Utilizing redox-mediated bergman cyclization toward the development of dual-action metalloenediyne therapeutics

Article abstract of DOI:10.1021/ja308190q

Reaction of 2 equiv of 1,2-bis((diphenylphosphino)ethynyl)benzene (dppeb, 1) with Pt(cod)Cl₂ followed by treatment with N₂H ₄ yields the reduced Pt(0) metalloenediyne, Pt(dppeb)₂, 2. This complex is stable to both air oxidation and metal-mediated Bergman cyclization under ambient conditions due to the nearly idealized tetrahedral geometry. Reaction of 2 with 1 equiv of I₂ in the presence of excess 1,4-cyclohexadiene (1,4-CHD) radical trap rapidly and near-quantitatively generates the cis-Bergman-cyclized, diiodo product 3 (³¹P: δ = 41 ppm, J_Pt-P = 3346 Hz) with concomitant loss of 1 equiv of uncyclized phosphine chelate (³¹P: δ = -33 ppm). In contrast, addition of 2 equiv of I₂ in the absence of additional radical trap instantaneously forms a metastable Pt(dppeb)₂²⁺ intermediate species, 4, that is characterized by δ = 51 ppm in the ³¹P NMR (J_Pt-P = 3171 Hz) and ν_{Ci? - C} = 2169 cm^-1 in the Raman profile, indicating that it is an uncyclized, bis-ligated complex. Over 24 h, 4 undergoes ligand exchange to form a neutral, square planar complex that spontaneously Bergman cyclizes at ambient temperature to give the crystalline product Pt(dppnap-I₂)I ₂ (dppnap-I₂ = (1,4-diiodonaphthalene-2,3-diyl) bis(diphenylphosphine)), 5, in 52% isolated yield. Computational analysis of the oxidation reaction proposes two plausible flattened tetrahedral structures for intermediate 4: one where the phosphine core has migrated to a trans-spanning chelate geometry, and a second, higher energy structure (3.3 kcal/mol) with two cis-chelating phosphine ligands (41 dihedral angle) via a restricted alkyne-terminal starting point. While the energies are disparate, the common theme in both structures is the elongated Pt-P bond lengths (>2.4 A?), indicating that nucleophilic ligand substitution by I^- is on the reaction trajectory to the cyclized product 5. The efficiency of the redox-mediated Bergman cyclization reaction of this stable Pt(0) metalloenediyne prodrug and resulting cisplatin-like byproduct represents an intriguing new strategy for potential dual-threat metalloenediyne therapeutics.

Full text of DOI:10.1021/ja308190q

Article
pubs.acs.org/JACS
Utilizing Redox-Mediated Bergman Cyclization toward the
Development of Dual-Action Metalloenediyne Therapeutics
Sarah E. Lindahl,† Hyunsoo Park,‡ Maren Pink,‡ and Jeffrey M. Zaleski*,†
‡
†Department of Chemistry and Molecular Structure Center, Indiana University, Bloomington, Indiana 47405, United States
S
* Supporting Information
ABSTRACT: Reaction of 2 equiv of 1,2-bis((diphenyl-
phosphino)ethynyl)benzene (dppeb, 1) with Pt(cod)Cl2
followed by treatment with N2H4 yields the reduced Pt(0)
metalloenediyne, Pt(dppeb)2, 2. This complex is stable to both
air oxidation and metal-mediated Bergman cyclization under
ambient conditions due to the nearly idealized tetrahedral
geometry. Reaction of 2 with 1 equiv of I2 in the presence of
excess 1,4-cyclohexadiene (1,4-CHD) radical trap rapidly and near-quantitatively generates the cis-Bergman-cyclized, diiodo
product 3 (31P: δ = 41 ppm, JPt−P = 3346 Hz) with concomitant loss of 1 equiv of uncyclized phosphine chelate (31P: δ = −33
ppm). In contrast, addition of 2 equiv of I2 in the absence of additional radical trap instantaneously forms a metastable
Pt(dppeb)22+ intermediate species, 4, that is characterized by δ = 51 ppm in the 31P NMR (JPt−P = 3171 Hz) and νCC = 2169
cm−1 in the Raman profile, indicating that it is an uncyclized, bis-ligated complex. Over 24 h, 4 undergoes ligand exchange to
form a neutral, square planar complex that spontaneously Bergman cyclizes at ambient temperature to give the crystalline
product Pt(dppnap-I2)I2 (dppnap-I2 = (1,4-diiodonaphthalene-2,3-diyl)bis(diphenylphosphine)), 5, in 52% isolated yield.
Computational analysis of the oxidation reaction proposes two plausible flattened tetrahedral structures for intermediate 4: one
where the phosphine core has migrated to a trans-spanning chelate geometry, and a second, higher energy structure (3.3 kcal/
mol) with two cis-chelating phosphine ligands (41° dihedral angle) via a restricted alkyne-terminal starting point. While the
energies are disparate, the common theme in both structures is the elongated Pt−P bond lengths (>2.4 Å), indicating that
nucleophilic ligand substitution by I− is on the reaction trajectory to the cyclized product 5. The efficiency of the redox-mediated
Bergman cyclization reaction of this stable Pt(0) metalloenediyne prodrug and resulting cisplatin-like byproduct represents an
intriguing new strategy for potential dual-threat metalloenediyne therapeutics.
active in cisplatin- and oxaliplatin-resistant cell lines.10−12
Although considerable evidence exists for DNA platination by
these complexes, their activities in cisplatin-resistant cells,
combined with the lack of cell cycle interference, suggests that
INTRODUCTION
■
In 1965, Rosenberg’s interest in the effects of alternating
current electric fields on Escherichia coli proliferation using Pt-
mesh electrodes led to the curious observation of filamentous
cell growth due to the arrest of cell division. Rosenberg traced
the phenomenon to Pt(IV) and Pt(II) species generated in situ
by oxidation of the metallic Pt electrodes within the ammonium
chloride-containing growth medium. This fundamental inquiry
ultimately led to the serendipitous discovery of cisplatin, (cis-
targets other than DNA and alternate mechanisms leading to
cell death may be operative.12
Ligand structural compositions beyond am(m)ines, specifi-
cally Pt-phosphine or mixed phosphine/am(m)ine complexes,
also show considerable antitumor activity.13−30 Complexes with
open or exchangeable coordination positions appear to operate
Pt(NH3)2Cl2), the most celebrated inorganic medicinal agent
since its FDA approval in 1978.1,2 The mechanism of action of
in the more classic cisplain-like manner via DNA adduct
formation,13,18,19,21,23,26−30 while coordinatively saturated struc-
cisplatin derives from aquation of the Pt(II) center to form a
tures, especially those with chelating lipophilic phosphines, are
cationic complex that binds DNA predominately through 1,2-
proposed to function by a unique anti-mitochondrial
intrastrand guanine N7 (GG) cross-links that kink the DNA
mechanism.18,19,21 This functional divergence may be the
backbone at ∼40°, leading to disruption of DNA synthesis and
ultimately cell death.2−8
reason that these cationic complexes are active against cisplatin-
resistant cells.
Rosenberg also recognized that Pt(IV) compounds may be
The impact of Rosenberg’s fundamental discovery has fueled
development of second-generation compounds such as
carboplatin and oxaliplatin.2,7,9 Simultaneously, considerable
viable as anti-proliferation agents, though many have been
effort has gone into probing trans-Pt(II) constructs,10−12
despite the fact that transplatin itself has no therapeutic
shown to be reduced to active Pt(II) species within the
cell.9,31,32 Nevertheless, recent chemical strategies have taken
activity. Indeed, trans-Pt(II) structures supporting sterically
hindered amines and iminoethers restore antitumor activities
mirroring the action of cisplatin and, more remarkably, are
Received: August 17, 2012
Published: February 22, 2013
© 2013 American Chemical Society
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advantage of the solubility enhancement and favorable
pharmacokinetics of redox-active Pt(IV) complexes as potential
cisplatin prodrugs.9,31−34 In addition, Pt(IV) complexes have
been recognized as a viable photochemically active route to
two-electron-reduced cisplatin-like structures. Here, UV
photolysis of all trans-Pt(N3)2(OH)2 am(m)ine/imine deriva-
tives leads to azide-to-Pt(IV) ligand-to-metal charge transfer
(LMCT), resulting in Pt(II) formation with concomitant azide
radical dissociation.35−40 While the Pt(II) product is capable of
forming DNA adducts analogous to those of traditional
cisplatin derivatives, the release of reactive nitrogen species is
also proposed to account for cytotoxicity by an alternative
autophagy mechanism.40
Our interest in metal-enediyne complexes bearing reactive
radical-generating ligands41−51 capable of H-atom abstraction
like their parent enediyne natural products52,53 has led to an
ongoing investigation of the reactive 1,2-bis((diphenyl-
phosphino)ethynyl)benzene (dppeb, 1) ligand with platinum
originally reported by Buchwald.54 We have demonstrated that
geometric modulation controls metal-enediyne conformations
and, consequently, reactivities/stabilities toward Bergman
cyclization. For comparable structure types, tetrahedral geo-
metries are markedly more stable to Bergman cyclization than
their planar metalloenediyne counterparts, to upward of 100
°C.43,55,56 The question we propose is, can a metal-based redox
process be used to rapidly and efficiently switch these stable
constructs to reactive molecules capable of Bergman cycliza-
tion, similar to the way Pt(IV) LMCT photolysis leads to
formation of reduced cisplatin derivatives? While redox-
controlled Bergman cycloaromatization has been examined
within an organic hydroquinone/quinone couple,57 metal
oxidation/reduction-triggered cyclization has not been demon-
strated.
crystallographic analysis reveals that 2 has a tetrahedral
geometry about the metal center, with nearly idealized P−
Pt−P angles of 109°. The interalkynyl distance, 3.46 Å, which is
similar to other d10 homologues,41,42 is found to be reduced
relative to free ligand 1, but increased with respect to the
proposed square planar, Pt(II) analogue.54 As a consequence,
the Bergman cyclization temperature of 2 is high (231 °C) in
the solid state as evaluated from the maximum of the
differential scanning calorimetry trace, consistent with other
tetrahedral metalloenediynes.41−43,58
In an effort to explore whether in situ oxidation can be used
to promote Bergman cyclization of thermally robust d10
metalloenediynes, 1 equiv of I2 was added to a solution of 2
in the presence of excess 1,4-CHD in deoxygenated CD2Cl2 at
room temperature (Scheme 2). Immediately upon addition, an
Scheme 2. Redox-Mediated Bergman Cyclization of 2 in the
Presence of Excess 1,4-CHD To Yield the Benzannulated
a
Product 3
a
Thermal ellipsoids are illustrated at 50% probability and H-atoms
have been omitted for clarity.
orange-to-yellow color change is observed and 31P NMR
reveals near quantitative conversion of the starting material (δ =
−13 ppm, JPt−P = 3923 Hz) to a single platinated species, 3 (δ =
41 ppm, JPt−P: 3346 Hz) and free ligand, 1 (δ = −33 ppm,
Figure 1).59 The only other 31P NMR signal observed is at δ =
Within this theme, we report a chemical rendering of
Rosenberg’s original Pt-electrode oxidation to form cisplatin in
situ. Here, oxidation of a tetrahedral Pt(0) phosphino-
metalloenediyne complex generates a square planar cis-Pt(II)
phosphine dihalide product via a reactive diradical intermediate
capable of H-atom abstraction. The base Pt-phosphine
structural motif parallels established Pt-phosphines with
antitumor activity. More importantly, both the diradical
intermediate and the final square planar product have the
potential to attack biological substrates by different mechanisms
and thus represent a conceptual design for the development of
metal-mediated dual-threat therapies.
RESULTS AND DISCUSSION
■
The air-stable Pt(0) metalloenediyne, 2, was prepared by
reacting 2 equiv of 154 with Pt(cod)Cl2 followed by addition of
N2H4 (Scheme 1). Purification and recrystallization from cold
EtOH affords 2 as an orange solid that has been fully
characterized in both solution and the solid state. X-ray
Figure 1. 31P NMR spectra showing the oxidation of 2 in the presence
of I2 and excess 1,4-CHD leading to the instantaneous generation of 3
in near quantitative yield.
Scheme 1. Synthesis of Bis(1,2-
bis((diphenylphosphino)ethynyl)benzene)platinum(0), 2
6.86 ppm (∼ 7%) and can be attributed to trace formation of
phosphine-iodine adducts.60−65 The reaction is complete within
5 min and complex 3 is stable in solution as no further changes
are observed in the 31P NMR spectrum over a matter of 3 d.
The Pt satellites, 31P chemical shift, and JPt−P: 3346 Hz
indicate that 3 is a Pt(II) structure with one chelating
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phosphine ligand.66 To verify the 31P chemical shift of the
Pt(II) complex and determine the cyclization state of the ligand
upon oxidation, 3 was independently synthesized by reaction of
Pt(cod)I2 and 1 in a 1:1 molar ratio in the presence of excess
1,4-CHD and toluene at 80 °C for 3 h (Scheme 3).67 The
product. The second equivalent of I2 serves as a stoichiometric
radical trap, quenching the 1,4-diradical intermediate generated
upon cyclization. From the X-ray structure of 5 it is clear that
the reduced quencher concentration fortuitously reveals the
presence of intermediate 4, which is not detected during the
formation of 3 with excess 1,4-CHD. Finally, the divalent metal
center of 5 exhibits a nearly idealized square planar
coordination environment with the naphthalene ring lying
approximately 5° below the plane of the metal center.
Scheme 3. Independent Synthesis of Diiodo-(2,3-
bis(diphenylphosphino)naphthalene)platinum(II), 3
Though 5 is confirmed as the oxidized, cyclized product, the
structure and geometry of intermediate 4 with 31P NMR signal
at δ = 51 ppm are ambiguous. The transformation from 2 to 5
requires both oxidation and cyclization of the starting material;
however, it is unclear whether those are concerted or stepwise
events.
To fully understand this oxidation-induced transformation
via intermediate 4, a solution of 2 in deoxygenated CD2Cl2 was
subject to sequential in situ oxidation and reduction. Upon the
addition of 2 equiv of iodine, quantitative oxidation of 2 is
confirmed by the presence of the 31P signal at δ = 51 ppm.
Immediately following oxidation, excess reducing equivalents in
the form of hydrazine were added to the reaction mixture and
the 31P NMR spectrum acquired. The addition of N2H4
regenerates the starting material 2 (Figure 2), as well as the
phosphine-oxide analogue of the free ligand 6, which has been
confirmed and characterized by independent synthesis.68 The
reduction of 4 back to uncyclized starting material suggests that
4 must possess uncyclized alkynes, as a long-lived diradical
species is not plausible and conversion from a benzannulated
product back through a diradical intermediate is an energeti-
cally uphill process.69 Moreover, this oxidation has been found
to be electrochemically reversible as shown by the single
anodic, quasi-reversible wave at Epa = −361 mV (vs Fc/Fc+) in
the cyclic voltammogram of 2 (Figure 3), further demonstrat-
ing that 4 must be a soluble, uncyclized Pt(II) complex
containing both phosphine ligands.
reaction affords the Bergman cyclized diiodo product, 3 in 82%
yield, as confirmed by the loss of the alkyne carbons in the 13C
NMR spectrum and high-resolution mass analysis (see
Experimental Section for full characterization).
Interestingly, the addition of 2 equiv of I2 to a deoxygenated
solution of 2 in CD2Cl2 devoid of 1,4-CHD at room
temperature does not accelerate the oxidation reaction. Rather,
immediately upon addition an orange-to-yellow color change is
observed and 31P NMR reveals quantitative conversion of the
starting material (δ = −13 ppm, JPt−P = 3923 Hz) to a single
phosphorus-containing species, 4 (δ = 51 ppm, JPt−P = 3171
Hz) of different chemical shift than 3 (Figure 2). After
Off-resonance (λ = 785 nm, 2 mW) Raman spectroscopy was
also used to probe the ligand functional group composition of 4
and determine whether the alkynes remain unactivated in
solution (Figure 4). The Raman spectrum of 2 shows an
intense alkyne stretching vibration at 2150 cm−1 as well as
phenyl ring and 1,2-disubstituted benzene stretching and
bending vibrations between 1600 and 600 cm−1. The Raman
spectrum of 5 is devoid of an alkyne vibration as expected due
to the cyclized nature of the complex. Intense νCC stretching
modes and δC−H in-plane and out-of-plane aromatic deforma-
tions are still observed throughout the spectrum; however, the
appearance of new signals at 1357 and 1319 cm−1, characteristic
of mono- or disubstituted naphthalenes,70 provides an
additional spectroscopic handle for the identification of cyclized
enediyne moieties. The Raman spectrum of 4 is quite similar to
that of 2, with a strong, broad alkyne vibration at 2169 cm−1.
The presence of this feature, coupled with the lack of
substituted naphthalene signals between 1400 and 1300 cm−1,
indicates that the in situ species 4 possesses uncyclized alkyne
functionalities.
Figure 2. 31P NMR spectra showing the oxidation of 2 to 4 and
subsequent reduction of 4 to regenerate starting material. The
designated (*) signal corresponds to the phosphine-oxide analogue of
the free ligand, 6, which is generated during the reduction reaction and
has been confirmed and characterized by independent synthesis.
approximately 24 h, the 31P signal corresponding to 4 decreases
in intesity concomitant with the formation of a yellow
crystalline precipitate, 5 (Scheme 4). Complex 5 was isolated
in 52% yield and found to be insoluble in both polar and
nonpolar solvents. During the precipitation of 5, multiple weak
31P signals (10−50 ppm) are observed that are attributed to
phosphine-iodine adducts of the liberated phosphine li-
gand.60−65
The X-ray crystal structure of 5 reveals that this Bergman-
cyclized product results from the two-electron oxidation of the
platinum center by 1 equiv of iodine with loss of one
phosphine-enediyne ligand to generate the diiodo cisplatin-like
Though 4 could not be isolated and analyzed crystallo-
graphically, speculations regarding the geometry of this species
can be made from the available experimental data. The 31P
NMR spectrum of 4 shows conversion to a single phosphorus-
containing species implying that 4 is a four-coordinate
structure, with a chemical shift indicative of a Pt(II) complex.
The highly comparable Raman spectra of 2 and 4 also mandate
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a
Scheme 4. Oxidation and Subsequent in Situ Bergman Cyclization of 2 To Generate the Benzannulated Complex 5
a
Thermal ellipsoids are illustrated at 50% probability and H-atoms have been omitted for clarity.
planar, d8 metalloenediynes of 1 to be highly reactive toward
Bergman cyclization at or below ambient temperatures in
solution.54 Given the reversibility of the oxidation reaction and
the observation that 4 persists in solution for several days, it is
unreasonable to predict that 4 adopts a perfectly square planar
geometry in solution; rather, 4 must have a flattened tetrahedral
(∼D2d) structure forming a metastable species that persists in
solution. Over 24 h, intermediate 4 exchanges one phosphine
chelate for two iodide ligands neutralizing the charge of the
complex and relieving the strain about the metal center. This
allows a reactive cis-square planar geometry to trigger facile
Bergman cyclization in situ at ambient temperature. The neutral
analogue then crystallizes out of deuterated dichloromethane to
afford 5.
To better envision the structural rearrangement that converts
the Pt(0), tetrahedral bis-chelate complex 2, to the Pt(II)
cisplatin-like products 3 and 5 upon two-electron oxidation, as
well as further probe the structure of proposed intermediate 4,
density functional theory (DFT) calculations were employed.
Geometry optimizations and vibrational analyses were
performed with Gaussian 0971 using the B3LYP72−74 density
functional and an ultrafine grid. The 6-31G** basis set was
used to model C, H, and P while the LANL2 pseudopotential
with the LANL2DZ75−77 basis set was applied to all metal
atoms. This was followed by single point energy calculations in
dichloromethane (dielectric constant ε = 8.93) using the PCM
model78−82 at the same level of theory.
Figure 3. Cyclic voltammogram showing the quasi-reversible oxidation
of 2.
The computed structure of 2 was obtained by minimization
of the X-ray crystal structure of the starting material. The
optimized structure of 2 contains no imaginary frequencies and
the primary metal−ligand structural parameters are in good
agreement with the crystallographic data. The geometry of 2 in
the Pt(II) oxidation state was then used as the starting point for
the optimization of intermediate 4. To adapt to the Pt(II)
oxidation state and approach a square planar geometry, the
optimized structure of 4 maintains a bis-chelate with uncyclized
enediyne ligands that adopt an expanded P−Pt−P angle of
∼138° toward a pseudo-trans-spanning configuration, which is
consistent with 31P NMR and Raman spectroscopic analyses
(Figure 5). This distorted or flattened tetrahedron con-
sequently increases the interalkynyl distance from 3.51 Å in 2
to 3.76 Å in 4. Moreover, relative to 2 (∼168°) one CC−P
angle decreases to ∼164° while the other increases to ∼171°,
with the more bent CC−P angle corresponding to the
chelate arm with the shorter Pt−P bond. An increase in the
linearity of the CC−P angle shifts the νCC stretching
vibration to higher energy, which is consistent with both the
calculated and experimental Raman spectra of 4. Vibrational
analysis of 4 shows two alkyne stretching frequencies at 2158
Figure 4. Off-resonance Raman spectra of complexes 2, 4, and 5,
obtained at 2 mW and λ = 785 nm.
similar functional group composition for these two complexes.
The change in platinum oxidation state from 0 to +2 suggests
an accompanying change in geometry from tetrahedral to
square planar. Though crystal field theory encourages 4 to be a
square planar complex, a previous study has shown square
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Table 1. Bond Angles (°) and Interatomic Distances (Å) for
Complexes 2, 4, and 4′ Computed Using B3LYP/6-31G**
and the LANL2DZ Pseudopotential
bond angles (deg) and lengths (Å)
2
4
4′
P4−Pt−P2
109.2
168.6
166.9
2.38
138.4
170.9
164.3
2.39
95.6
162.5
171.8
2.49
2.43
3.29
C48−C26−P2
C72−C6−P4
Pt−P4
Pt−P2
interalkynyl C6−C26
2.40
2.45
3.52
3.76
phosphine in the 31P NMR. Whether the cis-chelated
intermediate 4′ or the modestly lower energy trans-chelated
structure 4 is the valid transient species, both routes can be
expected to lead to phosphine lability and cis-promoted
cyclization.
CONCLUSIONS
■
Analogously to Rosenberg’s electrochemical generation of
cisplatin, chemical oxidation of the bis-phosphinoenediyne
chelated Pt(0) complex generates a transient Pt(II) species
with a flattened tetrahedral geometry and elongated Pt−P
bonds that is prone to phosphine ligand substitution by halide.
Ligand dissociation subsequently leads to the structural
freedom to adopt a cis-chelate conformation that spontaneously
Bergman cyclizes to generate the corresponding cisplatin-like
product. Redox-activated metalloenediyne prodrugs that lead to
cisplatin-like species have significant potential for development
into dual-mode therapeutics. While it remains to be seen what
the therapeutic potential of this conceptual approach is, the
diradical intermediate capable of H-atom abstraction combined
with the DNA-cross-linking viability of the dihaloplatinum
product suggests that coupling of these reactive elements into a
triggerable, efficient molecular agent could lead to an advanced
generation of cisplatin analogues, much like their redox-
activated Pt(IV) counterparts.
Figure 5. Reaction trajectory for generation of 5 by I2 oxidation of 2
via computed structural intermediates 4 or 4′. Calculated structures
are viewed with the same phosphine-chelate perspective and phenyl
rings at the phosphorus atoms have been reduced to only the ipso
carbons for clarity.
and 2174 cm−1, respectively, while the experimental spectrum
finds a single broad νCC stretching vibration centered at 2169
cm−1.
More importantly, the Pt−P bond lengths of 4 are
lengthened relative to the tetrahedral starting material 2 (Pt−
P ∼2.38 Å), with one Pt−P bond close to that of 2 (2.39 Å)
while the other is appreciably longer at 2.45 Å. Bond elongation
indicates decreased metal−ligand orbital overlap, which
provides an operative pathway for ligand substitution by
nucleophilic I− to form the monochelated, cisplatin-like,
cyclized diiodo product. The observation of 4 in solution by
31P NMR and its 24 h metastability is consistent with a
substitution-based reaction trajectory toward formation of a cis-
planar structure and consequential Bergman cyclization.
While the structural characteristics of 4 are consistent with
the reaction pathway and spectroscopically observable species,
we questioned whether a planar cis-chelated structure for
intermediate 4 is accessible via dihedral angle rotation (4′). To
probe this structure and evaluate its energetic disposition
relative to the trans-chelate 4, the interalkynyl separation
(C6···C26) was reduced from 3.51 Å in 2 to 3.1 Å as a
geometric minimization starting point. The optimized structure
of 4′ is once again a distorted tetrahedron, but with a cis- rather
than trans-chelated structure like that of 4 and a dihedral angle
of 41°. The P−Pt−P bond angles are accordingly reduced to
∼96°. Interestingly, all Pt−P bond lengths are markedly
increased from 2.39 Å in 2 to an average of 2.47 Å for 4′
(Table 1) due to steric clashes of the phenyl rings. While the
energy of this structure is 3.3 kcal/mol higher than that of 4
and the structure was realized using a constrained geometric
starting point, the increase in Pt−P bond length is a reoccurring
theme. This facilitates ligand substitution by I− and formation
of a transient, uncyclized Pt(II)-iodo complex that adopts a cis-
chelate structure, which is wholly consistent with formation of
cis-cyclized product 5 and concomitant observation of free
EXPERIMENTAL SECTION
■
Materials. All reactions were carried out using standard drybox and
Schlenk techniques under inert nitrogen atmosphere unless otherwise
specified. All chemicals and solvents were purchased from commercial
sources and used as received. Solvents were dried and distilled
according to standard procedures unless otherwise noted. Deuterated
solvents were dried over 4 Å molecular sieves and degassed with three
cycles of freeze−pump−thaw.
Physical Measurements. NMR spectroscopy was collected on a
Varian Inova 400 or 500 MHz NMR spectrometer using the residual
proton resonance of the solvent as an internal reference. All 31P
spectra were externally referenced using an 85% H3PO4 standard. Mass
spectrometry data were obtained on a Bruker Autoflex III MALDI-
TOF mass spectrometer or an Agilent 1200 HPLC-6130 MSD mass
spectrometer. Differential scanning calorimetry (DSC) measurements
were made on a TGA Q10 DSC system with a TA Instruments
thermal analyzer at a heating rate of 10 °C min−1. Raman
spectroscopic data were collected on a Renishaw 1000B micro-
Raman instrument using a λexc = 785 nm excitation wavelength and
analyzed using the GramsAI software package. Elemental analyses
were obtained from Robertson Microlit Laboratories, Inc. X-ray
crystallographic data were obtained by the Indiana University
Molecular Structure Center on a Bruker APEX II Kappa Duo
diffractometer using Mo Kα radiation (graphite monochromator) at
150 (2) and 200 K (5). Details of the X-ray analyses can be found in
Supporting Information.
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Electrochemical Measurements. Cyclic voltammetry (CV)
experiments were carried out using a three-electrode setup with a
platinum disk (2.0 mm diameter), platinum wire, and a Ag/AgCl
electrode as the working (WE), auxiliary (AE), and reference
electrodes (RE), respectively. Data were collected on an E2 Epsilon
(BAS) Autolab potentiostat-galvanostat equipped with standard BAS
software and exported to Excel for manipulation and analysis.
Potentials in CV were calibrated using the Fc/Fc+ redox couple (0.0
V). Controlled-potential (bulk) electrolyses were performed using a
PARC model 173 potentiostat−galvanostat. Current−time curves
were obtained with the aid of locally written Labview software and
integrated with OriginPro 8.6 software to acquire coulometric n values.
The potentials for coulometry experiments are quoted with respect to
a reference electrode consisting of a cadmium-saturated mercury
amalgam in contact with DMF saturated with both cadmium chloride
and sodium chloride; this electrode has a potential of −0.76 V versus
the aqueous saturated calomel electrode (SCE) at 25 °C.83−85 The
glass cell employed for potentiostatic coulometry consisted of two
separate compartments. In the upper compartment, a graphite rod,
which serves as the auxiliary electrode, was immersed in a 0.3 M
TBAPF6−THF solution, separated from the analyte by a fine-porosity
sintered-glass disk and backed with a methyl-cellulose-electrolyte plug.
The working electrode is attached to a metal plunger contact housed
in the bottom compartment of the cell along with a stir bar to add
convection. Working electrodes for controlled-potential (bulk)
electrolyses were reticulated vitreous carbon discs (RVC 2X1-100S,
Energy Research and Generation, Inc., Oakland, CA) approximately
17 mm in diameter and 3 mm in thickness that were cut from longer
rods. Information regarding the fabrication, cleaning, and handling of
these electrodes can be found elsewhere.86 A solution of 2 (1.44 mg,
0.0012 mmol) in 10 mL of deoxygenated THF was added to the
bottom compartment and the entire cell purged with argon for 15 min
after which time a 1.30 V potential was applied to the cell to ensure
exhaustive oxidation of 2. The coulometric n value for the oxidation of
2 was determined to be n = 1.9 by integration of the exponential
current decay vs time profile.
Computational Methods and Vibrational Analysis. Geometry
optimizations and vibrational analyses were performed using DFT with
the B3LYP72−74 functional, 6-31G** basis set, and an ultrafine grid
using Gaussian 09.71 The LANL2DZ effective core potential was used
to model the transition metal atoms.75−77 Single point energy
calculations in dichloromethane (dielectric constant ε = 8.93) were
performed using the PCM model78−82 at the same level of theory to
account for energetic contributions from solvation. The calculated
vibrational frequencies were scaled uniformly by a factor of 0.962 for
comparison with the observed Raman spectra, resulting in very good
overall agreement between all computational and experimental values.
Bis(1,2-bis((diphenylphosphino)ethynyl)benzene)platinum-
(0) (2). To a solution of Pt(cod)Cl2 (37.0 mg, 0.0989 mmol) in
CH2Cl2 (20 mL) was added a solution of dppeb 154 (96.4 mg, 0.1945
mmol) in CH2Cl2 (5 mL) via syringe. The solution was allowed to stir
at room temperature overnight, during which time the color changed
from yellow to orange. Hydrazine was added until bubbling ceased.
Solvent was removed under vacuum, resulting in a crude orange solid,
which was dissolved in a minimal amount of CH2Cl2 and precipitated
using cold EtOH. Crystals suitable for characterization by X-ray
crystallography were grown from vapor diffusion of diethyl ether into a
saturated CH2Cl2 solution. Yield: 48%. NMR: δH (400 MHz, 298 K,
CD2Cl2) 7.53−7.44 (m, 8H), 7.26 (d, J = 5.6 Hz, 16H), 6.99 (t, J = 7.6
Hz, 8H), 6.82 (t, J = 7.6 Hz, 16H); δC (500 MHz, 298 K, CD2Cl2)
140.2, 131.7, 131.1, 129.2, 128.1, 127.8, 125.2, 109.3, 96.4; δP (400
MHz, 298 K, CD2Cl2) −13.27 (s, J = 3923 Hz). HRMS-ESI MS: m/z
1184.2415 (M+). DSC: 231 °C (maximum). Elemental analysis, calcd
for C68H48P4Pt: C, 68.98; H, 4.09. Found: C, 68.71; H, 3.85.
h, after which time pentane (50 mL) was added. Complex 3 was
isolated as a pale yellow precipitate by filtration and washed copiously
with hexanes to remove residual traces of unreacted starting materials.
Yield: 82%. NMR: δH (500 MHz, 298 K, CD2Cl2) 8.06 (d, J = 11.5 Hz,
2H), 7.85 (dd, J = 3 Hz, 9.5 Hz, 2H), 7.78−7.82 (m, 8H), 7.62 (dd, J =
2.5 Hz, 9.5 Hz, 2H), 7.51−7.54 (m, 4H), 7.42−7.46 (m, 8H); δC (500
MHz, 298 K, CD2Cl2) 134.7, 134.6, 132.04, 132.02, 130.2, 129.8,
129.0, 128.9, 128.8; δP (400 MHz, 298 K, CD2Cl2) 41.03 (s, J = 3346
Hz). HRMS-ESI MS: m/z 818.0236 (M+ − I−). Elemental analysis,
calcd for C34H26P2I2Pt: C, 43.20; H, 2.77. Found: C, 43.19; H, 2.61.
Method B. A solution of 2 (2.700 mg, 0.0028 mmol) in CD2Cl2
(1.0 mL) was charged to an NMR tube and sealed under N2 at room
temperature. Excess 1,4-CHD (0.02 mL, 0.228 mmol) and 1 equiv of
an I2 solution (0.09 mL, 25.2 mM in CD2Cl2) were subsequently
added, and the reaction was monitored by 31P NMR spectroscopy.
The addition of I2 in the presence of 2 and 1,4-CHD led to the
instantaneous and nearly quantitative generation of 3 and liberated
free ligand 1, with only ∼7% (by NMR integration) unidentified
phosphorus-containing side product. No further reactions of these
species were observed over several days. NMR: δP (400 MHz, 298 K,
CD2Cl2) 41.03 (s, J = 3346 Hz), 6.86 (s), −33.48 (s).
Bis(1,2-bis((diphenylphosphino)ethynyl)benzene)platinum-
(II) Iodide (4). A solution of Pt(dppeb)2 2 (2.500 mg, 0.00211 mmol)
in dry, degassed CD2Cl2 (0.8 mL) was charged to an NMR tube sealed
under N2. To this was added 2 equiv of an I2 solution (0.214 mL, 19.7
mM in CD2Cl2). An immediate color change was observed from
orange to yellow. The reaction was monitored by 31P NMR, which
determined 4 to be generated in quantitative yield upon I2 addition.
NMR: δP (400 MHz, 298 K, CD2Cl2) 50.85 (s, J = 3171 Hz).
Diiodo-(1,4-diiodonaphthalene-2,3-diyl)bis(diphenyl-
phosphine)platinum(II) (5). The oxidation of 2 with 2 equiv of I2
was monitored over time, and after 24 h yellow crystalline material
began precipitating from a solution of 4 and was isolated after 3 d.
Complex 5 proved insoluble in typical polar and nonpolar solvents;
however, crystals suitable for characterization by X-ray crystallography
were obtained directly from the reaction mixture. Yield: 52% isolated.
MALDI MS: m/z 1069.84 (M+ − I−). Elemental analysis, calcd for
C34H24P2I4Pt·CH2Cl2: C, 32.79; H, 2.04. Found: C, 32.92; H, 1.79.
(1,2-Phenylenebis(ethyne-2,1-diyl))bis(diphenylphosphine
oxide) (6). To a solution of 1 (150 mg, 0.303 mmol) in degassed
acetone was added excess hydrogen peroxide (30% by wt), and the
mixture was allowed to stir at room temperature overnight. Solvent
was removed under vacuum, resulting in a pale yellow solid. The crude
product was dissolved in a minimal amount of dichloromethane, and
an excess of diethyl ether was added. The mixture was allowed to stand
overnight at 0 °C, resulting in a shiny, white precipitate which was
washed with diethyl ether and dried in vacuo. Yield: 63%. NMR: δH
(400 MHz, 298 K, CD2Cl2) 7.8−7.7 (m, 10H), 7.5−7.4 (m, 14H); δC
(400 MHz, 298 K, CD2Cl2) 134.0, 132.8, 132.6 (d, J = 3 Hz), 131.2 (d,
J = 11 Hz), 130.9, 129.2 (d, J = 14 Hz), 123.5, 102.0 (d, J = 28 Hz),
89.0, 87.4; δP (400 MHz, 298 K, CD2Cl2), 7.09 (s). HRMS-ESI MS:
m/z 549.1143 (M+ + Na+). DSC: 160 °C (minimum), 293 °C
(maximum).
ASSOCIATED CONTENT
■
S
* Supporting Information
DSC traces, controlled-potential (bulk) electrolysis traces, and
crystallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Diiodo-(2,3-bis(diphenylphosphino)naphthalene)platinum-
(II) (3). The preparation of 3 was performed in a manner parallel to
that of the previously synthesized dichloro analogue.67
Method A. To a Schlenk flask were charged 1 (94.2 mg, 0.190
mmol), Pt(cod)I2 (105.9 mg, 0.190 mmol), 1,4-CHD (0.36 mL, 3.80
mmol), and 10 mL of toluene. The mixture was stirred at 80 °C for 3
Corresponding Author
zaleski@indiana.edu
Notes
The authors declare no competing financial interest.
3831
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Journal of the American Chemical Society
Article
(32) Chin, C. F.; Wong, D. Y. Q.; Jothibasu, R.; Ang, W. H. Curr.
Top. Med. Chem. 2011, 11, 2602.
(33) Hall, M. D.; Hambley, T. W. Coord. Chem. Rev. 2002, 232, 49.
(34) Reisner, E.; Arion, V. B.; Keppler, B. K.; Pombeiro, A. J. L. Inorg.
Chim. Acta 2008, 361, 1569.
(35) Mackay, F. S.; Moggach, S. A.; Collins, A.; Parsons, S.; Sadler, P.
J. Inorg. Chim. Acta 2009, 362, 811.
(36) Farrer, N. J.; Woods, J. A.; Salassa, L.; Zhao, Y.; Robinson, K. S.;
Clarkson, G.; Mackay, F. S.; Sadler, P. J. Angew. Chem., Int. Ed. 2010,
49, 8905.
ACKNOWLEDGMENTS
■
The generous support of the National Science Foundation
(CHE-0956447) is gratefully acknowledged. The authors thank
members of the Mindiola (Keith Searles) and Peters (Elizabeth
Wagoner) research groups for their technical assistance with
the electrochemical measurements. We also thank Dr. David F.
Dye as well as the Raghavachari group (Victoria Erdely) for
technical assistance with the calculations and computing time.
(37) Farrer, N. J.; Woods, J. A.; Munk, V. P.; Mackay, F. S.; Sadler, P.
J. Chem. Res. Toxicol. 2010, 23, 413.
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