Design and Synthesis of Tris-Heteroleptic Cyclometalated Iridium(III) Complexes Consisting of Three Different Nonsymmetric Ligands Based on Ligand-Selective Electrophilic Reactions via Interligand HOMO Hopping Phenomena

In this article we report on the successful synthesis and isolation of cyclometalated Ir complexes having three different nonsymmetric ligands based on ligand-selective electrophilic reactions via interligand HOMO (highest occupied molecular orbital) hopping phenomena. It was hypothesized that the electrophilic substitution reactions of bis-heteroleptic Ir complexes having 8-benzenesulfonamidoquinoline as an ancillary ligand, <b>5a</b> and <b>7</b>, would proceed at the 5 position of the quinoline ring of these Ir complexes to afford <b>18</b> and <b>19</b>, because their HOMOs are localized on the quinoline rings, as predicted by density functional theory (DFT) calculations. In these products, the HOMO is transferred to one of two ppy ligands, in which the phenyl group is <i>trans</i> to the Ir–N (1 position of quinoline) bond, and hence, the iodination or formylation of <b>18</b> and <b>19</b> occurs at the 5′ position of the ppy ligand to provide <b>20a</b>, <b>23</b>, and <b>24</b>. Furthermore, we carried out the functionalization of <b>20a</b> using cross-coupling reactions to obtain tris-heteroleptic Ir complexes containing three different ligands in good yields with negligible diastereomer formation. Photochemical properties, especially dual emission, and response to pH change, of new dual-emissive tris-heteroleptic cyclometalated Ir complexes, <b>21</b>–<b>24</b>, are also reported

Synthesis and Photochemical Properties of pH Responsive Tris-Cyclometalated Iridium(III) Complexes That Contain a Pyridine Ring on the 2‑Phenylpyridine Ligand

In our previous publication, it was reported that <i>fac</i>-Ir­(atpy)₃ <b>3</b> (atpy = 2-(5′-amino-4′-tolyl)­pyridine), which contains three amino groups at the 5′-position of the atpy ligands, exhibits a pH-dependent change in the color of the emitted radiation. Aqueous solution of <b>3</b> shows a weak red emission (at around 613 nm) under neutral or basic conditions, but the emission color changes to green (at around 530 nm) under acidic conditions, where the NH₂ group is protonated to become an electron-withdrawing (NH₃)⁺ group. In this manuscript, we report on the preparation of some new pH-responsive Ir­(III) complexes; <i>fac</i>-Ir­(4Pyppy)₃ <b>5</b> and <i>fac</i>-Ir­(3Pyppy)₃ <b>6</b> that contain three pyridyl groups at the 5′-position of the 2-phenylpyridine (ppy) ligand, and Ir­(4Pyppym)₃ <b>7</b> and Ir­(3Pyppym)₃ <b>8</b> that contain a pyridyl group at the same position of the 2-phenylpyrimidine (ppym) ligand. The introduction of three pyridyl groups on iodinated Ir­(ppy)₃ and Ir­(ppym)₃ was achieved via Suzuki–Miyaura cross-coupling reaction assisted by microwave irradiation. Solutions of the acid-free Ir­(III) complexes <b>5</b>, <b>6</b>, <b>7</b>, and <b>8</b> showed a strong green emission (at around 500 nm) in dimethylsulfoxide (DMSO). Protonation of three pyridyl groups of <b>5</b> and <b>7</b> causes a significant red-shift in the emission wavelength (at around 600 nm) with a decrease in emission intensity. The pH-dependent emission change of these complexes is also discussed. The generation of singlet oxygen (¹O₂) by the photoirradiation of the Ir complexes <b>5</b> and <b>6</b> was evidenced by the decomposition of 1,3-diphenylisobenzofuran (DPBF), the oxidation of thioanisole, and the oxidation of 2,2,5,5-tetramethyl-3-pyrroline-3-carboxamide (TPC). The induction of necrosis-like cell death of HeLa-S3 cells upon photoirradiation of <b>5</b> at 465 nm is also reported

¹¹B NMR Sensing of d-Block Metal Ions in Vitro and in Cells Based on the Carbon–Boron Bond Cleavage of Phenylboronic Acid-Pendant Cyclen (Cyclen = 1,4,7,10-Tetraazacyclododecane)

Noninvasive magnetic resonance imaging (MRI) including the “chemical shift imaging (CSI)” technique based on ¹H NMR signals is a powerful method for the in vivo imaging of intracellular molecules and for monitoring various biological events. However, it has the drawback of low resolution because of background signals from intrinsic water protons. On the other hand, it is assumed that the ¹¹B NMR signals which can be applied to a CSI technique have certain advantages, since boron is an ultratrace element in animal cells and tissues. In this manuscript, we report on the sensing of biologically indispensable d-block metal cations such as zinc, copper, iron, cobalt, manganese, and nickel based on ¹¹B NMR signals of simple phenylboronic acid-pendant cyclen (cyclen = 1,4,7,10-tetraazacyclododecane), L⁶ and L⁷, in aqueous solution at physiological pH. The results indicate that the carbon–boron bond of L⁶ is cleaved upon the addition of Zn²⁺ and the broad ¹¹B NMR signal of L⁶ at 31 ppm is shifted upfield to 19 ppm, which corresponds to the signal of B(OH)₃. ¹H NMR, X-ray single crystal structure analysis, and UV absorption spectra also provide support for the carbon–boron bond cleavage of ZnL⁶. Because the cellular uptake of L⁶ was very small, a more cell-membrane permeable ligand containing the boronic acid ester L⁷ was synthesized and investigated for the sensing of d-block metal ions using ¹¹B NMR. Data on ¹¹B NMR sensing of Zn²⁺ in Jurkat T cells using L⁷ is also presented

Design and Synthesis of Heteroleptic Cyclometalated Iridium(III) Complexes Containing Quinoline-Type Ligands that Exhibit Dual Phosphorescence

The design and synthesis of some cyclometalated iridium­(III) complexes containing quinoline-type ligands as ancillary ligands are reported. The emission spectra of Ir­(III) complexes containing a quinolinolate (<b>6</b>, <b>8</b>, <b>10</b>) moiety exhibit a single emission peak at ca. 590 nm, resulting in a red colored emission. However, Ir­(III) complexes containing 8-sulfonamidoquinoline ligands (<b>11</b>, <b>13</b>–<b>21</b>) exhibit two different emission peaks (dual emission) at ca. 500 nm and ca. 600 nm upon excitation at 366 nm, resulting in a red-colored emission for <b>11</b> and a pale yellow-colored emission for <b>14</b>–<b>18</b> at 298 K. Especially, a white emission was observed for <b>19</b> at 298 and 77 K in dimethyl sulfoxide. The mechanistic studies based on time-dependent density functional theory calculations and time-resolved emission spectroscopy suggest that this dual emission originates from two independent emission states

¹¹B NMR Sensing of d-Block Metal Ions in Vitro and in Cells Based on the Carbon–Boron Bond Cleavage of Phenylboronic Acid-Pendant Cyclen (Cyclen = 1,4,7,10-Tetraazacyclododecane)

Noninvasive magnetic resonance imaging (MRI) including the “chemical shift imaging (CSI)” technique based on ¹H NMR signals is a powerful method for the in vivo imaging of intracellular molecules and for monitoring various biological events. However, it has the drawback of low resolution because of background signals from intrinsic water protons. On the other hand, it is assumed that the ¹¹B NMR signals which can be applied to a CSI technique have certain advantages, since boron is an ultratrace element in animal cells and tissues. In this manuscript, we report on the sensing of biologically indispensable d-block metal cations such as zinc, copper, iron, cobalt, manganese, and nickel based on ¹¹B NMR signals of simple phenylboronic acid-pendant cyclen (cyclen = 1,4,7,10-tetraazacyclododecane), L⁶ and L⁷, in aqueous solution at physiological pH. The results indicate that the carbon–boron bond of L⁶ is cleaved upon the addition of Zn²⁺ and the broad ¹¹B NMR signal of L⁶ at 31 ppm is shifted upfield to 19 ppm, which corresponds to the signal of B(OH)₃. ¹H NMR, X-ray single crystal structure analysis, and UV absorption spectra also provide support for the carbon–boron bond cleavage of ZnL⁶. Because the cellular uptake of L⁶ was very small, a more cell-membrane permeable ligand containing the boronic acid ester L⁷ was synthesized and investigated for the sensing of d-block metal ions using ¹¹B NMR. Data on ¹¹B NMR sensing of Zn²⁺ in Jurkat T cells using L⁷ is also presented

Design and Synthesis of Amphiphilic and Luminescent Tris-Cyclometalated Iridium(III) Complexes Containing Cationic Peptides as Inducers and Detectors of Cell Death via a Calcium-Dependent Pathway

Cationic amphiphilic peptides have the potential to function as agents for the treatment of microbial infections and cancer therapy. The cationic and hydrophobic parts of these molecules allow them to associate strongly with negatively charged bacterial or cancer cell membranes, thus exerting antimicrobial and anticancer activities through membrane disruption. Meanwhile, cyclometalated iridium­(III) complexes such as <i>fac</i>-Ir­(ppy)₃ (ppy = 2-phenylpyridine) and <i>fac</i>-Ir­(tpy)₃ (tpy = 2-(4′-tolyl)­pyridine) possess <i>C</i>₃-symmetric structures and excellent photophysical properties as phosphorescence materials, which make them important candidates for use in biological applications such as chemosensors, biolabeling, living cell staining, in vivo tumor imaging, and anticancer agents. We recently reported on some regioselective substitution reactions of Ir­(tpy)₃ and Ir­(ppy)₃ at the 5′-position (<i>p</i>-position with respect to the C–Ir bond) on the 2-phenylpyridine ligands and their subsequent conversions to a variety of functional groups. We report here on the design and synthesis of amphiphilic and luminescent tris-cyclometalated Ir complexes in which cationic peptides are attached through alkyl chain linkers that work as inducers and detectors of cell death. Ir complexes containing cationic peptides such as a KKGG sequence and alkyl chain linkers of adequate length (C6 and C8) exhibit considerable cytotoxicity against cancer cells such as Jurkat, Molt-4, HeLa-S3, and A549 cells, and that dead cells are well stained with these Ir complexes. Furthermore, an Ir complex in which the KKGG peptide is attached through a C6 linker displayed lower cytotoxicity against normal mouse lymphocytes. Mechanistic studies suggest that Ir complexes containing the KKGG peptide interact with anionic molecules on the cell surface and/or membrane receptors to trigger the Ca²⁺ dependent pathway and intracellular Ca²⁺ response, resulting in necrosis accompanied by membrane disruption

Design and Synthesis of a Luminescent Cyclometalated Iridium(III) Complex Having <i>N</i>,<i>N</i>‑Diethylamino Group that Stains Acidic Intracellular Organelles and Induces Cell Death by Photoirradiation

Cyclometalated iridium­(III) complexes have received considerable attention and are important candidates for use as luminescent probes for cellular imaging because of their potential photophysical properties. We previously reported that <i>fac</i>-Ir­(atpy)₃ <b>4</b> (atpy = 2-(5′-amino-4′-tolyl)­pyridine) containing three amino groups at the 5′-position of the atpy ligand shows a maximum red emission (at around 600 nm) under neutral and basic conditions and a green emission (at 531 nm) at acidic pH (pH 3–4). In this Article, we report on the design and synthesis of a new pH-sensitive cyclometalated Ir­(III) complex containing a 2-(5′-<i>N</i>,<i>N</i>-diethylamino-4′-tolyl)­pyridine (deatpy) ligand, <i>fac</i>-Ir­(deatpy)₃ <b>5</b>. The complex exhibits a considerable change in emission intensity between neutral and slightly acidic pH (pH 6.5–7.4). Luminescence microscopic studies using HeLa-S3 cells indicate that <b>5</b> can be used to selectively stain lysosome, an acidic organelle in cells. Moreover, complex <b>5</b> is capable of generating singlet oxygen in a pH-dependent manner and inducing the death of HeLa-S3 cells upon photoirradiation at 377 or 470 nm

Photochemical Properties of Red-Emitting Tris(cyclometalated) Iridium(III) Complexes Having Basic and Nitro Groups and Application to pH Sensing and Photoinduced Cell Death

Cyclometalated iridium­(III) complexes, because of their photophysical properties, have the potential for use as luminescent probes for cellular imaging. We previously reported on a pH-activatable iridium complex that contains three <i>N</i>,<i>N</i>-diethylamino groups, namely, <i>fac</i>-Ir­(deatpy)₃ <b>5</b>, which was synthesized via a regioselective aromatic substitution reaction at the 5′-position with tolylpyridine groups of <i>fac</i>-Ir­(tpy)₃ <b>2</b>. It was found that <b>5</b> shows a considerable enhancement in emission intensity in the pH range from neutral to slightly acidic (pH 6.5–7.4) in aqueous solution and selectively stains lysosome in HeLa-S3 cells, due to the protonation of the diethylamino groups. In addition, <b>5</b> functions as a pH-dependent singlet oxygen (¹O₂) generator and induces necrosis-like cell death. However, observing the green emission of <b>5</b> is often hampered by autofluorescence emanating from nearby tissues. To overcome this problem, we designed and synthesized a series of new pH-activatable Ir­(III) complexes that contain diethylamino, guanidyl, and iminoimidazolidinyl groups on the mpiq ligand of Ir­(mpiq)₃ <b>7</b> and the tfpiq ligand of Ir­(tfpiq)₃ <b>8</b>, which exhibit a red emission, namely, Ir­(deampiq)₃ <b>13</b>, Ir­(gmpiq)₃ <b>14</b>, Ir­(imzmpiq)₃ <b>15</b>, and Ir­(imztfpiq)₃ <b>16</b>. The emission intensity of these Ir complexes is enhanced substantially by protonation of their basic groups, and they induce the necrosis-like cell death of HeLa-S3 cells by photoirradiation at 465 nm. A strong orange-red emission of Ir­(mpiq-NO₂)₃ <b>9</b> and Ir­(tfpiq-NO₂)₃ <b>10</b> is also reported

Efficient Synthesis of Tris-Heteroleptic Iridium(III) Complexes Based on the Zn²⁺-Promoted Degradation of Tris-Cyclometalated Iridium(III) Complexes and Their Photophysical Properties

We report on the efficient synthesis of tris-heteroleptic iridium (Ir) complexes based on the degradation of tris-cyclometalated Ir complexes (IrL₃, L: cyclometalating ligand) in the presence of Brønsted and Lewis acids such as HCl (in 1,4-dioxane), AlCl₃, TMSCl, and ZnX₂ (X = Br or Cl), which affords the corresponding halogen-bridged Ir dimers (μ-complexes). Tris-cyclometalated Ir complexes containing electron-withdrawing groups such as fluorine, nitro, or CF₃ moieties on the ligands were less reactive. This different reactivity was applied to the selective degradation of heteroleptic Ir complexes such as <i>fac</i>-Ir­(tpy)₂(F₂ppy) (<i><b>fac</b></i><b>-12</b>) (tpy: 2-(4′-tolyl)­pyridine and F₂ppy: 2-(4′,6′-difluorophenyl)­pyridine), <i>mer</i>-Ir­(tpy)₂(F₂ppy) (<i><b>mer</b></i><b>-12</b>), and <i>mer</i>-Ir­(mpiq)₂(F₂ppy) (<i><b>mer</b></i><b>-15</b>) (mpiq: 1-(4′-methylphenyl)­isoquinoline). For example, the reaction of <i><b>mer</b></i><b>-12</b> with ZnBr₂ gave the heteroleptic μ-complex [{Ir­(tpy)­(F₂ppy)­(μ-Br)}₂] <b>27b</b> as a major product, resulting from the selective elimination of the tpy ligand of <i><b>mer</b></i><b>-12</b>, and treatment of <b>27b</b> with acetylacetone (acacH) afforded the corresponding tris-heteroleptic Ir complex Ir­(tpy)­(F₂ppy)­(acac)<b>18</b>. In addition, another tris-heteroleptic Ir complex <b>35a</b> having 8-benzene­sulfonyl­amido­quinoline (8BSQ) ligand was synthesized. Mechanistic studies of this degradation reaction and the photochemical properties, especially a dual emission, of these newly synthesized tris-heteroleptic Ir complexes are also reported

Stereospecific Synthesis of Tris-heteroleptic Tris-cyclometalated Iridium(III) Complexes via Different Heteroleptic Halogen-Bridged Iridium(III) Dimers and Their Photophysical Properties

Herein, we report on the stereospecific synthesis of two single isomers of tris-heteroleptic tris-cyclometalated iridium­(III) (Ir­(III)) complexes composed of three different nonsymmetric cyclometalating ligands via heteroleptic halogen-bridged Ir dimers [Ir­(tpy)­(F₂ppy)­(μ-Br)]₂ <b>17b</b> and [Ir­(mpiq)­(F₂ppy)­(μ-Br)]₂ <b>27b</b> (tpyH: (2-(4′-tolyl)­pyri­dine) and F₂ppyH: (2-(4′,6′-di­fluoro­phenyl)­pyridine), and mpiqH: (1-(4′-methyl­phenyl)­iso­quinoline)) prepared by Zn²⁺-promoted degradation of Ir­(tpy)₂­(F₂ppy) <b>21</b> and Ir­(mpiq)₂­(F₂ppy) <b>26</b>, as reported by us. Subsequently, <b>17b</b> and <b>27b</b> were converted to the tris-heteroleptic tris-cyclometalated Ir complexes Ir­(tpy)­(F₂ppy)­(mpiq) <b>25</b> consisting of tpy, F₂ppy, and mpiq, as confirmed by spectroscopic data and X-ray crystal structure analysis. The first important point in this work is the selective synthesis of specific isomers among eight possible stereoisomers of Ir complexes having the same combination of three cyclometalating ligands. Namely, two meridional forms of <b>25</b> were synthesized and isolated. The second finding is that the different stereoisomers of <b>25</b> have different stability. Finally, different stereoisomers exhibit different emission spectra. Namely, one of its stereoisomers <b>25a</b> exhibits a single broad emission from <i>ca</i>. 550 nm to <i>ca</i>. 650 nm (orange emission), while stereoisomer <b>25c</b> emits dual emission at <i>ca</i>. 509 nm and <i>ca</i>. 600 nm (pale pink emission), as supported by time-dependent density functional theory calculation. To the best of our knowledge, this is the first report of the selective and efficient synthesis of different stereoisomers of tris-heteroleptic tris-cyclometalated Ir­(III) complexes that have different stabilities and different photophysical properties