Synthesis, Structure, and Photophysical Properties of Platinum(II) (N,C,N′) Pincer Complexes Derived from Purine Nucleobases

The synthesis of a series of Pt{κ3-N,C,N′-[L]}X (X = Cl, RC≡C) pincer complexes derived from purine and purine nucleosides is reported. In these complexes, the 6-phenylpurine skeleton provides the N,C-cyclometalated fragment, whereas an amine, imine, or pyridine substituent of the phenyl ring supplies the additional N′-coordination point to the pincer complex. The purine N,C-fragment has two coordination positions with the metal (N1 and N7), but the formation of the platinum complexes is totally regioselective. Coordination through the N7 position leads to the thermodynamically favored [6.5]-Pt{κ3-N7,C,N′-[L]}X complexes. However, the coordination through the N1 position is preferred by the amino derivatives, leading to the isomeric kinetic [5.5]-Pt{κ3-N1,C,N′-[L]}X complexes. Extension of the reported methodology to complexes having both pincer and acetylide ligands derived from nucleosides allows the preparation of novel heteroleptic bis-nucleoside compounds that could be regarded as organometallic models of Pt-induced interstrand cross-link. Complexes having amine or pyridine arms are green phosphorescence emitters upon photoexcitation at low concentrations in CH2Cl2 solution and in poly(methyl methacrylate) (PMMA) films. They undergo self-quenching at high concentrations due to molecular aggregation. The presence of intermolecular π–π stacking and weak Pt···Pt interactions was also observed in the solid state by X-ray diffraction analysis.


■ INTRODUCTION
The coordination of DNA fragments to metals is of fundamental importance in many bioinorganic processes. 1 Most of the reported studies in this field focused on the interaction of platinum complexes with DNA and nucleobases, very likely because most of the current antitumor drugs for clinical use are based on platinum complexes. 2−5 The high toxicity of these compounds due to concomitant DNA damage 6 keeps alive the interest for studies that combine Pt and nucleobases to the development of new models of interaction. In this regard, platinum complexes bearing tridentate ligands have attracted particular interest, as they can bind to and intercalate DNA, 7 trigger the formation of Gquadruplexes, 8,9 cause interstrand cross-links (ICL), and generate extensive conformational alterations. 10 The luminescent properties associated with many of these complexes 11−14 have helped the study of interaction models 15,16 and have also been used to investigate intracellular processes in vivo. 17 Our research group is a pioneer in the development of methodologies to prepare cyclometalated transition metal complexes [M = Ir(III), Rh(III), Os(IV)] derived from nucleobases, nucleosides, and nucleotides. 18−21 In these studies, purine derivatives were excellent substrates to carry out cyclometalation reactions, and we reasoned that they could be interesting scaffolds to build cyclometalated platinum(II) (pincer) complexes. The idea was challenging, as purine nucleobase derivatives are highly functionalized systems with many positions prone to interact with the metal.
Most of the reported tridentate cyclometalated platinum(II) complexes are derived from symmetrical ligands. This is remarkable, as unsymmetrical N,C,N′-pincer ligands would offer a great opportunity to tune the properties of the platinum complex by combining the steric and electronic characteristics of the donor N and N′ atoms. In our approach, the 6phenylpurine skeleton would provide the rigid framework to build unsymmetrical N,CH,N′-pro-ligands I ( Figure 1) by incorporation of the adequate N′-branches in the phenyl ring. Pro-ligands I offer two possible coordination modes to the metal since both N1 and N7 can bind to form isomers II and III, respectively. Our previous results showed that cyclometalation reactions of 6-phenylpurine derivatives promoted by group 8 and group 9 metal complexes exclusively involve the N1 atom of the nucleobase in the process of metallacycle formation. 19−21 However, the coordination of N7 to many Pt(II) complexes is well known, 2−5 whereas the participation of N7 in C-metalations has also been reported. 22 The donor monodentate ligand (X) that occupies the fourth coordination position of isomers II and III will also be relevant for the chemical and photophysical properties of the complexes now reported. The trans effect of the cyclometalated carbon is behind the lability of the Pt−Cl bond in Pt{κ 3 -N,C,N′-[L]}Cl complexes, which will allow us to make further structural modifications by incorporation of diverse alkynyl ligands. Here, we describe the synthesis, reactivity, and the study of the photophysical properties of a new class of Pt{κ 3 -N,C,N′-[L]}X (X = Cl, RC�C) complexes, derived from biomolecules: purine nucleobases and nucleosides. The methodology reported in this work is a step ahead in the design of a new class of photoluminescent complexes built on biocompatible moieties. Combination, in the metal coordination sphere, of a pincer containing a purine nucleoside arm together with purine nucleoside-substituted alkynyl ligands will allow us to furthermore generate complexes that can be viewed as organometallic interstrand cross-link models. In this context, it should be mentioned that interstrand cross-link is one of the most important pathways for DNA damage. 10 ■ RESULTS AND DISCUSSION Scheme 1 summarizes the preparation of the N,CH,N′-proligands 2a−c. The synthesis of 2a and 2b was designed in a stepwise manner using a common precursor, aldehyde 1. This compound was generated through a Suzuki coupling between 6-chloro-9-ethylpurine and 3-formylboronic acid, using Pd-(PPh 3 ) 4 as a catalyst precursor and K 2 CO 3 as a co-catalytic base. Amine 2a was generated by reductive amination of 1, with dimethylamine and NaBH 3 CN, using Ti(O i Pr) 4 as a catalyst; while imine 2b was made by the reaction of 1 with panisidine. In turn, pyridine derivative 2c was synthesized in one step from 6-chloro-9-ethylpurine by Pd(PPh 3 ) 4 /K 2 CO 3 -mediated Suzuki coupling with 3-(2-pyridynyl)phenylboronic acid pinacol ester.
Pro-ligands 2a−c were subsequently used to prepare the respective chlorido-complexes Pt{κ 3 -N,C,N′-[L]}Cl: 3a−c. The synthetic procedure involves the reaction of the salt K 2 PtCl 4 with the organic molecules, in glacial acetic acid, under reflux (Scheme 2). 23 Complexes 3a and 3b were obtained as pure products in 56 and 46% isolated yields, respectively, after chromatography of the reaction crude on silica gel. In contrast, complex 3c was directly obtained (52% yield) by precipitation from the reaction medium with methanol and subsequent washing with methanol and diethyl ether. The three compounds were characterized by NMR spectroscopy and X-ray diffraction (XRD) analysis. The main bond distances and angles are given in Table S1. Figure 2 shows views of the molecules. The ligand environment around the platinum(II) center adopts the expected square-planar coordination, featuring a tridentate κ 3 -N,C,N′-ligand and a chloride anion trans to the metalated carbon atom. The atoms of the 6-phenylpurine scaffold are roughly coplanar in all cases. It should be pointed out that the  Inspection of the packing within the crystals of complexes 3a (Figure 3), 3b (Figure S1), and 3c (Figures 4 and S2) reveals that the planes defined by the 6-phenylpurine scaffolds are close to each other (less than 4 Å) and arranged in an approximately or totally parallel manner, which points to the existence of intermolecular π−π stacking interactions. The asymmetric units contain four (two pairs in 3a) or two close molecules (3c), which in the crystal generate stacks, with Pt··· Pt distances of 3.835−3.861 Å for 3a and 4.279 Å for 3c; indicating the existence of significant metal−metal interactions ( Figure 3). 25 The asymmetric units of complex 3b contain only one molecule (see the Supporting Information (SI)), and the closest intermolecular Pt···Pt distance in the crystal is 6.750 Å, longer than 2 × r vdw (Pt) = 4.6 Å, 26 which rules out the existence of significant metal−metal interactions in this case.
The study of the 1 H NMR spectra was congruent with the crystal structures. The coordination through the N7 position of the purine ring in complexes 3b and 3c was confirmed by the noticeable deshielding of the signals of purine H8, from 8.17 ppm in pro-ligands 2b and 2c to 9.29 (J H−Pt = 11.2 Hz) and 9.37 ppm (J H−Pt = 14.2 Hz) for 3b and 3c, respectively. However, in complex 3a, the signal coupled to the neighboring platinum in the 1 H NMR spectrum was that of purine H2 (9.40 ppm, J H−Pt = 11.5 Hz), being also deshielded with regard to that of pro-ligand 2a (8.98 ppm).
The N1 coordination of the purine arm in 3a is in line with our previous results in Ir(III)-, Rh(III)-, and Os(IV)chemistry, which pointed out that only the N1 position of the purine ring was involved in the cyclometalation reactions of 6-phenylpurine derivatives, on complexes of these ions. 19,21 To understand the difference in behavior between the proligands, we analyzed the equilibrium between the isomers [5.5] Based on these studies, we first tested the isomerization 3a to 3d in acetic acid, at 200°C, in a sealed tube. Unfortunately, complete decomposition to a black solid occurred. Thence, we tried the process in toluene. To our delight, this time, the clean and quantitative transformation of 3a into the more stable species 3d took place after 120 h (Scheme 3). In agreement with 3b and 3c, the 1 H NMR spectrum of 3d showed a clean singlet at 8.99 ppm due to H2, while the signal corresponding to H8 showed platinum satellites ( 3 J( 1 H− 195 Pt) = 10. 5 Hz). The formation of 3d was confirmed by XRD. Inspection of the crystal packing did not reveal significant Pt···Pt interactions in this case (Scheme 3 and Figure S3).
The chloride ligand of complexes 3a−d was further replaced by acetylide ligands. Reaction with phenylacetylene, in the presence of NaOH, at room temperature (rt), in methanol led to acetylido derivatives 4a−d, which were isolated as yelloworange solids in 65−79% yields by precipitation in the reaction media and subsequent washing with cold methanol and diethyl ether (Scheme 4). Extension of this methodology to more sensitive acetylide ligands was tested by the reaction of 3a−d with freshly prepared 6-ethynyl-9-ethylpurine. In this case,  complexes 5a−d were also obtained in high yields (65−80%) as yellow solids (Scheme 4).
Acetylido derivatives were characterized by NMR and mass spectrometry and, in the case of 4b, 4d, and 5a, by XRD (Scheme 4 and Figures S4−S6). The C�C bond distances of 1.202(9), 1.190(5), and 1.20(2) Å, respectively, compare well with those reported for the compounds of this class previously characterized by XRD. 27 This fact is indicative of the lack of significant π-back-bonding from the Pt atoms to the alkynyl ligands.
To go a step ahead, we explored this methodology to prepare both types of [5.5]-and [6.5]-Pt{κ 3 -N,C,N′-[L]}X (X = Cl, RC�C) pincer complexes in purine nucleosides as ligand precursors (Scheme 5). Pro-ligands 7a and 7b were obtained in quantitative yields from aldehyde 6 (see the SI) using the reaction conditions previously employed for the preparation of 3a and 3b. However, the synthesis of the respective chlorido compounds [5.5]-Pt{κ 3 -N,C,N′-[L]}Cl could not be achieved by the reaction of 7a and 7b with K 2 PtCl 4 , in glacial acetic acid, under reflux, as these harsh conditions caused the decomposition of the pro-ligands. Chlorido derivatives 8a and 8b were successfully prepared by refluxing 7a and 7b with [PtCl 2 (DMSO) 2 ] (DMSO = dimethyl sulfoxide) in toluene for 48 h, in 49 and 28% yields, after chromatography on silica gel. Further, the reaction of 8a and 8b with freshly prepared ethynylpurine nucleoside 9 (see SI) in a NaOH solution in methanol afforded heteroleptic bisnucleoside compounds 10a and 10b in 57 and 41% yields, respectively. Complexes 10a and 10b join two purine nucleosides in their structures through the alkynyl−Pt complex and could be regarded as simple organometallic models of interstrand cross-link (ICL) in oligonucleotides. 10 Photophysical Properties of Emissive Complexes. The square-planar platinum(II) d 8 -complexes are considered one of the noble families of phosphorescent emitters. [11][12][13][14]28 This fact, along with the novelty of the purine−pincer−platinum(II) skeleton prompted us to study the absorption and emission characteristics of the emissive compounds prepared, which were those of the 3, 4, and 5-types bearing an amine-or pyridine arm (imine derivatives were not emissive).
The UV−vis spectra of complexes 3, 4, and 5 (10 −5 M, in dichloromethane (DCM), at room temperature) are depicted in Figure 6, and the selected absorptions (assigned by timedependent density functional theory calculations (TD-DFT-B3LYP-D3/def2-SVP) in dichloromethane) are shown in Tables S3−S6. The frontier molecular orbitals of complexes 3−5 are provided in Figures S10−S14. The lowest unoccupied molecular orbitals (LUMOs) are very similar, mainly localized on the cyclometalating (N,C) fragments of the pincer ligand. For the chloride complexes 3a−d, the highest occupied molecular orbitals (HOMOs) are composed of the Pt and halide centers with some contribution of the phenyl moiety. In There is a good agreement between the computed selected transitions and the experimental absorption maxima. Emissions take place upon photoexcitation and occur in the green region of the spectrum (476−571 nm). Measurements were performed in doped poly(methyl methacrylate) films at 5 and 2 wt % (PMMA 5% and PMMA 2% ) at 298 K and in dichloromethane (CH 2 Cl 2 ) and 2-methyltetrahydrofuran (2-MeTHF) at 298 and at 77 K. Table 1 summarizes the main features of the emissions, which occur from the respective T 1 excited states as supported by the excellent agreement observed between the maximum of the emission wavelengths in CH 2 Cl 2 and the calculated values in the same solvent for the differences in energy between the optimized triplet states T 1 and the singlet states S 0 . According to the spin density distribution calculated for the T 1 states in their minimum energy geometries (Table S8 and Figures S102−S110), the emissions appear to have a mixed MLTC/LC/LLCT character in all cases. Consistently, the bands are highly structured.
Amine kinetic isomers 3a, 4a, and 5a display moderated quantum yields in PMMA 5% (0.36−0.50). The values significantly increase for the thermodynamic counterparts, which lie in the range 0.70−0.48 and decrease in the sequence 3d > 4d > 5d. Two factors play in favor of the thermodynamic isomers. A comparison of the molecular packing for 3a and 3d reveals that the aggregation is higher in the kinetic isomers and is known to favor self-quenching. 29 In addition, increasing emission efficiency with emitter stability is a common effect,

Inorganic Chemistry
pubs.acs.org/IC Article which has also been previously observed for N,C,N-pincer emitters of osmium(IV) and iridium(III). The rise in stability is ascribed to the approach of the pincer bite angles to the ideal values corresponding to the coordination polyhedron of the complex. 30 The emission spectrum of 3a, in CH 2 Cl 2 , at 298 K is independent of the emitter concentration, in the range (1 × 10 −3 )−(1 × 10 −6 ) M, and superimposable with that observed in PMMA 5% (Figure 7a). The lifetime increases from 0.8 to 11.9 μs, and the quantum yields from 0.05 to 0.60 as the emitter concentration decreases. This is indicative of selfquenching induced by ground-state aggregation. 31 Although excimer emission is not observed in the 700 nm region, 32 the rate of emission decay (k obs = 1/τ) fits well to the modified Stern−Volmer expression shown in eq 1, where k q is the rate constant for the excimer formation, [Pt] is the emitter concentration, and k 0 (=1/τ 0 ) is the rate of excited-state decay at infinite dilution. A plot of k obs versus [Pt] ( Figure S15) provides values for the self-quenching rate constant k q and the intrinsic lifetime τ 0 of 1.2 × 10 9 M −1 s −1 and 11.5 μs, respectively. 33 At 77 K, the excimer life rises. As a consequence, at this temperature, the emission spectra of solutions, more concentrated than 1 × 10 −6 M, clearly show the excimer broadband at about 700 nm, which increases its intensity as the emitter concentration also increases ( Figure  7b). An analogous behavior was observed for the phenylacetylide derivative 4a, which displays k q and τ 0 values of 0.9 × 10 9 M −1 s −1 and 10.6 μs, respectively (see Figure S16). These values compare well with those reported for other emissive platinum complexes. 31,33a,34  Table 1 summarizes the data in Table S7. b Solutions 1 × 10 −5 M. The most intense peak is in bold. (exc) λ em excimer. c Computed values (SMD(CH 2 Cl 2 )-B3LYP-D3/def2-SVP) obtained from the differences in energy between the optimized triplet states T 1 and the singlet states S 0 . d Relative amplitudes (%) are given in parentheses for biexponential decays. e Absolute quantum yield.

Inorganic Chemistry pubs.acs.org/IC Article
The solvent has a dramatic influence on the emission. For example, 2-MeTHF prevents self-quenching of 4a, as shown in Figure S101, although changes in the relative intensity of the structured band peaks are observed as a consequence of variations in the emitter concentration. In addition, a mitigation of the quantum yield in PMMA 5% from 0.22 to a constant value of about 0.06 also occurs. The effect can be assigned to the different solvation abilities of the solvents and to a noticeable coordinating ability of the ether, which protects the unsaturated monomers.
There are significant differences between 4a and its thermodynamic isomer 4d in CH 2 Cl 2 . At 298 K, the structured emission of the latter consists of two peaks of similar intensity at 493 and 524 nm and a shoulder at 562 nm. As for 4a, this shape is independent of the emitter concentration, in the range (1 × 10 −3 )−(1 × 10 −6 M) (Figures S63−S66) and   However, in contrast to 4a, the quantum yield for 4d is constant in the concentration range and about ten times lower than in PMMA 5% (0.61 versus 0.07). Although the relative intensity of the peaks of the emission changes at 77 K, an excimer band is not observed. In this case, the significant mitigation of the quantum yields in CH 2 Cl 2 appears to be due to a notable increase of the nonradiative rate constant in solution, which is an order of magnitude higher than that in PMMA 5% (5.1 × 10 4 versus 5.2 × 10 5 s −1 (1 × 10 −3 M)). Acetylido derivatives with a pyridine substituent 4c and 5c undergo self-quenching in the solid state ( Figure 8). 35 Thus, the emission spectra in PMMA show an excimer broadband centered around 640 nm, in addition to the structured pattern of two peaks and a shoulder in the 490−570 nm region, which is characteristic of this class of complexes. As expected, the excimer emission significantly rises its intensity as the emitter concentration increases, being the most intense band at 5 wt %. The increase of the intensity of this band is accompanied by a decrease of the quantum yield of the emission, which diminishes from 0.26 to 0.15 for 4c and from 0.50 to 0.35 for 5c when the emitter concentration in the film increases from 2 to 5 wt %.
The behavior of emitter 5c was also studied in solution, as a function of its concentration, in the range (1 × 10 −3 )−(1 × 10 −6 ) M, in CH 2 Cl 2 , at 298 and 77 K. Consistently with the behavior in the PMMA film, 5c undergoes self-quenching in the solvent at both temperatures ( Figure 9). As the emitter concentration rises, the intensity of the excimer broadband around 640 nm increases at the expense of peaks between 480 and 560 nm of the structured emission. At 298 K, the values obtained for the self-quenching rate constant k q and the intrinsic lifetime τ 0 are 1.9 × 10 9 M −1 s −1 and 7.8 μs, respectively.

■ CONCLUSIONS
We describe an efficient methodology to prepare a new class of pincer complexes, with structures C,}X (X = Cl, RC�C), built on 6-phenyl purines. The nucleobase skeleton provides an N,C-cyclometalated fragment, which was additionally functionalized with an amine, imine, or pyridine arm to afford the N,C,N′-pincer structure. The reactions were totally regioselective. Although the formation of [5.5]-bicycle compounds, bearing the purine bonded by N1, is kinetically favored for the amine arm, the [6.5]-bicycle isomers resulting from the N7 coordination of the purine are more stable in all of the cases. The combination of purine nucleoside pincer ligands with ethynylpurine nucleosides has furthermore allowed the preparation of novel heteroleptic bis-nucleoside compounds, which may be viewed as organometallic models of Pt-induced interstrand cross-link. The pincer compounds Pt{κ 3 -N,C,N′-[L]}X (X = Cl, RC�C) [Pt(N∧C∧N′)L] are square-planar complexes having the monodentate X ligand trans to the cyclometalated phenyl ring. In the solid state, noncovalent interactions between adjacent molecules have been observed by XRD. The complexes bearing an amine or pyridine arm are phosphorescent green emitters upon photoexcitation, displaying high quantum yields in PMMA and dichloromethane at low concentrations. At high concentrations, they undergo selfquenching favored by molecular aggregation of monomers through aromatic π−π interactions that are reinforced by weak platinum−platinum interactions. ■ EXPERIMENTAL SECTION General Methods. Unless stated otherwise, all of the reactions were carried out under an Ar atmosphere using anhydrous solvents. The reaction work-ups were performed in air. Commercially available reagents were used as received without further purification. 6-Chloro-9-ethylpurine, 36 3-(2-pyridynyl)phenylboronic acid pinacol ester, 37 6ethynyl-9-ethylpurine, 38 and PtCl 2 (DMSO) 2 39 were prepared according to reported protocols. 1 H and 13 C{ 1 H} NMR spectra were recorded at ambient temperature in CDCl 3 or CD 2 Cl 2 on Bruker 500 or 300 MHz spectrometers. Chemical shifts are expressed in ppm and are referenced to residual solvent peaks. Through the experimental part, in the NMR spectra, the numbering of the purine ring system has been used to denote the positions C2 (H2) and C8 (H8) of the nucleobase. Fourier transform infrared (FT-IR) spectra (attenuated total reflection (ATR)) were recorded with solid or films (by slow evaporating CHCl 3 solutions of the compounds) on a Bruker Alpha spectrometer. Electrospray ionization-high-resolution mass spectrometry (ESI-HRMS) was performed on an Agilent 6500 accurate mass spectrometer with a Q-TOF analyzer. UV−visible spectra were registered on an Evolution 600 spectrophotometer. Steady-state photoluminescence spectra were recorded with either a Jobin-Yvon Horiba Fluorolog FL-3-11 Tau 3 spectrometer (PMMA films) or with a PicoQuant FluoTime 300 spectrometer (CH 2 Cl 2 and 2-MeTHF solutions). Lifetime measurements were performed at the maximum emission wavelength of the complexes either on a Jobin-Yvon Horiba Fluorolog FL-3-11 Tau 3 spectrometer (PMMA films) or a PicoQuant FluoTime 300 spectrometer (CH 2 Cl 2 and 2-MeTHF solutions). Data were fitted to either monoexponential or biexponential functions. Quantum yields were measured using the Hamamatsu Absolute PL Quantum Yield Measurement System C11347-11.