Optical Resolution of Carboxylic Acid Derivatives of Homoleptic Cyclometalated Iridium(III) Complexes via Diastereomers Formed with Chiral Auxiliaries

Abstract

We report on a facile method for the optical resolution of cyclometalated iridium(III) (Ir(III)) complexes via diastereomers formed with chiral auxiliaries. The racemic carboxylic acids of Ir(III) complexes (fac-4 (fac-Ir(ppyCO₂H)₃ (ppy: 2-phenylpyridine)), fac-6 (fac-Ir(tpyCO₂H)₃ (tpy: 2-(4′-tolyl)pyridine)), and fac-13 (fac-Ir(mpiqCO₂H)₃ (mpiq: 1-(4′-methylphenyl)isoquinoline))) were converted into the diastereomers, Δ- and Λ-forms of fac-9 (from fac-6), fac-10 (from fac-4), fac-11 (from fac-6), and fac-14 (from fac-13), respectively, by the condensation with (1R,2R)-1,2-diaminocyclohexane or (1R,2R)-2-aminocyclohexanol. The resulting diastereomers were separated by HPLC (with a nonchiral column) or silica gel column chromatography, and their absolute stereochemistry was determined by X-ray single-crystal structure analysis and CD (circular dichroism) spectra. Spectra of all diastereomers of the Ir(III) complexes are reported. Hydrolysis of the ester moieties of Δ- and Λ-forms of fac-10, fac-11, and fac-14 gave both enantiomers of the corresponding carboxylic acid derivatives in the optically pure forms, Δ-fac and Λ-fac-4, -6, and -13, respectively.

Short abstract

We report on an efficient method for the optical resolution of carboxylic acids of the homoleptic cyclometalated iridium(III) (Ir(III)) complexes via diastereomeric amides and esters formed by the condensation with (1R,2R)-1,2-diaminocyclohexane and (1R,2R)-2-aminocyclohexanol, respectively. The resulting diastereomers were separated by HPLC or silica gel column chromatography, and their absolute stereochemistry was determined by X-ray single-crystal structure analysis and CD (circular dichroism) spectra. Hydrolysis of the ester moieties of Δ- and Λ- fac-10, fac-11, and fac-14 gave the corresponding carboxylic acid derivatives in the optically pure forms.

Introduction

Homoleptic cyclometalated Ir(III) complexes such as facial fac-Ir(tpy)₃ (tpy: 2-(4′-tolyl)pyridine) and fac-Ir(ppy)₃ (ppy: 2-phenylpyridine) have C₃-symmetric structures and exhibit excellent photophysical properties, large Stokes shifts, high quantum yields, and long lifetimes for their luminescence emission. Because of their attractive photochemical properties, considerable interest has developed in applications for not only organic light-emitting diodes (OLEDs) as phosphorescent emitters,¹ but also bioimaging probes,² pH sensors,³ anticancer reagents,⁴ photoredox catalysts,⁵ and related applications.⁶

In our group, regioselective electrophilic reactions at the 5′-position of phenylpyridine units and subsequent conversions of tris cyclometalated Ir(III) complexes, a process that is referred to as “post-complexation functionalization (PCF)”, were developed for the synthesis of a series of Ir(III) complexes that exhibit blue, green, and red emissions.⁷ For example, Ir complexes functionalized with amino and pyridyl groups exhibit emission color changes between green and red due to the protonation and deprotonation of their basic groups in aqueous solutions.⁸ We conducted the preparation of Ir(III) complexes bearing biologically active peptides for therapy and the luminescent imaging of cancer cells.^9,10 It was reported that the hybrid compounds of the Ir(III) complex with cyclic peptides (Ir(III) complex-peptide hybrids, IPHs) bind to death receptors (DRs) that are expressed on cancer cells,⁹ and those with cationic peptides containing lysine (K) and glycine (G)¹⁰ induce programmed cell death (PCD) such as apoptosis, necroptosis, and paraptosis in cancer cells. A number of other Ir(III) complexes that exhibit red, green, blue, and white colorless luminescence emission and that have long emission lifetimes were also synthesized.^7,11,12

Intrinsically, Ir(III) complex cores adopt 6-coordinate octahedral or pseudo-octahedral structures and hence possess metal-centered chirality, for example, delta (Δ) and lambda (Λ) forms.^13,14 There are only limited methods currently available for separating these metal-centered enantiomers, one of which involves the use of chiral HPLC columns for the separations of several homoleptic and heteroleptic complexes^15,16 and acetylacetone (acac) complexes.¹⁷ A method for synthesizing a five-coordinate Ir(III) complex and separating the resulting enantiomers by chiral HPLC followed by conversion to heteroleptic complexes has also been reported, in which enantiomers of Ir(III) complexes are separated by means of an HPLC chiral stationary phase using amylose or cellulose derivatives.¹⁸

Meggers’ group reported the separation of Λ- and Δ-isomers of Ir(III) complexes by introducing chiral ligands such as (S)-4-tert-butyl-2-(2′-hydroxyphenyl)-2-oxazoline analogues, l-proline, and l-α-methylproline.¹⁹ Similar methods for the enantioselective synthesis of bis-heteroleptic Ir complexes were carried out via the complexation with l- and d-serine.²⁰ Zuo and co-workers reported on the separation of 1–3 by chiral HPLC columns and the CD (circular dichroism) and CPL (circularly polarized luminescence) spectra of the purified enantiomers (Chart 1). They also conducted the complexation of the μ-complex {Ir(dfppy)₂(μ-Cl)}₂ (dfppy: 4,6-difluorophenylpyridine) with optically pure ancillary ligands, (R)- and (S)-2-(4-ethyl-4,5-dihydrooxazol-2-yl)phenol (edp), to obtain four enantiomeric Ir(III) complexes, Λ- and Δ-forms of Ir(dfppy)₂(R-edp) and Ir(dfppy)₂(S-edp).²¹ A more direct method includes the diastereoselective formation of the fac-Λ-complex from a tripodal ligand having three optically pure cyclometalating ligand units, 2-(2′-phenyl)-4,5-pinenopyridine (pppy), and a separation with a silica preparative plate.²²

Chart 1. Chemical Structures and Absolute Configuration of Representative Cyclometalated Ir(III) Complexes.

This background has prompted us to conduct the optical resolution of homoleptic cyclometalated Ir(III) complexes that contain carboxylic acid moieties, which are important products and intermediates of the postcomplexation functionalization,⁷ via their corresponding diastereomeric intermediates to produce optically pure Ir(III) complexes. In this work, we incorporate optically active diamine or amino alcohol units into the complexes to convert the two enantiomers to diastereomeric isomers in order to separate the Δ-forms and Λ-forms from one another (Chart 2). Namely, carboxylic acid derivatives of racemic mixtures, fac-4 (fac-Ir(ppyCO₂H)₃), 6 (fac-Ir(tpyCO₂H)₃), and 13 (fac-Ir(mpiqCO₂H)₃, mpiq: 1-(4′-methylphenyl)isoquinoline), which were synthesized from fac-1, -5, and -12 by PCF,^8a were converted into the corresponding diastereomers by introducing the chiral units (1R,2R)-1,2-diaminocyclohexane ((1R,2R)-1,2-DAH, (R,R)-7)²³ and (1R,2R)-2-aminocyclohexanol ((1R,2R)-2-ACH, (R,R)-8)²⁴ to give fac-9, fac-10, and fac-11, respectively (Chart 2). These stereoisomers were then separated by normal-phase HPLC or silica gel column chromatography to obtain Δ- and Λ-fac-9, -10, and -11, respectively. Optically pure Δ- and Λ-fac-4 and -6 were then isolated by the hydrolysis of Δ- and Λ-fac-10 and -11, respectively. In addition, fac-13 was also converted to the two diastereomers of fac-14, which were converted to Δ-fac-13 and Λ-fac-13 by a similar procedure (Chart 2). This method allows us to obtain both enantiomers at the same time on a large scale via the diastereomeric intermediates conjugated with one enantiomer of chiral auxiliary units.²⁵

Chart 2. Optical Resolution of Cyclometalated Ir(III) Complexes.

Results and Discussion

Design and Synthesis of Diastereomeric Amides (fac-9) and Esters (fac-10, -11, and -14)

Methods for the optical resolution of chiral organic carboxylic acids can generally be classified into the following methods: (i) diastereomeric salt formation with chiral amines, (ii) the formation of diastereomeric esters by forming covalent bonds with chiral alcohols, and (iii) kinetic resolution by enzymatic or nonenzymatic reactions (e.g., stereoselective hydrolysis of the corresponding racemic esters).¹³ We initially attempted to produce salts of fac-6^8a with optically active amines such as quinidine, cinchonidine, (R)-1-(1-naphthyl)ethylamine, l-arginine, (R,R)-diphenyldiaminoethane, and (1R,2R)-1,2-diaminocyclohexane in several solvents and carried out the recrystallization of the resulting salts. However, these efforts resulted in a negligible enrichment of enantiomers (data not shown).

Therefore, we synthesized diastereomeric esters of fac-6 by reactions with optically pure alcohols such as (1R,2S,5R)-menthol, l-prolinol, and its derivatives for optical resolution. However, the separation of these diastereomers by nonchiral HPLC and/or column chromatography was also not successful (data not shown). We then conducted the condensation reactions of fac-6 with (R,R)-7 in the presence of benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) and N,N-diisopropylethylamine (DIEA) to obtain fac-9 as a diastereomeric mixture, as shown in Charts 2 and 3 (top half). Separation using normal-phase and nonchiral HPLC gave Δ-fac-9 (33%) and Λ-fac-9 (36%). It should be noted here that the introduction of only one enantiomer of 1,2-DAH or 2-ACH ((R,R)-forms in this work) was sufficient to permit the Δ-forms and Λ-forms to be separated from one another. Note that Δ-fac-9 and Λ-fac-9 are actually Δ-(R,R)-fac-9 and Λ-(R,R)-fac-9, respectively, because they contain three (1R,2R)-1,2-DAH units, and their nomenclature is abbreviated to Δ-fac-9 and Λ-fac-9 for clarity in this manuscript.

Chart 3. Synthesis of Optically Pure fac-9 and fac-6 from Racemic fac-6.

Next, the synthesis of fac-11 from fac-6 and (R,R)-8 was attempted (Chart 2). The initial condensation reaction of fac-11 with (R,R)-8 using 2-methyl-6-nitrobenzoic anhydride (MNBA)²⁶ gave fac-11 as a diastereomeric mixture, which was separated by silica gel column chromatography to afford Λ- and Δ-forms of fac-11 in 0.7% and 0.4% yields, respectively (Table 1, entry 1). Increasing the amount of MNBA and reaction time used in the reaction somewhat improved the chemical yields of the desired products (Table 1, entries 2 and 3). The use of polar solvents such as N-methylpyrrolidone (NMP) resulted in similar yields (Table 1, entries 4 and 7), and THF afforded even higher yields, possibly because of the higher solubility of fac-6 in THF (Table 1, entry 8). The results shown in entries 8–14 of Table 1 suggest that carrying out the condensation reactions at higher temperature (entries 8–10 vs entry 7) and at high concentrations (entries 10 and 13 (Chart 3, bottom half) and 14 vs entry 12) gave higher chemical yields. Eventually, 150–160 mg of Λ-fac-11 and Δ-fac-11 were obtained in entry 13. The separated Δ-fac-11 and Λ-fac-11 were converted to Δ-fac-6 and Λ-fac-6, respectively, by hydrolysis with aqueous NaOH in MeOH/H₂O.

Table 1. Examination of the Reaction Conditions for the Synthesis of fac-11.

						time		yield (%)
entry	(R,R)-8 (equiv)	MNBA (equiv)	solvent	concentration of 6 (M)	reaction temp	Xa	Xb	Λ-fac-11	Δ-fac-11
1	3.6	3.6	CH2Cl2	0.1	rt	10 min	27.5 h	0.7	0.4
2	7.1	3.6	CH2Cl2	0.1	rt	15 min	48 h	8	11
3	7.5	7.0	CH2Cl2	0.1	rt	25 min	120 h	4	3
4	3.6	3.6	MeCN	0.1	rt	30 min	96 h	2	2
5	3.8	3.6	CHCl3	0.1	rt	20 min	60 h	not obtained
6	7.1	3.6	DMF	0.1	rt	15 h	41 h	4	2
7	6.3	3.6	NMP	0.1	40 °C	20 min	26 h	4	5
8	5.9	3.6	THF	0.05	reflux	10 min	19 h	9	14
9	7.1	3.6	NMP	0.1	60 °C	30 min	18 h	16	14
10a	7.1	3.6	NMP	0.1	80 °C	1.5 h	1 h	24	19
	3.1	3.5
11b		3.7	NMP	0.1	100 °C	11 h		not obtained
12	7.2	7.1	NMP	0.07	rt	10 min	13 h	6	3
13	7.1	3.6	NMP	0.3	80 °C	4 h	2 h	35	38
14	7.1	3.6	NMP	0.5	80 °C	4 h	2.5 h	30	35

^a(R,R)-8 and MNBA were added to the reaction mixtures in two batches.

^bThe reaction was performed at 100 °C from the reaction to form the mixed anhydride in the first step.

Fac-10 and fac-14 were synthesized from fac-4 and fac-13 (Chart 2), respectively, by using MNBA and 2-fluoro-6-(trifluoromethyl)benzoic anhydride (FTFBA) (Chart 3 and Table 2). In both cases, better chemical yields were obtained when FTFBA was used in daylight (Table 2, entries 3 and 6 vs entries 1, 2, and 4). In the synthesis of fac-14 using MNBA as a condensation reagent, the mixed anhydride intermediate was observed to decompose under daylight conditions (entries 4 and 5 in Table 2), possibly due to the decomposition of the anhydride intermediates, whose nitro groups may absorb UV–visible light. Fortunately, the use of FTFBA under daylight conditions afforded fac-14 in moderate chemical yield (Table 2, entry 6).

Table 2. Syntheses of fac-10 and fac-14 from fac-4 and fac-13, Respectively.

				time		products
entry	substrate	condensation reagent	temp	Xa	Xb
1	fac-4	MNBA	80 °C	2.5 h	2 h	Λ-fac-10 (15%)	Δ-fac-10 (16%)
2	fac-4	FTFBA	rt	15 min	5 h	Λ-fac-10 (16%)	Δ-fac-10 (14%)
3	fac-4	FTFBA	80 °C	2.5 h	3 h	Λ-fac-10 (23%)	Δ-fac-10 (20%)
4a	fac-13	MNBA		1 day		not obtained
5b	fac-13	MNBA	80 °C	30 min	3 h	Λ-fac-14 (19%)	Δ-fac-14 (23%)
6	fac-13	FTFBA	80 °C	2 h	2.5 h	Λ-fac-14 (9%)	Δ-fac-14 (10%)

^aMixed anhydride intermediate was decomposed.

^bThe reaction was performed under dark conditions.

X-ray Crystal Structures of Δ-fac-9, Δ-fac-11, and Λ-fac-11

The absolute configurations of Δ-fac-9, Δ-fac-11, and Λ-fac-11 were determined by X-ray single-crystal structure analysis of the yellow crystals obtained by recrystallization from hexanes/CHCl₃ as shown in Figure 1 (typical parameters of this X-ray crystal structure analysis are given in Table S1 in the Supporting Information). The average N(tpy)–Ir bond lengths for Δ-fac-9, Δ-fac-11, and Λ-fac-11 are 2.12, 2.14, and 2.13 Å, respectively, and the average C(tpy)–Ir bond distances are 2.00, 1.99, and 2.01 Å, respectively (Table S2 in the Supporting Information), which are consistent with other reported values for fac-1, fac-5, and analogues thereof.^8,11,27

Figure 1.

ORTEP drawings of single crystal structures of Δ-fac-9, Δ-fac-11, and Λ-fac-11: (a, b) top and side views of Δ-fac-9 (horizontal conformer), (c, d) top and side views of Δ-fac-11 (horizontal conformer), and (e, f) top and side views of Λ-fac-11 (vertical confomer) with thermal ellipsoids (50% probability). For clarity, CHCl₃ and hexane included in the crystal were omitted.

Figure 1 also shows the difference in the conformations of Δ-fac-9 and -11 and Λ-fac-11. Namely, the (1R,2R)-1,2-DAH groups and (1R,2R)-2-ACH groups in Δ-fac-9 and -11 are extended horizontally with respect to the central Ir(III) cores, as indicated by the plain arrows in Figure 1b,d (horizontal conformer). In contrast, the three (1R,2R)-2-ACH groups in Λ-fac-11 are oriented vertically (slightly directed toward the pyridine rings of the Ir(III) cores) with respect to the Ir(tpy)₃ core (vertical conformer), as indicated with dashed arrows in Figure 1f. It is likely that this difference is due to the relationship between the stereochemistry of the Ir(tpy)₃ core (Δ- or Λ-form) and the (1R,2R)-1,2-DAH or (1R,2R)-2-ACH units.

We performed DFT calculations on Δ-fac-9, Λ-fac-9, Δ-fac-11, and Λ-fac-11 in an attempt to predict the most stable structures. It should be mentioned that the calculations were initiated from different conformers of these complexes from the structures found in the X-ray crystal structure analysis (actually, initiated from conformers in which their (1R,2R)-1,2-DAH or (1R,2R)-2-ACH units are located between those in “horizontal conformers” and “vertical conformers”). The result of DFT calculations presented in Figure S1 in the Supporting Information indicates that the (1R,2R)-1,2-DAH or (1R,2R)-2-ACH units in Δ-fac-9 and Δ-fac-11 are extended horizontally, as indicated by the plain arrows in Figure S1a,b,e,f in the Supporting Information. In contrast, (1R,2R)-1,2-DAH and (1R,2R)-2-ACH units in Λ-fac-9 (crystal structure was not obtained) and Λ-fac-11 are oriented vertically, as indicated with the dashed arrows in Figure S1c,d,g,h in the Supporting Information. These estimated structures are similar to the aforementioned X-ray crystal structures displayed in Figure 1. The estimated energy levels of the HOMO and LUMO of Δ- and Λ-fac-9 and -11 are summarized in Figure S2 in the Supporting Information as well as that of fac-5.¹¹ It was found that these energies are almost the same regardless of the direction of the chiral units. The Gibbs free energies of these most stable structures were found to be almost same between the Δ- and Λ-forms (Figure S3 in the Supporting Information). It is likely that different conformations between Δ-fac-11 (Figure 1c,d) (and Δ-fac-9 (Figure 1a,b)) and Λ-fac-11 (Figure 1e,f) is due to the packing effect in the crystals, while findings and applications of some different reactivities between these diastereomers in specific solvents might be our next work.²⁸

HPLC Analysis of Diastereomeric Amides and Esters

Figure 2a,b shows typical HPLC chromatograms for fac-9 and fac-11 by normal-phase HPLC before (top) and after (middle and bottom) their separation by HPLC (normal phase) and silica gel column chromatography, respectively. Figure 2c,d shows the normal-phase (nonchiral) HPLC chromatograms for a mixture of 10 and 14 (top) and their Δ- and Λ-forms (middle and bottom, respectively) after the isolation, which confirm the purity of these diastereomers.

Figure 2.

HPLC (normal-phase) chromatograms of diastereomeric amides and esters on SenshuPak PEGASIL Silica SP100 (achiral column). (a) HPLC chromatograms of a diastereomeric mixture of fac-9 (top), Δ-fac-9 (middle), and Λ-fac-9 (bottom). Eluent: CHCl₃/MeCN = 1/2, flow rate 1.0 mL/min, UV detection at 254 nm. (b) HPLC chromatograms of Δ-fac-11 (middle) and Λ-fac-11 (bottom). Eluent: hexanes/CHCl₃ = 1/5, flow rate 1.0 mL/min, UV detection at 254 nm. (c) HPLC chromatograms of a diastereomeric mixture of fac-10 (top), Δ-fac-10 (middle), and Λ-fac-10 (bottom). Eluent: CHCl₃ only, flow rate 1.0 mL/min, UV detection at 254 nm. (d) HPLC chromatograms of a diastereomeric mixture of fac-14 (top), Δ-fac-14 (middle), and Λ-fac-14 (bottom). Eluent: hexanes/CHCl₃ = 1/2, flow rate 1.0 mL/min, UV detection at 254 nm.

¹H NMR Spectra of Each Diastereomer

¹H NMR spectra (aromatic region) of each diastereomer of fac-9 and fac-11 in CDCl₃ are shown in Figure 3. The chemical shifts of the aromatic protons are slightly different between those of Δ-fac-9 and Λ-fac-9. In addition, a larger difference in chemical shift was observed for Δ-fac-11 and Λ-fac-11 than for Δ-fac-9 and Λ-fac-9. It is likely that these phenomena are due to different interactions between the optically pure Ir(III) complex core and the chiral side chains, as was observed in their X-ray crystal structures (Figure 1) and DFT calculations (Figure S1 in the Supporting Information).²⁹ A significant upfield or downfield shift of aliphatic proton signals of (1R,2R)-1,2-DAH and (1R,2R)-2-ACH units in the corresponding diastereomers (Δ-fac-9 vs Λ-fac-9 and Δ-fac-11 vs Λ-fac-11) was not observed.

Figure 3.

¹H NMR spectra (400 MHz in CDCl₃) of a diastereomeric mixture (a), Δ-form (b), and Λ-form (c) of fac-9 and a diastereomeric mixture (d), Δ-form (e), and Λ-form (f) of fac-11 (aromatic region).

Hydrolysis Reaction of Diastereomeric Esters

The hydrolysis of fac-10, -11, and -14 was conducted using NaOH in MeOH/H₂O (4/1) (Chart 2), and the resulting products were analyzed by HPLC using CHIRALCEL OJ-H. Only a single peak was observed in the cases of Δ- and Λ-fac-4, -6, and -13 after the hydrolysis, respectively, as presented in Figure S4 in the Supporting Information, indicating that the purity of the Ir(III) complex was >99% ee and that negligible isomerization occurred during the hydrolysis.

Photophysical Properties of Each Diastereomer and Enantiomer of Ir(III) Complexes

UV/vis absorption and luminescent spectra of all diastereomers of fac-4, fac-6, fac-9, fac-10, fac-11, fac-13, and fac-14 in degassed DMSO at 25 °C are shown in Figure 4, and their photophysical data are summarized in Table 3. The UV/vis absorption at ca. 280 nm of fac-6, fac-9, fac-11, and fac-14 was assigned to the ¹π–π* transition of the tpy ligands, and that at ca. 360 nm was assigned to a spin-allowed singlet-to-singlet metal-to-ligand charge transfer (¹MLCT) transition, a spin-forbidden singlet-to-triplet (³MLCT) transition, and ³π–π* transitions, as were those of the corresponding racemic compounds. In the emission spectra of fac-9 and fac-11, a green emission was observed with an emission maximum at ca. 490–500 nm. Their quantum yields were determined based on the Φ value of fac-5 in CH₂Cl₂ (Φ = 0.5), which was used as a standard reference.^1d Both diastereomers of fac-9 and fac-11 were found to exhibit nearly the same UV/vis absorption and emission spectra in DMSO. Typical photophysical parameters of the carboxylates, Δ- and Λ-forms of fac-4, fac-6, and fac-13, are given in Table S3 of the Supporting Information.

Figure 4.

UV/vis absorption spectra and emission spectra of all diastereomers of (a) fac-9, (b) fac-11, (c) fac-6, (d) fac-10, (e) fac-4, (f) fac-14, and (g) fac-13 (10 μM) in degassed DMSO at 298 K (excitation at 366 nm, au = arbitrary units). Blue dashed curves: UV/vis absorption spectra of Δ-forms. Red dashed curves: UV/vis absorption spectra of Λ-forms. Blue plain curves: emission spectra of Δ-forms. Red plain curves: emission spectra of Λ-forms.

Table 3. Photophysical Properties of fac-9, fac-10, fac-11, and fac-14 in Degassed DMSO at 298 K ([compound] = 10 μM).

compound	λabs (nm) (ε (M–1 cm–1))	λem (nm)a	Φa	τ (μs)
Δ-fac-9	287 (7.6 × 104), 366 (1.5 × 104)	502	0.39b	1.37d
Λ-fac-9	287 (7.6 × 104), 362 (1.3 × 104)	502	0.40b	1.39d
Δ-fac-10	283 (4.6 × 104), 322 (2.2 × 104)	488	0.60b	1.23d
Λ-fac-10	284 (4.0 × 104), 322 (2.1 × 104)	488	0.62b	1.21d
Δ-fac-11	285 (6.9 × 104)	488	0.43b	1.27d
Λ-fac-11	287 (6.2 × 104)	490	0.40b	1.29d
Δ-fac-14	319 (4.3 × 104), 397 (1.3 × 104)	587	0.39c	2.45e
Λ-fac-14	317 (4.0 × 104), 395 (1.2 × 104)	589	0.29c	2.32e

^aExcitation at 366 nm.

^bQuinine sulfate in 0.1 M H₂SO₄ (Φ = 0.55) was used as a reference.

^cfac-Ir(mpiq)₃ in toluene (Φ = 0.26) was used as a reference.

^dA 475 nm long wave pass filter was used.

^eA 550 nm long wave pass filter was used.

Circular Dichroism (CD) Spectra of Each Diastereomer and Enantiomer of Ir(III) Complexes

CD spectra of fac-4, -6, -9, -10, -11, -13, and 14 in DMSO at 25 °C are shown in Figure 5, in which symmetrical spectra were obtained for all compounds. Positive and negative Cotton effects were observed at ca. 300 nm for the Λ- and Δ-forms, respectively, in the CD spectra of fac-4, -6, -9, -10, and -11, and positive and negative Cotton effects were observed at ca. 350 nm in CD spectra of Λ- and Δ-fac-13 and -14, respectively. These results are similar to the previously reported CD spectrum of optically active fac-1 that had been separated using chiral columns.¹⁸ It should be noted that the CD and CPL spectra (described in the next section) of two diastereomers of fac-9 and fac-11 were observed as mirror images (Figures 5 and 6), although Δ- and Λ-forms of 9 and 11 are diastereomers, respectively, suggesting a weak effect of chiral auxiliaries such as (R,R)-1,2-DAH and (R,R)-1-ACH on their CD and CPL spectra.

Figure 5.

CD spectra of (a) fac-9, (b) fac-11, (c) fac-6, (d) fac-10, (e) fac-4, (f) fac-14, and (g) fac-13 (10 μM) in DMSO at 298 K. Blue curves: Δ-forms. Red curves: Λ-forms.

Figure 6.

CPL spectra of (a) fac-9 and (b) fac-11 (100 μM) in DMSO (excitation at 288 nm for fac-9 and at 286 nm for fac-11) at 298 K. Blue curves: Δ-forms. Red curves: Λ-forms.

Circularly Polarized Luminescence (CPL) Spectra of fac-9 and fac-11

Circularly polarized luminescence (CPL) spectra of Δ- and Λ-forms of fac-9 (excitation at 288 nm) and 11 (excitation at 286 nm) are shown in Figure 6. Positive and negative CPL signals were observed at ca. 503 nm for Λ- and Δ-fac-9 (g_CPL = 2.0 × 10^–3 and −2.0 × 10^–3). Similarly, positive and negative CPL signals were observed at ca. 485 nm for Λ- and Δ-fac-11 (g_CPL = 1.7 × 10^–3 and −1.4 × 10^–3). The CPL signals and g_CPL values for various Ir(III) complexes have been reported, and it is known that the CPL signal varies depending on the structure of the ligand.^17,21,30 Zuo’s group reported the g_CPL values of some Ir(III) complexes (g_CPL = 3.15 × 10^–3 for Δ-fac-1, −3.29 × 10^–3 for Λ-fac-1, 0.915 × 10^–3 for Δ-fac-2, −1.33 × 10^–3 for Λ-fac-2, 1.22 × 10^–3 for Δ-fac-3, −1.66 × 10^–3 for Λ-fac-3).²¹ Bernhard’s group reported that the g_CPL values of Λ-fac-2 is 0.78 × 10^–3 at 525 nm (excitation at 400 nm),¹⁷ implying that the order (digits) of these g_CPL values are similar to those of the g_CPL values for Λ- and Δ-forms of fac-9 and 11. In addition, the Δ-forms of fac-9 and -11 exhibit negative signals and the Λ-forms exhibit positive signals, respectively, which are similar to the spectral data reported by Bernhard’s group.¹⁷ The CPL spectra of the Δ- and Λ-forms of fac-4 and fac-6 are shown in Figure S5 in the Supporting Information.

Stability of Each Diastereomer against Light and Heat and in the Presence of Silica Gel

The stabilities of the separated diastereomers (fac-9 and 11) to heat, light, and silica gel were evaluated (Chart 4). Solutions of each of the Ir(III) complexes (1 mM) in toluene³¹ were subjected to the given reaction conditions and then analyzed using normal-phase HPLC (SenshuPak PEGASIL Silica SP100, eluent CHCl₃/MeCN = 1/2 for fac-9, hexanes/CHCl₃ = 1/5 for fac-11, flow rate 1.0 mL/min, wavelength 254 nm). To evaluate the photostability of Δ- and Λ-fac-9 and -fac-11, each solution in toluene was irradiated with light at a wavelength of 365 nm by using Twinlight (RELYON, Japan) at room temperature. Negligible decomposition and racemization were observed after the photoirradiation of these complexes for 1 h, while irradiation for a longer time induced their decomposition to some extent (observed on their emission spectra) rather than epimerization.²⁸ The stability of fac-9 and -11 in toluene at 100 °C was confirmed by heating solutions of each Ir(III) complex for 3 h. In addition, negligible epimerization of Δ- and Λ-forms of fac-9 and -11 was observed when these complexes were treated with silica gel in toluene at room temperature for 1–3 h, implying negligible epimerization during the purification with silica gel chromatography and on HPLC.

Chart 4. Stability Evaluation of fac-9 and fac-11 upon Photoirradiation, Heating, and Treatment with Silica Gel.

Conclusion

In summary, we report on the successful optical resolution of carboxylate derivatives of cyclometalated Ir(III) complexes via diastereomers that were formed by conjugation with chiral auxiliaries such as (1R,2R)-1,2-diaminocyclohexane ((1R,2R)-1,2-DAH) and (1R,2R)-2-aminocyclohexanol ((1R,2R)-2-ACH) groups. The racemic Ir(III) complexes fac-4, -6, and -13 were converted to the corresponding diastereomers by condensation of (1R,2R)-1,2-DAH and (1R,2R)-2-ACH and successfully separated by silica gel column chromatography or normal-phase and nonchiral HPLC, not by the use of chiral HPLC columns. The absolute configurations of all of the Ir(III) complexes were determined from an X-ray single crystal structure analysis and CD spectra of fac-9, -10, -11, and -14. It should be noted that both diastereomers (both enantiomers with respect to the Ir(III) complex core) were obtained on a large scale. In addition, spectroscopic measurements of the synthesized diastereomeric Ir(III) complexes were also performed. Moreover, the hydrolysis of the diastereomeric esters was carried out and the resulting carboxylic acid derivative was found to be optically pure by an analysis using chiral HPLC columns. The synthesis and evaluation of anticancer activity of stereochemically pure Ir(III) complex-peptide hybrids are now in progress in our research group.

It is well-known that tris-homoleptic cyclometalated Ir(III) complexes such as Ir(tpy)₃ complexes adopt facial (fac) forms and meridional (mer) forms and that fac-forms are generally more stable than mer-forms.^1c,1d In this study, we have focused on the optical resolution of the carboxylates of fac-Ir(tpy)₃, fac-Ir(ppy)₃, and fac-Ir(mpiq)₃, which are readily accessible and important intermediates for many purposes as described in our previous publications, to demonstrate our methods.⁷⁻¹¹ Our next work will be the optical resolution of mer-Ir complexes and the related derivatives. The results presented herein provide useful information for the future design and synthesis of optically active Ir(III) complexes and their applications as biological reagents, medicinal chemistry, photocatalysts, and related fields.^5,32

Experimental Procudures

General Information

All reagents and solvents were of the highest commercial quality and were used without further purification unless otherwise noted. Anhydrous N,N-dimethylformamide (DMF), N-methyl-pyrrolidone (NMP), and CH₂Cl₂ were obtained by distillation from calcium hydride. Anhydrous MeCN was obtained by distillation from phosphorus(V) oxide. Anhydrous THF was obtained by distillation from sodium and benzophenone. All aqueous solutions were prepared with deionized water. IrCl₃·3H₂O was purchased from KANTO CHEMICAL Co. Melting points were measured on a Yanaco micro melting point apparatus. ¹H (300 and 400 MHz) and ¹³C (100 and 150 MHz) NMR spectra were recorded on a JEOL Always 300 (JEOL, Tokyo, Japan), a JNM-ECZ400S (JEOL), and Bruker AVANCE600 spectrometers. Tetramethylsilane (TMS) was used as an internal reference for the ¹H NMR and ¹³C NMR spectroscopy measurements of samples in CDCl₃, DMSO-d₆, and CD₃OD. IR spectra were recorded on a PerkinElmer FTIR Spectrum 100 (ATR) instrument (PerkinElmer, Massachusetts, USA). Electrospray ionization (ESI) mass spectra were recorded on a Sciex X500R QTOF (AB SCIEX, Framingham, Massachusetts, USA) and Varian 910-MS (Varian Medical Systems, California, USA) spectrometers. Elemental analyses were performed on a PerkinElmer CHN 2400 analyzer (PerkinElmer). Optical rotations were determined with a JASCO P-1030 digital polarimeter (JASCO, Tokyo, Japan) in 50 mm cells using the D line of sodium (589 nm). Thin-layer (TLC) and silica gel column chromatographies were performed using a Merck Art. 5554 (silica gel) TLC plate and Fuji Silysia Chemical FL-100D, respectively. Commercially available DMSO and CH₂Cl₂ (spectrophotometric grade, FUJIFILM WAKO PURE CHEMICAL Co.) were used for the measurement of photophysical data. Photoisomerization experiments were performed with a Twin LED Light (RELYON, Tokyo, Japan) equipped with 365 nm light sources. UV/vis spectra were recorded on a JASCO V-630 spectrometer, and emission spectra were recorded on a JASCO FP-8300 spectrofluorometer. CD spectra were recorded on a Chirascan (Applied Photophysics) spectrophotometer, and CPL spectra were obtained using a JASCO CPL-300 spectrofluoropolarimeter. Gel permeation chromatography (GPC) experiments were carried out using a system (LabACE LC-5060) equipped with a UV detector (Japan Analytical Industry Co., Ltd.) and a gel permeation column (JAIGEL-2HR). Normal-phase HPLC experiments were carried out using a system consisting of a PU-980 intelligent HPLC pump (JASCO, Japan), a UV-970 intelligent UV–visible detector (JASCO), a Rheodine injector (Model No. 7125), and a Chromatopac C-R6A (Shimadzu, Japan). For analytical HPLC, a Senshupak Pegasil silica SP100 column (Senshu scientific Co., Ltd.) (4.6ϕ × 250 mm, No. 2103193S) and a CHIRALCEL OJ-H column (DAICEL CHEMICAL INDUSTRIES, Ltd.) (4.6ϕ × 250 mm, No. OJH0CE-OL015) were used. For preparative HPLC, a Senshu Pak Pegasil Silica SP100 column (Senshu scientific Co., Ltd.) (10ϕ × 250 mm, No. 2104062S) was used.

Synthesis.²⁹

Δ-fac-9 and Λ-fac-9

PyBOP (176 mg, 0.338 mmol) was added to a solution of racemic fac-6^8a (82 mg, 0.098 mmol) and DIEA (101 μL, 0.580 mmol) in DMF (2 mL), and the reaction mixture was stirred at room temperature for 2 h. To the reaction mixture was added a mono-Boc-protected (1R,2R)-1,2-diaminocyclohexane ((R,R)-7)²³ (69 mg, 0.324 mmol), and the reaction mixture was stirred at room temperature for 20 h. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl₃/MeOH = 10:1) and GPC (CHCl₃) to afford a diastereomeric mixture of fac-9 as a yellow solid (154 mg, quant.). Fac-9 was separated by normal-phase HPLC (CHCl₃/MeCN = 1/2, flow rate 3.0 mL/min, t_r (retention time) = 13.2 min (Δ-fac-9), 20.7 min (Λ-fac-9)), and the solvent was removed under reduced pressure to afford Δ-fac-9 (46 mg, 33% yield) and Λ-fac-9 (51 mg, 36% yield) as yellow solids, respectively. Δ-fac-9: mp >300 °C. IR (ATR): ν 3319, 2930, 2858, 1690, 1635, 1600, 1505, 1472, 1425, 1389, 1365, 1317, 1255, 1162, 1069, 1012, 908, 869, 778, 750, 521, 454, 441, 429, 420. 410 cm^–1. ¹H NMR (400 MHz, CDCl₃/TMS): δ 7.96 (d, J = 8.4 Hz, 3H), 7.74 (s, 3H), 7.61 (dt, J = 7.8, 1.6 Hz, 3H), 7.39 (d, J = 5.2 Hz, 3H), 6.85 (t, J = 6.0 Hz, 3H), 6.62 (s, 3H), 6.15 (d, J = 8.8 Hz, 3H), 4.96 (d, 8.4 Hz, 3H), 3.88–3.83 (m, 3H), 3.45–3.40 (m, 3H), 2.25 (s, 9H), 2.13–2.05 (m, 6H), 1.77 (m, 6H), 1.39–1.26 (m, 39H) ppm. ¹³C NMR (100 MHz, CDCl₃/TMS): δ 171.4, 165.8, 164.8, 156.6, 146.9, 141.4, 139.7, 137.8, 136.3, 127.6, 122.7, 121.9, 119.0, 79.5, 54.9, 53.7, 33.1, 32.8, 28.4, 25.0, 24.9, 20.7 ppm. ESI-MS (m/z): calcd for C₇₂H₉₁N₉O₉¹⁹¹Ir [M + H]⁺ 1416.6540; found 1416.6540. Anal. Calcd for C₇₂H₉₀N₉O₉Ir·0.8hexane·0.5CHCl₃·1.5MeCN: C, 59.43; H, 6.59; N, 9.05%. Found: C, 59.46; H, 6.52; N, 9.12%. Λ-fac-9: mp >300 °C. IR (ATR): ν 3318, 2929, 2857, 1691, 1634, 1600, 1505, 1471, 1425, 1389, 1364, 1318, 1255, 1161, 1068, 1012, 933, 908, 779, 749, 515, 464, 440, 422, 416 cm^–1. ¹H NMR (400 MHz, CDCl₃/TMS): δ 7.90 (d, J = 8.4 Hz, 3H), 7.71 (s, 3H), 7.60 (t, J = 7.6 Hz, 3H), 7.35 (d, J = 5.6 Hz, 3H), 6.82 (t, J = 6.4 Hz, 3H), 6.69 (s, 3H), 6.13 (d, J = 8.4 Hz, 3H), 4.98 (d, J = 8.8 Hz, 3H), 3.87–3.86 (m, 3H), 3.42–3.40 (m, 3H), 2.25 (s, 9H), 2.17–2.14 (m, 3H), 2.08–2.06 (m, 3H), 1.78–1.76 (m, 6H), 1.39–1.27 (m, 39H) ppm. ¹³C NMR (100 MHz, CDCl₃/TMS): δ 171.7, 165.7, 164.6, 156.5, 146.9, 141.5, 139.5, 137.2, 136.2, 128.0, 122.8, 121.8, 118.9, 79.3, 54.9, 53.8, 33.1, 32.8, 28.3, 25.0, 24.8, 20.6 ppm. ESI-MS (m/z): calcd for C₇₂H₉₀N₉O₉¹⁹¹Ir [M + H]⁺ 1416.6540; found 1416.6545. Anal. Calcd for C₇₂H₉₀N₉O₉Ir·0.8hexane·0.5CHCl₃·1.5MeCN: C, 59.43; H, 6.59; N, 9.05%. Found: C, 59.47; H, 6.48; N, 9.25%.

Δ-fac-10 and Λ-fac-10

FTFBA (55 mg, 0.139 mmol) was added to a solution of racemic fac-4^8a (30 mg, 0.037 mmol) and DIEA (47 μL, 0.267 mmol) in NMP (130 μL), and the reaction mixture was stirred at room temperature for 2.5 h. To the reaction mixture were added Boc-protected (1R,2R)-2-aminocyclohexanol ((R,R)-8)²⁴ (62 mg, 0.277 mmol) and DMAP (2.4 mg, 0.020 mmol), and the reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was diluted with CHCl₃ and washed with a saturated aqueous solution of NH₄Cl and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexanes/CHCl₃ = 1:1 to 1:2) and GPC (CHCl₃) to afford a diastereomeric mixture of fac-10 as a yellow solid (24 mg, 47% yield). fac-10 was separated by preparative normal-phase HPLC (CHCl₃ only, t_r = 21.5 min (Δ-fac-10), 23.5 min (Λ-fac-10), 3.0 mL/min), and solvent was removed under reduced pressure to afford Δ-fac-10 (10 mg, 20% yield) and Λ-fac-10 (12 mg, 23% yield) as yellow solids, respectively. Δ-fac-10: mp 248 °C. IR (ATR): ν 3311, 2928, 2857, 1699, 1677, 1588, 1531, 1476, 1452, 1426, 1364, 1320, 1302, 1243, 1158, 1111, 1063, 1028, 998, 913, 865, 842, 787, 762, 724, 641, 494, 418 cm^–1. ¹H NMR (400 MHz, CDCl₃/TMS): δ 8.41 (s, 3H), 8.15 (d, J = 8.4 Hz, 3H), 7.69 (dt, J = 7.8, 1.6 Hz, 3H), 7.51 (d, J = 4.8 Hz, 3H), 7.40 (dd, J = 7.8, 1.4 Hz, 3H), 6.95 (dt, J = 6.6, 1.2 Hz, 3H), 6.81 (d, J = 8.0 Hz, 3H), 4.77–4.73 (m, 3H), 4.55 (d, J = 9.2 Hz, 3H), 3.75–3.73 (m, 3H), 2.09 (d, J = 12.4 Hz, 6H), 1.76–1.73 (m, 6H), 1.53–1.26 (m, 21H), 1.19, (s, 27H) ppm. ¹³C NMR (100 MHz, CDCl₃/TMS): δ 170.2, 167.9, 165.5, 155.6, 146.9, 144.1, 136.9, 136.8, 130.5, 125.4, 122.6, 122.3, 119.8, 79.2, 75.6, 53.5, 32.3, 31.2, 28.2, 24.6, 24.1 ppm. ESI-MS (m/z): calcd for C₆₉H₈₅N₇O₁₂¹⁹¹Ir [M + NH₄]⁺ 1394.5857; found 1394.5875. Anal. Calcd for C₆₉H₈₁N₆O₁₂Ir·0.86hexane·0.29CHCl₃: C, 60.12; H, 6.32; N, 5.65%. Found: C, 60.40; H, 6.02; N, 5.35%. Λ-fac-10: mp 207 °C. IR (ATR): ν 3355, 2929, 2859, 1687, 1587, 1561, 1504, 1476, 1452, 1412, 1390, 1364, 1321, 1302, 1234, 1160, 1111, 1061, 1028, 998, 953, 911, 867, 844, 787, 759, 724, 665, 641, 493, 432, 417 cm^–1. ¹H NMR (400 MHz, CDCl₃/TMS): δ 8.37 (s, 3H), 8.11 (d, J = 8.4 Hz, 3H), 7.69 (dt, J = 8.0, 1.6 Hz, 3H), 7.46–7.42 (m, 6H), 6.92 (t, J = 6.0 Hz, 3H), 6.89 (d, J = 7.6 Hz, 3H), 4.75–4.73 (m, 3H), 4.55 (d, J = 9.6 Hz, 3H), 3.73–3.72 (m, 3H), 2.10 (d, J = 12.4 Hz, 6H), 1.77–1.72 (m, 6H), 1.53–1.48 (m, 6H), 1.36 (t, J = 10.4 Hz, 6H), 1.23 (s, 27H) ppm. ¹³C NMR (100 MHz, CDCl₃/TMS): δ 170.2, 168.0, 165.5, 155.5, 146.8, 144.0, 137.0, 136.8, 130.7, 125.3, 122.5, 122.4, 119.7, 79.0, 75.4, 53.6, 32.4, 31.2, 28.2, 24.6, 24.1 ppm. ESI-MS (m/z): calcd for C₆₉H₈₅N₇O₁₂¹⁹¹Ir [M + NH₄]⁺ 1394.5857; found 1394.5862.

Δ-fac-11 and Λ-fac-11

MNBA (374 mg, 1.087 mmol) was added to a solution of racemic fac-6 (249 mg, 0.300 mmol) and DIEA (368 μL, 2.113 mmol) in NMP (1 mL), and the reaction mixture was stirred at room temperature for 4 h. To the reaction mixture were added Boc-protected (1R,2R)-2-aminocyclohexanol ((R,R)-8) (472 mg, 2.122 mmol) and DMAP (11 mg, 0.090 mmol), and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with CHCl₃ and washed with a saturated aqueous solution of NH₄Cl and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexanes/CHCl₃ = 1/0 to 1/1) to afford Δ-fac-11 (324 mg, a mixture of Δ-fac-11 and (R,R)-8) and Λ-fac-11 (150 mg, 35% yield) as yellow solids, respectively. The mixture of Δ-fac-11 and (R,R)-14 was reprecipitated from hexanes/CHCl₃ to afford Δ-fac-11 (161 mg, 38% yield) as a yellow solid. Δ-fac-11: mp 220 °C (dec.). IR (ATR): ν 3313, 2929, 2858, 1698, 1677, 1584, 1526, 1473, 1452, 1424, 1380, 1364, 1318, 1294, 1271, 1229, 1197, 1157, 1087, 998, 910, 883, 867, 851, 777, 754, 723, 699, 658, 630, 524, 501, 489, 441, 425, 406 cm^–1. ¹H NMR (400 MHz, CDCl₃/TMS): δ 8.46 (s, 3H), 8.19 (d, J = 8.0 Hz, 3H), 7.66 (td, J = 7.8, 1.2 Hz, 3H), 7.44 (d, J = 5.19, 3H), 6.88 (t, J = 6.2 Hz, 3H), 6.62 (s, 3H), 4.73 (td, J = 10.2, 3.7 Hz, 3H), 4.53 (d, J = 9.6 Hz, 3H), 3.82–3.80 (m, 3H), 2.36 (s, 9H), 2.09 (m, 6H), 1.77 (m, 6H), 1.39–1.27 (m, 12H), 1.18 (s, 27H) ppm. ¹³C NMR (100 MHz, CDCl₃/TMS): δ 169.3, 168.1, 165.6, 155.8, 146.7, 142.3, 141.8, 140.1, 136.5, 127.1, 122.2, 120.7, 119.8, 79.3, 75.3, 53.4, 32.6, 31.4, 28.3, 24.8, 24.2, 22.4 ppm. ESI-MS (m/z): calcd for C₇₂H₉₁N₇O₁₂¹⁹¹Ir [M + NH₄]⁺ 1436.6326; found 1436.6329. Anal. Calcd for C₇₂H₈₇N₆O₁₂Ir·0.2CHCl₃·MeCN: C, 59.99; H, 6.12; N, 6.60%. Found: C, 59.80; H, 6.08; N, 6.53%. Λ-fac-11: mp 195 °C (dec). IR (ATR): ν 3356, 2932, 2860, 1703, 1584, 1561, 1510, 1473, 1451, 1390, 1365, 1318, 1293, 1230, 1195, 1168, 1082, 997, 911, 850, 777, 749, 722, 523, 494, 458, 443, 433 cm^–1. ¹H NMR (400 MHz, CDCl₃/TMS): δ 8.34 (s, 3H), 8.09 (d, J = 8.4 Hz, 3H), 7.65 (td, J = 7.8, 1.6 Hz, 3H), 7.31 (d, J = 5.6 Hz, 3H), 6.84 (t, J = 6.4 Hz, 3H), 6.75 (s, 3H), 4.78 (td, J = 10.6, 3.9 Hz, 3H), 4.60 (d, J = 8.4 Hz, 3H), 3.75–3.73 (m, 3H), 2.39 (s, 9H), 2.13 (t, J = 16.0 Hz, 6H), 1.80–1.70 (m, 6H), 1.42–1.27 (m, 12H), 1.20 (s, 27H) ppm. ¹³C NMR (100 MHz, CDCl₃/TMS): δ 169.0, 168.6, 165.6, 155.6, 146.6, 142.1, 141.8, 140.3, 136.5, 126.7, 121.9, 121.1, 120.0, 78.9, 74.8, 53.8, 32.7, 31.5, 28.3, 24.6, 24.2, 22.4 ppm. ESI-MS (m/z): calcd for C₇₂H₈₇N₆O₁₂¹⁹¹Ir [M]⁺ 1418.5982; found 1418.5995. Anal. Calcd for C₇₂H₈₇N₆O₁₂Ir·0.2CHCl₃: C, 60.03; H, 6.08; N, 5.82%. Found: C, 59.80; H, 6.15; N, 6.08%.

Racemic fac-13

Phosphorus oxychloride (830 μL) was added dropwise to DMF (8.3 mL), and the resulting mixture was stirred at 0 °C for 1 h, to which fac-12^8d (245 mg, 0.289 mmol) was then added to produce a yellow solution. After stirring at 80 °C for 21 h, the deep red reaction mixture was allowed to cool at 0 °C, and the pH was adjusted to 11 by adding 3 N aqueous NaOH. The red solid was isolated by filtration and washed with H₂O. The resulting residue was diluted with CHCl₃ and dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The formylated compound (fac-tris[1-(5′-formyl-4’methylphenyl)isoquinoline]iridium(III) (Ir(mpiq-CHO)₃) was obtained as an orange powder by reprecipitation from hexanes/CHCl₃ (258 mg, 96% yield). Mp: 275 °C (dec). IR (ATR): ν 2162, 1669, 1566, 1500, 1434, 1390, 1348, 1281, 1216, 1145, 1088, 1018, 927, 814, 739, 722, 679, 656, 631, 578, 558, 518, 460, 450, 421 cm^–1. ¹H NMR (400 MHz, CDCl₃/TMS): δ 10.20 (s, 3H), 8.98 (d, J = 8.0 Hz, 3H), 8.62 (s, 3H), 7.81–7.71 (m, 9H), 7.32 (d, J = 6.0 Hz, 3H), 7.23 (d, J = 6.4 Hz, 3H), 6.85 (s, 3H), 2.45 (s, 9H) ppm. ¹³C NMR (100 MHz, CDCl₃/TMS): δ 192.1, 176.3, 165.8, 144.3, 141.9, 140.1, 139.2, 136.8, 132.2, 130.9, 128.6, 128.0, 127.3, 127.1, 126.5, 121.3, 19.5 ppm. ESI-MS (m/z): calcd for C₅₁H₃₇N₃O₃¹⁹¹Ir [M + H]⁺ 930.2435; found 930.2454.

A mixture of NaClO₂ (740 mg, 8.2 mmol) and NaH₂PO₄·2H₂O (1264 mg, 8.1 mmol) in H₂O (2.5 mL) was added dropwise to a solution of Ir(mpiq-CHO)₃ (258 mg, 0.277 mmol) and 2-methyl-2-butene (853 μL, 8.1 mmol) in DMSO (10 mL) at room temperature. After stirring for 22 h, the pH of the reaction mixture was adjusted to 1 by adding 2 N aqueous HCl. The resulting solid was isolated on a filter and washed with H₂O to afford fac-13 as an orange solid (298 mg, quantitative yield). Mp: 297 °C (dec). IR (ATR): ν 2921, 1697, 1577, 1548, 1519, 1500, 1435, 1347, 1298, 1279, 1235, 1165, 1145, 1088, 1012, 947, 914, 816, 784, 755, 739, 697, 675, 631, 603, 558, 497, 465, 422, 415 cm^–1. ¹H NMR (400 MHz, DMSO-d₆/TMS): δ 8.87 (d, J = 8.0 Hz, 3H), 8.76 (s, 3H), 7.99 (dd, J = 8.0, 1.2 Hz, 3H), 7.90–7.82 (m, 6H), 7.56 (d, J = 6.4 Hz, 3H), 7.41 (d, J = 4.4 Hz, 3H), 6.72 (s, 3H), 2.27 (s, 9H) ppm. ¹³C NMR (100 MHz, DMSO-d₆/TMS): δ 171.0, 168.9, 164.7, 143.3, 140.2, 139.4, 139.2, 136.3, 131.5 131.0, 128.9, 127.7, 125.9, 125.5, 121.5, 121.4, 22.1 ppm. ESI-MS (m/z): calcd for C₅₁H₃₇N₃O₆¹⁹¹Ir [M + H]⁺ 978.2283; found 978.2299. Anal. Calcd for C₅₁H₃₆N₃O₆Ir·0.75CHCl₃·4H₂O: C, 54.49; H, 3.95; N, 3.68%. Found: C, 54.33; H, 3.77; N, 3.50%.

Δ-fac-14 and Λ-fac-14

MNBA (76 mg, 0.221 mmol) was added to a solution of racemic fac-13 (59 mg, 0.060 mmol) and DIEA (76 μL, 0.437 mmol) in NMP (200 μL), and the reaction mixture was stirred at room temperature for 45 min. To the reaction mixture were added (R,R)-8 (97 mg, 0.434 mmol) and DMAP (1.8 mg, 0.015 mmol), and the resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with CHCl₃ and washed with a saturated aqueous solution of NH₄Cl and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexanes/CHCl₃ = 2:1 to 1:3) and GPC (CHCl₃) to afford a diastereomeric mixture of fac-14. fac-14 was separated by normal-phase HPLC (hexanes/CHCl₃ = 1/4, t_r = 19.5 min (Δ-fac-14), 21.0 min (Λ-fac-14), 3.0 mL/min), and solvent was removed under reduced pressure to afford Δ-fac-14 (22 mg, 23% yield) and Λ-fac-14 (18 mg, 19% yield) as red solids, respectively. Δ-fac-14: mp 278 °C. IR (ATR): ν 3378, 2926, 2854, 1693, 1578, 1502, 1452, 1391, 1364, 1317, 1266, 1239, 1202, 1168, 1079, 1028, 992, 911, 869, 815, 775, 753, 741, 707, 676, 633, 604, 507, 418, 406 cm^–1. ¹H NMR (400 MHz, CDCl₃/TMS): δ 9.11 (d, J = 8.8 Hz, 3H), 8.92 (s, 3H), 7.84 (t, J = 7.4 Hz, 3H), 7.76–7.67 (m, 6H), 7.43 (d, J = 5.6 Hz, 3H), 7.16 (d, J = 6.4 Hz, 3H), 6.88 (s, 3H), 4.83 (td, J = 10.0, 4.0 Hz, 3H), 4.66 (d, J = 9.2 Hz, 3H), 3.76–3.75 (m, 3H), 2.37 (s, 9H), 2.12 (d, J = 12.4 Hz, 3H), 2.02 (d, J = 12.0 Hz, 3H), 1.77–1.70 (m, 6H), 1.38–1.30 (m, 3H), 1.25 (s, 9H), 1.18 (s, 27H) ppm. ¹³C NMR (100 MHz, CDCl₃/TMS): δ 172.7, 168.4, 166.0, 155.6, 143.6, 142.0, 140.2, 139.3, 136.7, 132.4, 130.6, 128.5, 126.9, 126.6, 120.7, 79.0, 74.4, 53.8, 32.6, 31.3, 29.7, 28.2, 24.5, 24.2, 22.4, 14.1 ppm. ESI-MS (m/z): calcd for C₈₄H₉₇N₇O₁₂¹⁹¹Ir [M + NH₄]⁺ 1586.6796; found 1586.6797. Λ-fac-14: mp 152 °C. IR (ATR): ν 3361, 2926, 2857, 1697, 1578, 1502, 1451, 1391, 1364, 1348, 1318, 1238, 1203, 1164, 1078, 1027, 991, 914, 868, 814, 776, 754, 739, 709, 676, 633, 601, 451, 416 cm^–1. ¹H NMR (400 MHz, CDCl₃/TMS): δ 9.03 (d, J = 8.4 Hz, 3H), 8.90 (s, 3H), 7.80–7.67 (m, 12H), 7.14 (d, J = 5.6 Hz, 3H), 6.87 (s, 3H), 4.85 (td, J = 10.4, 4.4 Hz, 3H), 4.67 (d, J = 8.4 Hz, 3H), 3.71–3.67 (m, 3H), 2.40 (s, 9H), 2.13–2.10 (m, 6H), 1.78–1.72 (m, 6H), 1.36 (t, J = 9.4 Hz, 3H), 1.25 (s, 9H), 1.07 (s, 27H) ppm. ¹³C NMR (100 MHz, CDCl₃/TMS): δ 172.5, 168.6, 166.3, 155.5, 143.6, 142.0, 140.4, 139.2, 136.7, 132.5, 130.6, 128.2, 127.6, 127.0, 126.5, 120.6, 78.9, 74.2, 54.1 ppm. ESI-MS (m/z): calcd for C₆₉H₈₅N₇O₁₂¹⁹¹Ir [M + NH₄]⁺ 1586.6796; found 1586.6821.

Δ-fac-6

A 5 N solution of NaOH in water (350 μL) was added to a solution of Δ-fac-11 (70 mg, 49 μmol) in MeOH (1.4 mL), and the reaction mixture was stirred at 80 °C for 19 h. After the mixture was cooled to room temperature, the solvent was removed under reduced pressure. After saturated aqueous NaHCO₃ was added, the solution was washed with AcOEt. To the aqueous layer was added a 2 N aqueous solution of HCl to adjust the pH to 1, and the resulting solution was extracted with AcOEt. The combined organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexanes/CHCl₃ = 1/0 to 0/1, AcOEt/MeOH = 1/0 to 10/1) to afford Δ-fac-6 (29 mg, 71% yield, 99% ee) as a yellow solid. Mp: >300 °C. IR (ATR): ν 2926, 1672, 1581, 1560, 1522, 1472, 1419, 1294, 1239, 1157, 1069, 909, 778, 748, 679, 626, 524, 494, 429, 412 cm^–1. ¹H NMR (300 MHz, DMSO-d₆/TMS): δ 8.24 (s, 1H), 8.17 (d, J = 8.4 Hz, 3H), 7.85 (t, J = 7.7 Hz, 3H), 7.43 (d, J = 4.8, 3H), 7.18 (t, J = 6.2, 3H), 6.58 (s, 3H), 1.36 (s, 9H) ppm. ¹³C NMR (100 MHz, DMSO-d₆/TMS): δ 210.1, 189.5, 169.1, 167.8, 164.0, 146.7, 142.2, 139.7, 139.2, 123.2, 121.8, 119.2, 22.2 ppm. ESI-MS (m/z): calcd for C₃₉H₃₁¹⁹¹IrN₃O₆ [M + H]⁺ 828.1813; found 828.1828. Anal. Calcd for C₃₉H₃₀N₃O₆Ir·0.4hexane·0.1CHCl₃: C, 56.95; H, 4.11; N, 4.80%. Found: C, 56.72; H, 4.41; N, 4.56%.

Λ-fac-6

Λ-fac-6 was prepared by using a procedure similar to that for Δ-fac-6. A 5 N NaOH solution in water (350 μL) was added to a solution of Λ-fac-11 (70 mg, 49 μmol) in MeOH (1.4 mL), and the reaction mixture was stirred at 80 °C for 5.5 h. After cooling to room temperature, the solvent was removed under reduced pressure. After addition of saturated aqueous NaHCO₃, the solution was washed with AcOEt. To the aqueous layer was added a 2 N aqueous solution of HCl to adjust the pH to 1, and the resulting solution was extracted with AcOEt. The combined organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexanes/CHCl₃ = 1/0 to 0/1, AcOEt/MeOH = 1/0 to 10/1) to afford Λ-fac-6 (37 mg, 91% yield, >99% ee) as a yellow solid. Mp: >300 °C. IR (ATR): ν 2924, 1667, 1580, 1521, 1471, 1411, 1298, 1239, 1156, 1069, 908, 777, 747, 669, 626, 575, 523, 498, 477, 465, 454, 435, 426, 417, 410 cm^–1. ¹H NMR (300 MHz, DMSO-d₆/TMS): δ 8.24 (s, 3H), 8.17 (d, J = 8.1 Hz, 3H), 7.85 (t, J = 7.8 Hz, 3H), 7.43 (d, J = 4.8 Hz, 3H), 7.18 (t, J = 6.0 Hz, 3H), 6.58 (s, 3H), 1.36 (s, 9H) ppm. ¹³C NMR (150 MHz, DMSO-d₆/TMS): δ 169.2, 167.8, 164.2, 146.8, 142.3, 139.8, 139.3, 137.7, 125.9, 123.3, 121.9, 119.3, 22.3 ppm. ESI-MS (m/z): calcd for C₃₉H₃₀¹⁹¹IrN₃O₆ [M]⁺ 827.1735; found 827.1735. Anal. Calcd for C₃₉H₃₀N₃O₆Ir·0.45H₂O: C, 55.96; H, 3.72; N, 5.02%. Found: C, 56.22; H, 3.62; N, 4.76%.

Δ-fac-4

Δ-fac-4 was prepared using a procedure similar to that for Δ-fac-6. A 5 N NaOH solution in H₂O (100 μL) was added to a solution of Δ-fac-10 (10 mg, 7.4 μmol) in MeOH (400 μL), and the reaction mixture was stirred at 80 °C for 3 h. After cooling to room temperature, the solvent was removed under reduced pressure. After the addition of saturated aqueous NaHCO₃, the solution was washed with AcOEt. To the aqueous layer was added a 2 N aqueous solution of HCl to adjust the pH to 1, and the resulting solution was extracted with AcOEt. The combined organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was reprecipitated from hexanes/THF to afford Δ-fac-4 (6 mg, quantitative, >99% ee) as a yellow solid. Mp: >300 °C. IR (ATR): ν 2487, 2160, 1978, 1670, 1584, 1533, 1475, 1456, 1414, 1382, 1298, 1211, 1101, 1061, 1048, 1028, 997, 844, 786, 765, 736, 669, 640, 556, 486, 463, 427, 420, 410 cm^–1. ¹H NMR (600 MHz, DMSO-d₆/TMS): δ 12.36 (bs, 3H), 8.30 (d, J = 1.2 Hz, 3H), 8.28 (d, J = 8.4 Hz, 3H), 7.89 (td, J = 7.8, 1.2 Hz, 3H), 7.51 (dd, J = 5.4, 0.6 Hz, 3H), 7.28 (dd, J = 8.4, 1.8 Hz, 3H), 7.24 (td, J = 6.6, 1.2 Hz, 3H), 6.73 (d, J = 7.8 Hz, 3H) ppm. ¹³C NMR (150 MHz, DMSO-d₆/TMS): δ 169.3, 169.0, 168.2, 163.9, 147.0, 144.4, 136.1, 129.8, 124.8, 123.9, 122.9, 119.7 ppm. ESI-MS (m/z): calcd for C₃₆H₂₅¹⁹¹IrN₃O₆ [M + H]⁺ 786.1344; found 786.1344.

Λ-fac-4

Λ-fac-4 was prepared by using a procedure similar to that for Δ-fac-6. A 5 N NaOH solution in H₂O (100 μL) was added to a solution of Λ-fac-10 (10 mg, 7.3 μmol) in MeOH (400 μL), and the reaction mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the solvent was removed under reduced pressure. After saturated aqueous NaHCO₃ was added, the solution was washed with AcOEt. To the aqueous layer was added a 2 N aqueous solution of HCl to adjust the pH to 1, and the resulting solution was extracted with AcOEt. The combined organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was reprecipitated from hexanes/THF to afford Λ-fac-4 (7 mg, quantitative, >99% ee) as a yellow solid. Mp: >300 °C. IR (ATR): ν 3051, 1673, 1586, 1475, 1415, 1212, 1061, 1029, 847, 747, 668, 641, 505, 430, 416, 405 cm^–1. ¹H NMR (600 MHz, DMSO-d₆/TMS): δ 12.33 (bs, 3H), 8.30 (d, J = 1.8 Hz, 3H), 8.28 (d, J = 8.4 Hz,3H), 7.90 (td, J = 7.8, 1.2 Hz, 3H), 7.51 (dd, J = 5.4, 0.6 Hz, 3H), 7.28 (dd, J = 7.8, 1.8 Hz, 3H), 7.24 (td, J = 6.6, 1.2 Hz, 3H), 6.73 (d, J = 7.8 Hz, 3H) ppm. ¹³C NMR (150 MHz, DMSO-d₆/TMS): δ 185.9, 168.3, 164.1, 147.1, 144.5, 138.0, 136.2, 136.1, 129.8, 122.9, 119.8, 106.1 ppm. ESI-MS (m/z): calcd for C₃₆H₂₅¹⁹¹IrN₃O₆ [M + H]⁺ 786.1344; found 786.1348. Anal. Calcd for C₃₆H₂₄N₃O₆Ir·0.4CHCl₃·1.5MeOH: C, 51.58; H, 3.47; N, 4.76%. Found: C, 51.80; H, 3.29; N, 4.50%.

Δ-fac-13

Δ-fac-13 was prepared by using a procedure similar to that for Δ-fac-6. A 5 N NaOH solution in H₂O (500 μL) was added to a solution of Δ-fac-14 (10 mg, 6.3 μmol) in MeOH (2 mL), and the reaction mixture was stirred at 80 °C for 4 days. After cooling to room temperature, the solvent was removed under reduced pressure. After saturated aqueous NaHCO₃ was added, the solution was washed with AcOEt. To the aqueous layer was added a 2 N aqueous solution of HCl to adjust the pH to 1, and the resulting solution was extracted with AcOEt. The combined organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford Δ-fac-13 (7 mg, quantitative, >99% ee) as a orange solid. Mp: 297 °C (dec). IR (ATR): ν 2921, 2851, 2524, 2161, 1672, 1573, 1548, 1500, 1407, 1377, 1348, 1244, 1165, 1094, 1029, 914, 801, 752, 737, 699, 674, 632, 603, 580, 558, 516, 479, 460, 445, 429, 418, 406 cm^–1. ¹H NMR (600 MHz, DMSO-d₆/TMS): δ 12.26 (bs, 3H), 8.87 (d, J = 8.4 Hz, 3H), 8.75 (s, 3H), 7.99 (dd, J = 8.4, 1.2 Hz, 3H), 7.88 (td, J = 7.8, 1.2 Hz, 3H), 7.84 (td, J = 7.2, 1.2 Hz, 3H), 7.56 (d, J = 6.0 Hz, 3H), 7.40 (d, J = 6.6 Hz, 3H), 2.26 (s, 9H) ppm. ¹³C NMR (150 MHz, DMSO-d₆/TMS): δ 171.1, 169.1, 164.8, 143.4, 140.3, 139.5, 139.3, 136.5, 131.6, 131.2, 130.7, 129.0, 127.8, 126.0, 125.6, 121.6, 22.2 ppm. ESI-MS (m/z): calcd for C₅₁H₃₆¹⁹¹IrN₃O₆ [M]⁺ 977.2205; found 977.2206.

Λ-fac-13

Λ-fac-13 was prepared by using a procedure similar to that for Δ-fac-6. A 5 N aqueous NaOH solution (200 μL) was added to a solution of Λ-fac-14 (10 mg, 6.3 μmol) in MeOH (800 μL), and the reaction mixture was stirred at 80 °C for 3 h. After cooling to room temperature, the solvent was removed under reduced pressure. After saturated aqueous NaHCO₃ was added, the solution was washed with AcOEt. To the aqueous layer was added a 2 N aqueous solution of HCl to adjust the pH to 1, and the resulting solution was extracted with AcOEt. The combined organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford Λ-fac-13 (8 mg, quantitative, >99% ee) as an orange solid. Mp: 297 °C (dec). IR (ATR): ν 2923, 2852, 2512, 2162, 2034, 1672, 1574, 1547, 1518, 1501, 1434, 1377, 1348, 1269, 1244, 1165, 1094, 1031, 915, 813, 781, 752, 737, 700, 674, 632, 602, 557, 499, 483, 461, 440, 416, 423, 410 cm^–1. ¹H NMR (600 MHz, DMSO-d₆/TMS): δ 12.26 (bs, 3H), 8.87 (d, J = 8.4 Hz, 3H), 8.75 (s, 3H), 7.99 (dd, J = 8.1, 1.2 Hz, 3H), 7.88 (td, J = 7.8, 1.8 Hz, 3H), 7.84 (td, J = 7.5, 1.2 Hz, 3H), 7.56 (d, J = 6.0 Hz, 3H), 7.40 (d, J = 6.6 Hz, 3H), 6.71 (s, 3H), 2.26 (s, 9H) ppm. ¹³C NMR (150 MHz, DMSO-d₆/TMS): δ 168.9, 143.3, 140.2, 139.4, 139.2, 136.3, 131.5, 131.1, 128.9, 127.7, 125.9, 125.5, 121.4, 22.1 ppm. ESI-MS (m/z): calcd for C₅₁H₃₆¹⁹¹IrN₃O₆ [M]⁺ 977.2205; found 977.2207.

X-ray Data Collection and Refinement of Δ-fac-9, Δ-fac-11, and Λ-fac-11

Yellow crystals of Δ-fac-9, Δ-fac-11, and Λ-fac-11 suitable for X-ray analysis were obtained by the slow vapor diffusion of hexanes into their CHCl₃ solutions at room temperature. The synchrotron X-ray diffraction study for Δ-fac-9 was carried out at the BL02B1 beamline at Spring-8 with the approval of the Japan Synchrotron Radiation Research Institute (JASRI) with a diffractometer equipped with a Rigaku Mercury2CCD detector. The collected diffraction data were processed with the RAPID AUTO software program. The structure was solved by the charge-flipping method and refined by full-matrix least squares on F² by using the SHELX program suite. The single-crystal X-ray diffraction study for Δ-fac-11 and Λ-fac-11 was carried out using a Rigaku X-ray diffractometer equipped with a molybdenium MicroMax-007 and Saturn 724+ detector, and the measurement was performed at 293 K. The structure was solved by direct methods (SHELX) and refined by full-matrix least squares methods on F² using the Yadokari-XG program. OMIT was used to exclude the most disagreeable reflections (error/esd >10) for the refinement of Δ-fac-9, whereas DELU, SIMU, and ISOR were used for the refinement of Δ-fac-11. All non-hydrogen atoms were refined anisotropically in the structure. The crystal data in this manuscript can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Crystal data for Δ-fac-9:

formula C₃₈H₄₇Cl₆Ir_0.5N_4.5O_4.5; FW = 947.60, triclinic, space group P1, a = 13.5883(6) Å, b = 14.0191(7) Å, c = 14.0425(7) Å, α = 101.692(7)°, β = 115.010(8)°, γ = 110.375(8)°, V = 2070.9(2) ų, Z = 2, T = 100 K, D_calcd = 1.520 g cm^–3, μ(synchrotron) = 0.503 cm^–1, 2θ_max = 16.00°, λ(synchrotron) = 0.4126 Å, 62001 reflections measured, 18641 unique, 18451 (I > 2σ(I)) were used to refine 976 parameters, 3 restraints, wR2 = 0.1223, R1 = 0.0459 (I > 2σ(I)), GOF = 1.020. A total of 62001 reflections were collected, among which 616 reflections were independent (R_int = 0.0466). CCDC 2236350 contains the supplementary crystallographic data for the sample, and representative parameters are also given in Table S1 in the Supporting Information.

Crystal data for Δ-fac-11:

formula C₇₆H₉₁Cl₁₂IrN₆O₁₂; FW = 1898.14, triclinic, space group P1, a = 13.3507(3) Å, b = 13.9918(3) Å, c = 14.3988(3) Å, α = 108.231(2)°, β = 113.667(2)°, γ = 104.028(2)°, V = 2120.17(9) ų, Z = 1, T = 293 K, D_calcd = 1.487 g cm^–3, μ(Mo Kα) = 2.013 cm^–1, 2θ_max = 30.2610°, λ(Mo Kα) = 0.71073 Å, 42682 reflections measured, 19538 unique, 17790 (I > 2σ(I)) were used to refine 976 parameters, 3 restraints, wR2 = 0.0974, R1 = 0.0438 (I > 2σ(I)), GOF = 0.992. A total of 42682 reflections were collected, among which 17790 reflections were independent (R_int = 0.0432). CCDC 2119640 contains the supplementary crystallographic data for the product, and representative parameters are also given in Table S1 in the Supporting Information.

Crystal data for Λ-fac-11:

formula C₈₆H₁₁₇Cl₆IrN₆O₁₂; FW = 1831.75, orthorhombic, space group P2₁2₁2₁, a = 14.2878(3) Å, b = 21.3264(4) Å, c = 30.3367(6) Å, α = 90°, β = 90°, γ = 90°, V = 9243.8(3) ų, Z = 4, T = 293 K, D_calcd = 1.316 g cm^–3, μ(Mo Kα) = 1.676 cm^–1, 2θ_max = 30.2970°, λ(Mo Kα) = 0.71073 Å, 93431 reflections measured, 25814 unique, 20843 (I > 2σ(I)) were used to refine 1012 parameters, 188 restraints, wR2 = 0.1261, R1 = 0.0540 (I > 2σ(I)), GOF = 1.082. A total of 93431 reflections were collected, among which 34850 reflections were independent (R_int = 0.0466).

Measurements of UV–Vis Absorption and Luminescence Spectra

UV–vis spectra were recorded on a JASCO V-630 spectrometer, and emission spectra were recorded at 25 °C on a JASCO FP-8300 spectrofluorometer. Sample solutions in quartz cuvettes equipped with Teflon septum screw caps were degassed by bubbling Ar through the solution for 10 min prior to luminescence measurements. The luminescence quantum yields (Φ) were determined by comparison with the integrated corrected emission spectrum of quinine sulfate (Φ = 0.55 in 0.1 M H₂SO₄) when excited at 366 nm. Equation 1 was used for calculating the emission quantum yields, in which Φ_s and Φ_r denote the quantum yields of the sample and reference of the solvents used for the measurements of the sample and reference compound, respectively, and η_s and η_r are the refractive indexes of the solvents used for the measurements of the sample and reference, respectively (η: 1.33 for H₂O, 1.42 for CH₂Cl₂, 1.50 for toluene, and 1.48 for DMSO). A_s and A_r denote the absorbances of the sample and reference, respectively.

1

The luminescence lifetimes of sample solutions in degassed DMSO or aqueous solutions at 298 K were measured on a TSP1000-M-PL (Unisoku, Osaka, Japan) instrument using THG (355 nm) of a Nd:YAG laser Minilite I (Continuum, CA) as the excitation source. The signals were monitored with an R2949 photomultiplier. Data were analyzed by using a nonlinear least-squares procedure.

Measurements of CD Spectra and CPL Spectra

CD spectra were recorded on a Chirascan (Applied Photophysics) spectrophotometer, and CPL spectra were measured using a JASCO CPL-300 spectrofluoropolarimeter.

Stability of fac-9 and fac-11 against Light and Heat and in the Presence of Silica Gel

Δ- and Λ-fac-9 and -11 were dissolved in toluene (1 mM), respectively. For photostability, each solution was irradiated at room temperature with light at a wavelength of 365 nm for 1 h using Twinlight (RELYON, Tokyo, Japan), equipped with an LED (365 nm). For stability against heat, each solution was heated to 100 °C for 1 h. For stability in the presence of silica gel, silica gel was added to each solution, and the mixture was then stirred at room temperature for 1 h. Each solution was then filtered and analyzed by normal-phase HPLC (SenshuPak PEGASIL Silica SP100, eluent CHCl₃/MeCN = 1/2 for fac-9, hexanes/CHCl₃ = 1/5 for fac-11; flow rate 1.0 mL/min; UV detection at 254 nm).

Theoretical Calculations

Density functional theory (DFT) calculations were carried out using the Gaussian09 program (PBE1PBE functional, the LanL2DZ basis set for Ir and the 6-31G basis set for H, C, O, and N atoms). The molecular orbitals were visualized using Jmol software (an open-source Java viewer for chemical structures in 3D, http://www.jmol.org/).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.inorgchem.3c00685.

• Predicted most stable structures of Δ-fac-9, Λ-fac-9, Δ-fac-11, and Λ-fac-11, energy diagram for the HOMO and LUMO of fac-5, Δ-fac-9, Λ-fac-9, Δ-fac-11, and Λ-fac-11, Gibbs free energies of the most stable structures of Δ-fac-9, Λ-fac-9, Δ-fac-11, and Λ-fac-11, HPLC chromatograms of carboxylic acid derivatives, crystal data and structure refinement for Δ-fac-9, Δ-fac-11, and Λ-fac-11, representative parameters for the crystal structure analysis of Δ-fac-9, Δ-fac-11, and Λ-fac-11, photophysical properties of fac-4, fac-6, and fac-13 in degassed DMSO, CPL spectra of Δ- and Λ-fac-4 and -6, and ¹H NMR and ¹³C NMR spectra of racemic fac-13 and Δ- and Λ-fac-9, -10, -11, -14, -6, -4, and -13 (PDF)

The authors declare no competing financial interest.