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.

Nuclear 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-H2).[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-H2 into it. Instead, it utilizes a metal complex to simultaneously bind p-H2, and the hyperpolarization target. When so assembled, polarization flows from the p-H2-derived spins at low magnetic field to those of the target, which upon dissociation can be detected with high sensitivity.

Crabtree’s catalyst, [Ir(COD)(PCy3)(py)][BF4] (COD = cyclooctadiene, Cy = cyclohexyl, and py = pyridine), exhibits roles in hydrogenation[11] and hydrogen isotope exchange (HIE),[12] where it is used in the production of labeled compounds and radiopharmaceuticals.[13] When it reacts with p-H2 and py though, it forms the active magnetization transfer catalyst [Ir(H)2(PCy3)(py)3][BF4].[14] Interrogation of the free py’s 1H NMR signals after magnetization transfer revealed signal enhancements of >100-fold in the corresponding 1H, 13C, and 15N NMR spectra. This process has now been refined to extend the level of signal gain,[15−18] the range of applications,[19,20] the nuclei that can be polarized,[21−25] and the classes of substrates that can be employed.[26−28] So far, IrCl(COD)(IMes)[29] [IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene][4] reflects one of the better SABRE catalysts because its ligand exchange rates match those of the spin-spin couplings associated with polarization flow, but slow catalyst activation can be a problem.[30,31] We set out here to develop a rapidly activating and readily available air-stable precursor for SABRE and now describe the ensuing observations.

Initially, the COD ligand of IrCl(COD)(IMes) was replaced with cyclooctene (COE), in the form of IrCl(COE)2(IMes),[32] by adding IMes to [IrCl(COE)2]2 (1). IrCl(COE)2(IMes) proved unstable, although [Ir(H)2(IMes)(py)3][Cl] forms upon reaction with py and H2. As a consequence, we treated a tetrahydrofuran (THF-d8) solution of 1 with py and H2 alone. 1 rapidly formed IrCl(H)2(η2-COE)(py)2 (2), as detailed in Figure .

Figure 1

Reaction scheme for the formation of 2 from 1 and the associated ORTEP for 2.

The COE ligand of 2 binds in an η2 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 (η2-COE)(Me)Ir(PMe3)3[33] and 2.2865(7) and 2.307(7) Å [(iPrN-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)2IMes(py)3]Cl for sites trans to hydride and carbene, respectively.[35]

The 1H 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 15N chemical shifts of its py ligands appear at δpy-eq 254.7 and δpy-ax 224.7, with the former exhibiting a large JH15N 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 15N 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 H2 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 H2 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 [tBu4C]Cl) in addition to py and H2, 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 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.

Scheme 1

Ligand-Exchange Pathways Observed by NMR for 2 in a THF-d8 Solution

When the H2 gas used in these control experiments was replaced by D2, a loss of the hydride ligand signals of 2 was observed over a few seconds, with slow 2H incorporation into the bound cycloctene CH= groups being evident at a rate of 1.3 (±0.5) × 10–5 s–1. Furthermore, when p-H2 is used, the corresponding hydride ligand signals exhibit the PHIP effect, as detailed in Figure . These observations confirm that 2 undergoes reversible H2 loss, and when the same sample was exposed to p-H2 in a low magnetic field for 10 s prior to making the high-field NMR measurement, the SABRE effect was observed. Figure b 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.

Figure 2

Hyperpolarized 1H NMR spectra of 2. (a) Hydride region showing PHIP-enhanced signals for cis–cis 2 and its minor cis–trans isomer (298 K). Organic region showing (b) the normal spectrum, (c) SABRE-enhanced free and bound py signals (298 K), and (d) SABRE-enhanced signals for the COE ligand of 2 (313 K).

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 >210-fold 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 1H NMR spectra at δ −24.72, −25.9, and −28.95 for (Cl)(H)(py)(μ-Cl)(μ-H)(κ-μ-NC5H4)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-NC5H4)Ir(H)(py)2 of Figure .

Figure 3

Reaction scheme for the formation of 4 alongside an ORTEP of 4.

The distance between the two iridium centers of 4 is 2.73319(18) Å, while the corresponding Ir−C and Ir−N bond lengths of the bridging pyridyl moiety are 1.998(3) Å and 2.013 (3) Å, respectively. A related iridium dimer studied by Cotton and Poli[37] had analogous Ir–C and Ir–N bond lengths of 1.983(13) and 2.024(12) Å, respectively, with an Ir–Ir distance of 2.518(1) Å. The Ir1–N2, Ir1–Cl2, and Ir1–Cl1 bond lengths are 2.068(3), 2.3897(8), and 2.5732(8) Å, respectively, in accordance with the asymmetry in the bridging chloride. The corresponding Ir2–N4, Ir2–N3, and terminal Ir2–Cl2 bond lengths are 2.152(3), 2.072(3), and 2.5579(8) Å, respectively, with the hydride ligands again clearly exhibiting a trans-labializing influence, although the Ir–N bond lengths are all shorter than those of the labile site in 2. The key bond angles for Ir1, N2–Ir1–Cl2, Cl2–Ir1–Cl1, and N1–Ir1–Cl1, are 86.92(8)°, 93.72(3)°, and 84.45(8)°, respectively, while those for Ir2, N3–Ir2–Cl1, C5–Ir2–Cl1, and N4–Ir2–Cl1, are 98.53(8)°, 85.38(10)°, and 92.89(8)°, respectively. The ligand arrangement around both iridium centers is therefore close to octahedral.

Complex 4 is SABRE inactive and its hydride ligand signals fail to exhibit PHIP. However, when 4 is shaken with 2 under p-H2, the 1H 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-d5 to the 1H-labeled 4 under H2 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 . 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-d5 proved to be slower still.

Figure 4

Intensity fall of appropriate 1H NMR resonances in 1H-containing 4 at 273 K upon exposure to pyridine-d5 revealing the slow and selective exchange of its py-based ligands.

In addition to these changes, the slow replacement of the 2H labels of pyridine-d5 with 1H nuclei is observed. After 48 h at 313 K, 33% of its ortho py 2H sites became 1H 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 D2/H2.[12] When 3 bar of D2 was employed with a pyridine-h5 to 4 ratio of 25:1, the rate of 2H 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(PCy3)(py)3][BF4] referred to earlier, we added AgPF6 to 2 to form [Ir(H)2(COE)(py)3]PF6 (6) of Scheme . 6 was also prepared independently from [Ir(COE)2(py)2]PF6 (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 PCy3.

Scheme 2

Routes to 6

In summary we have established that readily available air-stable 1 reacts with py and H2 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-H2 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]