Metal-Mediated Catalytic Polarization Transfer from para Hydrogen to 3,5-Dihalogenated Pyridines

Abstract

The neutral catalysts [IrCl(H)₂(NHC)(substrate)₂] or [IrCl(H)₂(NHC)(substrate)(sulfoxide)] are used to transfer polarization from para hydrogen (pH₂) to 3,5-dichloropyridine and 3,5-dibromopyridine substrates. This is achieved in a rapid, reversible, and low-cost process that relies on ligand exchange within the active catalyst. Notably, the sulfoxide-containing catalyst systems produced NMR signal enhancements between 1 and 2 orders of magnitude larger than its unmodified counterpart. Consequently, this signal amplification by reversible exchange hyperpolarization method can boost the ¹H, ¹³C, and ¹⁵N nuclear magnetic resonance (NMR) signal intensities by factors up to 4350, 1550, and 46,600, respectively (14.0, 1.3, and 15.4% polarization). In this paper, NMR and X-ray crystallography are used to map the evolution of catalytically important species and provide mechanistic rational for catalytic efficiency. Furthermore, applications in spontaneous radiofrequency amplification by stimulated emission and NMR reaction monitoring are also shown.

Figure 1

(a) Depiction of the SABRE hyperpolarization process whereby an iridium precatalyst, 1, is reacted with a substrate and H₂ to form a typical SABRE catalyst of the form [Ir(H)₂(IMes)(NSub)₃]Cl where NSub is an N-donor substrate. The SABRE effect is observed when the complex undergoes reversible exchange of both parahydrogen and substrate. In this work, NSub is 3,5-dichloropyridine (A) or 3,5-dibromopyridine (B). (b) Representative SABRE hyperpolarized ¹H NMR spectrum when 1 (5 mM) and A (25 mM) are shaken with 3 bar pH₂ for 10 s at ca 6.5 mT in methanol-d₄. Resonances marked with filled shapes refer to sites in free A, whereas outline shapes indicate the analogous site bound in [IrCl(H)₂(IMes)(A)₂]. Resonances for free A are broadened due to exchange with the metal center, and the effect is more pronounced when lower ligand excesses relative to Ir are used. (c) The effect of substrate loading and solvent on ¹H NMR signals enhancements (left-hand axis) and ¹H T₁ times (right-hand axis) for A in methanol-d₄ (upper left) and dichloromethane-d₂ (upper right) and B in methanol-d₄ (lower left) and dichloromethane-d₂ (lower right). (d) SABRE hyperpolarized ¹³C NMR spectrum when 1 (5 mM) and B (25 mM) in dichloromethane-d₂ are shaken with 3 bar pH₂ for 10 s at 1 μT. (e) SABRE hyperpolarized ¹⁵N NMR spectrum when 1 (5 mM) and B (50 mM) in dichloromethane-d₂ are shaken with 3 bar pH₂ for 10 s at 6 μT. (f) The effect of substrate loading and solvent on meta¹³C (left) and ¹⁵N (right) NMR signals enhancements. Note that in (b), (d) and (e) thermally polarized spectra are shown below the hyperpolarized counterpart.

Figure 2

(a) Formation of SABRE active complexes 6 and 7 from the precatalyst 1. For 2_A, 4_A, 5_A, 6_A, and 7_A L is 3,5-dichloropyridine and for 2_B, 4_B, 5_B, 6_B, and 7_B L is 3,5-dibromopyridine. The structure of 6_A determined using X-ray crystallography is shown with thermal ellipsoids at 50% probability and all nonhydride hydrogen atoms omitted for clarity (gray is carbon, blue is nitrogen, white is hydrogen, green is chlorine and orange is iridium). The structure for 6_B is given in the Supporting Information. (b) Representative single-scan ¹H NMR spectra recorded at 243 K after addition of parahydrogen to an equilibrium mixture of 1 and 2_A in methanol-d₄. The spectra are recorded (upper to lower) ca 2 min, 20 min, 45 min, and a few hours after parahydrogen addition at 243 K. The lower spectrum is recorded at 298 K after the sample was warmed to room temperature and left for 2 days. Signals denoted as M correspond to a methanol or water-bound complex.

Figure 3

(a) Summary of ¹H NMR signal enhancements for A (upper left) and B (upper left) and meta¹³C (lower left) and ¹⁵N (lower right) NMR signal enhancements achieved using different conditions (either DMSO or DPSO coligand in either methanol-d₄ or dichloromethane-d₂) (b) representative SABRE hyperpolarized ¹³C (upper) and ¹⁵N (lower) NMR spectra when 1 (5 mM), DMSO (25 mM) and B (10 50 mM) are shaken with 3 bar pH₂ for 10 s at 1 μT in methanol-d₄ (upper) and dichloromethane-d₂ (lower). Enhanced signals for the IMes ligand bound in 8_B are marked. Analogous thermally polarized spectra are shown below the hyperpolarized counterpart. (c) Structure of 9_B determined from X-ray crystallography. All nonhydride hydrogen atoms and solvent of crystallization have been removed for clarity and thermal ellipsoids are shown at 50% probability.

Figure 4

(a) ¹H Free induction decay after a hyperpolarized sample containing 1 (5 mM), DMSO (25 mM), A (50 mM) and pH₂ (3 bar) in methanol-d₄ is excited using a 90° pulse. (b) ¹H free induction decay with a longer acquisition time after a hyperpolarized sample containing 1 (5 mM), DMSO-d₆ (25 mM) and A (100 mM) and pH₂ (3 bar) in dichloromethane-d₄ is excited using a 1° pulse (c) ¹H free induction decay recorded with no radiofrequency excitation using the sample from (b). (d) ¹H NMR spectra recorded without radiofrequency excitation (1 s acquisition) using the sample in (a). All spectra are recorded at 9.4 T and are not to the same vertical scale. Parts of the FID, colored in orange, are shown expanded in the orange inserts.

Figure 5

(a) Reaction of A with the methylating agent CF₃SO₂OCH₃, the methylated product is confirmed from X-ray crystallography. (b) Example hyperpolarized ¹H NMR spectra recorded after CF₃SO₂OCH₃ (50 mM) is added to a sample of hyperpolarized A in THF-d₈. A is hyperpolarized by shaking a solution of 1 (5 mM), DMSO (25 mM) and A (50 mM) with 3 bar pH₂ for 10 s in the stray field of a 9.4 T magnet. After this process the lid is removed and CF₃SO₂OCH₃ is added. Spectra are single-scanned and are recorded with a 5° flip angle. These three examples are taken 20 s (black), 30 s (blue) and 50 s (red) after the spectral acquisition commenced. (c) The signal intensities of reactant and product in hyperpolarized ¹H NMR spectra over the time course of the spectral acquisition. Each data point took 2 s to acquire and each is recorded immediately after the previous data point. Time t = 0 corresponds to the starting point of spectral acquisition, which is ca 5–10 s after addition of CF₃SO₂OCH₃. Note that each signal is normalized to its intensity in the first spectrum. (d) Example hyperpolarized ¹⁵N NMR spectra recorded for A by shaking a solution of 1 (5 mM), DMSO (50 mM) and A (250 mM) with 3 bar pH₂ for 10 s at 2 μT in DCM-d₂ before CF₃SO₂OCH₃ addition (upper) and immediately after (lower) reshaking with pH₂ and addition of CF₃SO₂OCH₃ (250 mM). Both spectra recorded with a single 90° pulse. The signal at δ 195 is the IMes ligand in 8A.