Synthesis and Crystallographic Characterization of Heteroleptic Ir(III) Complexes Containing the N -oxide Functional Group and Crystallographic Characterization of Ir(III) N -oxide Precursors

: The N -oxide functional group has been exploited for synthetic strategies and drug de-sign, and it has been utilized in imaging agents. Herein, we present rare examples of neutral heteroleptic cyclometallated Ir(III) compounds that contain an uncoordinated N -oxide functional group. These species, along with others described within, were verified by NMR, EA, HRMS, and single-crystal X-ray analysis. N -oxide-containing Ir(III) species were prepared selectively in high yields > 66% from chloro-bridged Ir(III) dimers with Acipimox, a picolinate-type ligand containing the N -oxide functional group. Non-N -oxide analogs were synthesized in a similar fashion (yields > 77%). Electrochemical comparison (cyclic voltammetry) indicates that the presence of an N -oxide functional group anodically shifts the reduction potential, suggesting that the N -oxide is acting as an electron-withdrawing group in these species. Crystallographic studies were pursued to examine the coordination behavior of these N -oxides compared to their non-oxidized congeners. The Ir(III) complexes with Acipimox indeed leave the N -oxide uncoordinated and exposed on the complexes. The uncoordinated N -oxide group is influential in directing the packing structures of these complexes directly through C-H ··· O and O ··· π interactions at the N -oxide. The crystallographic characterization of cationic Ir(III) compounds with uncoordinated nitrogen atoms is also presented. The C-H ··· N interactions between these complexes form a variety of dimers, finite chains, and continuous chains. Future work will focus on functionalizing the cationic Ir(III) species into their corresponding N -oxide derivatives and rigorously characterizing how the N -oxide functional group impacts the optical properties of transition metal compounds in both cationic and neutral complexes.


Introduction
N-oxide-containing compounds have been exploited for various applications, including synthetic intermediates [1], drug molecules [2], and imaging agents [3][4][5].The N-oxide functional group can be cleaved in a hypoxic environment.This has been utilized in the design of various prodrugs and imaging agents that change form in tumor cells, where the concentration of oxygen is low [2,[4][5][6][7].For instance, an N-oxide on the chemotherapeutic Tirapazamine (Figure 1) is cleaved under hypoxic conditions to generate reactive radical species [6].Regarding imaging agents, Knox et al. have shown that BODIPY dyes containing cleavable N-oxides can be exploited for ratiometric imaging [4,5].radical species [6].Regarding imaging agents, Knox et al. have shown that BODIPY dyes containing cleavable N-oxides can be exploited for ratiometric imaging [4,5].Recently, transition metal compounds have gained the attention of the scientific community as imaging agents due to their typically large Stokes shift, long fluorescent lifetimes, and tunable luminescence [8][9][10].To develop other imaging agents, mainly to monitor hypoxia, we envisioned a strategy that parallels the work of Knox et al. [4,5] using transition metal compounds that contain N-oxide functional groups instead of BODIPY dyes.Of interest are cyclometallated Ir(III) systems because of their ability to detect hypoxia in animals [11].However, cyclometallated Ir(III) complexes containing external Noxide groups on heterocyclic ligands have not been extensively structurally characterized, with one reported example describing a TEMPO radical [12].More commonly, Ir(III) complexes involving a heterocyclic N-oxide ligand coordinate via the oxygen atom of the Noxide group [13][14][15][16][17][18][19].The tendency to coordinate the oxygen atom of a heterocyclic Noxide group is generally favored in most transition metal complexes [20][21][22][23], largely due to the hardness of the N-oxide as a donor.Strategies for orienting the oxygen atom of the N-oxide group externally on a metal complex (that is, not coordinated to the metal) may include utilizing ligands with favorable coordination sites away from the N-oxide or oxidizing the exposed external nitrogen atom of a coordinated ligand [24][25][26][27][28][29][30][31][32].For the former, ligands such as 5-methypyrazine-2-carboxylate (5 mpca) and its corresponding N-oxide (Acipimox, 5 mpcaO, Figure 1) may be promising [33].For the latter, crystallographically characterizing those complexes where nitrogen atoms are external to the complex and available for oxidation is an appropriate first step.
Herein, we report rare examples of structurally characterized cyclometallated Ir(III) species that have an N-oxide functional group that is not involved in coordination to the metal center.Ultimately, our group desires to exploit these compounds as imaging agents.In this initial report, we focus on the structural characterization of these derivatives and other Ir(III) compounds that can serve as precursors for other unbound N-oxide-containing transition metal species.Although a number of these other Ir(III) complexes having Biologically relevant N-oxide-containing compounds: (a) Tirapazamine is utilized as a chemotherapeutic [6]; (b) BODIPY dyes are utilized in ratiometric imaging [4,5]; (c) synthetic scheme for neutral Ir(III) compounds and abbreviations used within.
Recently, transition metal compounds have gained the attention of the scientific community as imaging agents due to their typically large Stokes shift, long fluorescent lifetimes, and tunable luminescence [8][9][10].To develop other imaging agents, mainly to monitor hypoxia, we envisioned a strategy that parallels the work of Knox et al. [4,5] using transition metal compounds that contain N-oxide functional groups instead of BODIPY dyes.Of interest are cyclometallated Ir(III) systems because of their ability to detect hypoxia in animals [11].However, cyclometallated Ir(III) complexes containing external N-oxide groups on heterocyclic ligands have not been extensively structurally characterized, with one reported example describing a TEMPO radical [12].More commonly, Ir(III) complexes involving a heterocyclic N-oxide ligand coordinate via the oxygen atom of the N-oxide group [13][14][15][16][17][18][19].The tendency to coordinate the oxygen atom of a heterocyclic N-oxide group is generally favored in most transition metal complexes [20][21][22][23], largely due to the hardness of the N-oxide as a donor.Strategies for orienting the oxygen atom of the N-oxide group externally on a metal complex (that is, not coordinated to the metal) may include utilizing ligands with favorable coordination sites away from the N-oxide or oxidizing the exposed external nitrogen atom of a coordinated ligand [24][25][26][27][28][29][30][31][32].For the former, ligands such as 5-methypyrazine-2-carboxylate (5 mpca) and its corresponding N-oxide (Acipimox, 5 mp-caO, Figure 1) may be promising [33].For the latter, crystallographically characterizing those complexes where nitrogen atoms are external to the complex and available for oxidation is an appropriate first step.
Herein, we report rare examples of structurally characterized cyclometallated Ir(III) species that have an N-oxide functional group that is not involved in coordination to the metal center.Ultimately, our group desires to exploit these compounds as imaging agents.In this initial report, we focus on the structural characterization of these derivatives and other Ir(III) compounds that can serve as precursors for other unbound N-oxide-containing transition metal species.Although a number of these other Ir(III) complexes having nonoxidized external nitrogen atoms have been reported in the synthetic literature, they have heretofore not been studied crystallographically. Electrochemical data are also presented to demonstrate that the presence of an N-oxide functional group can be used to tune the electronic properties of a transition metal center.

General Methods
UV-Vis: The reported molar extinction coefficients were obtained through the same method for complexes 1-4.An Agilent Cary 60 UV-Vis spectrometer equipped with a xenon lamp was utilized for data collection.Sample solutions were prepared by weighing ~5 mg of each complex and creating a stock solution using MeOH (100 mL).Aliquots from this stock solution were used to prepare 90-10% concentrations, yielding a total of 10 solutions.A background was obtained using MeOH in a 1 cm quartz cuvette.Sample collection was performed at a 24,000 nm/min scan rate within a 300 to 700 nm window.The absorption maxima at each peak were plotted against a concentration curve to obtain molar extinction coefficients.
Cyclic voltammograms: Data were recorded using a BASi εpsilon electrochemical workstation and a BASi cell stand.Conditions for data collection: [Ir]~1 mM in CH 2 Cl 2 (0.1 M TBAPF 6 , where TBA = tetrabutylammonium), glassy carbon working electrode, and Ag/Ag + reference electrode.The x-axis reports voltages vs. ferrocene (FcH) as determined by running a voltammogram of FcH before and after data collection.
NMR spectra: 1 H NMR, 19 F NMR, and 31 P NMR spectra were recorded on a JEOL ECX 400 MHz spectrometer. 1 H NMR resonances were referenced against tetramethylsilane using residual proton signals.Standards were run for 19 F NMR (fluorobenzene) and 31 P NMR (triphenylphosphine) prior to data acquisition: fluorobenzene (−113 ppm, CDCl 3, and d-DMSO) and triphenylphosphine (−6 ppm, d-DMSO).All NMR spectra were acquired at room temperature (solutions of the complex in CDCl 3 for 1-4, and in DMSO-d 6 for 6).
HRMS: Mass spectra were obtained with an Agilent accurate-mass 6520B Q-TOF mass spectrometer operating in positive-ion mode with a 3500 V capillary voltage and 120 V fragmentor voltage.The dual-spray electrospray ionization (ESI) source operated with a nebulizer pressure of 40 psi and 340 • C N 2 drying gas flowing at 12 L/min.The instrument was calibrated with the Agilent ESI-L tuning mix.During measurements, a reference solution containing ammonium trifluoroacetate, purine ([M + H] + 121.0509) and hexakis (1H, 1H, 3H-tetrafluoropropoxy)phosphazine (HP-0921, C 18 H 18 F 24 N 3 O 6 P 3 ) ([M + H] + 922.0098) was continuously introduced into the ESI source to allow for internal mass calibration.Samples were introduced into the mass spectrometer, without chromatographic separation, in a mobile phase consisting of 0.1% formic acid in methanol at a flow rate of 0.300 mL/min.Mass spectra were analyzed using MassHunter Qualitative Analysis Software (B.06 and B.08, Agilent, Santa Clara, CA, USA).
General procedure 1 (GP1) for the preparation of Ir(CˆN) 2 (NˆO) derivatives (where CˆN = ppy or dfppy and NˆO = a picolinic acid derivate) was as follows: For [(CˆN) 2 Ir(µ-Cl)] 2 , 3 equivalents of the appropriate NˆO ligand, and 6 equivalents of K 2 CO 3 were added in an oven-dried pressure tube with acetone (~20 mL).After sparging the mixture with N 2 , the pressure tube was sealed, and the reaction mixture was heated to 60 • C overnight, (~15 h).After cooling, the solvent was removed from the mixture, and the product was purified using a SiO 2 column and eluted with 5% MeOH/95% CH 2 Cl 2 .(Note: the column was typically packed with CH 2 Cl 2 and CH 2 Cl 2 could be initially used as an eluant to remove the excess ligand.)Fractions containing the product (as indicated by luminescent spots on the TLC) were dried in vacuo, resulting in a yellowish powder.The resulting solid was sonicated with hexanes (~10 mL), collected using vacuum filtration, and washed with hexanes.
Compound 5 was prepared according to a procedure reported in the literature (similar to GP1) and 1 H NMR data matched previously reported data for this compound; see Ref. [35].Crystals were grown using vapor-vapor diffusion using CH 2 Cl 2 as the dissolving solvent and hexanes as the precipitating solvent.
Compound 8, GP2: 1 H NMR data matched previously reported data for this compound [38].Crystals were grown using vapor-vapor diffusion using CH 2 Cl 2 as the dissolving solvent and Et 2 O as the precipitating solvent.

Single-Crystal X-ray Diffraction
Single-crystal X-ray diffraction data were collected at 100 K using a Bruker D8 Venture diffractometer.The data were collected using phi and omega scans (0.50 • oscillations) with a Mo Kα (λ = 0.71073 Å) microfocus source and Photon 2 detector.Data were processed (SAINT) and corrected for absorption using the multi-scan approach (SADABS), both within the Apex3 suite [39].The structures were solved by intrinsic phasing and subsequently refined by full-matrix least squares on F 2 using the SHELXTL (2016/6) software package [40].All non-hydrogen atoms were refined anisotropically.Hydrogen atoms attached to carbon atoms were refined in calculated positions using the appropriate riding models.Most of the complexes studied were found to crystallize as solvates:  1 and 2. CCDC 2335789-2335797 contain the supplementary crystallographic data for this paper and can be obtained from the Cambridge Crystallographic Data Centre.

Synthesis of Iridium(III) N-oxide Complexes
To generate N-oxide derivates in which the N-oxide is not coordinated to the metal center, chlorobridged-Ir(III) dimers, [(dfppy) 2 Ir(µ-Cl)] 2 , and [(ppy) 2 Ir(µ-Cl)] 2 were heated in the presence of 5-methylpyrazine-2-carboxylic acid 4-oxide (Acipimox) and K 2 CO 3 using acetone as a solvent (Scheme 1), generating compound 1 and 3.The same strategy was utilized to develop the non-N-oxide analogs, exploiting 5-methyl-2-pyrazinecarboxylic acid as the NˆO chelating ligand, generating compounds 2 and 4 (Scheme 1).This strategy resulted in no observable N-oxide metal coordination and the formation of one major product.The purity of all of these newly synthesized compounds was verified by elemental analysis, and their composition was supported by HRMS (Supporting Information, Figures S1-S5).Xing et al. also utilized the Acipimox ligand to generate Co(II) and Zn(II) coordination compounds and only observed one major species, where the selective coordination of the Acipimox ligand is due to the chelation effect imposed by the nitrogen and carboxylate formed in situ [33].Prior to exploiting N-oxide-containing ligands to append this functional group to Ir(III) compounds, we initially attempted to form the N-oxide by derivatizing synthesized Ir(III) species with uncoordinated nitrogen atoms.We envisioned oxidizing these nitrogen atoms with common oxidants often utilized to form N-oxides (e.g., mCPBA) [41].Initial attempts have been unsuccessful; however, we are continuing to screen other oxidants for this strategy.Many of these species, such as compound 5 (Scheme 1) and compounds 6-8 (Scheme 2), have been previously synthesized but not characterized crystallographically.
The procedures to generate cationic Ir(III) compounds of the form [Ir(C^N)2(N^N)]PF6 (where C^N = ppy or dfppy and N^N = a 2,2'-bipyridine derivative) exploited the cleavage of chlorobridged-Ir(III) dimers with neutral bidentate ligands (Scheme 2).For instance, heating [(dfppy)2Ir(µ-Cl)]2 and 2,2'-bipyrazine in ethylene glycol followed by the precipitation of the corresponding PF6 -salt using NH4PF6 (sat.aq.) afforded the heteroleptic Ir(III) compound, 6, which was verified by NMR, HRMS, and EA.Cationic compounds 7 and 8 have been previously reported in the literature, and we utilized 1 H-NMR spectroscopy to initially verify product formation, which was later supported by full crystallographic characterization.Future efforts will focus on functionalizing the uncoordinated nitrogen atoms in these species to N-oxides (vide infra).Prior to exploiting N-oxide-containing ligands to append this functional group to Ir(III) compounds, we initially attempted to form the N-oxide by derivatizing synthesized Ir(III) species with uncoordinated nitrogen atoms.We envisioned oxidizing these nitrogen atoms with common oxidants often utilized to form N-oxides (e.g., mCPBA) [41].Initial attempts have been unsuccessful; however, we are continuing to screen other oxidants for this strategy.Many of these species, such as compound 5 (Scheme 1) and compounds 6-8 (Scheme 2), have been previously synthesized but not characterized crystallographically.
1 H-NMR spectra of compounds 1-8 contained many key features that are worth describing (Supporting Information, Figures S6-S10).In the previously reported cationic Ir(III) complexes (6-8), the innate symmetry of these molecules afforded nine (compound 6), ten (compound 7), and eleven (compound 8) 1 H-resonances.The presence of the 2-2′bipyazine afforded many deshielded 1 H-resonances (~8 ppm) in compounds 6 and 8.For compound 7, the four equivalent homotopic methyl groups on the -NMe2 groups served as a key feature at ~3 ppm.Likewise, in compounds 1-4, where all of the bidentate ligands surrounding the metal became inequivalent due to the asymmetry imposed by the N^O chelating ligands, the methyl groups served as a valuable spectroscopic handle.In compounds 1-4, the methyl group on the 2-pyrazinecarboxylic acid portion of the molecule provided distinct resonances at 2.34 ppm (compound 1), 2.58 ppm (compound 2), 2.31 ppm (compound 3), and 2.50 ppm (compound 4).Even prior to structural validation from X-ray data, this indicated that only one major product had been synthesized in each case.

Structural Comparison of Iridium(III) N-oxide Complexes with Comparable Iridium(III) Complexes with Non-oxidized Ligands, 1-4
In all four complexes, iridium is a six-coordinate metal center, coordinating two atoms from each ligand and accumulating to the [Ir(C2N3O)] coordination (Figure 2).The bidentate coordination of the 5mpcaO and 5mpca ligands in all four complexes occurs through one of the carboxylate oxygen atoms and its nearest nitrogen atom, leaving the N-oxide (in 1 and 3) or its corresponding bare nitrogen atom (in 2 and 4) exposed.Each of the ligands is monoanionic, stabilizing the Ir(III) oxidation state.In 1 and 2, the asymmetric units consist of two unique Ir(III) complexes as well as disordered THF and CH2Cl2 molecules, respectively.In 3 and 4, the asymmetric units contain only one unique Ir(III) complex and two well-ordered CH2Cl2 molecules. 1H-NMR spectra of compounds 1-8 contained many key features that are worth describing (Supporting Information, Figures S6-S10).In the previously reported cationic Ir(III) complexes (6-8), the innate symmetry of these molecules afforded nine (compound 6), ten (compound 7), and eleven (compound 8) 1 H-resonances.The presence of the 2-2 ′ -bipyazine afforded many deshielded 1 H-resonances (~8 ppm) in compounds 6 and 8.For compound 7, the four equivalent homotopic methyl groups on the -NMe 2 groups served as a key feature at ~3 ppm.Likewise, in compounds 1-4, where all of the bidentate ligands surrounding the metal became inequivalent due to the asymmetry imposed by the NˆO chelating ligands, the methyl groups served as a valuable spectroscopic handle.In compounds 1-4, the methyl group on the 2-pyrazinecarboxylic acid portion of the molecule provided distinct resonances at 2.34 ppm (compound 1), 2.58 ppm (compound 2), 2.31 ppm (compound 3), and 2.50 ppm (compound 4).Even prior to structural validation from X-ray data, this indicated that only one major product had been synthesized in each case.

Structural Comparison of Iridium(III) N-oxide Complexes with Comparable Iridium(III) Complexes with Non-oxidized Ligands, 1-4
In all four complexes, iridium is a six-coordinate metal center, coordinating two atoms from each ligand and accumulating to the [Ir(C 2 N 3 O)] coordination (Figure 2).The bidentate coordination of the 5mpcaO and 5mpca ligands in all four complexes occurs through one of the carboxylate oxygen atoms and its nearest nitrogen atom, leaving the N-oxide (in 1 and 3) or its corresponding bare nitrogen atom (in 2 and 4) exposed.Each of the ligands is monoanionic, stabilizing the Ir(III) oxidation state.In 1 and 2, the asymmetric units consist of two unique Ir(III) complexes as well as disordered THF and CH 2 Cl 2 molecules, respectively.In 3 and 4, the asymmetric units contain only one unique Ir(III) complex and two well-ordered CH 2 Cl 2 molecules.
The six-coordinate Ir(III) in each complex is a distorted octahedron (Table 3).The angular distortion is similar for all of the octahedra, with complex 1 exhibiting the extremes of the trans-angles for the series, ranging from 169.52 (14) • to 175.83 (13) • .The complexes also all show a significant trans-effect in the Ir-O and Ir-N bond lengths for the 5mpcaO and 5mpca ligands, whose oxygen and nitrogen atoms occur opposite the coordinated carbon atoms of the difluorophenylpyridine (dfppy) and phenylpyridine (ppy) ligands., respectively, which are to our knowledge the only other metal complexes of 5mpcaO to be characterized crystallographically [33].These distances are on the shorter end of the N-O bond lengths surveyed in the literature for molecular N-oxide crystals [45], indicating some contribution of the N + =O resonance form in the Ir(III)-complexed ligand (Supporting Information, Figure S11).Complexes such as 2 and 4 involving the non-oxidized 5mpca ligand are somewhat more common in the structural literature, including one iridium complex of 5mpca and two 3,5-bis(trifluoromethyl)phenyl ligands [46].A similar transinfluence to that found in 2 and 4 affecting the Ir-O and Ir-N bond lengths is observed in that structure.The six-coordinate Ir(III) in each complex is a distorted octahedron (Table 3).The angular distortion is similar for all of the octahedra, with complex 1 exhibiting the extremes of the trans-angles for the series, ranging from 169.52(14)° to 175.83(13)°.The complexes also all show a significant trans-effect in the Ir-O and Ir-N bond lengths for the 5mpcaO and 5mpca ligands, whose oxygen and nitrogen atoms occur opposite the coordinated carbon atoms of the difluorophenylpyridine (dfppy) and phenylpyridine (ppy) ligands.The trans-effects of similar magnitudes are observed in other iridium complexes of dfppy and ppy [42][43][44].The N-O distances in 1 and 3 are similar to those of the Co(II) and Zn(II) complexes with 5mpcaO, [Co(5mpcaO)2(H2O)2] • 2H2O and [Zn(5mpcaO)2(H2O)2] • 2H2O, respectively, which are to our knowledge the only other metal complexes of 5mpcaO to be characterized crystallographically [33].These distances are on the shorter end of the N-O bond lengths surveyed in the literature for molecular N-oxide crystals [45], indicating some contribution of the N + =O resonance form in the Ir(III)-complexed ligand (Supporting Information, Figure S11).Complexes such as 2 and 4 involving the non-oxidized 5mpca ligand are somewhat more common in the structural literature, including one iridium complex of 5mpca and two 3,5-bis(trifluoromethyl)phenyl ligands [46].A similar transinfluence to that found in 2 and 4 affecting the Ir-O and Ir-N bond lengths is observed in that structure.The exposure of the N-oxide or its corresponding bare nitrogen atom on the outside of the complex is influential in establishing the intermolecular interactions and packing patterns that are observed in 1-4.In 1, the N-oxide oxygen atoms maintain short O•••π contacts between symmetry-equivalent complexes to form dimers, which then associate through C-H•••O interactions with the N-oxide oxygen atoms of the second unique complex (Figure 3).An offset π•••π stacking interaction further stabilizes the central dimer.The resulting clusters then assemble into a three-dimensional network via additional C-H•••O carboxylate interactions.The space between the complexes in 1 is occupied by disordered THF molecules (Supporting Information, Figure S12).In 2, the bare nitrogen atom of the 5mpca ligand of one of the unique complexes acts as an acceptor for a C-H•••N interaction originating from the second unique complex (Figure 3), with the interaction connecting neighboring complexes along [1 0 -1].The bare nitrogen atom of this second complex, however, does not maintain any short intermolecular contact with neighboring complexes.Additional C-H•••O carboxylate , C-H•••F, and π•••π interactions further extend the packing structure to three dimensions, where voids are occupied by water molecules and disordered CH 2 Cl 2 molecules (Supporting Information, Figure S13).The water molecules facilitate hydrogen bonding interactions that bridge the uncoordinated carboxylate oxygen atoms of neighboring complexes along the a-axis.The exposure of the N-oxide or its corresponding bare nitrogen atom on the outside of the complex is influential in establishing the intermolecular interactions and packing patterns that are observed in 1-4.In 1, the N-oxide oxygen atoms maintain short O•••π contacts between symmetry-equivalent complexes to form dimers, which then associate through C-H•••O interactions with the N-oxide oxygen atoms of the second unique complex (Figure 3).An offset π•••π stacking interaction further stabilizes the central dimer.The resulting clusters then assemble into a three-dimensional network via additional C-H•••Ocarboxylate interactions.The space between the complexes in 1 is occupied by disordered THF molecules (Supporting Information, Figure S12).In 2, the bare nitrogen atom of the 5mpca ligand of one of the unique complexes acts as an acceptor for a C-H•••N interaction originating from the second unique complex (Figure 3), with the interaction connecting neighboring complexes along [1 0 -1].The bare nitrogen atom of this second complex, however, does not maintain any short intermolecular contact with neighboring complexes.Additional C-H•••Ocarboxylate, C-H•••F, and π•••π interactions further extend the packing structure to three dimensions, where voids are occupied by water molecules and disordered CH2Cl2 molecules (Supporting Information, Figure S13).The water molecules facilitate hydrogen bonding interactions that bridge the uncoordinated carboxylate oxygen atoms of neighboring complexes along the a-axis.

Electronic Characterization of 1-4
To better understand the electronics of compounds 1-4, the cyclic voltammograms of each species were obtained (Figure 5).Based on literature precedent, we assigned the features at positive potentials to an Ir III /Ir IV oxidation [47].The potentials of these features depend on what cyclometallating ligand was utilized.For instance, when the electrondeficient 2-(2',4'-difluorophenyl)pyridine is used as a cyclometallating ligand, the metal center's oxidation occurs at a more positive potential (e.g., compound 1) as compared to when phenylpyridine is used as a cyclometallating ligand (e.g., compound 3).The reversible anodic features appearing between −1.84 and −2.00 V were assigned to the reduction of the pyrazinecarboxylic acid ligands based on literature precedent [48].In compounds 1 and 3, the presence of an N-oxide anodically shifts the reduction potential.For instance, in comparing compounds 1 and 2, the reversible reduction feature occurs at −1.84 and −1.99 V, respectively.Based on electrochemical data, this suggests that the N-oxide is acting as an electron-withdrawing group.This is of importance because although the oxygen is inductively withdrawing, it can act as an electron-donating group based on resonance (Figure S11).

Electronic Characterization of 1-4
To better understand the electronics of compounds 1-4, the cyclic voltammograms of each species were obtained (Figure 5).Based on literature precedent, we assigned the features at positive potentials to an Ir III /Ir IV oxidation [47].The potentials of these features depend on what cyclometallating ligand was utilized.For instance, when the electron-deficient 2-(2 ′ ,4 ′difluorophenyl)pyridine is used as a cyclometallating ligand, the metal center's oxidation occurs at a more positive potential (e.g., compound 1) as compared to when phenylpyridine is used as a cyclometallating ligand (e.g., compound 3).The reversible anodic features appearing between −1.84 and −2.00 V were assigned to the reduction of the pyrazinecarboxylic acid ligands based on literature precedent [48].In compounds 1 and 3, the presence of an Noxide anodically shifts the reduction potential.For instance, in comparing compounds 1 and 2, the reversible reduction feature occurs at −1.84 and −1.99 V, respectively.Based on electrochemical data, this suggests that the N-oxide is acting as an electron-withdrawing group.This is of importance because although the oxygen is inductively withdrawing, it can act as an electron-donating group based on resonance (Figure S11).

Structural Characterization of Iridium(III) Complexes with Additional Exposed Nitrogen
Atoms 5-8 The Ir(III) complexes 5-8 adopt similar six-coordinate environments to those in 1-4 (Figure 6).Each is coordinated in a bidentate fashion by three ligands.The dfppy ligands of 5-7, the ppy ligands of 8, and the pyrazine carboxylic acid ligand of 5 are all monoanionic, while the bipyrazine (bpz) ligands of 6 and 8 and the di(dimethylamino)-2,2'-bipyridine ligand of 7 are neutral.In this way, the resulting complexes with Ir(III) are neutral

Structural Characterization of Iridium(III) Complexes with Additional Exposed Nitrogen Atoms 5-8
The Ir(III) complexes 5-8 adopt similar six-coordinate environments to those in 1-4 (Figure 6).Each is coordinated in a bidentate fashion by three ligands.The dfppy ligands of 5-7, the ppy ligands of 8, and the pyrazine carboxylic acid ligand of 5 are all monoanionic, while the bipyrazine (bpz) ligands of 6 and 8 and the di(dimethylamino)-2,2'-bipyridine ligand of 7 are neutral.In this way, the resulting complexes with Ir(III) are neutral in the case of 5 and monocationic in the case of 6-8.Complexes 6-8 therefore crystallize as [PF 6 ] − salts.Furthermore, complex 6 was obtained as two different solvates having two slightly different solvent contents that resulted in packing differences.All the complexes exhibit a trans-lengthening effect for Ir-N (and Ir-O in the case of 5) bonds that are trans to the Ir-C bonds to dfppy or ppy ligands (Table 4).These species all contain uncoordinated nitrogen atoms, and our group is working to develop synthetic methodologies to oxidize these species to their corresponding N-oxide analogs using traditional methods commonly utilized in organic synthesis (e.g., mCPBA) [41].Although the N-oxide functional group has been incorporated into various organic motifs and has shown utility in various applications [1][2][3][4][5], including imaging hypoxia in tumor cells [3][4][5], there are limited examples of N-oxide-containing transition metal compounds where  These species all contain uncoordinated nitrogen atoms, and our group is working to develop synthetic methodologies to oxidize these species to their corresponding N-oxide analogs using traditional methods commonly utilized in organic synthesis (e.g., mCPBA) [41].Although the N-oxide functional group has been incorporated into various organic motifs and has shown utility in various applications [1][2][3][4][5], including imaging hypoxia in tumor cells [3][4][5], there are limited examples of

Crystals 2024 , 21 Figure 2 .
Figure 2. Crystal structure of complexes 1-4, shown as 50% probability ellipsoids.Iridium atoms are dark blue, carbon atoms are gray, nitrogen atoms are purple, oxygen atoms are red, and fluorine atoms are lime green.Hydrogen atoms and solvent molecules are omitted for clarity.For complexes 1 and 2, where two similar but crystallographically unique complexes occur in the asymmetric unit, only one complex is shown as a representative example.

Figure 2 .
Figure 2. Crystal structure of complexes 1-4, shown as 50% probability ellipsoids.Iridium atoms are dark blue, carbon atoms are gray, nitrogen atoms are purple, oxygen atoms are red, and fluorine atoms are lime green.Hydrogen atoms and solvent molecules are omitted for clarity.For complexes 1 and 2, where two similar but crystallographically unique complexes occur in the asymmetric unit, only one complex is shown as a representative example.

Figure 3 .Figure 3 .
Figure 3. Intermolecular interactions involving the N-oxide and bare nitrogen atoms of complexes 1 and 2. C-H•••O and C-H•••N interactions are shown as dashed blue lines, while O•••π and π•••π interactions are shown as dashed magenta lines to the nearest carbon atom.Iridium atoms are dark blue, carbon atoms are gray, nitrogen atoms are purple, oxygen atoms are red, fluorine atoms are lime green, and hydrogen atoms are white.Complexes 3 and 4 crystallized with an identical solvent content of two CH2Cl2 molecules per complex.Despite their similar compositions, space groups, and unit cell parameters (the unit cell volume of 3 is only about 1.4% larger than that of the non-oxidized 4), subtle perturbations are observed in the packing structure exerted by the oxygen atom in 3 compared to the bare nitrogen atom in 4. The N-oxide in 3 acts as a C-H•••O acceptor for two neighboring complexes and a Cl•••O halogen bond acceptor (Cl•••O = 2.963(6) Å, normalized halogen bond length = 0.89) for one of the CH2Cl2 molecules (Figure 4).The C-H•••O interactions, in particular, extend the intermolecular motif into a two-dimensional sheet parallel to (1 0 1).Additional C-H•••Ocarboxylate and C-H•••π interactions further extend Figure 3. Intermolecular interactions involving the N-oxide and bare nitrogen atoms of complexes 1 and 2. C-H•••O and C-H•••N interactions are shown as dashed blue lines, while O•••π and π•••π interactions are shown as dashed magenta lines to the nearest carbon atom.Iridium atoms are dark blue, carbon atoms are gray, nitrogen atoms are purple, oxygen atoms are red, fluorine atoms are lime green, and hydrogen atoms are white.Complexes 3 and 4 crystallized with an identical solvent content of two CH 2 Cl 2 molecules per complex.Despite their similar compositions, space groups, and unit cell parameters (the unit cell volume of 3 is only about 1.4% larger than that of the non-oxidized 4), subtle perturbations are observed in the packing structure exerted by the oxygen atom in 3 compared to the bare nitrogen atom in 4. The N-oxide in 3 acts as a C-H•••O acceptor for two neighboring complexes and a Cl•••O halogen bond acceptor (Cl•••O = 2.963(6) Å, normalized halogen bond length = 0.89) for one of the CH 2 Cl 2 molecules (Figure 4).The C-H•••O interactions, in particular, extend the intermolecular motif into a two-dimensional sheet parallel to (1 0 1).Additional C-H•••O carboxylate and C-H•••π interactions further extend the long-range structure to three dimensions, accommodating the additional CH 2 Cl 2 molecules (Supporting Information, Figure S14).Complex 4 appears to adopt the opposite relative chirality in space group P2 1 , and there are subtle positional differences of neighboring molecules compared to 3 that favor C-H•••π interactions since the equivalent C-H•••O interactions to the N-oxide in 3 are no longer operable in 4 (Figure 4).An equivalent C-H•••N interaction to the bare nitrogen atom does not appear to be enabled.Likewise, the nearest CH 2 Cl 2 molecule is arranged toward a Cl•••π interaction rather than Cl•••N (even though nitrogen is typically a good halogen bond acceptor) now that the Cl•••O interaction is removed.The packing is extended into three dimensions by the continuation of the numerous C-H•••π interactions as well as C-H•••O carboxylate interactions, again accommodating the cocrystallized CH 2 Cl 2 molecules (Supporting Information, Figure S15).

boring molecules compared to 3
that favor C-H•••π interactions since the equivalent C-H•••O interactions to the N-oxide in 3 are no longer operable in 4 (Figure4).An equivalent C-H•••N interaction to the bare nitrogen atom does not appear to be enabled.Likewise, the nearest CH2Cl2 molecule is arranged toward a Cl•••π interaction rather than Cl•••N (even though nitrogen is typically a good halogen bond acceptor) now that the Cl•••O interaction is removed.The packing is extended into three dimensions by the continuation of the numerous C-H•••π interactions as well as C-H•••Ocarboxylate interactions, again accommodating the cocrystallized CH2Cl2 molecules (Supporting Information, FigureS15).

Figure 4 .
Figure 4. Selected intermolecular interactions in complexes 3 and 4. C-H•••O, C-H•••N, and Cl•••O interactions are shown as dashed blue lines, while C-H•••π and Cl•••π interactions are shown as dashed magenta lines to the nearest carbon atom.Iridium atoms are dark blue, carbon atoms are gray, nitrogen atoms are purple, oxygen atoms are red, chlorine atoms are green, and hydrogen atoms are white.

Figure 4 .
Figure 4. Selected intermolecular interactions in complexes 3 and 4. C-H•••O, C-H•••N, and Cl•••O interactions are shown as dashed blue lines, while C-H•••π and Cl•••π interactions are shown as dashed magenta lines to the nearest carbon atom.Iridium atoms are dark blue, carbon atoms are gray, nitrogen atoms are purple, oxygen atoms are red, chlorine atoms are green, and hydrogen atoms are white.

Crystals 2024 , 21 Figure 6 . 6 .
Figure 6.Crystal structure of complexes 5-8, shown as 50% probability ellipsoids.Iridium atoms are dark blue, carbon atoms are gray, nitrogen atoms are purple, oxygen atoms are red, and fluorine atoms are lime green.Hydrogen atoms and solvent molecules are omitted for clarity.Two renderings are given for complex 6, derived from the two different solvate crystal structures obtained for 6.For complexes 5 and 6 • 0.5(DCM),0.5(Et2O),where two similar but crystallographically unique complexes occur in the asymmetric unit, only one complex is shown as a representative example.

Figure 7 .
Figure 7. Intermolecular interactions involving the formation of chains in 5. C-H•••O and C-H•••N interactions are shown as dashed blue lines, while C-H•••π and π•••π interactions are shown as dashed magenta lines to the nearest carbon atom.Iridium atoms are dark blue, carbon atoms are gray, nitrogen atoms are purple, oxygen atoms are red, fluorine atoms are lime green, and hydrogen atoms are white.In 6•(DCM), complexes form dimers through C-H•••N interactions involving one of the dfppy ligands of one complex and one of the external nitrogen atoms of the bpz ligands of a neighboring complex (Figure 8).Numerous short C-H•••F interactions to the [PF6] -anions, C-H•••Cl interactions to the CH2Cl2 solvent molecules, and C-F•••π contacts between neighboring complexes complete the three-dimensional packing network (Supporting Information, Figure S17).In 6•0.5(DCM),0.5(Et2O),a similar dimeric coupling of

Figure 7 .
Figure 7. Intermolecular interactions involving the formation of chains in 5. C-H•••O and C-H•••N interactions are shown as dashed blue lines, while C-H•••π and π•••π interactions are shown as dashed magenta lines to the nearest carbon atom.Iridium atoms are dark blue, carbon atoms are gray, nitrogen atoms are purple, oxygen atoms are red, fluorine atoms are lime green, and hydrogen atoms are white.

Figure 8 .
Figure 8. Selected intermolecular interactions involving the bipyrazine nitrogen atoms in 6 and 8. C-H•••N interactions are shown as dashed blue lines.Iridium atoms are dark blue, carbon atoms are gray, nitrogen atoms are purple, fluorine atoms are lime green, and hydrogen atoms are white.

Figure 9 .
Figure 9. Selected intermolecular interactions in 7. C-H•••π and π•••π interactions are shown as dashed magenta lines to the nearest carbon atom.Iridium atoms are dark blue, carbon atoms are gray, nitrogen atoms are purple, fluorine atoms are lime green, and hydrogen atoms are white.
We synthesized and characterized two rare examples of cyclometallated Ir(III) compounds containing the N-oxide functional group, where the N-oxide is not coordinated to the metal center.Electrochemical analysis results indicate that the N-oxide functional group acts as an electron-withdrawing group.Single-crystal X-ray diffraction analysis confirmed the ligand coordination and the exposed N-oxide group.The N-oxides enabled significant C-H•••O and O•••π interactions between neighboring complexes that distinguished the packing structures from the non-oxidized congeners.Moreover, the X-ray analysis results of several additional species, having exposed nitrogen atoms not coordinated to the Ir(III) center, are reported.The single-crystal analysis of these species indicated the prevalence of C-H•••N interactions in combination with π•••π and C-H•••π interactions.A distinguishing feature in some of these structures is the formation of C-H•••N dimers or finite chains versus infinite chains of C-H•••N interactions.

Figure 9 .
Figure 9. Selected intermolecular interactions in 7. C-H•••π and π•••π interactions are shown as dashed magenta lines to the nearest carbon atom.Iridium atoms are dark blue, carbon atoms are gray, nitrogen atoms are purple, fluorine atoms are lime green, and hydrogen atoms are white.
We synthesized and characterized two rare examples of cyclometallated Ir(III) compounds containing the N-oxide functional group, where the N-oxide is not coordinated to the metal center.Electrochemical analysis results indicate that the N-oxide functional group acts as an electron-withdrawing group.Single-crystal X-ray diffraction analysis confirmed the ligand coordination and the exposed N-oxide group.The N-oxides enabled significant C-H•••O and O•••π interactions between neighboring complexes that distinguished the packing structures from the non-oxidized congeners.Moreover, the X-ray analysis results of several additional species, having exposed nitrogen atoms not coordinated to the Ir(III) center, are reported.The single-crystal analysis of these species indicated the prevalence of C-H•••N interactions in combination with π•••π and C-H•••π interactions.A distinguishing feature in some of these structures is the formation of C-H•••N dimers or finite chains versus infinite chains of C-H•••N interactions.