Linear Bidentate Ligands (L) with Two Terminal Pyridyl N-Donor Groups Forming Pt(II)LCl2 Complexes with Rare Eight-Membered Chelate Rings

Article abstract of DOI:10.1021/acs.inorgchem.8b01943

NMR and X-ray diffraction studies were conducted on Pt(II)LCl₂ complexes prepared with the new N-donor ligands N(SO₂R)Me_ndpa (R = Me, Tol; n = 2, 4). These ligands differ from N(H)dpa (di-2-picolylamine) in having the cent

Full text of DOI:10.1021/acs.inorgchem.8b01943

Article
pubs.acs.org/IC
Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
Linear Bidentate Ligands (L) with Two Terminal Pyridyl N‑Donor
Groups Forming Pt(II)LCl2 Complexes with Rare Eight-Membered
Chelate Rings
Kokila Ranasinghe, Patricia A. Marzilli, Svetlana Pakhomova, and Luigi G. Marzilli*
Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, United States
S
* Supporting Information
ABSTRACT: NMR and X-ray diffraction studies were
conducted on Pt(II)LCl2 complexes prepared with the new
N-donor ligands N(SO2R)Mendpa (R = Me, Tol; n = 2, 4).
These ligands differ from N(H)dpa (di-2-picolylamine) in
having the central N within a tertiary sulfonamide group
instead of a secondary amine group and having Me groups at
the 6,6′-positions (n = 2) or 3,3′,5,5′-positions (n = 4) of the
pyridyl rings. The N(SO2R)3,3′,5,5′-Me4dpa ligands are
coordinated in a bidentate fashion in Pt(N(SO2R)3,3′,5,5′-
Me4dpa)Cl2 complexes, forming a rare eight-membered chelate ring. The sulfonamide N atom did not bind to Pt(II), consistent
with indications in the literature that tertiary sulfonamides are unlikely to anchor two meridionally coordinated five-membered
chelate rings in solutions of coordinating solvents. The N(SO2R)6,6′-Me2dpa ligands coordinate in a monodentate fashion to
form the binuclear complexes [trans-Pt(DMSO)Cl2]2(N(SO2R)6,6′-Me2dpa). The monodentate instead of bidentate
N(SO2R)6,6′-Me2dpa coordination is attributed to 6,6′-Me steric bulk. These binuclear complexes are indefinitely stable in
DMF-d7, but in DMSO-d6 the N(SO2R)6,6′-Me2dpa ligands dissociate completely. In DMSO-d6, the bidentate ligands in
Pt(N(SO2R)3,3′,5,5′-Me4dpa)Cl2 complexes also dissociate, but incompletely; these complexes provide rare examples of
association−dissociation equilibria of N,N bidentate ligands in Pt(II) chemistry. Like typical cis-PtLCl2 complexes, the
Pt(N(SO2R)3,3′,5,5′-Me4dpa)Cl2 complexes undergo monosolvolysis in DMSO-d6 to form the [Pt(N(SO2R)3,3′,5,5′-
Me4dpa)(DMSO-d6)Cl]+ cations. However, unlike typical cis-PtLCl2 complexes, the Pt(N(SO2R)3,3′,5,5′-Me4dpa)Cl2
complexes surprisingly do not react readily with the excellent N-donor bioligand guanosine. A comparison of the structural
features of over 50 known relevant Pt(II) complexes having smaller chelate rings with those of the very few relevant Pt(II)
complexes having eight-membered chelate rings indicates that the pyridyl rings in Pt(N(SO2R)3,3′,5,5′-Me4dpa)Cl2 complexes
are well positioned to form strong Pt−N bonds. Therefore, the dissociation of the bidentate ligand and the poor biomolecule
reactivity of the Pt(N(SO2R)3,3′,5,5′-Me4dpa)Cl2 complexes arise from steric consequences imposed by the −CH2−
N(SO2R)−CH2− chain in the eight-membered chelate ring.
[R = Me, p-tolyl (Tol)], in which the dangling group is
attached via a N−S bond. In addition, the central N-donor
atom is part of a tertiary sulfonamide group, which normally
binds to metals only when part of macrocyclic ligands.
Nevertheless, the N(SO2R)dpa- and N(SO2R)dien-type
ligands function as a new class of tridentate ligands and form
INTRODUCTION
■
New properties can be introduced into metal complexes by
linking dangling groups with targeting moieties or fluorophores
onto carrier ligands. Typically, the most useful linking
chemistry avoids creating new asymmetric centers in the
complexes, especially when the ultimate goal is to identify a
diagnostic or therapeutic agent. Often the central N atom of
N,N′,N″-donor tridentate ligands (Ltri) is used to attach the
dangling group (Figure 1).1−15 Various metal complexes of
tridentate-bound ligand derivatives of di-2-picolylamine
(N(H)dpa) or diethylenetriamine (dien) with a suitable
group attached to the central N possess useful properties,
such as enhanced targeting ability,2,7,8 fluorescence,3,10,13 high
anticancer/antitumor activity,9,11,12 or new bioconjugation
chemistry.4−6 In almost all cases, the dangling group is
attached to the chelate ligand via a N−C bond.
4
fac-[Re(CO)3 (N(SO2 R)dpa)]PF6 and fac-[Re-
5
(CO)3(N(SO2R)dien)]PF6 complexes that are the first
examples of any metal complex with the sulfonamide as part
of a noncyclic linear tridentate ligand having a normal metal−
N(sulfonamide) bond length (∼2.2 Å).4,5 The relevance of
such Re(I) complexes to the development of 99mTc(I) and
Re(I) diagnostic and therapeutic radiopharmaceutical agents
has been discussed.4,5 More recently, closely analogous
complexes of Mn(I) have been described.16,17
To expand the scope of dangling-group and donor-group
properties that can be employed, we have been investigating
N(SO2R)dpa-type (Figure 2) and N(SO2R)dien-type ligands
Received: July 12, 2018
© XXXX American Chemical Society
A
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Inorg. Chem. XXXX, XXX, XXX−XXX

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Article
possess a metal center, forming agents known to have
widespread use in biomedicine. In particular, Pt(II) complexes
with chelating ligands having dangling groups9−15,18,19 have
been widely explored because such complexes often exhibit
anticancer or antiviral activity.9,11,12,19
Adduct formation with biological molecules is usually not a
key feature for biological applications of Re(I) complexes.
However, Pt(II) complexes typically act by forming adducts
and require one or two leaving groups for functionality.
Because aromatic 1H NMR signals complicate studies of
adduct formation, we have utilized four new N(SO2R)Mendpa
ligands differing in methyl substitution patterns on the pyridyl
rings (Figure 2) to prepare Pt(II) complexes.
Figure 1. Components of a biological targeting therapeutic or
diagnostic metal-containing agent. The label * denotes a component
with no geometrical or optical isomers. The label # indicates a
nonchiral linking component attached to the central donor of the
chelate ligand, thereby avoiding the introduction of geometrical or
optical isomers.
Previous studies have shown that N(H)dpa (Figure 2) and
related ligands readily form [Pt(Ltri)Cl]+ complexes.20,21
However, the new N(SO2R)Mendpa ligands form Pt(II)
complexes with bidentate N(SO2R)Mendpa ligands having an
eight-membered chelate ring, in which the tertiary sulfonamide
nitrogen is not bound to Pt(II) but serves as an atom in the
−CH2−N(SO2R)−CH2− chain of the chelate ring. Structural
characterizations of Pt(II) complexes with bidentate ligands
having eight-membered chelate rings such as those found here
are very few in number compared with bifunctional Pt(II)
complexes with smaller five-, six-, or seven-membered chelate
rings of bidentate pyridyl/imidazolyl ligands22−44 or with two
pyridyl/imidazolyl monodentate ligands.45−49 The rarity and
unusual properties of the new bifunctional Pt(II) compounds
with a large eight-membered chelate ring described herein led
us to compare their structural features with those of related
bifunctional Pt(II) complexes. The relevance of binding at G
residues in DNA by anticancer-active Pt(II) com-
pounds22,27,37,38,49 has led to many studies of adduct formation
of guanine derivatives (G). Mono- and bifunctional Pt(II)
chloro complexes bearing carrier ligands with five- and six-
membered chelate rings readily form G adducts in various
solvents.20,21,50 Upon adduct formation, guanine ligands can
even disrupt and open a chelate ring.51 Surprisingly, the new
Pt(II) compounds do not readily form G adducts.
EXPERIMENTAL SECTION
Figure 2. Numbering scheme for N(H)dpa and N(SO2R)dpa, the
parent (P) ligand framework for N(SO2R)Mendpa ligands as follows:
N,N-bis(3,5-dimethyl-2-picolyl)methanesulfonamide, N(SO2Me)-
3,3′,5,5′-Me4dpa (1); N,N-bis(3,5-dimethyl-2-picolyl)-p-tolylsulfona-
mide, N(SO2Tol)3,3′,5,5′-Me4dpa (2); N,N-bis(6-methyl-2-picolyl)-
methanesulfonamide, N(SO2Me)6,6′-Me2dpa (3); and N,N-bis(6-
methyl-2-picolyl)-p-tolylsulfonamide, N(SO2Tol)6,6′-Me2dpa (4).
The numbering of the p-tolyl group is in italics to prevent confusion
with the numbering of the pyridyl rings.
■
Starting Materials. Methanesulfonamide (MeSO2NH2), p-
tolylsulfonamide (TolSO2NH2), 2,3,5-collidine, 6-methyl-2-pyridine-
methanol, tetraethylammonium chloride ([Et4N]Cl), and K2PtCl4
were used as received from Aldrich. cis-Pt(DMSO)2Cl2,52 2-
(chloromethyl)-6-methylpyridine,53 and 2-(chloromethyl)-3,5-dime-
thylpyridine54 were prepared by known methods.
1
NMR Measurements. H NMR spectra were recorded on a 400
MHz or an Avance III Prodigy 500 MHz Bruker spectrometer. Peak
positions are relative to tetramethylsilane (TMS) or the residual
solvent peak with TMS as the reference. All of the NMR data were
processed with TopSpin and MestReNova software. A presaturation
pulse to suppress the water peak was employed when necessary.
Mass Spectrometric Measurements. High-resolution mass
spectra were recorded on an Agilent 6210 electrospray ionization
(ESI) time of flight (TOF) LC−MS mass spectrometer.
X-ray Data Collection and Structure Determination.
Diffraction data were collected on a Bruker Kappa Apex II DUO
CCD diffractometer with Mo Kα radiation (λ = 0.71073 Å), equipped
with an Oxford Cryosystems Cryostream. All of the X-ray structures
were determined by direct methods and difference Fourier techniques
and refined by full-matrix least-squares using SHELXL201455 with H
atoms in idealized positions.
Resonance stabilization within the sulfonamide group causes
the sulfonamide nitrogen to lack a readily available lone pair of
electrons for metal coordination. For a M−N bond to form,
the bond must be energetically favorable enough to convert the
hybridization of the sulfonamide N from sp2 (resonance-
stabilized) to sp3 (stabilized by the M−N bond). A key factor
favoring coordination of the tertiary sulfonamide N of
N(SO2R)dpa- and N(SO2R)dien-type ligands to Re(I) is the
formation of two adjacent five-membered chelate rings, the
most favorable ring size for chelate formation. In this study, we
investigated whether under typical synthetic conditions a Pt−
N(sulfonamide) bond could also form in Pt(II) complexes of
N(SO2R)dpa-type ligands; in such a case, new types of
dangling groups could be employed with Pt(II) complexes that
General Synthesis of Ligands. A solution of the desired 2-
(chloromethyl)pyridine derivative (∼6 mmol), K2CO3 (∼1.7 g, 12
mmol), and the appropriate sulfonamide (∼2.5 mmol) in acetonitrile
B
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(95 mL) was heated at reflux under nitrogen for 18 h. After removal
of acetonitrile under reduced pressure, the residue was dissolved in
water (45 mL), and the solution was extracted with CH2Cl2 (3 × 45
mL). The organic layers were combined, washed with saturated
aqueous sodium chloride solution, dried over sodium sulfate, and
taken to dryness under reduced pressure. The residue was dissolved in
80:20 ethyl acetate/hexane and purified by chromatography on a silica
column with the same eluent. Fractions were collected and spotted on
TLC plates using the same eluent. The cleanest fractions, as assessed
NMR data were identical for the products obtained by methods A and
B.
Pt(N(SO2Me)3,3′,5,5′-Me4dpa)Cl2 (5). With N(SO2Me)3,3′,5,5′-
Me4dpa (1) (33 mg, 0.1 mmol) and cis-Pt(DMSO)2Cl2 (42 mg, 0.1
mmol), method A afforded a pale-yellow solid (26 mg, 44% yield).
Yellow crystals obtained by method B were characterized by single-
1
crystal X-ray crystallography. H NMR signals (ppm) in DMSO-d6:
8.98 (s, 2H, H6/6′), 7.56 (s, 2H, H4/4′), 5.99 (d, J = 14.7 Hz, 2H,
CH2), 5.37 (d, J = 14.9 Hz, 2H, CH2), 3.35 (s, 3H, CH3), 2.37 (s, 6H,
CH3), 2.23 (s, 6H, CH3). ESI-MS (m/z): [M − H]− = 597.0450
(calcd 597.0463).
1
by H NMR spectroscopy, were combined and taken to dryness by
rotary evaporation to afford the desired ligand in sufficient purity to
use in the synthesis of the corresponding Pt(II) complex.
Pt(N(SO2Tol)3,3′,5,5′-Me4dpa)Cl2 (6). With N(SO2Tol)3,3′,5,5′-
Me4dpa (2) (41 mg, 0.1 mmol) and cis-Pt(DMSO)2Cl2 (42 mg, 0.1
mmol), method A afforded a pale-yellow solid (25 mg, 37% yield).
Yellow crystals obtained by method B were characterized by single-
N(SO2Me)3,3′,5,5′-Me4dpa (1). The general ligand synthesis
described above was carried out with 2-(chloromethyl)-3,5-
dimethylpyridine (0.98 g, 6.2 mmol) and MeSO2NH2 (0.23 g, 2.4
mmol) and produced an orange residue that was purified by column
chromatography to afford N(SO2Me)3,3′,5,5′-Me4dpa as a white solid
1
crystal X-ray crystallography. H NMR signals (ppm) in DMSO-d6:
8.90 (s, 2H, H6/6′), 8.03 (d, J = 8.2 Hz, 2H, H2/6), 7.60 (d, J = 8.1
Hz, 2H, H3/5), 7.56 (s, 2H, H4/4′), 5.55 (d, J = 14.3 Hz, 2H, CH2),
5.47 (d, J = 14.3 Hz, 2H, CH2), 2.45 (s, 6H, CH3), 2.21 (s, 6H, CH3);
the phenyl methyl signal was masked by the solvent peak. ESI-MS
(m/z): [M + H]+ = 676.0926 (calcd 676.0913).
1
(0.54 g, 67% yield). H NMR signals (ppm) in CDCl3: 8.19 (s, 2H,
H6/6′), 7.23 (s, 1H, H4/4′), 4.60 (s, 4H, CH2), 3.15 (s, 3H, CH3),
1
2.28 (s, 6H, CH3), 2.21 (s, 6H, CH3). H NMR signals (ppm) in
DMSO-d6: 8.17 (s, 2H, H6/6′), 7.33 (s, 2H, H4/4′), 4.45 (s, 4H,
CH2), 3.13 (s, 3H, CH3), 2.23 (s, 6H, CH3), 2.12 (s, 6H, CH3). ESI-
MS (m/z): [M + H]+ = 334.1596 (calcd 334.1584).
[trans-Pt(DMSO)Cl2]2(N(SO2Me)6,6′-Me2dpa) (7). With
N(SO2Me)-6,6′-Me2dpa (3) (30 mg, 0.1 mmol) and cis-Pt-
(DMSO)2Cl2 (42 mg, 0.1 mmol), method A afforded a pale-yellow
solid (16 mg, 28% yield). 1H NMR signals (ppm) in DMSO-d6: 7.85
(t, J = 7.8 Hz, 2H, H4/4′), 7.68 (d, J = 7.9 Hz, 2H, H3/3′), 7.46 (d, J
= 7.8 Hz, 2H, H5/5′), 5.55 (s, 4H, CH2), 3.33 (s, 3H, CH3), 3.12 (s,
6H, CH3). ESI-MS (m/z): [M + H]+ = 993.9522 (calcd 993.9569).
[trans-Pt(DMSO)Cl2]2(N(SO2Tol)6,6′-Me2dpa) (8). With
N(SO2Tol)6,6′-Me2dpa (4) (38 mg, 0.1 mmol) and cis-Pt-
(DMSO)2Cl2 (42 mg, 0.1 mmol), method A afforded a pale-yellow
solid (14 mg, 22% yield). Yellow needle-shaped crystals obtained by
method B were characterized by single-crystal X-ray crystallography.
1H NMR signals (ppm) in DMSO-d6: 7.91 (d, J = 8.0 Hz, 2H, H2/6),
7.76 (t, J = 7.9 Hz, 2H, H4/4′), 7.57 (d, J = 8.0 Hz, 2H, H3/3′), 7.52
(d, J = 8.0 Hz, 2H, H3/5), 7.43 (d, J = 7.9 Hz, 2H, H5/5′), 5.46 (s,
4H, CH2), 3.11 (s, 6H, CH3), 2.43 (s, 3H, CH3). ESI-MS (m/z): [M
+ H]+ = 1069.9921 (calcd 1069.9884). The solvent of the clear, pale-
yellow filtrate from method A was removed under reduced pressure,
leaving a residue. The 1H NMR spectrum of this residue in DMSO-d6
showed peaks for free ligand 4 and for ligand 4 bound to Pt(II) in an
unsymmetric monodentate fashion.
N(SO2Tol)3,3′,5,5′-Me4dpa (2). The general ligand synthesis with
2-(chloromethyl)-3,5-dimethylpyridine (1.04 g, 6.6 mmol) and
TolSO2NH2 (0.46 g, 2.6 mmol) yielded an orange residue that was
purified by column chromatography to afford N(SO2Tol)3,3′,5,5′-
1
Me4dpa as a pale-yellow solid (0.88 g, 79% yield). H NMR signals
(ppm) in CDCl3: 7.98 (s, 2H, H6/6′), 7.70 (d, J = 8.1 Hz, 2H, H2/
6), 7.26 (masked by the solvent peak, 2H, H3/5), 7.07 (s, 2H, H4/
4′), 4.48 (s, 4H, CH2), 2.43 (s, 3H, CH3), 2.25 (s, 6H, CH3), 2.19 (s,
6H, CH3). 1H NMR signals (ppm) in DMSO-d6: 7.94 (s, 2H, H6/6′),
7.62 (d, J = 7.8 Hz, 2H, H2/6), 7.32 (d, J = 7.9 Hz, 2H, H3/5), 7.21
(s, 2H, H4/4′), 4.41 (s, 4H, CH2), 2.39 (s, 3H, CH3), 2.16 (s, 6H,
CH3), 2.13 (s, 6H, CH3). ESI-MS (m/z): [M + H]+ = 410.1876
(calcd 410.1897).
N(SO2Me)6,6′-Me2dpa) (3). The general ligand synthesis with 2-
(chloromethyl)-6-methylpyridine (0.90 g, 6.4 mmol) and MeSO2NH2
(0.24 g, 2.5 mmol) yielded an orange residue that was purified by
column chromatography to afford N(SO2Me)6,6′-Me2dpa as a
1
colorless oil (0.68 g, 88% yield). H NMR signals (ppm) in CDCl3:
7.55 (t, J = 7.7 Hz, 2H, H4/4′), 7.18 (d, J = 7.7 Hz, 2H, H5/5′), 7.05
(d, J = 7.7 Hz, 2H, H3/3′), 4.54 (s, 4H, CH2), 3.15 (s, 3H, CH3),
2.51 (s, 6H, CH3). 1H NMR signals (ppm) in DMSO-d6: 7.63 (t, J =
7.7 Hz, 2H, H4/4′), 7.12 (d, J = 7.8 Hz, 4H, H3/3′ and H5/5′), 4.42
(s, 4H, CH2), 3.14 (s, 3H, CH3), 2.41 (s, 6H, CH3). ESI-MS (m/z):
[M + H]+ = 306.1269 (calcd 306.1271).
Isolation of Crystals of trans-[Pt(DMSO)Cl2](N(SO2Tol)6,6′-
Me2dpa) (8a). In a preparation that led to the isolation of the new
complex detected in the residue just mentioned, an aqueous solution
of K2PtCl4 (0.208 g, 0.5 mmol in 10 mL) was heated to 70 °C and
treated with 70 μL (1 mmol) of DMSO followed after 10 min by 4
(191 mg, 0.5 mmol). The mixture was heated and stirred for 1 h at 95
°C. The yellow solid (78 mg, 15% yield) that precipitated was
collected by filtration, washed with methanol and ether, and identified
N(SO2Tol)6,6′-Me2dpa (4). The general ligand synthesis with 2-
(chloromethyl)-6-methylpyridine (1.00 g, 7.1 mmol) and Tol-
SO2NH2 (0.58 g, 3.4 mmol) yielded an orange residue that was
purified by column chromatography to afford N(SO2Tol)6,6′-Me2dpa
as a yellow oil (1.14 g, 89% yield). 1H NMR signals (ppm) in CDCl3:
7.71 (d, J = 8.1 Hz, 2H, H2/6), 7.43 (t, J = 7.7 Hz, 2H, H4/4′), 7.24
(d, J = 8.1 Hz, 2H, H3/5), 7.14 (d, J = 7.8 Hz, 2H, H3/3′), 6.92 (d, J
= 7.7 Hz, 2H, H5/5′), 4.56 (s, 4H, CH2), 2.42 (s, 3H, CH3), 2.37 (s,
6H, CH3). 1H NMR signals (ppm) in DMSO-d6: 7.67 (d, J = 8.2 Hz,
2H, H2/6), 7.53 (t, J = 7.7 Hz, 2H, H4/4′), 7.33 (d, J = 8.0 Hz, 2H,
H3/5), 7.04 (quasi-t, 4H, H3/3′ and H5/5′), 4.43 (s, 4H, CH2), 2.37
1
as complex 8 by its H NMR spectrum. Overnight this clear yellow
filtrate deposited yellow X-ray-quality crystals of 8a (53 mg, 15%
1
yield). The H NMR signals of the crystals of 8a in DMSO-d6 were
identical to those for the complex in the residue obtained with
method A (see above). 1H NMR signals (ppm) in DMSO-d6: 7.88 (t,
J = 8.0 Hz, 1H, H4b), 7.78 (d, J = 8.0 Hz, 2H, H2/6), 7.54 (t, J = 7.9
Hz, 1H, H4u), 7.49 (d, J = 8.0 Hz, 1H, H3b), 7.42 (d, J = 8.0 Hz, 3H,
H3/5 and H5b), 7.14 (d, J = 7.9 Hz, 1H, H3u), 7.04 (d, J = 7.9 Hz,
1H, H5u), 5.40 (s, 2H, CH2b), 4.50 (s, 2H, CH2u), 3.09 (s, 3H,
CH3b), 2.42 (s, 3H, CH3), 2.27 (s, 3H, CH3u). MALDI-TOF (m/z):
[M + Na]+ = 748.096 (calcd 748.052).
(s, 3H, CH3), 2.28 (s, 6H, CH3). ESI-MS (m/z): [M + H]+
=
382.1591 (calcd 382.1584).
General Synthesis of Complexes. A stirred solution of the
ligand (0.1 mmol) and cis-Pt(DMSO)2Cl2 (0.1 mmol) in methanol (5
mL) was heated at reflux overnight (∼16 h). The yellow precipitate
that formed overnight was collected by filtration, washed with
methanol and ether, and air-dried (method A). X-ray-quality crystals
were obtained by mixing equal volumes (1 mL) of solutions of cis-
Pt(DMSO)2Cl2 (12.5 mM) and the ligand (12.5 mM) in acetonitrile
and allowing the mixture to stand at room temperature. Needlelike
Solution Studies of 5. A solution of 5 (10 mM) in DMSO-d6
(solution 1) was monitored by H NMR spectroscopy for at least 21
1
days. Another 10 mM solution of 5 in DMSO-d6 was treated with 10
molar equiv of [Et4N]Cl (10 mg) after 1 day (solution 2). In another
experiment, 5 (3.6 mg) was added to a solution of [Et4N]Cl (100
mM) in DMSO-d6 to make the solution 10 mM in 5 (solution 3). In a
similar experiment, a sufficient amount of ligand 1 (1.3 mg) was
added to a solution containing cis-Pt(DMSO)2Cl2 (10 mM) and
[Et4N]Cl (100 mM) in DMSO-d6 to make the solution 10 mM in
1
crystals were obtained within 2 days to 2 weeks (method B). The H
C
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ligand 1 (solution 4). Another 10 mM solution of 1 in DMSO-d6 was
treated with 1 molar equiv of cis-Pt(DMSO)2Cl2 (1.7 mg) (solution
5). Solutions 2, 3, 4, and 5 were monitored over time by H NMR
numbering systems used to describe the solid-state data.
Selected bond lengths and angles are reported in Table 1.
Crystals of 6 contain two independent molecules in the
asymmetric unit, only one of which (B) is shown in Figure 6
and used in the discussion. The structural metrics of the two
halves of complex 8 are slightly different in the solid state and
are reported separately in Table 1 as Pt1 and Pt2.
The molecular structures of the Pt(II) complexes of ligands
1, 2, and 4 reveal that the sulfonamide N does not form a Pt−
N bond in any of the complexes (5, 6, 8, and 8a; Figures 5 and
6). The sulfonamide N of N(SO2Me)6,6′-Me2dpa (3) also
does not bind to Pt(II) (discussed later). The only Pt−N
bonds found in this work involve a pyridyl group. All of the
Pt−N bonds have lengths (Table 1) falling in the range
typically reported for Pt−N(sp2) bonds (1.99−2.08 Å).21,56
The bidentate coordination mode in the Pt(N(SO2R)3,3′,5,5′-
Me4dpa)Cl2 complexes [R = Me (5), R = Tol (6); Figure 5]
creates a relatively large and uncommon eight-membered
chelate ring.
1
spectroscopy. Solutions (10 mM) of 6 in DMSO-d6 or DMF-d7
(partially dissolved) and 7 and 8 in DMSO-d6 were kept at 25 °C and
1
monitored by H NMR spectroscopy.
RESULTS AND DISCUSSION
■
Synthesis of N(SO2R)Mendpa Derivatives and Their
Pt(II) Complexes. Our previous synthesis of N(SO2R)dpa
ligands4 (route 1, Figure 3) utilized commercially available
Structural Features Favoring Coordination of Ter-
tiary Sulfonamides. When a tertiary sulfonamide N is bound
to a metal center [e.g., Mn(I), Cu(II), Ni(II), Co(II),
Re(I)],1,4,5,16,17,57,58 the angles around the sulfonamide N
atom are consistent with sp3 hybridization. In contrast, the
angles around the tertiary sulfonamide N in 5 and 6 (Table 1)
are closer to 120° than to 109.5° (tetrahedral geometry),
indicating that sp2 hybridization of the sulfonamide N atom is
retained.
Figure 3. Synthetic routes for the ligands N(SO2R)dpa (route 1) and
N(SO2R)Mendpa (route 2). Conditions: (i) dioxane, room temper-
ature, 24 h; (ii) K2CO3, acetonitrile at reflux, N2, 18 h.
The N−S bond distances are generally longer (1.73−1.78
Å)1,4,5,16,17,57,58 in metal complexes with an N-coordinated
tertiary sulfonamide than in complexes with an uncoordinated
sulfonamide N (1.62−1.64 Å).1,4,57,59 Accordingly, the N−S
bond distances in the Pt(II) complexes reported here (Table
1) are shorter than those for such known complexes. Shorter
N−S bond distances in an uncoordinated sulfonamide group
indicate a considerable amount of double-bond character of
the N−S bond.1,4,60
N(H)dpa (Figure 2). However, the N(H)Mendpa parent
ligands needed in this study, N(H)3,3′,5,5′-Me4dpa and
N(H)6,6′-Me2dpa, are not commercially available. Thus, the
new N(SO2R)Mendpa ligands 1−4 were synthesized by a
different route in which the desired 2-chloromethylpyridyl
derivative (2 equiv) was coupled with the appropriate
sulfonamide under basic conditions (route 2, Figure 3).
Ligands 1−4 were treated with cis-Pt(DMSO)2Cl2 in methanol
at reflux to obtain complexes 5−8 (Figure 4).
X-ray Structural Results. Crystal data and structural
refinement details for 5, 6, 8, and 8a are summarized in the
Supporting Information. ORTEP plots of the molecular
structures of the complexes (Figures 5 and 6) show the
5
Except for fac-[Re(CO)3(N(SO2R)dien)]PF6 complexes,
the N(SO2R)dpa-type ligands are the only linear ligands found
thus far to have a bound tertiary sulfonamide in structurally
characterized complexes, e.g., fac-[Re(CO)3(N(SO2R)-
Mendpa)]PF6 (unpublished work using ligands 1−4 reported
here), fac-[Re(CO)3(N(SO2R)dpa)](PF6 or BF4), and fac-
[Mn(CO)3(N(SO2R)dpa)]CF3SO3.4,16,17 In these pseudo-
octahedral Re(I)/Mn(I) complexes, the three N-donor
atoms are facially coordinated. In structurally characterized
complexes with other metal centers, the metal-bound tertiary
sulfonamide nitrogen is within a macrocyclic ligand. In these
structures, the central sulfonamide nitrogen and the two
adjacent N-donor atoms occupy the face of an octahedron or
have a similar arrangement in complexes with other geometries
(such as distorted trigonal-bipyramidal or square-pyrami-
dal).4,16,61
In square-planar Pt(II) complexes, the central donor atom of
a tridentate ligand forming two five-membered chelate rings
must be able to accommodate the meridional coordination
mode. A clear case in which a tertiary sulfonamide group
anchors two chelate rings having a meridional disposition has
been reported for a square-planar Cu(II) complex of a
derivative of cyclam (a cyclic tetradentate macrocyclic N-
donor ligand with alternating five- and six-membered chelate
rings).61 One of the four donor nitrogens in the cyclam
derivative bears a tosyl group. The angles and other parameters
Figure 4. General reaction conditions for the formation of complexes
5−8.
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Figure 5. ORTEP plots of the complexes Pt(N(SO2Me)3,3′,5,5′-Me4dpa)Cl2 (5) and Pt(N(SO2Tol)3,3′,5,5′-Me4dpa)Cl2 (6). Thermal ellipsoids
are drawn with 50% probability.
Figure 6. ORTEP plots of the complexes [trans-Pt(DMSO)Cl2]2(N(SO2Tol)6,6′-Me2dpa) (8) and [trans-Pt(DMSO)Cl2](N(SO2Tol)6,6′-
Me2dpa) (8a). Thermal ellipsoids are drawn with 50% probability.
involving the sulfonamide N within the sulfonamide group are
normal for a coordinated sulfonamide, but the Cu−N-
(sulfonamide) bond is longer than all of the other Cu−N
bonds in the report. In the distorted sulfonamide complex, the
Cu(II) atom deviates by ∼0.2 Å from the planes defined either
by all four ligating N atoms or by any three ligating N atoms.
However, in the parent cyclam complex, the Cu(II) atom lies
in all such planes (deviation of ∼0.002 Å).
The structural features of complexes with M−N-
(sulfonamide) bonds reported in the literature, including the
Cu cyclam complexes just discussed, suggest a reason why
potentially tridentate ligands 1 and 2 coordinate in a bidentate
fashion in Pt(II) complexes 5 and 6, respectively, even when
the complexes are prepared using synthetic approaches known
to be successful with related ligands having a central amine N-
donor.20,50,51 These observations lead us to propose that a
E
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Table 1. Selected Bond Distances (Å) and Angles (deg) for Pt(N(SO2Me)3,3′,5,5′-Me4dpa)Cl2 (5), Pt(N(SO2Tol)3,3′,5,5′-
Me4dpa)Cl2 (6), [trans-Pt(DMSO)Cl2]2(N(SO2Tol)6,6′-Me2dpa) (8), and [trans-Pt(DMSO)Cl2](N(SO2Tol)6,6′-Me2dpa)
(8a)
8
5
6 (B)
2.027(3)
Pt1
Pt2
8a
Pt−N1
Pt−N2
Pt−N3
2.023(2)
3.693(2)
2.031(2)
2.2939(6)
2.2990(6)
1.436(3)
1.435(3)
1.6565(19)
−
2.062(9)
3.744(8)
−
2.303(2)
2.304(2)
1.429(8)
1.431(7)
1.642(8)
2.217(3)
−
−
2.0757(9)
4.5556(9)
−
2.2922(3)
2.3030(3)
1.4358(10)
1.4327(9)
1.6390(10)
2.2218(3)
−
a
3.317(3)
2.032(3)
2.2888(8)
2.3009(8)
1.430(3)
1.434(3)
1.630(3)
−
4.51(1)
2.066(8)
2.297(2)
2.320(3)
Pt−Cl1/3
Pt−Cl2/4
S1−O1
S1−O2
N2−S1
Pt−S2/3
N1−Pt−N3
S1−N2−C6
S1−N2−C7
2.219(3)
87.98(8)
113.77(17)
113.83(17)
95.21(10)
118.10(2)
117.0(2)
116.0(6)
118.9(6)
116.85(8)
118.66(7)
C6−N2−C7
114.78(17)
176.99(6)
89.51(6)
175.88(6)
90.22(6)
121.30(2)
176.62(8)
86.18(8)
178.51(7)
86.92(8)
115.3(7)
89.4(2)
86.9(2)
−
116.15(9)
89.70(3)
87.15(3)
−
N1−Pt−Cl2/4
N1−Pt−Cl1/3
N3−Pt−Cl1/3
N3−Pt−Cl2/4
Cl1/3−Pt−Cl2/4
−
−
86.2(2)
89.4(2)
175.57(9)
82.91
179.52
−
−
92.15(2)
90.66(3)
176.05(9)
75.13
173.49
5.15(1)
175.68(12)
85.23
174.16
4.632(1)
b
dihedral angle
77.18, 82.61
174.82, 174.23
2.816(3)
86.47, 87.17
169.84, 166.56
2.998(4)
Pt−N−centroid
a
N1−N3
a
b
Nonbonded distance between the two atoms. Angle between the coordination plane (defined by the Pt, N1, N3, and two Cl atoms) and the
pyridyl ring planes.
nitrogen atom in a central tertiary sulfonamide group with two
adjacent five-membered chelate rings can act as a donor in a
tridentate ligand only when the ligand is facially coordinated.
Comparison of Structural Features of the New
Pt(N(SO2R)3,3′,5,5′-Me4dpa)Cl2 Complexes with Those
of Other Bifunctional Pt(II) Complexes. The eight-
membered chelate ring in the Pt(N(SO2R)Mendpa)Cl2
complexes is a rare and hence interesting feature. Indeed,
only a few types of Pt(II) complexes containing eight-
membered chelate rings have molecular structures reported
to the Cambridge Crystallographic Data Centre (CCDC).
Most examples have very closely related bidentate ligand
derivatives with Pt(II) bound to the pyridyl N of a fused
bicyclic 7-azaindol-1-yl group.39,40,43 Only one Pt(II) complex
contains a linear ligand terminated with two simple aromatic
rings (pyridyl). Other complexes commonly have macrocyclic
N-donor (mostly sp3) ligands bound in a bidentate mode.41,42
In the CCDC database we found only three Pt(II) complexes
with an eight-membered chelate ring that contain two
aromatic-ring nitrogens (pyridyl/imidazolyl) and two halides
as the other ligating atoms;42−44 however, at the time of our
analysis there were 7, 17, and 108 complexes having seven-,
six-, and five-membered chelate rings, respectively.22−38
Structural data for 53 complexes (all of the complexes
containing eight-, seven-, and six-membered chelate rings
plus 26 randomly chosen complexes of five-membered chelate
rings) were utilized in the following comparison with the
structural data for 5 and 6.
N atoms in the ring) and the coordination plane (defined by Pt
and the four ligating atoms). If the dihedral angle is close to
90°, the aromatic ring is described as not being tilted. As the
angle decreases, the ring is said to become more tilted. The
two pyridyl rings in 5 and 6 are only slightly tilted, with
dihedral angles ranging from 77° to 87° (Table 1); thus, the
eight-membered ring allows the pyridyl rings to be oriented
roughly perpendicular to the coordination plane. In contrast,
other known bifunctional Pt(II) complexes with a bidentate
ligand terminated by pyridyl or imidazolyl rings [with the
remaining coordination site(s) occupied by halide(s)] and
forming five-, six-, or seven-membered chelate rings22−38 have
relatively smaller average dihedral angles (Figure 7). However,
the three known Pt(II) complexes with eight-membered
chelate rings42−44 used in the plot have large dihedral angles
(73−89°), values close to the dihedral angles observed in the
complexes reported here (Figure 7). Furthermore, the dihedral
angles of the known bifunctional Pt(II) complexes increase
almost linearly with increasing chelate ring size (Figure 7).
Therefore, the low degree of tilting in 5 and 6 probably reflects
the structural constraints mandated by the relatively large
eight-membered chelate ring.
The N1−Pt−N3 bite angle of 5 (87.98°) is at the high end
of the range reported for Pt(II) complexes with mono- or
bidentate-coordinated ligands terminated by pyridyl or
imidazolyl rings (78−91°).22−49 The bite angles of known Pt
complexes having eight-membered chelate rings (average
89.5°) are higher than for Pt complexes with smaller chelate
rings22−44 but are quite close to those for monodentate
complexes (average 89.4°)45−49 (Figure 8). We attribute this
finding to the greater spatial freedom provided by the larger
In bifunctional Pt(II) complexes with two cis aromatic
planar N-donor rings (one bidentate or two monodentate), the
tilting of each ring can be gauged by the dihedral angle
between the plane of the aromatic ring (defined by the C and
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ligands bound in a monodentate, bidentate, or tridentate
fashion.21−51,62−69 This angle averages 174.5° for 5 (Table 1),
which is similar to the value for monodentate ligands (176.7°;
see the Supporting Information); this is another indication that
the pyridyl rings in 5 are well-positioned to form a strong Pt−
N bond.
NMR Spectroscopy. All of the complexes (in DMSO-d6)
and ligands (in CDCl3 and DMSO-d6) reported here were
1
characterized by H NMR spectroscopy. In freshly prepared
DMSO-d6 solutions, all of the new complexes gave one set of
signals that were consistent with the presence of one time-
averaged symmetrical complex and in agreement with the
solid-state molecular structure when available. The atom
numbering scheme in Figure 2 was used to discuss the NMR
data; a modified version of this numbering used for 7a and 8a
is explained below. Signals were assigned by analyzing chemical
Figure 7. Relationship between average dihedral angle (blue line, left
axis, in degrees) and chelate ring size plotted for reported molecular
structures of bifunctional Pt(II) complexes with linear bidentate
ligands terminated by pyridyl or imidazolyl donor rings (with the
remaining two coordination sites occupied by halide ligands). The
orange line shows the number of donor rings utilized for each chelate
ring size. The red dot shows the average of the dihedral angles for 5
and 6 (83.4°). All of the published data in this figure are from the
Cambridge Crystallographic Data Centre, ConQuest 1.19. Of the 108
structures available for complexes with a five-membered chelate ring,
data for 26 randomly selected structures were used to prepare the
plot.
1
shifts, splitting patterns, integrations, and H−1H NOE cross-
peaks. 1H NMR shifts appear in Table 2 and in the
Experimental Section. Key assignment procedures are
described in the Supporting Information, along with more
1
NMR data and examples of spectra such as H−1H ROESY
spectra, which are useful for making assignments.
Effects of the Coordination Binding Mode on the
1
Methylene H NMR Signals of Ligands 1−4. Inversion at
the sulfonamide N of ligands 1−4 leads to time averaging and
makes the methylene protons magnetically equivalent, so the
1
methylene H NMR signal is a singlet. When the ligand is
coordinated in a bidentate fashion in the Pt(II) complexes, the
methylene protons are no longer made equivalent by a time-
averaging process. The protons projecting toward and away
from the Cl ligands are designated as endo-CH and exo-CH
protons, respectively (Figure 9). The observation of only one
set of 1H NMR signals (Figure 10 and the Supporting
Information) with the endo-CH and exo-CH protons
producing either two doublets (5) or an AB pattern (6) is
consistent with the presence of a symmetrical dichloro
complex with a bidentate chelate (Figure 5). Assignments of
the AB features/doublets as endo-CH or exo-CH for 5 and 6
(as explained in the Supporting Information) are presented in
Figure 10 and Table 2. The endo-CH signal is normally clearly
downfield of the exo-CH signal for 5, as previously reported for
[Pt(N(H)dpa)]Cl20 and [Pt(N(H)6,6′-Me2dpa)]Cl50,51 com-
plexes. For 6, these signals, which form an overlapped AB
pattern, were assigned by studying the temperature depend-
ence of the chemical shifts (see the Supporting Information).
Figure 8. Relationship of the average N−Pt−N bite angle (in degrees,
from reported molecular structures) to the chelate ring size of
bifunctional Pt(II) complexes of bidentate ligands terminated by
pyridyl or imidazolyl donor rings (with the remaining coordination
sites occupied by halide ligands). Of the 108 structures available for
complexes with a five-membered chelate ring, data for 26 randomly
selected structures were used to prepare the plot. The average of the
bite angles for eight cis bifunctional Pt(II) complexes of
monodentate-bound pyridyl or imidazolyl rings (89.4°) is plotted as
a red dot for comparison. All of the published data in this figure are
from the Cambridge Crystallographic Data Centre, ConQuest 1.19.
1
The H NMR signals of fresh DMSO-d6 solutions of 8 and
8a (Figure 11) are consistent with single species having the
molecular structures of 8 and 8a, respectively (Figure 6). The
NMR data (Table 2) for 7, 8, and 8a (Figure 11) and for 7a
(not shown) establish that the N(SO2R)6,6′-Me2dpa ligands
coordinate in a monodentate (not bidentate) fashion to form
binuclear or mononuclear complexes (Figures 4 and 6). As for
the free ligands, the methylene signals for all of the complexes
are singlets (Figure 11).
chelate ring; this freedom allows the N-donor rings to be
located in the same relative position as monodentate ligands.
Ideally, the Pt−N bond will lie close to the plane of an
aromatic N donor ligand to allow the lone pair of the N atom
to be positioned for excellent overlap with the Pt(II) bonding
orbital, thereby creating a strong bond. The angle between the
N-donor aromatic ring plane and the Pt atom is a good
structural parameter for assessing how close the Pt is to being
in this plane. This angle, defined as the Pt−N−centroid angle
(N = N1 or N3, centroid = aromatic ring center) should
approach ∼180°. The Pt−N−centroid angle ranges from 164−
180° for known Pt(II) complexes of imidazolyl or pyridyl
1H NMR Solution Studies of the Robustness and
Reactivity of Pt(II) Complexes of N(SO2R)3,3′,5,5′-
1
Me4dpa Ligands 1 and 2. H NMR spectra of solutions
(10 mM) of Pt(N(SO2R)3,3′,5,5′-Me4dpa)Cl2 complexes 5
and 6 indicate that these complexes do not undergo any
change over 7 days in DMF-d7 (see the Supporting
Information) but do change with time in DMSO-d6. We
examined the DMSO-d6 solution chemistry of complex 5 (R =
Me) in more detail than 6 because 5 has fewer and simpler
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1
Table 2. Selected H NMR Chemical Shifts (ppm, DMSO-d6, 25 °C) for N(SO2R)Mendpa Ligands 1−4 and Their Pt(II)
Complexes 5−8a
ligand or complex
H6/6′
H5/5′
H4/4′
7.33
H3/3′
CH2
6/6′-Me
SO2Me
1
5
2
6
3
7
7a
4
8
8.17
8.98
7.94
8.90
−
−
−
−
−
−
−
−
−
−
−
−
−
4.45
5.99, 5.37
−
−
3.13
3.35
−
a
b
a
7.56
7.21
7.56
7.63
7.85
4.41
5.55, 5.47
b
−
−
7.12
7.46
7.49, 7.16
7.04
7.12
7.68
7.57, 7.18
7.04
4.42
5.55
5.44, 4.52
2.41
3.12
3.23, 2.44
2.28
3.14
3.33
3.22
−
−
−
c
d
d
c
d
d
c
d
d
c
d
d
c
d
d
7.97, 7.60
7.53
4.43
5.46
5.40, 4.50
7.43
7.42, 7.04
7.76
7.88, 7.54
7.57
7.49, 7.14
3.11
3.09, 2.27
c
c
c
c
c
8a
b
−
a
c
d
endo-CH. exo-CH. Bound. Unbound.
center than are the H6/6′ protons, accounting for the presence
of an overlapped H4/4′ signal. A solution identical to solution
1 was allowed to stand for 24 h, and then 10 molar equiv of
[Et4N]Cl was added (solution 2). The changes at longer times
are described briefly below and in more detail in the
Supporting Information. Here we note that within 24 h the
5:5sol ratio changed from ∼6:4 to ∼40:1. The 5sol signals were
almost completely absent in another 10 mM solution of 5
(made by dissolving 3.6 mg of solid 5) in a DMSO-d6 solution
containing 100 mM [Et4N]Cl (solution 3, described in more
detail in the Supporting Information). The conversion of 5sol
into 5 in solution 2 and the suppression of the formation of 5sol
signals in solution 3 together with the features of the 5sol NMR
signals all establish without doubt that 5sol is [Pt(N(SO2Me)-
3,3′,5,5′-Me4dpa)(DMSO-d6)Cl]+. Pt(II)LCl2 complexes in
which L is an N,N bidentate ligand that have been reported to
undergo monosolvolysis in DMSO-d6 include examples in
which the N atoms are in pyridyl rings (Pt(bis(pyridine-2-
yl)amine)Cl237) and in amine groups (Pt(ethylenediamine)-
Figure 9. Designation of methylene endo-CH and exo-CH protons,
illustrated using the structure of 5.
70
Cl2 and Pt(DNSH-dienH)Cl210).
The NMR spectral changes over longer times in solutions of
5 in DMSO-d6 are revealing. In addition to the appearance of
NMR signals for 5sol in solution 1 as described above, signals of
the free ligand 1 became detectable a few hours after 5 was
dissolved (Figure 12). At 24 h, the 5:5sol:1 ratio was 59:34:7
(Figure 13). At 9 days, the major species was 5sol (5:5sol:1 =
12:46:42); this is the equilibrium composition, as no further
change in the ratio was detected even after 21 days.
At long times, solution 2 (created by addition of 10 molar
equiv of [Et4N]Cl to a 1-day-old 10 mM solution of 5; see the
Supporting Information) exhibited only NMR signals attrib-
utable to free 1 at ∼12 days. In solution 3, in which the
formation of 5sol was suppressed, 1H NMR peaks of free ligand
1 were first detected after a few hours until 100% free 1 was
present by ∼12 days (see the Supporting Information).
Collectively, this evidence indicates that the chloride ions
facilitate dissociation of ligand 1 from 5 or 5sol.
Two experiments in which 10 mM cis-Pt(DMSO)2Cl2 and 1
in DMSO-d6 were followed with time are described in the
Supporting Information. Solution 4, also containing 100 mM
[Et4N]Cl, showed no NMR signals for 5 or 5sol even after 4
days, indicating that a high chloride ion concentration prevents
1 from coordinating to Pt(II). Results with solution 5, also
having cis-Pt(DMSO)2Cl2 and 1 but no excess of competing
chloride ions, indicate that the affinity of ligand 1 at 10 mM for
Pt(II) is comparable to that of the DMSO-d6 molecules in the
solvent (“concentration” ∼ 14 M).
Figure 10. Selected region of the 1H NMR spectra in DMSO-d6 at 25
°C (shifts in ppm) of (a) ligand 1, (b) complex 5, (c) ligand 2, and
(d) complex 6.
NMR signals. One hour after “solution 1” (10 mM 5 in
DMSO-d6) was prepared, its spectrum showed, in addition to
1
the peaks for 5, a small but detectable new set of H NMR
peaks; these new peaks gradually increased with time (Figure
12). The intensity of the H6/6′ singlet of 5 at 8.98 ppm
gradually decreased. The shifts at 9.17 and 8.76 ppm of these
equally intense growing singlets indicate that the new product
contains Pt(II)-bound, geometrically inequivalent pyridyl
rings. These new aromatic H6 and H6′ signals are consistent
with the formation of the solvolysis product [Pt(N(SO2Me)-
3,3′,5,5′-Me4dpa)(DMSO-d6)Cl]+ (5sol). Unlike the H6/6′
protons, the H4/4′ protons of 5sol give rise to one overlapped
signal (7.74 ppm) with an intensity twice that of the H6 or H6′
signals. The H4/4′ protons are located farther from the Pt(II)
H
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1
Figure 11. Selected region of the H NMR spectra (ppm, fresh DMSO-d6 solutions, 25 °C) of (a) ligand 3, (b) complex 7, (c) ligand 4, (d)
complex 8, and (e) complex 8a (whose structure is shown as a line drawing at the right).
Figure 12. Selected region of the 1H NMR spectra of solution 1 (10 mM 5 in DMSO-d6) at 25 °C (shifts in ppm). Spectra at various times after
dissolution of 5 reveal its solvolysis to form [Pt(N(SO2Me)3,3′,5,5′-Me4dpa)(DMSO)Cl]+ (5sol) (shown as a line drawing at the right) and free
ligand 1. The top trace at 9 days corresponds to the equilibrated solution.
or seven-membered49 chelate rings and can adopt optimal
metrics not limited by the chelate ring (see the Supporting
Information). These structural metrics as well as the downfield
shifts of NMR signals noted above indicate that 5 has
enthalpically favorable pyridyl−Pt bonding interactions. As
discussed in the Supporting Information, there is evidence that
a head-to-head geometry of two cis pyridyl ligands with α-
carbon substituents such as the methylene groups of the
−CH2−N(SO2R)−CH2− chain is sterically unfavorable. Thus,
the unfavorable entropy component of an eight-membered
chelate ring and possibly steric strain within the large chelate
ring itself most likely account for the low robustness of 5 and 6
in DMSO-d6.
The reactivity of 5 with simple G derivatives was assessed at
25 °C by 1H NMR spectroscopy. In DMF-d7, a 1:2.5 mol/mol
Figure 13. Percent distribution of 5 (orange), 5sol (green), and free
ligand 1 (blue) in solution 1 (10 mM 5 in DMSO-d6) at 25 °C
mixture of 5 (5 mM) and guanosine (Guo) (the solution was
plotted vs time. Percent distribution values were calculated from
cloudy because of poor solubility) was monitored and
integrations of the H4/4′ signals of each species.
exhibited no changes even after 4 days. In DMSO-d6, 5 (10
mM) was treated with 2.5 molar equiv of 9-MeG or Guo. For
1
both solutions, new H NMR peaks for 5sol and free 1 were
first detectable after ∼1 and ∼4 h, respectively. These results
are very similar to those observed in the absence of added 9-
The Pt−N−centroid angles of 5 are similar to the values for
other bifunctional Pt(II) complexes of monodentate pyridyl
ligands, which have five-membered,20−22,51 six-membered,27,37
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MeG or Guo. Several new peaks consistent with the formation
of G adducts were observed only at later times. However, even
at 24 h the integration of these new peaks indicated a very low
amount of G adduct formation compared with the reactions
forming 5sol and free ligand 1. Results similar to those just
described for reaction mixtures of 5 with G derivatives were
found with other ligands known to bind Pt(II) (1-
methylimidazole, 5,5′-Me2bpy, and Me4dt).22,38,71 These
results in DMF-d7 and DMSO-d6 indicate that G derivatives
and other ligands do not promote chelate ring opening in 5. In
contrast, 9-EtG (2.5 equiv) immediately promoted chelate ring
opening of the tridentate ligand in [Pt(N(H)6,6′-Me2dpa)-
Cl]Cl.51
Solution Studies of the Robustness of Pt(II) Com-
plexes of N(SO2R)6,6′-Me2dpa Ligands 3 and 4. Whereas
complexes 5 and 6 released bidentate-bound ligands 1 and 2
only partially (∼40%), the release of monodentate-bound
ligands 3 and 4 from 7 and 8, respectively, was essentially
complete (>90%). This result indicates that the complexes
formed by bidentate ligands 1 and 2 are more thermodynami-
cally stable than the complexes formed by monodentate
ligands 3 and 4, as might be expected. The Pt−N bond
distances are 0.03 to 0.05 Å longer in 8 and 8a than in 5 and 6
(Table 2). Although the differences are not all statistically
significant, there are enough consistent reports on Pt(II)
structures to suggest that having a monodentate pyridine
substituted at both the 2- and 6-positions with groups having
CH2Y (Y = various groups, the simplest being OH) will
increase the Pt−N bond distance by ∼0.02 to ∼0.03 Å and
that having a trans DMSO ligand will add a further ∼0.01 to
∼0.02 Å.72−75 Therefore, it is likely that the known trans
influence of the DMSO ligand76,77 and the steric effect of the
substituents at the 2,6-positions weaken the Pt−N bond and
thus lead to the more complete release of ligands 3 and 4
compared with ligands 1 and 2. However, the monodentate
ligands 3 and 4 were released from complexes 7 and 8,
respectively, less quickly than the bidentate-bound ligands 1
and 2 were released from complexes 5 and 6, respectively.
These results and the role that the 6/6′ methyl groups play in
slowing ligand release and also in favoring monodentate over
bidentate binding by ligands 1 and 2 are presented in the
Supporting Information.
From an extensive analysis of structural data of relevant
Pt(II) complexes, we conclude that the pyridyl groups in the
new complexes occupy locations that allow the formation of
favorable Pt−N(pyridyl) bonds. We conclude that steric
repulsions within the −CH2−N(SO2R)−CH2− chain of the
eight-membered chelate ring may be sufficiently unfavorable to
overcome the likely small entropy term favoring the large
eight-membered chelate ring. As a consequence, an unusual
equilibrium is established between an N,N bidentate chelate
ligand bound in a Pt(II) complex and that ligand free in
solution.
The chelate ring in complexes 5 and 6 appears to restrict the
dihedral angle between the coordination plane and the plane of
the pyridyl rings to high values near 90°. Thus, the pyridyl
rings could sterically hinder the binding of N-donor ligands to
5 and 6. The N-donor nucleobase of guanosine is relatively
large, explaining the observed very unusual, perhaps even
unique, lack of reactivity of these Pt(II) chloro complexes
toward guanosine. Both the bidentate ligand release and the
lack of reactivity toward guanosine thus must be circumvented
in future ligand design. Because the ligands form bifunctional
(not monofunctional) Pt(II) complexes, we believe that new
ligands with smaller terminal donor groups will improve both
the stability and reactivity of the complexes while increasing
the potential utility of the complexes in biological applications.
A possible contributing reason why the N(SO2R)dpa-type
ligands did not form a Pt(II)−N(sulfonamide) bond is that the
N(sulfonamide) group would be a very poor donor if the
group were to anchor two adjacent five-membered chelate
rings in a meridional geometry. This suggestion is consistent
with extensive reported structural information on complexes
with a M−N(tertiary sulfonamide) bond; these results suggest
to us that the tertiary sulfonamide N-donor enforces facial
coordination. Because only a very few types of anchoring
donor groups in linear multidentate chelate ligands are known
to enforce facial stereochemistry,79 further studies assessing
tertiary sulfonamide donors within linear chelate ligands are
warranted.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.8b01943.
CONCLUSIONS
■
Table of selected crystal data and structure refinement
parameters for complexes 5, 6, 8, and 8a; plot relating
the average Pt−N−centroid angle to the chelate ring size
Past work has almost always incorporated tertiary sulfonamide
linking groups within macrocyclic ligands in order to overcome
the weak N(sulfonamide)-donor ability; such complexes have
distorted geometries and long M−N(sulfonamide) bonds
(even for the tight tacn macrocyclic ring).58,60,78 Pt(II)
complexes with tetradentate macrocyclic ligands lack func-
tional leaving ligands needed for reactions with biomolecules;
such reactivity is a major reason why Pt(II) compounds have
enjoyed wide use in both therapeutic and diagnostic
applications. In this work, we explored the extension of
N(SO2R)dpa-type tridentate ligand chemistry to Pt(II) chloro
compounds by using synthetic conditions applicable to
complexes intended for biological applications and known to
lead to Pt(II) complexes with chloride leaving ligands. Under
these conditions with N(SO2R)3,3′,5,5′-Me4dpa ligands, a Pt−
N(sulfonamide) bond did not form. Instead, the ligands bound
in a bidentate fashion, creating Pt(II) chloro complexes with
rarely observed eight-membered chelate rings.
1
of Pt(II) complexes; selected regions of 1D or 2D H
1
NMR spectra of complexes 5, 6, 7, 8, and 8a; H NMR
1
signal assignments for 5−8a; more complete H NMR
shift data for ligands 1−4 and complexes 5−8 (in
DMSO-d6 and DMF-d7); description of changes with
time in complexes of ligands 1−4 in DMSO-d6,
including effects of added [Et4N]Cl; and discussion of
possible reasons favoring monodentate coordination of
ligands 3 and 4 to Pt(II) (PDF)
Accession Codes
CCDC 1855002−1855004 and 1855006 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by e-mailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
J
DOI: 10.1021/acs.inorgchem.8b01943
Inorg. Chem. XXXX, XXX, XXX−XXX

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Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223
336033.
AUTHOR INFORMATION
Corresponding Author
*E-mail: lmarzil@lsu.edu.
■
ORCID
Kokila Ranasinghe: 0000-0001-9021-0076
Patricia A. Marzilli: 0000-0002-8103-9606
Luigi G. Marzilli: 0000-0002-0406-0858
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Upgrade of the diffractometer was made possible through
Grant LEQSF(2011-12)-ENH-TR-01, administered by the
Louisiana Board of Regents. We thank Dr. Frank Fronczek for
his help with some aspects of the X-ray structural studies.
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DOI: 10.1021/acs.inorgchem.8b01943
Inorg. Chem. XXXX, XXX, XXX−XXX