Iridium Cyclooctene Complex That Forms a Hyperpolarization Transfer Catalyst before Converting to a Binuclear C–H Bond Activation Product Responsible for Hydrogen Isotope Exchange

[IrCl(COE)2]2 (1) reacts with pyridine (py) and H2 to form crystallographically characterized IrCl(H)2(COE)(py)2 (2). 2 undergoes py loss to form 16-electron IrCl(H)2(COE)(py) (3), with equivalent hydride ligands. When this reaction is studied with parahydrogen, 1 efficiently achieves hyperpolarization of free py (and nicotinamide, nicotine, 5-aminopyrimidine, and 3,5-lutudine) via signal amplification by reversible exchange (SABRE) and hence reflects a simple and readily available precatayst for this process. 2 reacts further over 48 h at 298 K to form crystallographically characterized (Cl)(H)(py)(μ-Cl)(μ-H)(κ-μ-NC5H4)Ir(H)(py)2 (4). This dimer is active in the hydrogen isotope exchange process that is used in radiopharmaceutical preparations. Furthermore, while [Ir(H)2(COE)(py)3]PF6 (6) forms upon the addition of AgPF6 to 2, its stability precludes its efficient involvement in SABRE.


* S Supporting Information
ABSTRACT: [IrCl(COE) 2 ] 2 (1) reacts with pyridine (py) and H 2 to form crystallographically characterized IrCl(H) 2 (COE)(py) 2 (2). 2 undergoes py loss to form 16electron IrCl(H) 2 (COE)(py) (3), with equivalent hydride ligands. When this reaction is studied with parahydrogen, 1 efficiently achieves hyperpolarization of free py (and nicotinamide, nicotine, 5-aminopyrimidine, and 3,5lutudine) via signal amplification by reversible exchange (SABRE) and hence reflects a simple and readily available precatayst for this process. 2 reacts further over 48 h at 298 K to form crystallographically characterized (Cl)(H)(py)-(μ-Cl)(μ-H)(κ-μ-NC 5 H 4 )Ir(H)(py) 2 (4). This dimer is active in the hydrogen isotope exchange process that is used in radiopharmaceutical preparations. Furthermore, while [Ir(H) 2 (COE)(py) 3 ]PF 6 (6) forms upon the addition of AgPF 6 to 2, its stability precludes its efficient involvement in SABRE. N uclear Magnetic Resonance (NMR) spectroscopy is used widely in chemistry and biochemistry to characterize materials, while in medicine, magnetic resonance imaging is used to probe disease. Both methods suffer from low sensitivity, that can be overcome by employing hyperpolarization as exemplified by optical pumping, 1 dynamic nuclear polarization (DNP), 2 and parahydrogen (p-H 2 ). 3 The resulting molecules are starting to be featured as disease probes in clinical diagnosis. 4 Parahydrogen-induced polarization (PHIP) involves the chemical transfer of two hydrogen atoms into a suitable acceptor. 5 This approach was pioneered by Bowers and Weitekamp, 3 Eisenberg et al., 6 and Natterer and Bargon. 7 Examples of hydrogen acceptors include organic scaffolds leading to fumaric acid 8 and inorganic complexes such as the Vaska's complex. 9 One related PHIP approach, is known as signal amplification by reversible exchange (SABRE). 10 Like PHIP, it is able to hyperpolarize a target in seconds, but crucially it no longer involves the incorporation of p-H 2 into it. Instead, it utilizes a metal complex to simultaneously bind p-H 2 , and the hyperpolarization target. When so assembled, polarization flows from the p-H 2 -derived spins at low magnetic field to those of the target, which upon dissociation can be detected with high sensitivity.
The COE ligand of 2 binds in an η 2 fashion, trans to one of two inequivalent py ligands, while its hydride ligands lie trans to chloride and py. The py-N1−iridium alkene centroid bond angle in 2 is 101.6(6)°, while the py−iridium chlorine bond angles are 91.1(3)°and 92.4(3)°. Its structure is therefore close to octahedral, although the py ligand cis to the alkene is slightly displaced away from the equatorial plane. The corresponding alkene C1−Ir and C8−Ir bonds lengths are 2.152(11) and 2.187(10) Å, respectively, and compare with those of 2.1664(13) and 2.1494(14) Å in (η 2 -COE)(Me)Ir(PMe 3 ) 3 33 and 2.2865(7) and 2.307(7) Å [( i PrN-PCP)IrHCl(COE)]. 34 The Ir−N1 and Ir−N2 bond lengths of 2 are 2.216(9) and 2.106(8) Å, respectively, in accordance with the trans-labilizing influence of hydride and compare with those of 2.192(3) and 2.129(3) Å in [Ir(H) 2 IMes(py) 3 ]Cl for sites trans to hydride and carbene, respectively. 35 The 1 H NMR spectrum of 2 contains hydride ligand signals at δ −19.34 and −26.47 for sites trans to py and chloride, respectively, and two inequivalent CH proton signals for the COE ligand at δ 3.12 and 4.12. The 15 N chemical shifts of its py ligands appear at δ py-eq 254.7 and δ py-ax 224.7, with the former exhibiting a large J H15N splitting of 20 Hz due to a trans hydride ligand coupling. Diagnostic α-proton signals for these ligands appear at δ 9.37 and 9.25, respectively, with the low-field 15 N axial py chemical shift reflecting its shorter iridium bond length. 36 The ligands of 2 proved to exhibit dynamic effects that were quantified by exchange spectroscopy (EXSY) methods (Supporting Information). The rate of py loss for the equatorial site was determined to be 7.8 ± 0.1 s −1 at 298 K, and hydride site exchange into free H 2 proved to be limited at this temperature. In contrast, the two distinct hydride sites of 2 proved to interchange positions at a rate of 3.6 ± 0.1 s −1 , while the CH proton sites of COE interconvert at a rate of 3.8 ± 0.1 s −1 . When the concentrations of py and H 2 were varied (see sTable 1). None of the associated ligand exchange rates changed. Further samples were then examined that contained excesses of COE and Cl − (in the form of [ t Bu 4 C]Cl) in addition to py and H 2 , and no change in the rate was observed. Hence py dissociation from the site trans to hydride forms intermediate IrCl(H) 2 (COE)(py) (3) of Scheme 1 with equivalent hydrides. For symmetry reasons, reformation of 2 proceeds with interchange of the original hydride and alkene CH proton sites at approximately 50% of the py loss rate. In agreement with this conclusion, Eyring analysis of this behavior as a function of the temperature produces three slopes with identical gradients. The corresponding activation parameters for py loss are ΔH ⧧ = 90.6 ± 1 kJ mol −1 and ΔS ⧧ = 79 ± 4 J K −1 mol −1 and reflect the dissociative nature of this change.
When the H 2 gas used in these control experiments was replaced by D 2 , a loss of the hydride ligand signals of 2 was observed over a few seconds, with slow 2 H incorporation into the bound cycloctene CH groups being evident at a rate of 1.3 (±0.5) × 10 −5 s −1 . Furthermore, when p-H 2 is used, the corresponding hydride ligand signals exhibit the PHIP effect, as detailed in Figure 2. These observations confirm that 2 undergoes reversible H 2 loss, and when the same sample was exposed to p-H 2 in a low magnetic field for 10 s prior to making the high-field NMR measurement, the SABRE effect was observed. Figure 2b shows this as viewed through the +11 to −1 ppm region of the NMR spectrum for a sample containing 1 equiv of free py relative to 2. The bound py and COE proton signals referred to earlier are now hyperpolarized, and consequently 2 represents a catalyst for SABRE.
The degree of SABRE shown in these resonances depends on the excess of py. When the initial ratio of 1 to py was 1:8, a >210fold intensity gain in the ortho proton resonance of the free py signal is observed. This enhancement increases to >500-fold when the ligand ratio is 1:5.6 and can be increased further by warming to 313 K; sTable 4 contains data for nicotinamide, nicotine, 5-aminopyrimidine, and 3,5-lutudine to demonstrate scope. However, after the sample is left at 298 K for 24 h, three new hydride signals appear in the corresponding 1 H NMR spectra at δ −24.72, −25.9, and −28.95 for (Cl)(H)(py)(μ-Cl)(μ-H)(κ-μ-NC 5 H 4 )Ir(H)(py) 2 (4). Their intensity growth parallels a series of changes in the aromatic region of these NMR spectra, which suggests that 4 contains four distinct py-based ligands. Integration and COSY measurements show that one of these has just four protons and hence 4 is the C−H bond activation product (Cl)(H)(py)(μ-Cl)(μ-H)(κ-μ-NC 5 H 4 )Ir-(H)(py) 2 of Figure 3.
The distance between the two iridium centers of 4 is 2.73319 (18)  Complex 4 is SABRE inactive and its hydride ligand signals fail to exhibit PHIP. However, when 4 is shaken with 2 under p-H 2 , the 1 H NMR signals of free py are enhanced alongside those for the bound py ligands of 4, which provide ortho proton signals at δ 9.48 and 9.40, which suggests that ligand exchange is possible. The addition of pyridine-d 5 to the 1 H-labeled 4 under H 2 at 273 K confirms this effect, with the order of ligand exchange based on the fall in the ortho proton site resonance intensities being δ 9.40 > δ 9.48 ≫ δ 9.33, as detailed in Figure 4. We note that the corresponding Ir−N bond lengths for these groups are 2.068(3), 2.072(3), and 2.152(3) Å, respectively, and fit with these observations. Exchange of the pyridyl ligand with pyridine-d 5 proved to be slower still.
In addition to these changes, the slow replacement of the 2 H labels of pyridine-d 5 with 1 H nuclei is observed. After 48 h at 313 K, 33% of its ortho py 2 H sites became 1 H containing, with 5.4% incorporation into the para site and 3.1% into the meta site. 4 therefore facilitates py CH/CD exchange through transfer from D 2 /H 2 . 12 When 3 bar of D 2 was employed with a pyridine-h 5 to 4 ratio of 25:1, the rate of 2 H label incorporation proved to be 4.3 × 10 −5 s −1 (ortho), 3.85 × 10 −5 s −1 (meta), and 3.05 × 10 −5 s −1 (para) at 313 K.
Given the SABRE activity of [Ir(H) 2 (PCy 3 )(py) 3 ][BF 4 ] referred to earlier, we added AgPF 6 to 2 to form [Ir(H) 2 (COE)-(py) 3 ]PF 6 (6) of Scheme 2. 6 was also prepared independently from [Ir(COE) 2 (py) 2 ]PF 6 (5; Supporting Information). It proved to be SABRE-inactive at 298 K, in agreement with the py loss rate of 0.007 s −1 ; warming to 313 K produces limited SABRE, but the bound py signals are stronger than those of free py. 6 is therefore unsuited to SABRE, with the small ligand loss rate being consistent with the reduced steric effect of this ligand relative to PCy 3 .
In summary we have established that readily available air-stable 1 reacts with py and H 2 to form 2. 2 is highly effective for hyperpolarization of py via the SABRE effect in nonprotoic solvents and with its simple alkene coligand far easier to employ than the carbene complexes more usually used. When this process is undertaken with nicotinamide, nicotine, 5-aminopyrimidine, and 3,5-lutudine, good levels of SABRE are seen. Hence, 1 reflects a simple and readily available precatayst for this process.
Over 48 h, 2 reacts to form the novel C−H bond activation product 4 in a reaction inhibited by added py. This novel complex exhibits catalytic activity in the HIE reaction, which is used for the site-specific labeling of drugs. The presented results offer insight into the HIE process and suggest how ligand design might be used to improve its efficiency in the future. In addition, the high-field one-proton PHIP effect of Permin and Eisenberg 38 uses the chemical transfer of a single proton previously located in a molecule of p-H 2 to enable its detection as a hyperpolarized signal in an organic species. 38,39 While slow-reacting 4 does not behave in this way, its detection suggests that faster-reacting systems will show PHIP at high field. 40 ■ ASSOCIATED CONTENT

* S Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.6b02560.
Complex synthesis and NMR spectra (PDF) X-ray crystallographic data in CIF format for 2 (CIF) X-ray crystallographic data in CIF format for 4 (CIF) X-ray crystallographic data in CIF format for 5 (CIF) ■ AUTHOR INFORMATION Corresponding Author *E-mail: simon.duckett@york.ac.uk.

■ ACKNOWLEDGMENTS
We thank the Wellcome Trust for funding (Grants 092506 and 098335).