Modeling Ligand Exchange Kinetics in Iridium Complexes Catalyzing SABRE Nuclear Spin Hyperpolarization

Abstract

Large signal enhancements can be obtained for NMR analytes using the process of nuclear spin hyperpolarization. Organometallic complexes that bind parahydrogen can themselves become hyperpolarized. Moreover, if parahydrogen and a to-be-hyperpolarized analyte undergo chemical exchange with the organometallic complex it is possible to catalytically sensitize the detection of the analyte via hyperpolarization transfer through spin-spin coupling in this organometallic complex. This process is called Signal Amplification By Reversible Exchange (SABRE). Signal intensity gains of several orders of magnitude can thus be created for various compounds in seconds. The chemical exchange processes play a defining role in controlling the efficiency of SABRE because the lifetime of the complex must match the spin-spin couplings. Here, we show how analyte dissociation rates in the key model substrates pyridine (the simplest six-membered heterocycle), 4-aminopyridine (a drug), and nicotinamide (an essential vitamin biomolecule) can be examined. This is achieved for the most widely employed SABRE motif that is based on IrIMes-derived catalysts by ¹H 1D and 2D exchange NMR spectroscopy techniques. Several kinetic models are evaluated for their accuracy and simplicity. By incorporating variable temperature analysis, the data yields key enthalpies and entropies of activation that are critical for understanding the underlying SABRE catalyst properties and subsequently optimizing behavior through rational chemical design. While several studies of chemical exchange in SABRE have been reported, this work also aims to establish a toolkit on how to quantify chemical exchange in SABRE and ensure that data can be compared reliably.

Figure 1

Scheme of SABRE hyperpolarization of pyridine. pH₂ and a substrate (here: pyridine, Py) bind to form a transient complex, [Ir(H)₂(IMes)(Py)₃]Cl. Spin–spin interactions then drive spin order from IrHH (the pH₂-derived hydride spins) to the Py substrate, resulting in two hyperpolarized equatorial substrate ligands (red Py) and orthohydrogen (oH₂). IMes stands for 1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene. The two equatorial chemically equivalent pyridine ligands exchange via a dissociative (S_N1) mechanism.

Figure 2

EXSY (A) and SEXSY (B) NMR pulse sequences. The rounded pulse in the diagram is frequency-selective. Several delays were applied: d₁ stands for relaxation delay, d₀ is indirect dimension encoding delay, d₁₄ stands for evolution after shaped pulse, and d_mix (typically d₈ in TopSpin) stands for mixing time. Phases: φ₁ = [0°, 180°], φ₂ = 0°, and φ₃ = [0°, 0°, 180°, 180°, 90°, 90°, 270°, 270°], φ_rec = [0°, 180°, 180°, 0°, 90°, 270°, 270°, 90°]. In SEXSY sequence, the phase φ₁ and d_mix were selected with a random deviation (: r) up to 5%.

Figure 3

Schematic view of three models used to describe the substrate chemical exchange in SABRE with different degrees of simplification. In model A, C_SS₂↔C_SS+S, while both equatorial substrates can exchange, only one is involved at a time. As a simplification to model A, the C_SS₂↔S₂ model B assumes that both equatorial substrates exchange simultaneously (with half of the “actual” exchange rate constant). In model C, C₀S↔S, there is only one substrate, e.g., a bidentate ligand like pyruvate, which now exchanges in one step.

Figure 4

EXSY spectrum. (A) ¹H NMR spectrum of pyridine (Py) with Ir complex in methanol-d₄ with the assignment of Py peaks (f–free, e–equatorial, a–axial, α, β, and γ protons of Py). (B) 2D EXSY spectrum, which demonstrates the exchange between free (fPy) and bound equatorial (ePy) pyridine molecules measured at d_mix = 500 ms at 280 K and 7 T using a 2D EXSY sequence. Spectrum on the left was obtained separately using conventional 1D NMR and added here instead of a purely resolved spectrum projection. From (A), one can find the relative ratio in this experiment.

Figure 5

SEXSY spectra. Spectra (A) and fittings of the kinetics of free (fPy-α, red) and equatorial (ePy-α, blue) (B). Signal of Py as a function of mixing time d_mix at 280 K obtained using 1D SEXSY pulse sequence: fitting with biexponential decay function (solid line, R = 0.15 ± 0.02 s^–1, k = 1.55 ± 0.06 s^–1), fitting with models C_SS₂↔C_SS+S (dashed line, eq 6) and C_SS₂↔S₂ (dotted line, eq 9). Initial concentrations [Ir]⁰ = 4 mM, [Py]⁰ = 40 mM, and experimental estimation of concentrations ratio is (Figure 4A). The antiphase line shape of fPy-α at short d_mix results in an overall integral close to zero and does not affect the analysis of the net magnetization exchange.

Figure 6

Enthalpies ΔH^‡ (A) and entropies ΔS^‡ (B) of activation for IrIMes-derived complexes with Py, 4AP and NAM as a substrate. ΔH^‡ and ΔS^‡ values were obtained from dissociation exchange constants measured with the model C_SS₂↔C_SS+S (SEXSY, green), with the model C_SS₂↔S₂ (EXSY, purple), with the model C_SS₂↔S₂ (SEXSY, yellow), eigenvalues analysis (blue) and the values calculated using mean k_d (orange). The values are obtained by fitting k_d (Table 1, Figure S7, SI) and are given in Table S8, SI.