Capture and Release of Singlet Oxygen in Coordination-Driven Self-Assembled Organoplatinum(II) Metallacycles

Abstract

Singlet oxygen (¹O₂), as an important active reagent, has found wide applications in photodynamic therapy (PDT), synthetic chemistry and materials science. Organic conjugated aromatics serving as hosts to capture and release singlet oxygen have been systematically investigated over the last decades. Herein, we present a [6+6] organoplatinum(II) metallacycle by using ~180° dipyridylanthracene donor and ~120° Pt(II) acceptor as the building blocks, which enables the capture and release of singlet oxygen with relatively high photooxygenation and thermolysis rate constants. The photooxygenation of the metallacycle to the corresponding endoperoxide was performed by sensitized irradiation, and the resulting endoperoxide is stable at room temperature and can be stored under ambient condition over months. Upon simple heating the neat endoperoxide under inert atmosphere at 120 °C for 4 h, the resulting endoperoxide can be reconverted to the corresponding parent form and singlet oxygen. The photooxygenation and thermolysis products were characterized by NMR spectroscopy and ESI-TOF-MS analysis. Density functional theory calculations were conducted in order to reveal the frontier molecular orbital interactions and reactivity. This work provides a new material-platform for singlet oxygen related promising applications.

Graphical Abstract

INTRODUCTION

Singlet oxygen (¹O₂) is a metastable excited state of molecular oxygen with the ability to oxidize organic and biological compounds, providing a wide range of applications in synthetic organic chemistry,^1,2 materials science^3–12 and photodynamic therapy (PDT).^13–18 In general, there are two methods to generate singlet oxygen via the energy transfer based photoexcitation of ground-state oxygen (photosensitization), or as a product in a chemical reaction.^19–22 In the photosensitization of ground-state oxygen approach, a photosensitizer is photoexcited by light and then sensitizing the neigh-bouring ground-state oxygen to produce singlet oxygen. However, the photooxygenation technique involves some practical and technical challenges, especially for using on a large scale, such as the requirement of the simultaneous presence of molecular oxygen and a photosensitizer, light penetration of the reaction media, and the limited solubility of the molecular oxygen in solution. Another chemical method is also known as “dark” oxygenation, which is a promising alternative to address the controllable generation of singlet oxygen. Traditionally, the H₂O₂/catalyst and HOCl/catalyst based inorganic systems rely on cheap reagents and yield singlet oxygen quantitively, but typically require an aqueous media condition and show cytotoxicity to the cells. Recently, specific aromatic organic compounds have been reported to react with singlet oxygen to form the corresponding endoperoxides (EPOs), such as naphthalene, 2-pyridones and anthracene derivatives.^2,23–29 Many kinds of EPOs are able to convert back to the parent aromatic organic compounds and singlet oxygen under external thermal, photo or chemical stimuli, which allow a clean generation of singlet oxygen without remaining oxidation reagents and sensitizers, and are not restricted to the aqueous media. The reversibility of the reaction allows applications of EPOs in the area of singlet oxygen storage, fluorescent photo-switching and photodynamic therapy. We found that the reactivity of the anthracene-based EPOs is dependent on the substituents and the chemical conditions.^30,31 For instance, kinetics of the ortho, meta, and para isomers of 9,10-dipyridylanthracene are controlled by the substitution pattern and solvent.³² By using a simple chemical trigger at low temperature, the release of the reactive singlet oxygen from dipyridylanthracene EPOs in aqueous media has also been found.²⁵ Besides that, some EPOs are not stable at room temperature. The development of room temperature stable EPOs is still highly desired for the application of singlet oxygen storage.^33,34 Moreover, the reported EPOs are mainly based on the polycyclic aromatic hydrocarbons systems, which are still unexplored in the field of the discrete organic-inorganic hybrid frameworks.

Supramolecular coordination complexes (SCCs) arising from the methodology of coordination-driven self-assembly via the formation of metal-ligand bonds between the electron-poor metal acceptors and the rigid electron-rich organic donors, display attractive features such as well-defined shapes and sizes, facile building block functionalization and modularity, and increased solubilities.^35–45 A large number of functional SCCs have been produced for applications in host–guest chemistry, materials sciences and medical sciences, including two-dimensional (2D) metallacycles and three dimensional (3D) metallacages.^38,46–53 Very recently, an elegant dual-stage metallacycle by using a ¹O₂ generation porphyrin photosensitizer and diarylethene photochromic switch as the functional building blocks was reported, which shows the capability to reversibly control ¹O₂ generation via photosensitization.⁵⁴

Herein, we present a new discrete [6+6] organoplatinum(II) metallacycle containing six ~180° dipyridylanthracene responsive moieties, which are introduced to allow the capture and release of singlet oxygen in the multi reaction sites. Upon the photooxygenation process, the six anthracene groups in a discrete metallacycle skeleton react with singlet oxygen to afford the metallacycle endoperoxide (M-EPO). The obtained M-EPO is stable under ambient condition and can be stored over months. By using the dipyridylanthracene endoperoxide ligand as the starting material, the corresponding M-EPO can also be prepared by coordination-driven self-assembly. The release of singlet oxygen from the M-EPO was performed by heating the M-EPO solid at 120 °C for 4 h under inert condition, which was determined by adding a ¹O₂ trap reagent. Accordingly, the reversible capture and release of singlet oxygen in an organoplatinum(II) metallacycle are achieved, which provides a promising alternative for the polycyclic aromatic hydrocarbons singlet oxygen reactive reagents.

RESULTS AND DISCUSSION

Synthesis and Characterization.

The organic ligands 1and 3 were prepared according to our previous published procedures.³² Based on the coordination-driven self-assembly methodology, the pyridyl groups terminated 180 ° organic donor ligands (1, 3) react with 120° diplatinum(II) acceptor (2) to afford [6+6] metallacycles 4 and 5. For 4, the reaction was conducted in CH₂Cl₂/CH₃OH (1/1, v/v) at 50 °C for 10 h. Under similar conditions, metallacycle 5 was synthesized by stirring the starting materials at room temperature. The metallacycles were characterized by multinuclear NMR (¹H NMR, ³¹P{¹H} NMR, ¹³C NMR) and electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS) analysis. As shown in the ¹H NMR spectra of metallacycles 4 and 5 (Figure 2a), the peaks corresponding to the H_α and H_β protons of the pyridine groups show downfield shifts as compared to the spectra of the free ligands 1 and 3 (Δδ = −0.47, −0.52 ppm for the H_α, H_β of 4, Δδ = −0.46, −0.47 ppm for the H_α, H_β of 5, respectively), indicating the formation of Pt-pyridyl coordination bonds. In the ³¹P{¹H} NMR spectra of 4 and 5 (Figure 2b), the sharp singlets (ca. 16.72 ppm for 4, 17.54 ppm for 5) with concomitant ¹⁹⁵Pt satellites (J_Pt–P = 2294.9 Hz for 4 and 2294.5 Hz for 5) are observed for each of the metallacycles corresponding to a single phosphorus environment. Compared to the precursor Pt(II) acceptor 2, these peaks show an upfield shift by approximately 5.52 and 4.70 ppm for 4 and 5, respectively. Metallacycles 4 and 5 were also studied by ¹³C NMR. As shown in (Figure S7), the ¹³C NMR spectrum of 5 exhibits a characteristic peak at 83.26 ppm, suggesting the existence of C-O bonds. This signal is not observed in the ¹³C NMR spectrum of 4.

Figure 2.

(a) Partial ¹H NMR (500 MHz, acetone-d₆, 298 K), (b) ³¹P{¹H} NMR (121.4 MHz, acetone-d₆, 298 K) and (c, d) ESITOF-MS spectra of compounds studied in this work.

ESI-TOF-MS is a well established technique to provide evidence for the stoichiometric formation of the multi-charged supramolecular coordination complexes. As shown in Figures 2c, 2d, a series of mass peaks (from 6+ to 9+) owing to the loss of different numbers of trifluoromethanesulfonate groups (OTf⁻) are found in the ESI-TOF-MS spectra of 4 and 5. The isotopically resolved peaks with seven positive charges ([M – 7OTf]⁷⁺) at m/z = 1237.21 for 4, 1264.63 for 5 are in agreement with their calculated theoretical distributions (Figure S3, S6), further supporting the formation of the discrete [6+6] metallacyclic assemblies.

Spectroscopic characterizations.

As shown in Figure 3a, UV–Vis absorption of metallacycle 4 displays the intense vibronic band at 340–450 nm arising from the anthracene moieties. In contrast, this band is absent in the absorption spectrum of M-EPO 5 due to the formation of endoperoxide, which is consistent with the changes of the precursor ligand 1 and 3.³² The emission spectra of 4 and 5 show a similar phenomenon (Figure 3b). Metallacycle 4 is moderately emissive in acetone with the emission quantum yield of ca. 0.23. However, no obvious emission band was observed in the solution of M-EPO 5 under the same conditions. The distinct differences of the spectroscopic behaviors between 4 and M-EPO 5 afford a facile technique for monitoring the reaction of singlet oxygen and provide potential application in the responsive switches.

Figure 3.

(a) Absorption and (b) emission spectra of 4 and 5 in acetone (c = 2.0 × 10⁻⁶ M, λ_ex = 350 nm).

Photooxygenation of 4.

Compound 4 was rapidly photooxygenated to the corresponding endoperoxide (5’) in CD₃OD (40 mg/4 mL), using methylene blue as sensitizer. The obtained product was studied by NMR spectroscopic (¹H NMR, ³¹P{¹H} NMR, ¹³C NMR), ESI-TOF-MS and UV-vis spectral analysis. As shown in Figures 4, S7, the ¹H NMR, ³¹P{¹H} NMR and ¹³C NMR spectra of endoperoxide (5’) are in agreement with that of the as-prepared complex 5. The formation of 5’ was further determined by ESI-TOF-MS analysis. ESI-TOF-MS signals of 5’ at m/z = 1087.81, 1264.63 and 1500.40 were observed (Figure S8), which are consistent with the mass spectral results of the as-prepared complex 5. Hence, the photooxygenation of compound 4 affords the endoperoxide (5’) with the same molecular structure as complex 5.

Figure 4.

Partial (a) ¹H NMR (500 MHz, acetone-d₆, 298 K) and (b) ³¹P{¹H} NMR (121.4 MHz, acetone-d₆, 298 K) of complexes 4, 5’, 5.

UV/vis measurements were conducted to monitor the photooxygenation of 4 in methanol (or MeOH) under solution under pseudo first order reactions conditions (see experimental details in the SI). As shown in Figure S9, the absorption band at 340–450 nm gradually decreased during irradiation. To classify the reactivity of complex 4, we performed an analogous irradiation experiment with just the precursor ligand 1, which has been investigated in our previous work.³² It’s worth noting that complex 4 consists of six reacting anthracene moieties, while the ligand 1 has one anthracene group. Thus, to compare the reactivity of 1 and 4, concentrations were employed at a ratio of 6:1 for 1 and 4 respectively. Complex 4 shows a slower absorption decay at the characteristic band (340–450 nm) than the precursor ligand 1 (Figure 5). The slope fits reveal a ratio of ~2/1 between the reactivity of 1 and 4. The reduced reactivity of the complex can be ascribed to the appearance of the positive charges, which reduce the electron density of the reaction center. This behavior is in accordance with our previous studies on acceptor substituents at diarylanthracenes.⁵⁵ To further prove such influences, we also conducted the irradiation experiment with the positively charged methylated form 1-Me²⁺ (Figure 5). In this case the conversion proceeded significantly slower (k_1-Me2+/k₄~1/3.6). Thus, metal coordination of the pyridyl site reduces electron density to a minor extend as compared to covalent binding to a methyl group. Since the slope of the complex remains linear until completion, we can conclude that each anthracene moiety within the complex reacts independently with the absence of allosteric effects.

Figure 5.

The absorbance decays of complex 4, ligand 1 and its cationic methylated form 1-Me²⁺ caused by photooxygenation in CD₃OD, depicted as semilogarithmic plots.

To investigate the reaction possibility of Pt-phosphine ligand with singlet oxygen,^56,57 the control experiments by using a precursor ligand 6 without anthracene units were performed. In this precursor ligand 6, the labile OTf terminal groups of 120° diplatinum(II) acceptor (2) were replaced by iodide units. Under the similar photooxygenation conditions, there is no obvious shifts in ³¹P NMR Spectra of 6 before and after irradiation (Figure S10), indicating a lack of reactivity between Pt-phosphine ligand and singlet oxygen.

Theoretical calculations.

The reactivity of [4+2] cycloadditions between anthracenes and ¹O₂ can be predicted by the frontier molecular orbital (FMO) theory, based on the energy arising from the overlap between the termini of a diene and a dienophile.⁵⁸ The FMO theory indeed indicated a good correlation between the energy of the HOMO of an acene as diene and the rate constant of its reaction with ¹O₂.^{30,55,59–62}

Therefore, with the intention to explain the reduced rate of the complex 4 relative to ligand 1 and its enhanced reactivity relative to the cationic ligand 1-Me²⁺, DFT calculations of 1, 1-Me²⁺ and the model structure 6 holding the anthracene ligand 1 and two [(PMe₃)₂Pt(C≡CPh)] units, were performed on a B3LYP(LANL2DZ/6–31G*) level. Populations of the resulting frontier orbitals with their energies are shown in Figure 6. Interestingly, their HOMOs are differently populated: While the HOMOs of the bare ligand 1 and the cationic species 1-Me²⁺ show maximal density on the anthracene units, as is typical for anthracenes,³⁰ the maximal population of the HOMO of complex 6 is situated at the outer two ethynylphenyl units. TDDFT calculations further reveal that the first excited state of the complex 6 correspond to a charge transfer from these peripheral units into the LUMO (Table S1) at a wavelength of 442 nm, which is consistent with the red-shift in the UV/vis spectrum of 4 as compared to the free ligand 1 (Figure S11). The reason for the swap of the two orbital populations is that the pyridyl groups of 6 transfer partial charge from the anthracene moiety via the metal center towards the alkynyl moiety (see Mulliken charge populations in Figure S12). As a consequence of this difference, the [4+2] ¹O₂ cycloaddition of 6 cannot occur from its HOMO.

Figure 6.

Populations and energies of the HOMOs and HOMO–1 of the model complex 6, the ligand 1 and its methylated cationic form 1-Me²⁺.

The highest occupied orbital of model complex 6, which shows maximum population at the acene core lies energetically below the HOMO (HOMO–1) with an energy of −9.41 eV. HOMO–1 of 6 lies energetically between the HOMO energies of 1 and 1-Me²⁺, which is in line with the order of reactivities (Figure 6). In summary, FMO theory revealed that the calculated energies of the pertinent orbitals of the diene and the reactivities correlate well. Thus, N-metal coordination causes weaker stabilization of the acene towards ¹O₂ than the direct introduction of a formal positive charge at the nitrogen atom.

Thermolysis of the endoperoxides. The solid of the obtained endoperoxide 5’ and as-prepared complex 5 was directly heated at 120 °C for 4 h with no solvent to fully regenerate the parent complex (4’). Complex 4’ was characterized by ¹H NMR, ³¹P{¹H} NMR, and ESI-TOF-MS analysis. As shown in Figure 6, upon heating complex 5 at 120 °C in an inert atmosphere for 4 h, the ¹H NMR and ³¹P{¹H} NMR of 4’ exhibit the characteristics of complex 4. ESI-TOF-MS spectrum of 4’ shows a series of mass peaks at m/z = 928.95, 1040.32 and 1468.43 (Figure S13). These mass signals can also be observed in the mass spectrum of compound 4 (Figure S3), which further confirm the reconversion of the M-EPO.

An investigation of the reconversion M-EPO kinetics was complicated by the lack of a suitable solvent, in which the complex remained stable. High boiling solvents such as DMF or DMSO, cause the decomposition of the complex. However, we could investigate the reconversion of M-EPO by multiple cycles of heating the neat sample followed by measuring the UV/vis absorption spectrum in a defined volume of acetone and removal of solvent. As shown in Figure 8, the kinetics follows a clean first order process with a half-life of 2.6 h at 90°C. Thus, the M-EPO 5 reconverts significantly faster to its parent form than the free ligand EPO 3 (9.6 h at 90°C).³² Its worth noting that the complex remained stable throughout the thermolysis process since no traces of free ligand 1 were found in the ¹H NMR or UV/vis-spectra.

Figure 8.

(a) UV/vis spectra showing the reappearance of 4’ upon heating of 5 (colored curves) and the free ligand 1 for comparison; (b) semi-logarithmic plot of disappearing M-EPO 5 as derived from the absorbances.

Release of Singlet Oxygen.

In order to verify that a fraction of the released oxygen is in its singlet state, a solution of the ¹O₂ trapping reagent 1,3-diphenylisobenzofurane (DPBF) in toluene was added to the M-EPO. By measuring the DPBF absorbance at 413 nm, a full consumption of the trap was observed upon heating a tenfold excess of the M-EPO 5 at 110 °C (Figure 9). To quantify the amount of ¹O₂ released per M-EPO complex, transfer experiments to DPBF were performed with an excess of the trapping reagent in deuterated solvent in order to keep the fraction of ¹O₂ solvent quenching as low as possible. The average of these experiments revealed that 28±4% of the released oxygen is in its excited state.

Figure 9.

Reaction of DPBF with ¹O₂ generated upon thermolysis of the M-EPO 5.

CONCLUSION

In summary, we have prepared two supramolecular metallacycles by the coordination-driven self-assembly of a ~120° Pt(II) acceptor with a ~180° dipyridyl donor or its corresponding endoperoxide. As the comparative study with the corresponding as-prepared endoperoxide shows, the reversible capture and release of singlet oxygen was realized in this multidipyridylanthracene-bridged organoplatinum(II) metallacycle. The products of the photooxygenation and thermolysis were fully characterized by a combination of NMR experiments and ESI-TOF-MS measurements. UV/vis analysis provides further kinetic results about the photooxygenation and thermolysis of the metallacycle, indicating that the photooxygenation kinetic rate constant of the metallacycle lies between the rate constant of the free ligand and the rate of its corresponding dicationic form 1-Me²⁺. The thermolysis of the resulting M-EPO affords re-generation of the parent complex under release of singlet oxygen. Moreover, a faster re-generation of singlet oxygen from the M-EPO 5 is observed compared to the free ligand EPO 3. This work paves a new pathway to achieve the reversible capture and release of singlet oxygen by using supramolecular coordination complexes.

EXPERIMENTAL SECTION

Materials and Methods.

All reagents were commercially available and used as supplied without further purification (I assume that they are still available). ¹H NMR and ¹³C NMR spectra were recorded on a Varian Inova 500 MHz spectrometer. ³¹P{¹H} NMR spectra were measured on a Varian Unity 300 MHz spectrometer, using an external unlocked sample of 85% H₃PO₄ (δ = 0) as reference. ESI-TOF-MS were recorded on a Waters Synapt G2 mass spectrometer. Absorption and fluorescence spectra were recorded on a Hitachi U-4100 and Hitachi F-7000 Spectrophotometer, equipped with 1 cm quartz cuvettes from Starna Cells, Inc. DFT and TDDFT calculations were carried out using the B3LYP exchange correlation function and implemented in the Gaussian 09 package.⁶²

Synthesis of 4.

9,10-Bis(4-pyridyl)anthracene (1, 3.32 mg, 10.0 μmol) and 2 (12.85 mg, 10.0 μmol) were mixed in CH₂Cl₂/CH₃OH (3 mL/3 mL). The resulting solution was stirred at 50 °C for 10 h. After cooling to rt, the system was then concentrated by flushing with N₂ gas. The resulting yellow solid was collected without further purification to give compound 1 in quantitative yield (>99%). ¹H NMR (500 MHz, Acetone-d₆): δ 9.37 (d, J = 7.5 Hz, 24H), 8.04 (d, J = 7.0 Hz, 24H), 7.56–7.65 (m, overlapped, 48H), 7.44 (s, 6H), 7.33–7.34 (m, overlapped, 18H), 2.15–2.18 (m, overlapped, 144H), 1.32–1.40 (m, overlapped, 216H). ³¹P{¹H} NMR (121.4 MHz, Acetone-d₆): δ 16.72 (s, ¹⁹⁵Pt satellites, ¹J_Pt–P = 2294.9 Hz). ESI-TOF-MS calcd for [M – 7OTf]⁷⁺ (m/z): 1237.21. Found: 1237.21.

Synthesis of 5.

Complex 5 was prepared under the similar procedure for the synthesis of 4. Ligands 2 and 3 were stirred in CH₂Cl₂/CH₃OH (3 mL/3 mL) at room temperature for 10 h to afford the white solid product 5 in quantitative yield (>99%). ¹H NMR (500 MHz, Acetone-d₆): δ 9.38 (d, J = 8.0 Hz, 24H), 8.15 (d, J = 8.5 Hz, 24H), 7.22–7.41 (m, overlapped, 72H), 2.08–2.12 (m, overlapped, 144H), 1.27–1.38 (m, overlapped, 216H). ³¹P{¹H} NMR (121.4 MHz, Acetone-d₆): δ 17.01 (s, ¹⁹⁵Pt satellites, ¹J_Pt–P = 2294.5 Hz). ESI-TOF-MS calcd for [M – 7OTf]⁷⁺ (m/z): 1264.78. Found: 1264.77.

Preparative photooxygenation of 4 to give 5’.

To a solution of complex 4 in CD₃OD (40 mg/4 mL) in a pyrex glass tube was added methylene blue (1 mg). The tube was irradiated for 30 min by using a 300 W sodium lamp at 5 °C, while oxygen was bubbled through the solution.

Figure 1.

Synthetic routes to metallacycles M1 and M2.

Figure 7.

Partial (a) ¹H NMR (500 MHz, acetone-d₆, 298 K) and (b) ³¹P{¹H} NMR (121.4 MHz, acetone-d₆, 298 K) of complexes 5, 4’, 4.