermittently at
25–30 ◦C for 14 h over 4 days under nitrogen. The colour of the solution
changed from yellow to deep red after 6 h of heating and then to orange
as the reaction progressed. MnO2 (2 g) was added to degrade the
remaining H2O2. After workup, the solution was concentrated to 5 ml
and hexane (6 ml) was added. The solution was stored at ꢀ 10 ◦C and
bright yellow crystals of 1Cl were obtained.
4.7.2. Acetone
1 (0.139 g, 0.20 mmol) was dissolved in 20 ml acetone and a 30%
H2O2 solution (0.5 ml, 5.0 mmol, 25 fold excess) was added. The reac-
tion mixture was stirred for 2 days with occasional heating for 9 h over 2
days at 50 ◦C. The solution changed colour from yellow to dark orange
and then to bright yellow. MnO2 (2 g) was added to remove unreacted
hydrogen peroxide. After filtration and evaporation of the solution to
3–4 ml, distilled water was added until the solution turned turbid. (a) A
very small amount of orange coloured solid obtained by filtration was
identified as a mixture of the organoenamineamide complexes [Pt{(p-
BrC6F4)NCH=CHNEt2}Cl(py)], 1H and [Pt{(p-BrC6F4)NCH=C(Cl)NEt2}
Cl(py)], 1Cl by NMR only. Slight evaporation of the filtrate gave a dark
brown coloured oil which was divided into two parts. (b) The first part
was dissolved in acetone and crystallisation from acetone/hexane at
ꢀ 10 ◦C gave bright yellow crystals which were identified as 1H þ 1Cl
co-crystallized in a 1:1 ratio in the unit cell by single-crystal X-ray
diffraction, NMR and mass spectrometry. (c) An attempt was made to
isolate 1H and 1Cl from the second part of the oil. Column chroma-
tography was used with basic alumina as the stationary phase and ethyl
acetate and hexane in 1:1 ratio as the eluent. A yellow band was
collected in fractions and slow evaporation gave bright yellow crystals
which were identified as [Pt{(p-BrC6F4)NCH=C(H0.25/Br0.75)NEt2}Cl
(py)], 1H0.25Br0.75. The occupancies of H and Br were determined by X-
ray structural determination, however, it dissociates in the solution into
1H and 1Br in 1:3 ratio.
[Pt{(p-BrC6F4)NCH¼C(Cl)NEt2}Cl(py)] (1Cl): Metallic bright
yellow coloured blocks. (0.24 g, 39% crystalline yield (crude yield =
47%)). M.P. = 163 ◦C. 19F NMR ((CD3)2CO): ꢀ 148.0 [m, 2 F, F 2, 6],
ꢀ 137.7 [m, 2 F, F 3,5]. 1H NMR ((CD3)2CO): 1.55 [overlapping triplets,
6H, 3JH,H 7 Hz, NCH2CH3 (I1 þ I2)], 2.63 [m, 2H, NCHAHBCH3], 3.39
[m, 2H, NCHBHACH3], 6.57 [t with 195Pt satellites, 5JH,F 2 Hz, 3JH,Pt 40
5
Hz, 0.5H, CHN(p-BrC6F4), I1], 6.61 [t with 195Pt satellites, JH,F 2 Hz,
3JH,Pt 40 Hz, 0.5H, CHN(p-BrC6F4), I2], 7.07 [m, 2H, H3,5 (py)], 7.61
[tt, 3JH,H 7.7 Hz, JA,B 1 Hz, 1H, H4 (py)], 8.38 [d with 195Pt satellites,
3
3JH,H 5.6 Hz, JH,Pt 35 Hz, 2H, H2,6 (py)]. 195Pt NMR ((CD3)2CO):
ꢀ 2226.8 [s, br, 1Pt], ꢀ 2244.0 [s, br, 1Pt] ppm. IR: 2959w, 2924w,
2874w, 2101w, 2083w, 1979w, 1917w, 1702 m, 1654s, 1611s, 1465s,
1450w, 1376 m, 1312s, 1278w, 1261w, 1210 m, 1139s, 1104s, 1078w,
1018s, 969 s, 872 m, 831 s, 763 s, 738 s, 717w, 689 s cmꢀ 1. ESI m/z
652.1 (55% (1 + H)+) i.e., (C17H19BrClF4N3Pt + H+); acc. Mass MS/ESI
calcd for (1Cl) + H)+ i.e., (C17H16BrCl2F4N3Pt + H+): 683.9536, found:
683.9524. Elemental analysis Calcd for C17H16Br1Cl2F4N3Pt1 (M =
684.28): C, 29.84%; H, 2.36%; N, 6.14%. Found: C, 29.64%; H, 2.52%;
N, 5.91%.
Method 2
1 (0.139 g, 0.20 mmol) was dissolved in 20 ml dichloromethane and
a 30% solution of H2O2 (1 ml, 10.0 mmol, 50 fold excess) was added
dropwise. The solution was heated at near refluxing temperature, 30–35
◦C for 10 h over 2 days, during which time the solution changed colour
10

R. Ojha et al.
Journal of Inorganic Biochemistry 218 (2021) 111360
(a) Co-crystallized [Pt{(p-BrC6F4)NCH¼CHNEt2}Cl(py)] þ [Pt
1Cl co-crystallized
solution changed colour from yellow to red. The reaction mixture was
then heated to 40–50 ◦C for 4 h and stirred at room temperature for 4 d,
however, the colour of the solution remained red. The reaction mixture
was heated again at 40 ◦C for 9 h and then stirred at room temperature
for 2 d. MnO2 was added to the resulting orange-red solution and stirred
for 0.5 h. The solution was filtered through Celite and the solvent was
evaporated to 3 ml. Hexane (2 ml) was added and the reaction mixture
{(p-BrC6F4)NCH¼C(Cl)NEt2}Cl(py)], 1H
þ
(mole ratio 1:1): Metallic bright yellow coloured blocks. (0.045 g,
33% yield). 19F NMR (CDCl3): 1H: ꢀ 148.5 [m, 2 F, F 2, 6], ꢀ 137.6 [m, 2
F, F 3,5]; 1Cl ꢀ 148.3 [m, 2 F, F 2, 6], ꢀ 136.9 [m, 2 F, F 3,5]. 1H NMR
(CDCl3): 1.65 [m, 12H, 3JH,H 7 Hz, NCH2CH3, (1H þ 1Cl)], 2.30 [m, 2H,
NCHAHBCH3, (1H þ 1Cl)], 3.43 [m, 2H, NCHAHBCH3, (1H þ 1Cl)],
3.54 [m, 4H, NCHBHACH3, (1H þ 1Cl)], 3.75 [d with 195Pt satellites,
◦
was stored at ꢀ 10 C. An orange-red coloured oil formed, and bright
3
3JH,H 3.47 Hz, JH,Pt 33 Hz, 1H, CHNEt2, (1H)], 6.07 [m with 195Pt
gold flakes of ([Pt{(p-HC6F4)NCH2CH2NEt2}Cl(py)], 2 were obtained.
Gold flakes, (2): [Pt{(p-HC6F4)NCH2CH2NEt2}Cl(py)], Bright gold
flakes (0.02 g, 10%). m/z ESIþ: 574.0 (100% ([Pt{(p-HC6F4)
3
satellites JH,Pt 53 Hz, 1H, CHN(p-BrC6F4), (1H)], 6.48 [t with 195Pt
satellites, 5JH,F 2 Hz, 3JH,Pt 40 Hz, 0.5H, CHN(p-BrC6F4), (1Cl, I1)], 6.52
5
[t with 195Pt satellites, JH,F 2 Hz, 3JH,Pt 40 Hz, 0.5H, CHN(p-BrC6F4),
NCH2CH2NEt2}Cl(py)]
+
H)þ, 537.0 (12% ([Pt{(p-HC6F4)NCH2
(1Cl, I2)], 7.11 [m, 4H, H3,5 (py), (1H þ 1Cl)], 7.66 [m, 3JH,H 7.8 Hz,
4JH,H 1 Hz, 2H, H4 (py), (1H þ 1Cl)], 8.50 [t with 195Pt satellites, 3JH,H
CH2NEt2}Cl(py)] - Cl)þ. Elemental analysis Calcd for C17H20Cl1F4N3Pt1
(M = 572.9): C, 35.64%; H, 3.52%; N, 7.33%. Found: C, 35.72%; H,
3.47%; N, 7.28%. The 19F and 1H NMR and IR data (supporting infor-
mation) were in agreement with those recently reported [54].
3
6 Hz, JH,Pt 30 Hz, 4H, H2,6 (py), (1H þ 1Cl)]. IR: 3060w, 2962w,
2926w, 2868w, 2164w, 2050w, 1926w, 1662s, 1646 m, 1619s, 1580 m,
1469s, 1450w, 1372 m, 1355 m, 1288w, 1264w, 1224 m, 1190s, 1143s,
1087w, 1027 m, 972 s, 956 m, 876w, 819 s, 763 s, 741 s, 695 s, 641w,
4.8. Oxidation of [Pt{(p-HC6F4)NCH2CH2NEt2}Br(py)], 3 with 30%
hydrogen peroxide
607
s
cmꢀ 1
.
ESI m/z (+ve): 652.2 (20% (1
+
H)+) i.e.,
(C17H19BrClF4N3Pt + H+); acc. Mass MS/ESI calcd for ((1H) + H)+ i.e.,
(C17H17BrClF4N3Pt + H+): 649.9924, found: 649.9930; calcd for ((1Cl)
+ H)+ i.e., (C17H16BrCl2F4N3Pt + H+): 683.9536, found: 683.9545.
(b) [Pt{(p-BrC6F4)NCH¼C(H0.25Br0.75)NEt2}Cl(py)], (1H0.25Br
0.75): Metallic yellow coloured triangles. (0.027 g, 7% yield). Elemental
analysis Calcd for C17H16.25Br1.75Cl1F4N3Pt1 (M = 728.68): C, 28.80%;
H, 2.31%; N, 5.92%. Found: C, 28.15%; H, 2.25%; N, 5.81%. Acc. Mass
MS/ESI calcd for ((1Br) + H)+ i.e., (C17H16Br2ClF4N3Pt + H+):
[Pt{(p-HC6F4)NCH2CH2NEt2}Br(py)], (0.41 g, 0.66 mmol) was dis-
solved in 10 ml acetonitrile and 30% solution of H2O2 (1 ml, 10.0 mmol)
was added dropwise. The solution was heated at 60 ◦C for 7 h and then
stirred for 15 h, during which time the solution changed colour from the
initial yellow to deep red colour and then to orange. MnO2 (2 g) was
then added. Following filtration and evaporation to dryness, the residue
was dissolved in 2 ml of acetone and 2 ml hexane was added. The so-
lution was stored at ꢀ 10 ◦C and orange crystals of [Pt{(p-HC6F4)NCH=C
(Br)NEt2}Br(py)] were obtained.
729.9025, found: 729.9020, calcd for ((1H)
(C17H17BrClF4N3Pt + H+): 649.9929, found: 649.9911.
+
H)+ i.e.,
All of the analytically pure sample of 1H0.25Br0.75 was used for mi-
croanalyses and MS measurements. The sample used for the NMR
spectra retained some ethyl acetate from the isolation procedure, but
indicated clear dissociation into a 1:3 ratio of 1H:1Br (see Supporting
Information).
[Pt{(p-HC6F4)NCH¼C(Br)NEt2}Br(py)], 3Br Orange coloured
needles. (0.1018 g, 22% crystalline yield. M.P. = 137 ◦C. 19F NMR
((CD3)2CO): ꢀ 149.3 [m, 2 F, F 2, 6], ꢀ 142.1 [m, 2 F, F 3,5]. 1H NMR
3
((CD3)2CO): 1.69 [t, 6H, JH,H 6 Hz, NCH2CH3,], 2.70 [m, 2H,
NCHAHBCH3,], 3.60 [m, 2H, NCHBHACH3,], 6.69 [t with 195Pt satellites,
3
3
4
3JH,H 3 Hz, JH,Pt 40 Hz, 1H, 6.93 [tt, JH,F 10 Hz, JH,F 7 Hz, 1H, p-
HC6F4, 7.30 [t, 3JH,H 2Hz 2H, H3,5 (py)], 7.87 [m, 1H, H4 (py)], 8.58 [d
with 195Pt satellites, 3JH,H 5 Hz, 3JH,Pt 40 Hz, 2 H, H2,6 (py)]. IR: 1624s,
1608 m, 1500 vs, 1475 m, 1452s, 13,765 m, 1316s, 1277w, 1225vs,
1173s, 1168s, 1142s, 1100s, 1076w, 1020s, 966 s, 934vs, 880w, 837 m,
4.7.3. Acetonitrile
A solution of 1 (0.139 g, 0.20 mmol) in 20 ml acetonitrile was treated
with 30% solution of H2O2 (1 ml, 10.0 mmol, 50 fold excess) and the
reaction mixture was heated at refluxing temperature 75–80 ◦C for 10 h
over 2 days. The colour of the solution changed from yellow, to red and
then bright yellow and MnO2 (2 g) was added. After filtration and
evaporation to 3–4 ml, distilled water (5–6 ml) was added and the so-
lution turned a little cloudy with no oil formed this time. After
concentrating the cloudy solution by slight evaporation, it was stored at
818 m, 779w, 763 s, 726 m, 712 m, 690 s, 672w, 662w, 638w cmꢀ 1
.
ESMS: 696 (100%) (M + H)+ = (C17H18Br2F4N3Pt1 + H+). Elemental
analysis Calcd for C17H17Br2F4N3Pt1 (M = 694.22): C, 29.76%; H,
2.51%; N, 6.12%. Found: C, 29.41%; H, 2.47%; N, 6.05%.
ꢀ 10 ◦C. Bright yellow crystals of [Pt{(p-BrC6F4)NCH=C(H0.25Br0.75
)
4.9. Synthesis of pro-ligand {p-BrC6F4)NHCH2CH2NEt2}
NEt2}Cl(py)], 1H0.25Br0.75 (0.01 g, 7%) were obtained and identified
with X-ray crystallography. An attempt was made to isolate the product
from the filtrate with ethyl acetate and it gave 2–3 crystals of
1H0.25Br0.75 along with a small amount of oily free ligand.
Free pro-ligand 19F NMR (CD3CN) -136.8 [m, 2 F, F 3,5] -160.1 [m, 2 F,
F 2,6].
Bromopentafluorobenzene (125 mmol) and N,N-diethylethane-1,2-
diamine (250 mmol) in ethanol (20 ml) were refluxed under nitrogen
for 18 h. The solution was evaporated under the reduced pressure and an
orange coloured frothy gel was obtained which was shaken with ether/
water in a separating funnel. The ether layer was collected and added to
a further 3 ether extractions from the aqueous layer. All the combined
four extractions were dried over MgSO4 for 3 d and then evaporated
under the reduced pressure leaving a high boiling point liquid. During
the distillation, while heating, the liquid turned dark brown. Double
distillation under reduced pressure removed the colour of the liquid
largely and a very light yellow coloured liquid was obtained. In this
liquid some impurities of the other isomers were observed hence, it was
distilled again under reduced pressure but this method did not produce
high purity product, hence it was purified by column chromatography.
Silica gel was used as stationary phase and the solvent was chloroform.
After the evaporation of chloroform pure ligand was obtained in the
(See below for details of synthesis and characterisation of the free
pro-ligand; the crystal structure of {(p-BrC6F4)NHCH2CH2N+HEt2}Clꢀ
salt, crystal data, bond lengths and bond angles are provided in Fig. S24
and Table S6).
4.7.4. Acetone: with added tetrabutylammonium hydroxide (NBu4OH)
A stoichiometric amount of a 30% solution of hydrogen peroxide
(0.1 ml, 1.0 mmol) was added to a solution of 1 (0.325 g, 0.50 mmol) in
acetone, followed by addition of a 40% solution of tetrabutylammonium
hydroxide (0.65 ml, 1.0 mmol). The reaction mixture was stirred for 7
days in the dark under a low stream of nitrogen, during which time the
11

R. Ojha et al.
Journal of Inorganic Biochemistry 218 (2021) 111360
[19] S. Sultana, K. Verma, R. Khan, J. Pharm. Pharmacol. 64 (2012) 872–881.
[20] M. Kruidering, B. Van de Water, E. de Heer, G.J. Mulder, J.F. Nagelkerke,
J. Pharmacol. Exp. Ther. 280 (1997) 638–649.
form of a colourless high boiling point liquid.
(a) {(p-BrC6F4)NHCH2CH2NEt2} Colourless oil. B.p. 98 ◦C/5 ×
10ꢀ 2 mmHg. 19F NMR ((CDCl3): ꢀ 159.2 [d, 2F, F2,6], ꢀ 137.3 [d, 2F, F
3,5]. 1H NMR (CDCl3): 0.93 [t, 3JH,H 7 Hz, 6H, NCH2CH3], 2.45 [q, 3JH,H
7 Hz, 4H, NCH2CH3], 2.56 [t, 2H, 3JH,H 6 Hz, CH2NEt2], 3.30 [m, 2H,
CH2N(p-BrC6F4)], 4.82 [br, 1H, NH]. m/z ESIþ: 343.1(100% (M + H)þ);
acc. Mass MS/ESI calcd for (C12H15F4N2Br + H+): 343.0427, found:
343.0424.
[21] Y.I. Chirino, J. Pedraza-Chaverri, Exp. Toxicol. Pathol. 61 (2009) 223–242.
[22] A. Laurent, C. Nicco, C. Chereau, C. Goulvestre, J. Alexandre, A. Alves, E. Levy,
F. Goldwasser, Y. Panis, O. Soubrane, B. Weill, F. Batteux, Cancer Res. 65 (2005)
948–956.
[23] H. Masuda, T. Tanaka, U. Takahama, Biochem. Biophys. Res. Commun. 203 (1994)
1175–1180.
[24] A. Sodhi, P. Gupta, Int. J. Immunopharmacol. 8 (1986) 709–714.
´
[25] A.-B. Witte, K. Anestål, E. Jerremalm, H. Ehrsson, E.S.J. Arner, Free Radic. Biol.
After column chromatography, some off-white/cream coloured
crystals of {(p-BrC6F4)NHCH2CH2N+HEt2}Clꢀ were obtained from the
chloroform solution of oily ligand on slow evaporation of the solvent and
identified by X-ray crystallography as shown in Fig. S24.
Med. 39 (2005) 696–703.
[26] I. Judson, L.R. Kelland, Drugs 59 (2000) 29–36.
[27] M.R. McLemore, Clin. J. Oncol. Nurs. 10 (2006) 559–560.
[28] S.J. Shi, H.L. Sings, J.T. Bryan, B. Wang, Y. Wang, H. Mach, M. Kosinski, M.
W. Sitrin, M.W. Washabaugh, E. Barr, Clin. Pharmacol. Ther. 81 (2007) 259–264.
[29] M.J. Cleare, J.D. Hoeschele, Bioinorg. Chem. 2 (1973) 187–210.
[30] T.W. Hambley, Chem. Aust. 58 (1991) 154–156.
(b) {(p-BrC6F4)NHCH2CH2NþHEt2}Cl¡ Colourless crystals 19F
NMR ((CDCl3): ꢀ 158.5 [d, 2F, F2,6], ꢀ 137.05 [d, 2F, F 3,5]. 1H NMR
[31] K.S. Lovejoy, S.J. Lippard, Dalton Trans. (2009) 10651–10659.
[32] N. Farrell, Met. Ions Biol. Syst. 42 (2004) 251.
3
3
(CDCl3): 1.11 [t, JH,H 7 Hz, 6H, NCH2CH3], 2.69 [q, JH,H 7 Hz, 4H,
3
NCH2CH3], 2.78 [t, 2H, JH,H 6 Hz, CH2NEt2], 3.50 [m, 2H, CH2N(p-
[33] N.J. Wheate, J.G. Collins, Curr. Med. Chem. : Anti-Cancer Agents 5 (2005)
267–279.
BrC6F4)], 5.128 [br, 1H, NH].
[34] N.J. Wheate, J.G. Collins, Coord. Chem. Rev. 241 (2003) 133–145.
[35] L.K. Webster, G.B. Deacon, D.P. Buxton, B.L. Hillcoat, A.M. James, I.A.G. Roos, R.
J. Thomson, L.P.G. Wakelin, T.L. Williams, J. Med. Chem. 35 (1992) 3349–3353.
[36] T. Talarico, D.R. Phillips, G.B. Deacon, S. Rainone, L.K. Webster, Investig. New
Drugs 17 (1999) 1–15.
4.10. Biological testing
The cell culture of HT-29 colon carcinoma cells and MCF-7 breast
carcinoma cells were performed according to the recently used method
[77]. The determination of the antiproliferative effects of compounds 1
and 4 were undertaken by using the same method reported recently
[77].
[37] J. Czapla-Masztafiak, J. Nogueira, E. Lipiec, W.M. Kwiatek, B.R. Wood, G.
B. Deacon, Y. Kayser, D.L.A. Fernandes, M.V. Pavliuk, J. Szlachetko, L. Gonzalez,
J. Sa, J. Phys. Chem. Lett. 8 (2017) 805–811.
[38] R. Haputhanthri, R. Ojha, E.I. Izgorodina, S.-X. Guo, G.B. Deacon, D. McNaughton,
B.R. Wood, Vib. Spectrosc. 92 (2017) 82–95.
[39] E. Lipiec, F.S. Ruggeri, C. Benadiba, A.M. Borkowska, J.D. Kobierski, J. Miszczyk,
B.R. Wood, G.B. Deacon, A. Kulik, G. Dietler, W.M. Kwiatek, Nucleic Acids Res. 47
(2019), e108.
Conflict of interest
[40] K. Al-Jorani, A. Rüther, R. Haputhanthri, G.B. Deacon, H.L. Li, C. Cullinane, B.
R. Wood, Analyst 143 (2018) 6087–6094.
[41] K. Al-Jorani, A. Rüther, M. Martin, R. Haputhanthri, G.B. Deacon, H.L. Li, B.
R. Wood, Sensors 18 (2018) 4297.
Authors declare no conflict of interest.
Acknowledgements
[42] C.M. Giandomenico, M.J. Abrams, B.A. Murrer, J.F. Vollano, M.I. Rheinheimer, S.
B. Wyer, G.E. Bossard, J.D. Higgins, Inorg. Chem. 34 (1995) 1015–1021.
[43] M. Ravera, E. Gabano, I. Zanellato, F. Fregonese, G. Pelosi, J.A. Platts, D. Osella,
Dalton Trans. 45 (2016) 5300–5309.
This paper is dedicated to Prof. Wolfgang Kaim on the occasion of his
70th birthday. AMB gratefully acknowledges financial support from the
Australian Research Council (grant DP120101470). RO thanks the
Australian Government for the provision of an Australian Postgraduate
Award. We are thankful to Assoc. Prof. Kellie Tuck for valuable dis-
cussions and Dr. Alasdair McKay for recording the 195Pt NMR spectrum
at the CSIRO laboratories. We extend our gratitude to Prof. Ingo Ott and
Julia Schur for conducting biological testing of the compounds at the
Technical University of Braunschweig, Germany. X-ray crystallography
data collection in this research was undertaken on the MX1 beamline at
the Australian Synchrotron, which is a part of ANSTO.[78]
[44] S.X. Guo, D.N. Mason, S.A. Turland, E.T. Lawrenz, L.C. Kelly, G.D. Fallon, B.
M. Gatehouse, A.M. Bond, G.B. Deacon, A.R. Battle, T.W. Hambley, S. Rainone, L.
K. Webster, C. Cullinane, J. Inorg. Biochem. 115 (2012) 226–239.
[45] E.T. Lawrenz, PhD thesis, Monash University, 1996.
[46] R.A. Taylor, D.J. Law, G.J. Sunley, A.J.P. White, G.J.P. Britovsek, Chem. Commun.,
2008, pp. 2800–2802.
[47] S. Shamsuddin, C.C. Santillan, J.L. Stark, K.H. Whitmire, Z.H. Siddik, A.
R. Khokhar, J. Inorg. Biochem. 71 (1998) 29–35.
[48] Y.-A. Lee, K. Ho Yoo, O.-S. Jung, Inorg. Chem. Commun. 6 (2003) 249–251.
[49] G. Canil, S. Braccini, T. Marzo, L. Marchetti, A. Pratesi, T. Biver, T. Funaioli,
F. Chiellini, J.D. Hoeschele, C. Gabbiani, Dalton Trans. 48 (2019) 10933–10944.
[50] J. Abrams Michael, M. Giandomenico Christen, A. Murrer Barry, F. Vollano Jean,
Johnson Matthey Inc, US19910723971, 1991.
[51] I. Romero-Canelon, P.J. Sadler, Inorg. Chem. 52 (2013) 12276–12291.
[52] U. Jungwirth, C.R. Kowol, B.K. Keppler, C.G. Hartinger, W. Berger, P. Heffeter,
Antioxid. Redox Signal. 15, 2011, pp. 1085–1127.
Electronic Supplementary Material
[53] R. Ojha, A. Nafady, M.J.A. Shiddiky, D. Mason, J.F. Boas, A.A.J. Torriero, A.
M. Bond, G.B. Deacon, P.C. Junk, ChemElectroChem 2 (2015) 1048–1061.
[54] R. Ojha, J.F. Boas, G.B. Deacon, P.C. Junk, A.M. Bond, J. Inorg. Biochem. 162
(2016) 194–200.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jinorgbio.2021.111360.
[55] G.B. Deacon, B.M. Gatehouse, J. Ireland, Aust. J. Chem. 44 (1991) 1669–1681.
[56] P.S. Braterman, Reactions of Coordinated Ligands vol. 1, Plenum Press, New York,
Springer US, 1986.
References
[57] E. Wissing, J.T.B.H. Jastrzebski, J. Boersma, G. van Koten, J. Organomet. Chem.
459 (1993) 11–16.
[1] T.C. Johnstone, G.Y. Park, S.J. Lippard, Anticancer Res. 34 (2014) 471–476.
[2] E. Wong, C.M. Giandomenico, Chem. Rev. 99 (1999) 2451–2466.
[3] D. Wang, S.J. Lippard, Nat. Rev. Drug Discov. 4 (2005) 307–320.
[4] L. Kelland, Nat. Rev. Cancer 7 (2007) 573–584.
[58] G.V. Koten, K. Vrieze, in: F.G.A. Stone, R. West (Eds.), Advances in Organometallic
Chemistry Vol. 21, Academic Press, 1982, pp. 151–239.
´
[59] R. Campbell, P. García-Alvarez, A.R. Kennedy, R.E. Mulvey, Chem. Eur. J. 16
(2010) 9964–9968.
[5] S.P. Fricker, Dalton Trans. (2007) 4903–4917.
[60] M. Veith, B. Schillo, V. Huch, Angew. Chem. Int. Ed. 38 (1999) 182–184.
[61] M. Veith, A. Rammo, Z. Anorg. Allg. Chem. 623 (1997) 861–872.
[62] L. Pauling, The Nature of the Chemical Bond, 2nd ed., Cornell University Press,
New York, 1940.
[6] N.J. Wheate, S. Walker, G.E. Craig, R. Oun, Dalton Trans. 39 (2010) 8113–8127.
[7] N.P. Farrell, Curr. Top. Med. Chem. 11 (2011) 2623–2631.
[8] D.J. Stewart, Crit. Rev. Oncol. Hematol. 63 (2007) 12–31.
[9] C.A. Rabik, M.E. Dolan, Cancer Treat. Rev. 33 (2007) 9–23.
[10] R.B. Weiss, M.C. Christian, Drugs 46 (1993) 360–377.
[63] A.G. Orpen, L. Brammer, F.H. Allen, O. Kennard, D.G. Watson, R. Taylor, J. Chem.
Soc. Dalton Trans. (1989) S1–S83.
[11] S.J.L.P. Pill, J.R. Bertino, Vol. 1, Acedemic Press, San Diego, 1997.
[12] J.T. Hartmann, H.P. Lipp, Expert. Opin. Pharmacother. 4 (2003) 889–901.
[13] A.S. Abu-Surrah, M. Kettunen, Curr. Med. Chem. 13 (2006) 1337–1357.
[14] R.C. Todd, S.J. Lippard, Metallomics 1 (2009) 280–291.
[15] A.V. Klein, T.W. Hambley, Chem. Rev. 109 (2009) 4911–4920.
[16] R.P. Perez, Eur. J. Cancer 34 (1998) 1535–1542.
[64] S.C. Nyburg, C.H. Faerman, Acta Cryst B41 (1985) 274–279.
[65] T.W. Hambley, Inorg. Chem. 37 (1998) 3767–3774.
[66] R. Ojha, P.C. Junk, G.B. Deacon, A.M. Bond, Supramol. Chem. 30 (2018) 418–424.
[67] M.H. Chisholm, H.C. Clarck, L.E. Manzer, J. Am. Chem. Soc. 94 (1972) 5087–5089.
[68] T.G. Appleton, H.C. Clarck, L.E. Manzer, Coord. Chem. Rev. 10 (1973) 335–422.
[69] A.R. Battle, A.M. Bond, A. Chow, D.P. Daniels, G.B. Deacon, T.W. Hambley, P.
C. Junk, D.N. Mason, J. Wang, J. Fluor. Chem. 131 (2010) 1229–1236.
[17] U. Jungwirth, C.R. Kowol, B.K. Keppler, C.G. Hartinger, W. Berger, P. Heffeter,
Antioxid. Redox Signal. 15 (2011) 1085–1127.
[18] H. Barry, C.M. Veronique, L.L. Hua, FEBS Lett. 486 (2000) 10–13.
12

R. Ojha et al.
Journal of Inorganic Biochemistry 218 (2021) 111360
[70] T.M. McPhillips, S.E. McPhillips, H.J. Chiu, A.E. Cohen, A.M. Deacon, P.J. Ellis,
E. Garman, A. Gonzalez, N.K. Sauter, R.P. Phizackerley, S.M. Soltis, P. Kuhn,
J. Synchrotron Radiat. 9 (2002) 401–406.
[75] L.J. Barbour, J. Supramol. Chem. 1 (2001) 189–191.
[76] J.C. Oxley, J. Brady, S.A. Wilson, J.L. Smith, J. Chem. Health Saf. 19 (2012) 27–33.
¨
[77] C. Schmidt, L. Albrecht, S. Balasupramaniam, R. Misgeld, B. Karge, M. Bronstrup,
[71] in (Bruker AXS: Madison, WI), Apex2 v 2.0 ed, 2005.
[72] W. Kabsch, J. Appl. Crystallogr. 26 (1993) 795–800.
[73] G.M. Sheldrick, Acta Crystallogr. Sect. A 64 (2008) 112–122.
[74] G. Sheldrick, Acta Crystallogr. Sect. C 71 (2015) 3–8.
A. Prokop, K. Baumann, S. Reichl, I. Ott, Metallomics 11 (2019) 533–545.
[78] N.P. Cowieson, D. Aragao, M. Clift, D.J. Ericsson, C. Gee, S.J. Harrop, N. Mudie,
S. Panjikar, J.R. Price, A. Riboldi-Tunnicliffe, R. Williamson, T. Caradoc-Davies,
J. Synchrotron Radiat. 22 (2015) 187–190.
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