Formation of Iridium(III) and Rhodium(III) Amine, Imine, and Amido Complexes Based on Pyridine-Amine Ligands: Structural Diversity Arising from Reaction Conditions, Substituent Variation, and Metal Centers.

{"full_text": " pubs.acs.org/IC Article\n\n\n\n Formation of Iridium(III) and Rhodium(III) Amine, Imine, and Amido\n Complexes Based on Pyridine\u2212Amine Ligands: Structural Diversity\n Arising from Reaction Conditions, Substituent Variation, and Metal\n Centers\n Xueyan Hu, Lihua Guo,* Mengqi Liu, Mengru Sun, Qiuya Zhang, Hongwei Peng, Fanjun Zhang,\n and Zhe Liu*\n Cite This: Inorg. Chem. 2022, 61, 10051\u221210065 Read Online\nSee https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.\n\n\n\n\n ACCESS Metrics & More Article Recommendations *\n s\u0131 Supporting Information\n Downloaded via MOSCOW STATE UNIV on May 12, 2026 at 13:46:26 (UTC).\n\n\n\n\n ABSTRACT: Herein, we present the di\ufb00erent coordination modes of half-sandwich iridium(III) and rhodium(III) complexes based\n on pyridine\u2212amine ligands. The pyridyl\u2212amine iridium(III) and rhodium(III) complexes, the corresponding oxidation pyridyl\u2212\n imine products, and 16-electron pyridyl\u2212amido complexes can be obtained through the change in reaction conditions (nitrogen/\n adventitious oxygen atmosphere, reaction time, and solvents) and structural variations in the metal and ligand. Overall, the reaction\n of pyridine\u2212amine ligands with [(\u03b75-C5(CH3)5)MCl2]2 (M = Ir or Rh) in the presence of adventitious oxygen a\ufb00orded the oxidized\n pyridyl\u2212imine complexes. The possible mechanism for the oxidation of iridium(III) and rhodium(III) amine complexes was\n con\ufb01rmed by the detection of the byproduct hydrogen peroxide. Moreover, the formation of pyridyl\u2212amine complexes was favored\n when nonpolar solvent CH2Cl2 was used instead of CH3OH. The rarely reported complex with [(\u03b75-Cp*)IrCl3] anions can also be\n obtained without the addition of NH4PF6. The introduction of the sterically bulky i-Bu group on the bridge carbon of the ligand led\n to the formation of stable 16-electron pyridyl\u2212amido complexes. The pyridyl\u2212amine iridium(III) and rhodium(III) complexes were\n also synthesized under a N2 atmosphere, and no H2O2 was detected in the whole process. In particular, the aqueous solution stability\n and in vitro cytotoxicity toward A549 and HeLa human cancer cells of these complexes were also evaluated. No obvious selectivity\n was observed for cancer cells versus normal cells with these complexes. Notably, the represented complex 5a can promote an\n increase in the reactive oxygen species level and induce cell death via apoptosis.\n\n\n 1. INTRODUCTION that the cationic half-sandwich pyridyl\u2212imine iridium(III) and\n Platinum metal-based anticancer drugs have achieved great ruthenium(II) complexes could produce signi\ufb01cant levels of\n success in the treatment of various tumors.1\u22123 However, side ROS, disrupt the mitochondrial membrane, and show potent\n e\ufb00ects and drug resistance have stimulated exploration of anticancer activity toward A549 cancer cells (Scheme 1, II and\n alternative metal complexes.4\u22127 Among these complexes, half- III).31,32 Interestingly, some ruthenium(II) complexes achieved\n sandwich organometallic platinum group metal-based (ruthe- good selectivity toward cancer cells and normal cells.32,33 More\n nium, iridium, rhodium, and osmium) complexes with the recently, we further demonstrated that the metal variation in the\n piano-stool con\ufb01guration have been well studied as anticancer zwitterionic pyridyl\u2212imine half-sandwich complexes and the\n agents.8\u221228 These complexes have shown promising anticancer\n activity and some di\ufb00erent mechanisms of action (MoAs) with\n platinum drugs. For example, Sadler and co-workers reported Received: March 25, 2022\n that the high-potency phenylpyridine iridium(III) complexes Published: June 23, 2022\n (Scheme 1, I) induced a signi\ufb01cant increase in reactive oxygen\n species (ROS) in cancer cells, which involved catalytic hydride\n transfer from the coenzyme NADH to oxygen to generate the\n ROS hydrogen peroxide (H2O2).29,30 Our group has also found\n\n \u00a9 2022 American Chemical Society https://doi.org/10.1021/acs.inorgchem.2c00984\n 10051 Inorg. Chem. 2022, 61, 10051\u221210065\n\fInorganic Chemistry pubs.acs.org/IC Article\n\nScheme 1. Half-Sandwich Platinum-Group Metal Complexes Containing a Pyridyl Moiety\n\n\n\n\nScheme 2. Synthesis of Ligands 1a\u22121d\n\n\n\n\nintroduction of \ufb02uorinated substituents resulted in a signi\ufb01cant pyridyl\u2212imine products can be obtained respectively in good\nincrease in the anticancer activity (Scheme 1, IV).34\u221236 Notably, yields by adjusting reaction conditions (nitrogen/adventitious\nthe coordination fashion of the abovementioned pyridyl\u2212imine oxygen atmosphere, reaction time, and solvents). Notably, when\nhalf-sandwich iridium(III) complexes was imine-metal. Along a sterically demanding iso-butyl group on the bridge carbon\nthis line, we became interested in expanding our investigation to between the pyridyl moiety and amine moiety was introduced,\nthe synthesis and biological evaluation of the corresponding no oxidation was observed and a stable 16-electron pyridyl\u2212\namine\u2212metal and amido\u2212metal complexes (Scheme 1). amido complex was generated (Scheme 1, pyridyl\u2212amido\n In this present study, we initially intended to synthesize complex).\npyridyl\u2212amine iridium(III) and rhodium(III) complexes\n(Scheme 1, pyridyl\u2212amine complex) by the reaction of 2. RESULTS AND DISCUSSION\npyridyl\u2212amine ligands with the corresponding iridium(III)\nand rhodium(III) dimer precursors. However, the unexpected 2.1. Synthesis of Ligands. Pyridine\u2212amine ligands 1a\u22121d\nproducts of the oxidized imine complexes were generated under were synthesized in good yields by a reduction reaction of\nthe conditions of adventitious molecular oxygen, especially the pyridine\u2212imine ligands with LiAlH4, AlMe3,39 and Al(i-Bu)3\nreaction of dimer precursor [(\u03b7 5 -Cp*)IrCl 2 ]2 (Cp* = (Scheme 2). The steric hindrance of the substituents on the\nC5(CH3)5) with pyridyl\u2212amine ligands in the absence of bridge carbon between the pyridyl moiety and the amine moiety\nNH4PF6 a\ufb00orded rarely reported complex with [(\u03b75-Cp*)IrCl3] can be tuned using these di\ufb00erent reduction agents. Interest-\nanions.37,38 Moreover, the pyridyl\u2212amine iridium(III) and ingly, when Al(i-Bu)3 was employed to synthesize 1d, a mixture\nrhodium(III) complexes and the corresponding oxidation of 1c and 1d (ca. 1:1 molar ratio) was obtained, and they could\n 10052 https://doi.org/10.1021/acs.inorgchem.2c00984\n Inorg. Chem. 2022, 61, 10051\u221210065\n\fInorganic Chemistry pubs.acs.org/IC Article\n\nScheme 3. Synthesis of (i) Pyridyl\u2212Imine or (ii) Pyridyl\u2212Amine Complexes in the Presence of Small Amounts of Adventitious\nMolecular Oxygen When the Polar Solvent CH3OH Was Used\n\n\n\n\nFigure 1. X-ray crystal structure of complexes (i) 2a and (ii) 3c with the thermal ellipsoids drawn at the 50% probability level. The hydrogen atoms and\nPF6\u2212 anions have been omitted for clarity. (i) Bond angles around Ir(III) ions (deg): N1\u2212Ir1\u2212N2 = 76.07(14). Bond lengths (\u00c5): Ir1\u2212C(centroid) =\n1.8001, Ir1\u2212N1 = 2.108(3), Ir1\u2212N2 = 2.101(3), Ir1\u2212Cl1 = 2.3713(11), and C1\u2212N1 = 1.275(5); (ii) bond angles around Rh (III) ions (deg): N1\u2212\nRh1\u2212N2 = 76.59(11). Bond lengths (\u00c5): Rh1\u2212C(centroid) = 1.8045, Rh1\u2212N1 = 2.114(3), Rh1\u2212N2 = 2.142(3), Rh1\u2212Cl1 = 2.4081(9), and C16\u2212\nN2 = 1.286(4).\n\nbe readily separated by chromatography. The possible 2c and 3b\u22123c, Scheme 3(i)), were cleanly obtained in 64\u221278%\nmechanism for the production of 1c and 1d mixture is shown isolated yields. Notably, the pyridyl\u2212amine complex 5a was\nin Scheme S1. The intermediate pyridyl\u2212amido aluminum(III) synthesized under the same conditions without the formation of\ncomplex was generated by the reaction of Al(i-Bu)3 with the the oxidized pyridyl\u2212imine complex (Scheme 3(ii) vs Scheme\npyridyl\u2212imine compound. The mixture was then quenched with 3(i)), which indicated that the oxidation reaction in this system\nNaOH aqueous solution, and 1d was \ufb01nally obtained. In the could be attributed to the combinatorial action of the metal\nmeantime, \u03b2-H elimination of Al(i-Bu)3 at re\ufb02ux temperature center and the structure of the pyridyl\u2212amine ligand. Purity and\nmay result in the formation of [Al(i-Bu)2(\u03bc-H)]2.40 Sub- identity of 2a\u22122c and 3b\u22123c were con\ufb01rmed by 1H and 13C\nsequently, the in situ treatment of [Al(i-Bu)2(\u03bc-H)]2 with the NMR (Figures S8\u2212S17), mass spectrometry (Figures S40\u2212\npyridine\u2212imine compound led to the generation of 1c. This S44), elemental analysis (Figures S54\u2212S57), and single-crystal\nmechanism was further supported by the observation that only X-ray crystallography. In order to con\ufb01rm the formation of the\n1b was produced when AlMe3 (without \u03b2-H) was employed. oxidized pyridyl\u2212imine complexes, the pyridyl\u2212imine iridium-\n 2.2. Oxidative Dehydrogenation of Amine to Imine (III) and rhodium(III) complexes were also prepared by the\nComplexes. The initial design was to synthesize cationic half- reactions of the corresponding pyridine\u2212imine ligands with\nsandwich pyridyl\u2212amine iridium(III) and rhodium(III) com- [(\u03b75-Cp*)MCl2]2 (M = Ir or Rh), and they showed the same\nplexes. The reactions of pyridine\u2212amine ligands with [(\u03b75- NMR spectra with the abovementioned complexes generated\nCp*)MCl2]2 (M = Ir or Rh, Cp* = C5(CH3)5) were performed using pyridine\u2212amine ligands (Figures S34\u2212S37).\nfor 24 h and in the presence of small amounts of adventitious The crystalline samples of 2a and 3c suitable for X-ray\noxygen (the solution was not degassed with nitrogen), which di\ufb00raction analysis were obtained by slow di\ufb00usion of hexane (or\nwas usually employed to synthesize half-sandwich iridium(III) the mixture of hexane and diethyl ether) in a dichloromethane\nand rhodium(III) analogues in our previous work.31,35,36 (or acetonitrile) solution. The selected bond lengths are given in\nHowever, the corresponding oxidation products, that is, Figure 1. Planar \ufb01ve-member metallacycles were observed in\npyridyl\u2212imine iridium(III) and rhodium(III) complexes (2a\u2212 both 2a (Ir1\u2212N1\u2212C1\u2212C2\u2212N2) and 3c (Rh1\u2212N1\u2212C15\u2212\n 10053 https://doi.org/10.1021/acs.inorgchem.2c00984\n Inorg. Chem. 2022, 61, 10051\u221210065\n\fInorganic Chemistry pubs.acs.org/IC Article\n\nScheme 4. Synthesis of Pyridyl\u2212Imine or Pyridyl\u2212Amine Complexes in the Presence of Small Amounts of Adventitious\nMolecular Oxygen (i) under the Reaction Time of 2 h or (ii and iii) in the Non-Polar Solvent CH2Cl2\n\n\n\n\nScheme 5. Synthesis of Complex 6 with [(\u03b75-Cp*)IrCl3] Anion\n\n\n\n\nC16\u2212N2) due to the coplanar structure between the pyridyl obtained (Scheme 4(i) vs Scheme 3(i)), which further proved\nmoiety and C\ue0c8N bond. Moreover, the C1\u2212N1 (1.275(5) \u00c5) the oxidation mechanism. In this case, we were unable to\n(2a) and C16\u2212N2 (1.286(4) \u00c5) (3c) distances were in separate two kinds of complexes by standard puri\ufb01cation\nagreement with double bonds of C\ue0c8N. The bond angles and methods. The oxidation reaction was also dependent on the\nlengths are similar to those reported for pyridyl\u2212imine solvent used in this reaction. For example, when the non-polar\niridium(III) and rhodium(III) complexes obtained by the solvent CH2Cl2 was used instead of CH3OH, the formation of\nreaction of pyridine\u2212imine ligands with [(\u03b75-Cp*)MCl2]2.31,41 the imine complex 2b was not observed and the amine complex\nPrevious studies have shown that some pyridyl\u2212amine 4b was cleanly obtained (Scheme 4(ii) vs Scheme 3(i)). In\nruthenium(II) and iridium(III) complexes can be oxidized to another case, when 1a was employed to react with [(\u03b75-\nthe pyridyl\u2212imine complexes when molecular oxygen is not Cp*)IrCl2]2 in CH2Cl2, a mixture of the amine complex 4a\ntotally eliminated.42,43 The acidic N\u2212H proton on the pyridyl\u2212 (more than 50% determined by 1H NMR analysis) and the\namine ligands can promote the production of the oxidized imine imine complex 2a was generated (Scheme 4(iii) vs Scheme\ncomplexes.42,44,45 According to the reported mechanism by 3(i)). It seemed reasonable that the non-polar CH2Cl2 made the\nGo\u0301mez et al. for the oxidation of amine to imine ruthenium(II) deprotonation of the amine complexes di\ufb03cult, that is, lowered\ncomplexes,42 the proposed steps in this system are shown in the acidity of the N\u2212H proton and thus prevented or suppressed\nScheme S2. In the process of preparing 2a\u22122c, 3b, and 3c, the the formation of the oxidized imine complexes.\nformation of H2O2 in the oxidation reaction was unequivocally The reactions of pyridyl\u2212amine ligands with [(\u03b7 5 -\ncon\ufb01rmed in a peroxide test using a Quanto\ufb01x test stick (Scheme C5(CH3)5)MCl2]2 without the addition of NH4PF6 were also\nS2), which supported this oxidation mechanism. performed under the same reaction conditions. The oxidation\n Furthermore, when the reaction time changed from 24 to 2 h, product was also completely obtained. This pyridyl\u2212imine\na mixture of pyridyl\u2212imine and pyridyl\u2212amine complexes was iridium(III) complex showed a rarely reported structure with\n 10054 https://doi.org/10.1021/acs.inorgchem.2c00984\n Inorg. Chem. 2022, 61, 10051\u221210065\n\fInorganic Chemistry pubs.acs.org/IC Article\n\n[(\u03b75-Cp*)IrCl3] anions (Scheme 5, 6) and could be generated [(\u03b75-Cp*)IrCl3] displayed the same piano-stool geometry with\ncleanly even when the iridium(III) dimer [(\u03b75-Cp*)IrCl2]2 was the \u03b75-Cp* ligand occupying three coordination sites and the\nreacted with 2 equiv of the pyridyl\u2212amine ligand. Kennedy and three chloride atoms occupying three facial positions. The\nSmith have shown that the more weakly coordinating ligand average of Ir\u2212Cl bond lengths was 2.4123 \u00c5. The distance\ncould lead to the incomplete dissociation of the precursor [(\u03b75- (1.7623 \u00c5) between the centroid of the Cp* ring and the metal\nCp*)IrCl2]2 and a\ufb00ord anionic and cationic ion pairs in their center was slightly shorter than in the cationic parts (1.8127 \u00c5).\nsystem.37 However, in most cases, half-sandwich iridium The reaction of complex 6 with NH4PF6 a\ufb00orded the\ncomplexes with Cl\u2212 as counteranions were obtained in the monometallic complex 2b with PF6\u2212 as counteranions,\nabsence of an exogeneous source of a weakly coordinating anion indicating that NH4PF6 was simply a reaction reagent for\n(e.g., PF6\u2212).27,28,46 For example, when the common N,N- anion exchange in the oxidation process.\nchelating ligands 1,10-phenanthroline (phen), 2,2\u2032-bipyridine 2.3. Synthesis and Reactivity of Amido Complexes.\n(bpy) and ethylenediamine (en) were employed to react with The most notable observation was the formation of pyridyl\u2212\n[(\u03b75-C5(CH3)5)IrCl2]2 without addition of NH4PF6, the amido complex 7 when the sterically bulky i-Bu group on the\nformation of half-sandwich iridium complexes with Cl\u2212 as bridge carbon of the ligand was employed instead of H and CH3\nnon-coordinating counteranions was observed.27 Thus, the substituents (Scheme 6). The reaction conditions were the same\ngeneration of rare [(\u03b75-Cp*)IrCl3] anions seemed to be as those for complexes 2a\u22122c. However, the formation of the\nassociated with the relative binding strengths of the chelating oxidized imine complex was not observed, and the amido\nN-donor ligands. This complex with [(\u03b75-Cp*)IrCl3] anions was complex 7 was cleanly obtained in 70% isolated yield. This type\nvery stable in DMSO-d6 and CDCl3 solution over extended of half-sandwich 16-electron complex was rarely reported.\nperiods. The 1H NMR spectra of complex 6 showed two Notably, the \u03b2 hydrogen (CH(i-Bu), H proton at the \u03b2 position\ncharacteristic peaks (1.50 and 1.61 ppm) corresponding to the to the metal) on the bridge carbon existed in our system. The\nproton of the Cp* in the cationic part and anionic part, previously reported stable 16-electron ruthenium(II) analogues\nrespectively (Figure S30). Moreover, the presence of two molar could be obtained only when the \u03b2 hydrogen atom was avoided\nequivalents of bound Cp* per mol ligand was also observed. and the deprotonating agents (e.g., NaOMe) were added.42\n Complex 6 was also con\ufb01rmed by elemental analysis and Thus, the successful synthesis of stable pyridyl\u2212amido iridium-\nsingle-crystal X-ray crystallography (Figure 2). Similar to (III) complexes containing \u03b2 hydrogen atoms in this system was\ncomplexes 2a and 3c, the cationic part of complex 6 adopted likely due to the high steric requirements (i-Bu group) on the\nthe typical piano-stool conformation with the \ufb01ve-membered bridge carbon. The identity and purity of complex 7 were\nmetallocycle formed by the coordination of the pyridyl\u2212imine determined by 1H and 13C NMR (Figures S32 and S33), mass\nligand. The Ir\u2212N distances were also comparable to those spectrometry (Figure S53), elemental analysis, and single-crystal\npreviously reported for monometallic iridium(III) pyridyl\u2212 X-ray crystallography. The molecular structure of complex 7 is\nimine complexes containing counteranion PF6\u2212.31 The anion shown in Figure 3. Complex 7 adopted \ufb01ve-coordinated (16-\n electron) piano-stool geometry, and no leaving group Cl\u2212 bound\n to the metal center. Furthermore, a nonplanar \ufb01ve-member\n metallacycle was observed in complex 7, and the C6\u2212N2 (1.470\n \u00c5) distance was in agreement with the single bond of C\u2212N.\n The 1H NMR spectra of pyridyl\u2212amido complex 7 exhibited\n no obvious change over 24 h, suggesting that this type of\n iridium(III) complex was fairly stable in CDCl3 or DMSO-d6.\n Previous studies have displayed that the reactions of 16-electron\n half-sandwich iridium(III) and ruthenium(II) complexes with a\n series of two-electron donors can produce stable 18-valence\n electron compounds.47,48 When PPh3, CH3CN, or a CO\n atmosphere was introduced in a NMR tube containing a\n CDCl3 solution of 7, no additional 1H NMR peaks were\n observed over a period of 20 h, indicating that PPh3, CH3CN,\n and CO did not react with 7 (Figures S58\u2212S60). The stable\n nature of 7 may also support the oxidation mechanism shown in\n Scheme S2. The amido complex with the bulky i-Bu group might\n have been formed in situ by deprotonation of the amine complex\n in step (i) and showed a very stable nature. As a result, the step\n (ii) (the oxidation of the amido complex by oxygen) could be\n stopped. On the other hand, the 1H NMR chemical shifts as a\n measure of the N\u2212H acidity of the respective N\u2212H proton for\n 1a\u22121d could be considered.49 The chemical shift of the N\u2212H\n proton in 1d with the bulky i-Bu group (ca. 3.99 ppm) was lower\nFigure 2. X-ray crystal structure of complex 6 with the thermal than that of the N\u2212H protons in 1a\u22121c (4.05\u22124.61 ppm)\nellipsoids drawn at the 50% probability level. The hydrogen atoms have\n (Figures S2-S6). This means a lower acidity of the N\u2212H proton\nbeen omitted for clarity. Bond angles around Ir(III) ion (deg): N1\u2212\nIr1\u2212N2 = 75.8(7), Cl2\u2212Ir2\u2212Cl3 = 90.2(2), Cl2\u2212Ir2\u2212Cl4 = 86.7(2), in 1d, which could also be considered as a plausible mechanism\nand Cl3\u2212Ir2\u2212Cl4 = 88.1(2). Bond lengths (\u00c5): Ir1\u2212C(centroid) = for the absence of the oxidation. The reaction of 1d with [(\u03b75-\n1.8127, Ir1\u2212N1 = 2.089(18), Ir1\u2212N2 = 2.102(16), Ir1\u2212Cl1 = Cp*)RhCl2]2 was also performed under the same conditions.\n2.393(5), and C2\u2212N2 = 1.312(18); Ir2\u2212C(centroid) = 1.7623, Ir2\u2212 This reaction gave one new point on the thin-layer\nCl2 = 2.391(6), Ir2\u2212Cl3 = 2.422(6), and Ir2\u2212Cl4 = 2.424(7). chromatography plates, and complete puri\ufb01cation seemed to\n 10055 https://doi.org/10.1021/acs.inorgchem.2c00984\n Inorg. Chem. 2022, 61, 10051\u221210065\n\fInorganic Chemistry pubs.acs.org/IC Article\n\nScheme 6. Synthesis of 16-Electron Pyridyl\u2212Amido Complex 7 in the Presence of Small Amounts of Adventitious Molecular\nOxygen\n\n\n\n\n with adventitious oxygen, and the oxidized pyridyl\u2212imine\n complex could be observed over time. This observation is also\n consistent with the abovementioned proposed oxidation\n mechanism. Characterization of these complexes was performed\n by 1H and 13C NMR (Figures S18\u2212S29), mass spectrometry\n (Figures S45\u2212S50), elemental analysis, (Figures S54\u2212S57) and\n single-crystal X-ray crystallography (Figure 4). Notably, the\n secondary amine ligands have chiral nitrogen atoms, and the\n nonplanar \ufb01ve-membered chelate ring of the ligand is also a\n chiral entity.42,50 Hence, most of these complexes were found to\n be a mixture of diastereomers in solution, which can be\n con\ufb01rmed from the distinct peaks for the major and minor\n isomers. It should be noted that the diastereomeric behavior of\n the similar amine ruthenium(II) and iridium(III) complexes has\nFigure 3. X-ray crystal structure of complex 7 with the thermal been reported in detail.42,43 The two characteristic peaks in the\nellipsoids being drawn at the 50% probability level. The hydrogen 1\natoms and PF6\u2212 anions have been omitted for clarity. Bond angles\n H NMR spectra for these amine complexes were at ca. 3.64\u2212\naround Ir(III) ions (deg): N1\u2212Ir1\u2212N2 = 78.6(5). Bond lengths (\u00c5): 5.64 ppm and ca. 6.51\u22127.34 ppm, corresponding to the protons\nIr1\u2212C (centroid) = 1.7966, Ir1\u2212N1 = 2.053(12), Ir1\u2212N2 = 1.907(13), of the CH-R group (H on the bridge carbon, R = H or CH3) and\nand C6\u2212N2 = 1.470(17). N\u2212H protons, respectively. In the case of 4a, 5a, 4c, and 5c, the\n signals of each proton of the CH2 group displayed separately due\nbe achieved. The ESI-MS analysis showed the presence of the to the presence of the two diastereomeric protons, which was\ncorresponding 16-electron complexes. However, 1H NMR also in agreement with the previously reported amine\nspectra of the products were too complicated for the assignment complexes.43 In contrast to the abovementioned imine\nof signals, indicating that this complex may be unstable and complexes 2a and 3c, which showed planar \ufb01ve-member\nother species were formed in solution. metallacycles, nonplanar \ufb01ve-member metallacycles were\n 2.4. Synthesis and Characterization of Amine Com- observed in these amine complexes 4a (Ir1\u2212N1\u2212C11\u2212C12\u2212\nplexes. The pyridyl\u2212amine complexes 4a\u22124c and 5a\u22125c were N2), 5a (Rh1\u2212N1\u2212C2\u2212C1\u2212N2), and 5b (Rh1\u2212N1\u2212C3\u2212\nsynthesized (Scheme 7) in 60\u221271% isolated yields by the C2\u2212N2) due to the coordination of sp3 nitrogen (Figure 4). The\nreaction of the precursors [(\u03b75-Cp*)IrCl2]2 or [(\u03b75-Cp*)- C11\u2212N1 (1.466(5) \u00c5) (4a), C1\u2212N2 (1.466(7) \u00c5) (5a), and\nRhCl2]2 with pyridyl\u2212amine ligands 1a\u22121c in methanol or C2\u2212N2 (1.504(5) \u00c5) (5b) distances were longer than those in\nCH2Cl2 under a nitrogen atmosphere (the solution was imine complexes (C\ue0c8N bonds in 2a and 3c: 1.275\u22121.286 \u00c5)\ndegassed with nitrogen in the whole process). In this case, no and in agreement with single bonds of C\u2212N. Moreover, the\nH2O2 was detected in the peroxide test using a Quanto\ufb01x test coordination of leaving group Cl\u2212 to the metal center was\nstick (Figure S61). Except for 5a, these pyridyl\u2212amine observed. These results were consistent with the amine\u2212metal\ncomplexes were not stable in CDCl3 or DMSO-d6 solution coordination mode.\n\nScheme 7. Synthesis of Pyridyl\u2212Amine Complexes Under a Nitrogen Atmosphere\n\n\n\n\n 10056 https://doi.org/10.1021/acs.inorgchem.2c00984\n Inorg. Chem. 2022, 61, 10051\u221210065\n\fInorganic Chemistry pubs.acs.org/IC Article\n\n\n\n\nFigure 4. X-ray crystal structures of complexes (i) 4a, (ii) 5a, and (iii) 5b with the thermal ellipsoids drawn at the 50% probability level. Some hydrogen\natoms and the PF6\u2212 anion have been omitted for clarity. (i) Bond angles around Ir(III) ions (deg): N1\u2212Ir1\u2212N2 = 75.21(12). Bond lengths (\u00c5): Ir1\u2212\nC(centroid) = 1.7899, Ir1\u2212N1 = 2.174(3), Ir1\u2212N2 = 2.105(3), and Ir1\u2212Cl1 = 2.3873(11), C11\u2212N1 = 1.466(5); (ii) Bond angles around Rh(III)\nions (deg): N1\u2212Rh1\u2212N2 = 74.88(18). Bond lengths (\u00c5): Rh1\u2212C(centroid) = 1.7661, Rh1\u2212N1 = 2.096(5), Rh1\u2212N2 = 2.179(5), Rh1\u2212Cl1 =\n2.3738(17), and C1\u2212N2 = 1.466(7); (iii) bond angles around Rh(III) ions (deg): N1\u2212Rh1\u2212N2 = 77.33(13). Bond lengths (\u00c5): Rh1\u2212C(centroid) =\n1.7886, Rh1\u2212N1 = 2.105(3), Rh1\u2212N2 = 2.238(3), Rh1\u2212Cl1 = 2.3763(13), and C2\u2212N2 = 1.504(5).\n\n\n\n\nFigure 5. UV\u2212vis spectra for complexes 2b, 4b, 5a, and 7 recorded over a period of 24 h at 37 \u00b0C: (i) solution in 30% DMSO/70% PBS (v/v) of 2b, (ii)\nsolution in 30% DMSO/70% PBS (v/v) of 4b, (iii) solution in 30% DMSO/70% PBS (v/v) of 5a, and (iv) solution in 30% DMSO/70% PBS (v/v) of\n7.\n\n\n\n 10057 https://doi.org/10.1021/acs.inorgchem.2c00984\n Inorg. Chem. 2022, 61, 10051\u221210065\n\fInorganic Chemistry pubs.acs.org/IC Article\n\n 2.5. Aqueous Stability. It is essential to evaluate the susceptible to bind to the constituents of the cell culture\nstability of the metal complexes in aqueous media and under medium.\nphysiological conditions for drug development. Thus, the 2.6. In Vitro Cytotoxicity. Previously, we have synthesized\nstability of the complexes in this system was assessed using the pyridyl\u2212imine iridium(III) and ruthenium(II) complexes\nUV\u2212visible spectrophotometry in 70% phosphate bu\ufb00ered through the reactions of the pyridyl\u2212imine ligands with the\nsaline (PBS) (PBS is prepared from water pH: ca. 7.2)/30% corresponding metal precursors, and these complexes displayed\nDMSO (v/v) at 37 \u00b0C (Figures 5 and S62). Notably, we have appreciable biological activities.31,32 Hence, we sought to\npreviously reported that the similar pyridyl\u2212imine iridium(III) expand the investigation to the pyridyl\u2212imine rhodium(III)\ncomplexes, which were prepared by the reactions of the complexes prepared in this work. Moreover, to the best of our\ncorresponding pyridine\u2212imine ligands with [(\u03b75-Cp*)MCl2]2 knowledge, the biological activity of pyridyl\u2212amido and\nrather than the pyridine\u2212amine ligand-involved oxidation pyridyl\u2212amine iridium(III) and rhodium(III) complexes has\nreaction, could undergo hydrolysis of M\u2212Cl, that is, Cl\u2212/H2O never been investigated to date. As mentioned above, most of\nexchange in aqueous media,31 which represented an activation the pyridyl\u2212amine complexes would su\ufb00er from the oxidation\nstep for some metal-based anticancer complexes since aqua reaction if oxygen (even adventitious oxygen) is not rigorously\ncomplex M\u2212OH2 is usually more active than the chloride excluded. Thus, 5a would be more suitable as a typical complex\ncomplex M\u2212Cl.27,51 The absorption intensities changed in the for this exploratory work due to its resistance to oxidation\nspectra of the pyridyl\u2212imine complexes (2a\u22122c, 6, and 3b\u22123c) reaction. On the basis of these considerations, the cytotoxicity of\nin this system, and no obvious shift in the absorption bands was these complexes in the A549 lung cancer cell line and HeLa\ntested over a period of 24 h (e.g., 2b in Figure 5(i)). This result cervical cancer cell line was investigated using 3-[4,5-\nwas in agreement with our previous observation of the pyridyl\u2212 dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide\nimine iridium(III) analogues31 and indicated that the pyridyl\u2212 (MTT) assay using cisplatin as the positive control (Table 1).\nimine iridium(III) complexes 2a\u22122c and 6 and rhodium(III)\ncomplexes 3b\u22123c in this system also underwent hydrolysis Table 1. In Vitro Cytotoxic Activity of the Complexes after 48\nunder the test conditions. Conversely, a signi\ufb01cant change in the h of Incubation in Cancer and Normal Cell Lines and\nabsorption bands (both in the pattern and the intensity) was Comparison with Cisplatina\nobserved for the pyridyl\u2212amine complexes over a period of 24 h\n IC50 (\u03bcM)\n(e.g., 4b in Figure 5(ii)), which may be associated with the\nformation of the oxidized pyridyl\u2212imine complex. However, the complex A549 HeLa BEAS-2B selectivity indexb\noxidation process and hydrolysis of M\u2212Cl bonds may occur 2a 23.2 \u00b1 0.5 35.1 \u00b1 1.2 45.5 \u00b1 0.6 1.96\nsimultaneously in this case, and we could not identify any bands 2b 29.8 \u00b1 0.3 17.5 \u00b1 0.2 35.3 \u00b1 0.3 1.18\ncorresponding to any of the chloride or aqua complexes. This 2c 25.1 \u00b1 0.4 21.7 \u00b1 0.3 26.7 \u00b1 0.5 1.06\nspeculation was further supported by the observation that no 3b 37.1 \u00b1 0.3 29.3 \u00b1 0.7 37.8 \u00b1 0.1 1.02\nobvious shift in the absorption bands was found in the spectra of 3c 30.3 \u00b1 0.1 38.6 \u00b1 0.3 47.1 \u00b1 0.4 1.55\n5a due to its resistance to oxidation reaction (Figure 5(iii)), 5a 40.1 \u00b1 0.9 16.3 \u00b1 0.3 26.2 \u00b1 1.1 0.65\nwhich was consistent with the result that 5a was synthesized 6 22.5 \u00b1 0.5 13.6 \u00b1 0.1 32.2 \u00b1 0.3 1.43\nwithout the formation of the oxidized imine complex after 24 h. 7 >100 >100 - -\nMoreover, only minor changes in intensity were observed in the cisplatin 21.3 \u00b1 1.7 7.5 \u00b1 0.2 42.0 \u00b1 2.3 1.97\nUV\u2212vis spectra of 5a, also evidencing the stability of 5a in a\n The cytotoxicity is expressed as the IC50 values (\u03bcM) \u00b1 standard\naqueous solutions. To con\ufb01rm the stability of 5a, 1H NMR deviations (n = 3). bSelectivity index represents the IC50 ratio of\nanalysis was also performed in 85% DMSO-d6/15% PBS (PBS BEAS-2B normal cells to A549 cancer cells. (-) indicates no data are\nwas prepared from D2O) solutions at 37 \u00b0C (Figure S63). There available.\nwas no change in the spectra of 5a, and the assignment of\nprotons was completely consistent with its molecular structure, It should be noted that no cytotoxic activity (IC50 > 100 \u03bcM,\nwhich further evidenced the stability of 5a in aqueous media. As IC50: dose at which 50% cellular growth was inhibited) was\nmentioned above, amido complex 7 was stable in DMSO-d6 observed for all of the ligands and metal dimer precursors used in\nsolution and showed no reactivity toward two-electron donors this work (Table S8). Thus, the observed cytotoxicity against the\n(PPh3, CH3CN, and CO). However, some changes in tested cancer cells was attributed to the chelation. The pyridyl\u2212\nabsorption intensity in the UV\u2212vis spectra of 7 were observed imine iridium(III) complexes 2a\u22122c and 6 showed the\nafter 24 h (Figure 5(iv)), demonstrating that H2O was likely to cytotoxicity toward A549 and HeLa cells with IC50 values\nbind to the 16-electron parent complex 7 and the partial 18- ranging from 13.6 to 35.1 \u03bcM, which were comparable to those\nelectron aquated complex (Ir\u2212OH2) may have formed in of cisplatin and our previously reported pyridyl\u2212imine iridium-\naqueous solutions. Additionally, the 1H NMR spectra of 7 in (III) analogues.31 The complex 6 with [(\u03b75-Cp*)IrCl3] anion\n85% DMSO-d6/15% PBS solutions at 37 \u00b0C showed some was more active than the corresponding monometallic complex\nchanges over time, which further proved this speculation (Figure 2b, indicating that the counteranion also a\ufb00ected the\nS64). However, it can be estimated that most of the parent cytotoxicity of these complexes. Notably, the counteranion\ncomplex was present in 85% DMSO-d6/15% PBS solution over e\ufb00ect has also been found by our group for the bioactive half-\n24 h. The stability of these represented complexes 2b, 4b, 5a, sandwich iridium(III) complexes bearing the chelating bipyr-\nand 7 in the cell culture media [Dulbecco\u2019s modi\ufb01ed Eagle idine ligands.28 Changing the metal center from iridium(III) to\nmedium with 30% dimethyl sulfoxide (DMSO) to attain full rhodium(III) slightly decreased the cytotoxicity of the pyridyl\u2212\ndissolution] was also determined. The stability behavior was imine complexes (e.g., 2b vs 3b). The 16-electron amido\nsimilar with the abovementioned results obtained in PBS bu\ufb00er complex 7 gave the IC50 value greater than 100 \u03bcM and thus was\nmixture except 7 (Figure S1), which exhibited obvious changes deemed as inactive. Although the MoA was not clear for this\nover time, suggesting that this 16-electron complex was likely amido iridium(III) complex, we speculated that the speci\ufb01c 16-\n 10058 https://doi.org/10.1021/acs.inorgchem.2c00984\n Inorg. Chem. 2022, 61, 10051\u221210065\n\fInorganic Chemistry pubs.acs.org/IC Article\n\nelectron coordination mode of 7 and its instability in cell culture\nmedium were responsible for the low cytotoxicity. In addition,\nthe amine complex 5a displayed almost a similar IC50 value\ntoward A549 cancer cells and showed a slightly higher\ncytotoxicity against HeLa cancer cells in comparison with the\nimine rhodium(III) complexes (3b and 3c). Overall, it seemed\nthat the changing of the coordination mode from imine\u2212metal\nto amine\u2212metal was not sensitive to the cytotoxicity of the\ncomplexes in this system. MTT assay was also performed with\nnoncancerous BEAS-2B. Unfortunately, no obvious selectivity\nwas observed for cancer cells versus normal cells with these\ncomplexes, and the IC50 values of these complexes (26.2\u221247.1\n\u03bcM) were also comparable to or lower than those of cisplatin\n(42.0 \u03bcM). Thus, the ordinary toxicity of these complexes\ncannot be excluded. Figure 7. Apoptosis analysis of A549 cells after 48 h of exposure to\n 2.7. ROS Determination. It should be noted that our complex 5a at 37 \u00b0C determined by \ufb02ow cytometry using AV-\npreviously reported pyridyl\u2212imine iridium(III) and ruthenium- \ufb02uorescein isothiocyanate versus PI staining. Population of cells in four\n(II) complexes can increase ROS levels signi\ufb01cantly in A549 stages treated with complex 5a. Data are quoted as mean \u00b1 SD of three\ncells.31\u221233,52 Thus, we also became interested in the e\ufb00ect of replicates. p-values were calculated after a t test against the negative\nchanging the coordination mode from imine complexes to control data; *p < 0.05 and **p < 0.01.\namine complexes on ROS production. The levels of ROS in\nA549 cells induced by 5a at the concentrations of 0.25, 0.5, and 1 complex 5a can arouse the death of cancer cells by inducing\n\u00d7 IC50 were determined using an ROS assay kit (Figures 6 and apoptosis, which was similar with our previously reported imine\n iridium(III) complexes.31,52\n\n 3. CONCLUSIONS\n In conclusion, with an easy access to the required pyridine\u2212\n amine ligands, a series of pyridyl\u2212imine (2a\u22122c, 6, and 3b\u22123c),\n pyridyl\u2212amine (4a\u22124c and 5a\u22125c), and 16-electron pyridyl\u2212\n amido (7) iridium(III) and rhodium(III) complexes were\n synthesized and fully characterized. The coordination of these\n pyridine\u2212amine [N, NH] ligands activated their oxidation to\n pyridyl\u2212imine [N, N] complexes when molecular oxygen was\n not totally eliminated. The detection of hydrogen peroxide\n supported the oxidation mechanism. However, the oxidation of\n pyridyl\u2212amine complexes to pyridyl\u2212imine complexes was\n strongly dependent not only on the metal variation and ligand\n substitution but also on the reaction time and solvents. For\n example, in the presence of adventitious oxygen, the pyridyl\u2212\nFigure 6. Analysis of ROS levels using a \ufb02uorescence microscope after amine rhodium(III) complex 5a can be obtained without the\nA549 cells were treated with 5a for 24 h at 37 \u00b0C and stained with formation of the oxidized pyridyl\u2212imine complex, and the\nDCFH-DA. p-values were calculated after a t test against the negative pyridyl\u2212amine complex 4b was cleanly synthesized in the\ncontrol data, **p < 0.01. nonpolar solvent CH2Cl2. Notably, the oxidation complex 6\n with [(\u03b75-Cp*)IrCl3] anions was also synthesized without the\nS65). Compared to untreated cells, an increase in concentration- addition of the anion exchange reagent NH4PF6. The\ndependent ROS levels in the cells was observed. As a result, introduction of the bulky i-Bu group on the bridge carbon of\ninduction of ROS may contribute to the cytotoxicity of the pyridine\u2212amine ligands a\ufb00orded the stable 16-electron pyridyl-\namine complex 5a, which agrees with the results obtained by our amido complexes, even when the \u03b2 hydrogen atom was not\npreviously reported imine complexes.31\u221233,52 excluded and the deprotonating agents were not added. These\n 2.8. Apoptosis Assay. The pyridyl\u2212imine iridium(III) and compounds may represent one of the rarely reported 16-\nruthenium(II) complexes have been shown to promote cellular electron coordination mode of half-sandwich complexes. The\ndeath by activating apoptosis in our previous work.31\u221233,52 For corresponding pyridyl\u2212amine complexes 4a\u22124c and 5a\u22125c\ncomparison, the stable pyridyl\u2212amine rhodium(III) complex 5a were also readily prepared under a N2 atmosphere. The aqueous\nwas chosen to investigate whether the amine complexes can solution stability study showed that the pyridyl\u2212imine iridium-\ninduce cell apoptosis like imine complexes. A549 cells were (III) and rhodium(III) complexes underwent hydrolysis, which\nincubated with 1, 2, and 3 \u00d7 IC50 of 5a for 48 h and then was consistent with our previous observation of the pyridyl\u2212\nanalyzed by \ufb02ow cytometry (Figures 7 and S66). Clearly, imine iridium(III) analogues. The instability of pyridyl\u2212amine\ntreatment with 5a enhanced the late apoptotic cell populations complexes in aqueous solution could be associated with the\nof the A549 cancer cells compared with the control. formation of the oxidized pyridyl\u2212imine complexes. However,\nFurthermore, concentration-dependent of the proportion of 5a was stable due to its resistance to oxidation reaction. Most of\nlate apoptotic cells was also observed. When 5a was used at the the complexes in this system showed potent cytotoxicity\nmaximum concentration of 3 \u00d7 IC50, 92.5% of the treated cells comparable to that of cisplatin. Particularly, the stable amine\nwere in late apoptosis. These results indicated that the amine complex 5a displayed the similar IC50 value in comparison with\n 10059 https://doi.org/10.1021/acs.inorgchem.2c00984\n Inorg. Chem. 2022, 61, 10051\u221210065\n\fInorganic Chemistry pubs.acs.org/IC Article\n\nthe imine rhodium(III) complex. The MoA study showed that 142.14, 141.46, 140.45, 140.38, 130.49, 129.07, 128.99, 125.23,\n5a exerted its anticancer e\ufb03cacy by increasing the intracellular 124.52, 90.82 (C5Me5), 27.06 (CH(CH3)2), 26.81 (CH-\nROS level and inducing cell apoptosis. (CH3)2), 25.11 (CH(CH3)2), 24.73 (CH(CH3)2), 24.66\n (CH(CH3)2), 23.63 (CH(CH3)2), 21.79 (C\u2212CH3), 8.23\n4. EXPERIMENTAL SECTION (Cp*\u2212CH 3 ). ESI-MS (m/z): calcd for C 29 H 39 ClIrN 2 ,\n 643.2431; found, 643.2461 [M \u2212 PF6]+. Anal. Calcd for\n 4.1. General Information. All solvents and reagents were\npurchased from commercial sources. These solvents and reagents\n C29H39ClF6IrN2P: C, 44.19; H, 4.99; N, 3.55. Found: C, 44.03;\nwere used without further puri\ufb01cation unless otherwise claimed. The H, 4.97; N, 3.60.\nsynthetic routes for ligands 1a\u22121d are shown in Supporting\nInformation. The NMR spectroscopy and absorption spectroscopy\nwere performed using Bruker DPX 500 spectrometers and TU-1901 4.2.3. 2c.\nUV\u2212vis recording spectrophotometers, respectively. Mass spectra of\nthe rhodium(III) complexes and iridium(III) complexes were obtained\non a Thermo LTQ Orbitrap XL (ESI+) system. X-ray di\ufb00raction data\nwere determined using a Bruker Apex SMART CCD area detector\n(Tables S1\u2212S7) using graphite-monochromated Mo K\u03b1 radiation. C,\nH, and N elemental analysis was investigated using a Vario EL cube\n(Figures S54\u2212S57).\n 4.2. Synthesis of Pyridyl\u2212Imine iridium(III) and rhodium(III)\nComplexes. General method: [(\u03b75-Cp*)MCl2]2 (M = Ir/Rh)\nprecursors and amine ligands 1a\u22121c (2 equiv) were stirred in methanol\nfor 24 h with NH4PF6 (2 equiv) at room temperature. Methanol was Yield: 55.3 mg (71.5%). 1H NMR (500 MHz, DMSO-d6): \u03b4 9.64\nremoved under reduced pressure. The residue was dissolved in (s, 1H, CH\ue0c8N), 9.08 (d, J = 5.5 Hz, 1H), 8.47 (d, J = 7.0 Hz,\ndichloromethane and then \ufb01ltered through Celite. A large amount of\nn-hexane was added to the \ufb01ltrate, and the product was precipitated, 1H), 8.38\u22128.35 (m, 1H), 8.03\u22127.97 (m, 1H), 7.50\u22127.43 (m,\nfollowed by washing with n-hexane and diethyl ether and drying under 2H), 7.41\u22127.39 (m, 1H), 3.86\u22123.78 (m, 1H, CH(CH3)2),\nvacuum. 2.47\u22122.39 (m, 1H, CH(CH3)2), 1.45 (s, 15H, Cp*\u2212CH3), 1.31\n 4.2.1. 2a. (d, J = 6.7 Hz, 3H, CH(CH3)2), 1.26 (d, J = 6.7 Hz, 3H,\n CH(CH3)2), 1.14 (d, J = 6.6 Hz, 3H, CH(CH3)2), 0.89 (d, J =\n 6.6 Hz, 3H, CH(CH3)2). 13C NMR (151 MHz, DMSO-d6): \u03b4\n 175.14 (CH\ue0c8N), 155.45, 153.14, 144.65, 142.10, 142.36,\n 141.41, 131.38, 130.45, 129.77, 124.92, 124.46, 91.24 (C5Me5),\n 27.72 (CH(CH3)2), 27.63 (CH(CH3)2), 27.44 (CH(CH3)2),\n 26.30 (CH(CH3)2), 24.06 (CH(CH3)2), 21.82 (CH(CH3)2),\n 8.61 (Cp*\u2212CH3). ESI-MS (m/z): calcd for C28H37ClIrN2,\n 629.2275; found, 629.2429 [M \u2212 PF6]+. Anal. Calcd for\n C28H37ClF6IrN2P: C, 43.44; H, 4.82; N, 3.62. Found: C, 43.47;\nYield: 53.8 mg (78.0%). 1H NMR (500 MHz, DMSO-d6): \u03b4 9.34 H, 4.85; N, 3.60.\n(s, 1H, CH\ue0c8N), 9.05 (d, J = 5.3 Hz, 1H), 8.41 (d, J = 7.6 Hz,\n1H), 8.34 (m, 1H), 7.94 (m, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.44\n(d, J = 8.2 Hz, 2H), 2.43 (s, 3H, aryl-CH3), 1.43 (s, 15H, Cp*\u2212 4.2.4. 3b.\nCH3). 13C NMR (101 MHz, DMSO-d6): \u03b4 168.51 (CH\ue0c8N),\n155.40, 152.25, 146.41, 146.37, 140.59, 140.54, 139.48, 130.39,\n129.78, 129.75, 122.40, 89.69 (C5Me5), 20.73 (aryl-CH3), 7.97\n(Cp*\u2212CH 3 ). ESI-MS (m/z): calcd for C 23 H 27 ClIrN 2 ,\n559.1492; , 559.1715 [M \u2212 PF 6 ] + . Anal. Calcd for\nC23H27ClF6IrN2P: C, 39.23; H, 3.87; N, 3.98. Found: C,\n39.21; H, 3.90; N, 3.95.\n 4.2.2. 2b.\n\n Yield: 50.6 mg (71.2%). 1H NMR (500 MHz, CDCl3): \u03b4 8.93\n (d, J = 5.3 Hz, 1H), 8.19\u22128.16 (m, 1H), 8.08 (d, J = 7.7 Hz, 1H),\n 7.98\u22127.92 (m, 1H), 7.43\u22127.34 (m, 3H), 3.69\u22123.60 (m, 1H,\n CH(CH3)2), 2.71\u22122.63 (m, 1H, CH(CH3)2), 2.39 (s, 3H, C\u2212\n CH3), 1.50 (s, 15H, Cp*\u2212CH3), 1.41 (d, J = 6.6 Hz, 3H,\n CH(CH3)2), 1.27 (d, J = 6.7 Hz, 3H, CH(CH3)2), 1.04\u22121.00\n (m, 6H, CH(CH3)2). 13C NMR (151 MHz, DMSO-d6): \u03b4\n 178.44 (C\ue0c8N), 154.65, 152.98, 142.60, 141.71, 140.86, 140.69,\nYield: 51.0 mg (64.0%). 1H NMR (500 MHz, CDCl3): \u03b4 8.91 130.27, 129.04, 128.98, 125.72, 125.02, 98.23 (C5Me5), 27.06\n(d, J = 5.5 Hz, 1H), 8.18 (d, J = 4.0 Hz, 2H), 7.97\u22127.94 (m, 1H), (CH(CH3)2), 27.85 (CH(CH3)2), 27.46 (CH(CH3)2), 25.66\n7.43\u22127.31 (m, 3H), 3.62\u22123.54 (m, 1H, CH(CH3)2), 2.61\u22122.52 (CH(CH3)2), 25.20 (CH(CH3)2), 24.25 (CH(CH3)2), 22.40\n(m, 1H, CH(CH3)2), 2.43 (s, 3H, C\u2212CH3), 1.47 (s, 15H, Cp*\u2212 (C\u2212CH3), 8.99 (Cp*\u2212CH3). ESI-MS (m/z): calcd for\nCH3), 1.39 (d, J = 6.6 Hz, 3H, CH(CH3)2), 1.24 (d, J = 6.6 Hz, C29H39ClRhN2, 553.1857; found, 553.1884 [M \u2212 PF6]+. Anal.\n3H, CH(CH3)2), 1.05\u22121.01 (m, 6H, CH(CH3)2). 13C NMR Calcd for C29H39ClF6RhN2P: C, 49.83; H, 5.62; N, 4.01. Found:\n(126 MHz, DMSO-d6): \u03b4 180.01 (C\ue0c8N), 156.17, 152.24, C, 49.85; H, 5.63; N, 4.04.\n 10060 https://doi.org/10.1021/acs.inorgchem.2c00984\n Inorg. Chem. 2022, 61, 10051\u221210065\n\fInorganic Chemistry pubs.acs.org/IC Article\n\n 4.2.5. 3c. 143.45, 139.89, 139.87, 135.37, 129.44, 125.41, 122.33, 119.72,\n 87.28 (C5Me5), 58.30 (CH2), 20.32 (aryl-CH3), 7.64 (Cp*\u2212\n CH3). Minor isomer: \u03b4 159.30, 151.83, 143.63, 143.16, 140.06,\n 139.45, 135.14, 129.14, 125.99, 122.01, 119.26, 87.04 (C5Me5),\n 58.26 (CH2), 20.38 (aryl-CH3), 7.80 (Cp*\u2212CH3). ESI-MS (m/\n z): calcd for C23H29ClIrN2, 561.1649; found, 561.1486 [M \u2212\n PF6]+. Anal. Calcd for C23H29ClF6IrN2P: C, 39.12; H, 4.14; N,\n 3.97. Found: C, 39.15; H, 4.12; N, 3.98.\n 4.3.2. 4b.\n\nYield: 46.0 mg (66.7%). 1H NMR (500 MHz, CDCl3): \u03b4 8.89\n(d, J = 5.3 Hz, 1H, CH\ue0c8N), 8.38 (d, J = 2.2 Hz, 1H), 8.17 (t, J =\n7.7 Hz, 1H), 7.97\u22127.94 (m, 2H), 7.45\u22127.38 (m, 2H), 7.33 (d, J\n= 6.7 Hz, 1H), 3.97\u22123.89 (m, 1H, CH(CH3)2), 2.72\u22122.64 (m,\n1H, CH(CH3)2), 1.54 (s, 15H, Cp*\u2212CH3), 1.40 (d, J = 6.6 Hz,\n3H, CH(CH3)2), 1.34 (d, J = 6.7 Hz, 3H, CH(CH3)2), 1.22 (d, J\n= 6.6 Hz, 3H, CH(CH3)2), 0.91 (d, J = 6.6 Hz, 3H, CH(CH3)2).\n13\n C NMR (151 MHz, DMSO-d6): \u03b4 173.09 (CH\ue0c8N), 153.47,\n153.24, 144.58, 142.27, 141.76, 141.07, 130.74, 130.47, 129.35, Method 2, yield: 54.8 mg (70.8%). 1H NMR (500 MHz, CDCl3)\n125.06, 124.36, 98.04 (C5Me5), 27.88 (CH(CH3)2), 27.72 two isomers. Major isomer/minor isomer = 2:1 (molar ratio).\n(CH(CH3)2), 27.57 (CH(CH3)2), 26.15 (CH(CH3)2), 24.10 Major isomer: \u03b4 9.09 (d, J = 4.7 Hz, 1H), 8.07\u22128.04 (m, 1H),\n(CH(CH3)2), 21.84 (CH(CH3)2), 8.88 (Cp*\u2212CH3). ESI-MS 7.85\u22127.78 (m, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.25\u22127.26 (m,\n(m/z): calcd for C28H37ClRhN2, 539.1700; found, 539.1900 [M 1H), 7.24 (s, 2H), 7.23\u22127.16 (m, 1H, NH), 3.40\u22123.37 (m, 1H,\n\u2212 PF6]+. Anal. Calcd for C28H37ClF6RhN2P: C, 49.10; H, 5.45; CH(CH3)2), 2.95\u22122.87 (m, 1H, CH(CH3)2), 1.62 (s, 15H,\nN, 4.09. Found: C, 49.08; H, 5.43; N, 4.11. Cp*\u2212CH3), 1.35 (d, J = 5.9 Hz, 6H, CH(CH3)2 (3H) + CH\u2212\n 4.3. Synthesis of Pyridyl\u2212Amine iridium(III) and rhodium(III) CH3 (3H)), 1.28 (d, J = 5.3 Hz, 3H, CH(CH3)2), 1.23 (d, J = 6.0\nComplexes. Method 1 (methanol as solvent): Under a nitrogen Hz, 3H, CH(CH3)2), 1.10 (d, J = 5.8 Hz, 3H, CH(CH3)2).\natmosphere, [(\u03b75-Cp*)MCl2]2 (M = Ir/Rh) precursors and amine Minor isomer: \u03b4 8.70 (d, J = 4.6 Hz, 1H), 8.03\u22128.00 (m, 1H),\nligands 1a\u22121c (2 equiv) were stirred in methanol for 2 h with NH4PF6 7.64 (m, 1H), 7.47 (d, J = 6.5 Hz, 1H), 7.36 (d, J = 6.6 Hz, 1H),\n(2 equiv) at room temperature. Methanol was removed under reduced\n 7.31 (m, 2H), 6.86 (m, 1H, NH), 5.26 (m, 1H, CH\u2212CH3),\npressure. The residue was dissolved in dichloromethane and then\n\ufb01ltered through Celite. A large amount of n-hexane was added to the\n 3.33\u22123.29 (m, 1H, CH(CH 3 ) 2 ), 2.75\u22122.68 (m, 1H,\n\ufb01ltrate, and the product was precipitated, followed by washing with n- CH(CH3)2), 1.75 (d, J = 6.3 Hz, 3H, CH\u2212CH3), 1.45\u22121.42\nhexane and diethyl ether and drying under vacuum. (d, 3H, CH(CH3)2), 1.41 (s, 15H, Cp*\u2212CH3), 1.40\u22121.39 (m,\n Method 2 (dichloromethane as solvent): Under a nitrogen 3H, CH(CH3)2), 1.40\u22121.38 (m, 6H, CH(CH3)2). 13C NMR\natmosphere, [(\u03b75-Cp*)MCl2]2 (M = Ir/Rh) precursors and amine (151 MHz, DMSO-d6) major isomer: \u03b4 180.48, 156.68, 152.68,\nligands 1a\u22121c (2 equiv) were stirred in dichloromethane for 2 h at 147.90, 142.72, 141.97, 140.97, 129.52, 125.73, 124.21, 100.96,\nroom temperature. The solvent was removed under reduced pressure. 91.35 (C5Me5), 61.09 (CH\u2212CH3), 27.58 (CH(CH3)2), 25.59\nThe residue was dissolved in a small amount of ethanol, and then the (CH(CH3)2), 25.22 (CH(CH3)2), 24.71 (CH(CH3)2), 24.55\nsolution was treated with NH4PF6 (2 equiv) and plenty of water. The (CH(CH3)2), 24.11 (CH(CH3)2), 22.28 (CH\u2212CH3), 8.74\nproduct was precipitated, followed by washing with n-hexane and (Cp*\u2212CH3). Minor isomer: \u03b4 180.36, 156.64, 153.04, 147.75,\ndiethyl ether and drying under vacuum. 143.57, 142.62, 140.89, 130.98, 125.81, 125.03, 100.32, 92.65\n 4.3.1. 4a. (C5Me5), 60.95 (CH\u2212CH3), 27.31 (CH(CH3)2), 25.46 (CH-\n (CH3)2), 25.14 (CH(CH3)2), 24.67 (CH(CH3)2), 24.20\n (CH(CH3)2), 23.89 (CH(CH3)2), 21.53 (CH\u2212CH3), 9.13\n (Cp*\u2212CH 3 ). ESI-MS (m/z): calcd for C 29 H 41 ClIrN 2 ,\n 645.2588; found, 645.2537 [M \u2212 PF6]+. Anal. Calcd for\n C29H41ClF6IrN2P: C, 44.07; H, 5.23; N, 3.54. Found: C, 44.03;\n H, 5.27; N, 3.55.\n 4.3.3. 4c.\n\n\nMethod 1, yield: 44.0 mg (63.5%). 1H NMR (500 MHz,\nDMSO-d6) two isomers. Major isomer/minor isomer = 3:1\n(molar ratio). Major isomer: \u03b4 8.73 (d, J = 4.2 Hz, 1H), 8.38 (d, J\n= 8.8 Hz, 1H), 8.17\u22128.13 (m, 1H), 7.94 (d, J = 6.9 Hz, 1H),\n7.69\u22127.63 (m, 2H), 7.34\u22127.33 (m, 3H, aryl-H (2H) + NH\n(1H)), 5.04\u22124.95 (m, 1H, CH2), 4.60 (d, m, 1H, CH2), 2.37 (s,\n3H, aryl-CH3), 1.28 (s, 15H, Cp*\u2212CH3). Minor isomer: \u03b4 9.02\n(d, J = 8.3 Hz, 1H), 8.81 (d, J = 4.5 Hz, 1H), 8.22\u22128.18 (m, 1H), Method 2, yield: 49.1 mg (63.6%). 1H NMR (500 MHz, CDCl3)\n7.84 (d, J = 7.7 Hz, 1H), 7.41\u22127.35 (m, 3H), 7.32 (s, 1H), 7.30 two isomers. Major isomer/minor isomer = 2:1 (molar ratio).\n(m, 1H, NH), 4.86\u22124.81 (m, 1H, CH2), 4.60 (d, 1H, CH2), 2.36 Major isomer: \u03b4 8.92 (d, J = 5.6 Hz, 1H), 8.03\u22127.99 (m, 1H),\n(s, 3H, aryl-CH3), 1.43 (s, 15H, Cp*\u2212CH3). 13C NMR (101 7.80\u22127.76 (m, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 9.5 Hz,\nMHz, DMSO-d6) major isomer: \u03b4 159.58, 151.65, 143.48, 1H), 7.30 (d, J = 4.6 Hz, 2H), 7.27 (m, 1H, NH), 5.18 (m, 1H,\n 10061 https://doi.org/10.1021/acs.inorgchem.2c00984\n Inorg. Chem. 2022, 61, 10051\u221210065\n\fInorganic Chemistry pubs.acs.org/IC Article\n\nCH2), 4.39 (d, 1H, CH2), 3.15\u22123.05 (m, 1H, CH(CH3)2), Method 1, yield: 41.6 mg (60.3%). 1H NMR (500 MHz, CDCl3)\n2.08\u22121.99 (m, 1H, CH(CH3)2), 1.51 (d, J = 6.3 Hz, 3H, two isomers. Major isomer/minor isomer = 1:1 (molar ratio).\nCH(CH3)2), 1.38 (s, 15H, Cp*\u2212CH3), 1.29 (d, J = 6.8 Hz, 3H, Major isomer: \u03b4 8.73 (d, J = 5.3 Hz, 1H), 7.99 (t, J = 7.3 Hz, 1H),\nCH(CH3)2), 1.18 (d, J = 6.5 Hz, 3H, CH(CH3)2), 1.03 (d, J = 7.38\u22127.27 (m, 4H), 7.08\u22126.93 (m, 1H), 6.51 (d, J = 5.0 Hz, 1H,\n6.5 Hz, 3H, CH(CH3)2). Minor isomer: \u03b4 9.10 (d, J = 5.7 Hz, NH), 5.04\u22124.96 (m, 1H, CH\u2212CH3), 3.43\u22123.36 (m, 1H,\n1H), 8.03\u22127.99 (m, 1H), 7.80\u22127.76 (m, 2H), 7.25\u22127.23 (m, CH(CH3)2), 2.70\u22122.61 (m, 1H, CH(CH3)2), 1.65 (d, J = 6.9\n4H, aryl-H (3H) + NH (1H)), 3.64 (s, 2H, CH2), 3.24\u22123.15 (m, Hz, 3H, CH\u2212CH3), 1.51 (d, J = 10.0 Hz, 6H, CH(CH3)2), 1.45\n2H, CH(CH3)2), 1.61 (s, 15H, Cp*\u2212CH3), 1.37\u22121.36 (d, 6H, (s, 15H, Cp*\u2212CH3), 1.27 (m, 6H, CH(CH3)2). Minor isomer:\nCH(CH3)2), 1.14 (d, J = 6.7 Hz, 6H, CH(CH3)2). 13C NMR \u03b4 8.63 (d, J = 4.1 Hz, 1H), 7.71\u22127.64 (m, 1H), 7.53 (t, J = 8.2\n(101 MHz, DMSO-d6) major isomer: \u03b4 165.27, 151.92, 149.94, Hz, 1H), 7.38\u22127.27 (m, 1H), 7.16\u22127.13 (m, 1H), 7.08\u22126.93\n143.26, 139.49, 127.58, 125.67, 124.94, 124.48, 123.94, 121.80, (m, 3H, aryl-H (2H) + NH (1H)), 4.20\u22124.16 (m, 1H, CH\u2212\n89.29 (C5Me5), 75.62 (CH2), 27.79 (CH(CH3)2), 26.72 CH3), 3.26\u22123.15 (m, 2H, CH(CH3)2), 1.45 (s, 15H, Cp*\u2212\n(CH(CH3)2), 24.77 (CH(CH3)2), 9.10(Cp*\u2212CH3). Minor CH3), 1.39 (d, J = 6.4 Hz, 3H, CH\u2212CH3), 1.22 (d, J = 6.8 Hz,\nisomer: \u03b4 164.69, 153.07, 149.16, 145.35, 139.86, 128.31, 6H, CH(CH3)2), 1.05 (d, J = 6.8 Hz, 6H, CH(CH3)2). 13C\n126.10, 125.07, 124.19, 123.43, 121.47, 92.65 (C5Me5), 54.53 NMR (101 MHz, DMSO-d6) major isomer: \u03b4 172.38, 167.27,\n(CH2), 27.79 (CH(CH3)2), 27.59 (CH(CH3)2), 24.47 (CH- 163.39, 149.21, 142.02, 141.86, 136.82, 131.91, 128.90, 123.47,\n(CH 3 ) 2 ), 8.74(Cp*\u2212CH 3 ). ESI-MS (m/z): calcd for 121.76, 99.14 (C5Me5), 60.90 (CH\u2212CH3), 42.34 (CH(CH3)2),\nC28H39ClIrN2, 631.2431; found, 631.2388 [M \u2212 PF6]+. Anal. 30.23 (CH(CH3)2), 27.18 (CH(CH3)2), 24.27 (CH(CH3)2),\nCalcd for C28H39ClF6IrN2P: C, 43.32; H, 5.06; N, 3.61. Found: 21.28 (CH(CH3)2), 18.89 (CH(CH3)2), 13.78 (CH\u2212CH3),\nC, 43.34; H, 5.03; N, 3.60. 8.82 (Cp*\u2212CH3). Minor isomer: \u03b4 172.30, 166.32, 161.10,\n 147.79, 141.94, 141.79, 135.99, 131.79, 129.90, 123.17, 122.50,\n 4.3.4. 5a. 99.07 (C5Me5), 65.31 (CH\u2212CH3), 44.66 (CH(CH3)2), 31.51\n (CH(CH3)2), 30.93 (CH(CH3)2), 29.04 (CH(CH3)2), 22.33\n (CH(CH3)2), 22.18 (CH(CH3)2), 14.19 (CH\u2212CH3), 8.71\n (Cp*\u2212CH3). ESI-MS (m/z): calcd for C29H42ClF6RhN2P,\n 701.1739; found, 701.3000 [M + H]+. Anal. Calcd for\n C29H41ClF6RhN2P: C, 49.69; H, 5.90; N, 4.00. Found: C,\n 49.71; H, 5.87; N, 4.02.\n 4.3.6. 5c.\n\n\n\nMethod 1, yield: 39.0 mg (64.7%). 1H NMR (500 MHz,\nDMSO-d6) two isomers. Major isomer/minor isomer = 2:1\n(molar ratio). Major isomer: \u03b4 8.73 (d, J = 3.5 Hz, 1H), 8.42\u2212\n8.27 (m, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H),\n7.74\u22127.65 (m, 2H), 7.51\u22127.42 (m, 1H), 7.33 (m, 2H, aryl-H\n(1H) + NH (1H)), 4.99\u22124.91 (m, 1H, CH2), 4.37\u22124.29 (m,\n1H, CH2), 2.33 (s, 3H, aryl-CH3), 1.29 (s, 15H, Cp*\u2212CH3).\nMinor isomer: \u03b4 8.80 (d, J = 4.7 Hz, 1H), 8.13 (d, J = 8.2 Hz, Method 1, yield: 41.8 mg (61.9%). Many of the NMR\n1H), 7.63 (d, J = 7.1 Hz, 2H), 7.51\u22127.42 (m, 1H), 7.28 (m, 4H, resonances corresponding to the minor isomer are obscured\naryl-H (3H) + NH (1H)), 4.58\u22124.52 (m, 1H, CH2), 4.37\u22124.29 by those from the major isomer and are therefore not reported.\n(m, 1H, CH2), 2.33 (s, 3H aryl-CH3), 1.44 (s, 15H, Cp*\u2212CH3).\n 1\n H NMR (500 MHz, CDCl3) major isomer: \u03b4 8.93 (d, J = 5.5\n13\n C NMR (151 MHz, DMSO-d6) major isomer: \u03b4 159.45, Hz, 1H), 7.97 (td, J = 7.7, 1.2 Hz, 1H), 7.79 (t, J = 6.5 Hz, 1H),\n152.42, 143.66, 140.26, 140.21, 135.35, 130.11, 126.59, 123.17, 7.35 (d, J = 7.8 Hz, 1H), 7.31\u22127.28 (m, 3H), 7.11\u22127.08 (m, 1H,\n122.48, 120.05, 96.08 (C5Me5), 57.22 (CH2), 20.92 (aryl-CH3), NH), 5.00\u22124.95 (m, 1H, CH2), 4.14 (d, 1H, CH2), 3.23\u22123.13\n8.40(Cp*\u2212CH3). Minor isomer: \u03b4 159.55, 150.84, 144.35, (m, 1H, CH(CH3)2), 2.12\u22122.04 (m, 1H, CH(CH3)2), 1.51 (d, J\n137.09, 137.04, 136.63, 130.19, 129.84, 126.47, 122.72, 122.44, = 6.3 Hz, 3H, CH(CH3)2), 1.43 (s, 15H, Cp*\u2212CH3), 1.25 (d, J\n95.85 (C5Me5), 60.70 (CH2), 21.06 (aryl-CH3), 8.60 (Cp*\u2212 = 6.7 Hz, 3H, CH(CH3)2), 1.21 (d, J = 6.6 Hz, 3H, CH(CH3)2),\nCH3). ESI-MS (m/z): calcd for C23H29ClRhN2, 471.1074; 1.00 (d, J = 6.5 Hz, 3H, CH(CH3)2). 13C NMR (151 MHz,\nf o u n d , 4 7 1 . 0 0 0 0 [ M \u2212 P F 6 ] + . A n a l. C a l cd f o r DMSO-d6) major isomer: \u03b4 156.75, 146.35, 144.57, 143.18,\nC23H29ClF6RhN2P: C, 44.79; H, 4.74; N, 4.54. Found: C, 142.32, 142.26, 141.75, 125.59, 125.06, 124.46, 124.32, 99.35\n44.81; H, 4.77; N, 4.52. (C5Me5), 55.41 (CH2), 27.57 (CH(CH3)2), 24.77 (CH-\n (CH 3 ) 2 ), 9.10 (Cp*\u2212CH 3 ). ESI-MS (m/z): calcd for\n 4.3.5. 5b. C28H39RhN2, 506.2; found, 506.1 [M \u2212 Cl\u2212PF6]+. Anal.\n Calcd for C28H39ClF6RhN2P: C, 48.96; H, 5.72; N, 4.08. Found:\n C, 48.93; H, 5.69; N, 4.11.\n 4.4. Synthesis of Complexes with [(\u03b75-Cp*)IrCl3] Anions. The\n [(\u03b75-Cp*)IrCl2]2 precursor and amine ligand 1b (2 equiv) were stirred\n in methanol for 24 h at room temperature. Methanol was removed\n under reduced pressure. The residue was dissolved in dichloromethane,\n and then, a large amount of n-hexane was added to the \ufb01ltrate, and the\n product was precipitated, followed by washing with n-hexane and\n diethyl ether and drying under vacuum.\n\n 10062 https://doi.org/10.1021/acs.inorgchem.2c00984\n Inorg. Chem. 2022, 61, 10051\u221210065\n\fInorganic Chemistry pubs.acs.org/IC Article\n\n 4.4.1. 6. Details of the experimental section, proposed mecha-\n nisms, 1H and 13C NMR spectra, ESI-MS spectra,\n C,H,and N elemental analysis of the complexes, UV-vis\n spectra for complexes, time-dependent 1 H NMR\n spectroscopic stability study, apoptosis analysis of A549\n cells, bond lengths and angles, and IC50 values (PDF)\n Accession Codes\n CCDC 2160775, 2160785, 2160944, 2160963, and 2160992\u2212\n 2160994 contain the supplementary crystallographic data for\nYield: 35.0 mg (65.7%). 1H NMR (500 MHz, CDCl3): \u03b4 9.18 this paper. These data can be obtained free of charge via\n(d, J = 4.3 Hz, 1H), 8.54\u22128.45 (m, 2H), 8.40\u22128.34 (m, 1H), www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_\n7.40\u22127.36 (m, 2H), 7.34\u22127.31 (m, 1H), 3.62\u22123.54 (m, 1H, request@ccdc.cam.ac.uk, or by contacting The Cambridge\nCH(CH3)2), 2.50 (s, 3H, C\u2212CH3), 2.47\u22122.45 (m, 1H, Crystallographic Data Centre, 12 Union Road, Cambridge\nCH(CH3)2), 1.61 (s, 15H, Cp*\u2212CH3), 1.50 (s, 15H, Cp*\u2212 CB2 1EZ, UK; fax: +44 1223 336033.\nCH3), 1.38 (d, J = 6.6 Hz, 3H, CH(CH3)2), 1.23 (d, J = 6.6 Hz,\n3H, CH(CH3)2), 1.04 (d, J = 6.7 Hz, 3H, CH(CH3)2), 1.01 (d, J\n= 6.6 Hz, 3H, CH(CH3)2). 13C NMR (101 MHz, DMSO-d6): \u03b4\n \u25a0 AUTHOR INFORMATION\n Corresponding Authors\n179.97 (C\ue0c8N), 156.10, 152.23, 142.08, 141.41, 140.40, 140.31, Lihua Guo \u2212 School of Chemistry and Chemical Engineering,\n130.46, 129.05, 128.93, 125.19, 124.46, 92.04 (C5Me5), 90.77 Qufu Normal University, Qufu 273165, P. R. China;\n(C5Me5), 27.01 (CH(CH3)2), 26.76 (CH(CH3)2), 25.08 orcid.org/0000-0002-0842-9958; Email: guolihua@\n(CH(CH3)2), 24.69 (CH(CH3)2), 24.61 (CH(CH3)2), 23.59 qfnu.edu.cn\n(CH(CH3)2), 21.77 (C\u2212CH3), 8.21 (Cp*\u2212CH3). ESI-MS (m/ Zhe Liu \u2212 School of Chemistry and Chemical Engineering, Qufu\nz): calcd for C29H39ClIrN2, 643.2431; found, 643.2500 [M \u2212 Normal University, Qufu 273165, P. R. China; orcid.org/\nC10H15Cl3Ir]+; ESI-MS (m/z): calcd for C39H53Cl4Ir2N2, 0000-0001-5796-4335; Email: liuzheqd@163.com\n1076.2202; found, 1076.2087 [M \u2212 H]\u2212. Anal. Calcd for\nC39H54Cl4Ir2N2: C, 43.49; H, 5.05; N, 2.60. Found: C, 43.47; H, Authors\n5.02; N, 2.61. Xueyan Hu \u2212 School of Chemistry and Chemical Engineering,\n 4.5. Synthesis of Pyridyl\u2212Amido Complexes. Complex 7 was Qufu Normal University, Qufu 273165, P. R. China\nsynthesized by the reaction of [(\u03b75-Cp*)IrCl2]2 with 1d using the same Mengqi Liu \u2212 School of Chemistry and Chemical Engineering,\nprocedure as for the synthesis of pyridyl\u2212imine iridium(III) and Qufu Normal University, Qufu 273165, P. R. China\nrhodium(III) complexes (2a\u22122c, 3b, and 3c). Mengru Sun \u2212 School of Chemistry and Chemical Engineering,\n 4.5.1. 7. Qufu Normal University, Qufu 273165, P. R. China\n Qiuya Zhang \u2212 School of Chemistry and Chemical Engineering,\n Qufu Normal University, Qufu 273165, P. R. China\n Hongwei Peng \u2212 School of Chemistry and Chemical\n Engineering, Qufu Normal University, Qufu 273165, P. R.\n China\n Fanjun Zhang \u2212 School of Chemistry and Chemical\n Engineering, Qufu Normal University, Qufu 273165, P. R.\n China\n Complete contact information is available at:\nYield: 55.1 mg (69.8%). 1H NMR (500 MHz, CDCl3): \u03b4 9.10 https://pubs.acs.org/10.1021/acs.inorgchem.2c00984\n(d, J = 5.7 Hz, 1H), 8.01 (t, J = 7.7 Hz, 1H), 7.84 (t, J = 6.5 Hz,\n1H), 7.64 (d, J = 8.0 Hz, 1H), 7.25 (s, 2H), 7.23\u22127.19 (m, 1H), Notes\n3.42\u22123.33 (m, 2H, CH(CH 3 ) 2 ), 2.85\u22122.75 (m, 1H, The authors declare no competing \ufb01nancial interest.\n\n \u25a0\nCH(CH3)2), 1.63 (s, 15H, Cp*\u2212CH3), 1.44 (d, J = 6.8 Hz,\n3H, CH(CH3)2), 1.22 (m, 11H, CH(CH3)2 (9H) + CH2 (2H)), ACKNOWLEDGMENTS\n0.83 (d, J = 6.3 Hz, 3H, CH(CH3)2), 0.76 (d, J = 6.3 Hz, 3H,\nCH(CH3)2). 13C NMR (126 MHz, CDCl3): \u03b4 168.24, 151.78, We thank the Young Talents Invitation Program of Shandong\n148.86, 143.76, 143.56, 138.59, 127.23, 126.07, 124.70, 124.33, Provincial Colleges and Universities, the Taishan Scholars\n121.28, 89.49 (C5Me5), 82.48 (CH\u2212N), 43.45 (CH2), 27.30 Program, the National Natural Science Foundation of China\n(CH(CH3)2), 26.95 (CH(CH3)2), 26.78 (CH(CH3)2), 26.39 (grant no. 21901140), and the Key Laboratory of Polymeric\n(CH(CH3)2), 26.28 (CH(CH3)2), 26.20 (CH(CH3)2), 25.79 Composite & Functional Materials of Ministry of Education\n(CH(CH3)2), 23.59 (CH(CH3)2), 21.05 (CH(CH3)2), 9.45 (PCFM-2021A01) and Natural Science Foundation of\n Shandong Province (ZR2019BB078) for support.\n\n \u25a0\n(Cp*\u2212CH3). 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