Iridium(III) Hydrido N-Heterocyclic Carbene–Phosphine Complexes as Catalysts in Magnetization Transfer Reactions

The hyperpolarization (HP) method signal amplification by reversible exchange (SABRE) uses para-hydrogen to sensitize substrate detection by NMR. The catalyst systems [Ir(H)2(IMes)(MeCN)2(R)]BF4 and [Ir(H)2(IMes)(py)2(R)]BF4 [py = pyridine; R = PCy3 or PPh3; IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene], which contain both an electron-donating N-heterocyclic carbene and a phosphine, are used here to catalyze SABRE. They react with acetonitrile and pyridine to produce [Ir(H)2(NCMe)(py)(IMes)(PPh3)]BF4 and [Ir(H)2(NCMe)(py)(IMes)(PCy3)]BF4, complexes that undergo ligand exchange on a time scale commensurate with observation of the SABRE effect, which is illustrated here by the observation of both pyridine and acetonitrile HP. In this study, the required symmetry breaking that underpins SABRE is provided for by the use of chemical inequivalence rather than the previously reported magnetic inequivalence. As a consequence, we show that the ligand sphere of the polarization transfer catalyst itself becomes hyperpolarized and hence that the high-sensitivity detection of a number of reaction intermediates is possible. These species include [Ir(H)2(NCMe)(py)(IMes)(PPh3)]BF4, [Ir(H)2(MeOH)(py)(IMes)(PPh3)]BF4, and [Ir(H)2(NCMe)(py)2(PPh3)]BF4. Studies are also described that employ the deuterium-labeled substrates CD3CN and C5D5N, and the labeled ligands P(C6D5)3 and IMes-d22, to demonstrate that dramatically improved levels of HP can be achieved as a consequence of reducing proton dilution and hence polarization wastage. By a combination of these studies with experiments in which the magnetic field experienced by the sample at the point of polarization transfer is varied, confirmation of the resonance assignments is achieved. Furthermore, when [Ir(H)2(pyridine-h5)(pyridine-d5)(IMes)(PPh3)]BF4 is examined, its hydride ligand signals are shown to become visible through para-hydrogen-induced polarization rather than SABRE.


Sample preparation for experiments with parahydrogen.
10 mg of either (3a) or (4a) were dissolved in 0.5 mL of d 4 -methanol and 4 µL pyridine was added into the solution. The combined solution was taken up by syringe and transferred into an NMR tube fitted with a Young`s tap. The sample in the NMR tube was degassed on a high-vacuum line via three `cool`-pump-thaw cycles (the sample was cooled to -78°C rather than frozen in liquid N 2 to avoid cracking of the NMR tube upon thawing). Parahydrogen, at pressure of 3 atmospheres was then admitted into the NMR tube.

Polarization step
The sample was shaken (to replenish p-H 2 in solution) for approximately 10 seconds in a magnetic field of about 65 G, and then rapidly (within 5 seconds) inserted into the NMR spectrometer, after which NMR spectra were immediately acquired.

Calculations of the enhancement factor
For calculation of the enhancement factor of a 1 H NMR signal, the following formula was used: ‫ܧ‬ ൌ S ୮୭୪ S ୳୬୮୭୪ E = enhancement S pol = signal of polarized sample S unpol = signal of unpolarized (reference) sample Experimentally, reference spectra were acquired on the same sample that was used for the hyperpolarized measurements but after it had fully relaxed (typically 5-10 minutes at high magnetic field). The reference and polarized spectra were collected using identical acquisition parameters. The raw integrals of the relevant resonances in the polarized and unpolarized spectra were then used to determine the enhancement level.

Kinetics of hydride exchange
The ligand exchange studies were completed using the EXSY protocol. 1 A selected resonance was probed and the magnetisation flow was followed as a function of the reaction time between zero and 1 second, in steps typically of 0.1 seconds. The intensity data was then simulated using a differential model, bases on a least-mean squares fit to experiment, in order to extract the associated experimental exchange rate constants.
A larger temperature range is not possible due to very slow exchange below 280 K and rapid deuteration at the higher temperatures, coupled with a 338 K boiling point; lineshape analysis did not prove suitable under these conditions.

X-Ray structure studies of 3c and 5
Diffraction data were collected at 110 K on an Oxford Diffraction SuperNova diffractometer with Mo-K α radiation (λ = 0.71073 Å) using an EOS CCD camera. The crystal was cooled with an Oxford Instruments Cryojet. Diffractometer control, data collection, initial unit cell determination, frame integration and unit-cell refinement was carried out with "Crysalis". 2 Face-indexed absorption corrections were applied using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. 3 OLEX2 4 was used for overall structure solution, refinement and preparation of computer graphics and publication data. Within OLEX2, the algorithm used for structure solution was Superflip charge-flipping. 5 Refinement by full-matrix least-squares used the SHELXL-97 6 algorithm within OLEX2. 4 All non-hydrogen atoms were refined anisotropically. Hydrogen atoms except for hydrides were placed using a "riding model" and included in the refinement at calculated positions. Hydrides were initially located by difference map and allowed to refine.
For structure 3c, the fluorines on tetraflouroborate were disordered and so were modelled in two positions with the ADP of the pairs of fluorines constrained to be equal. The B-F bond lengths were restrained to be equal; the F-B-F distances were restrained to be equal. The Ir-H distances were restrained to 1.603 A (see CCDC entry DETSOK) and the ADP of the methyl group on the acetonitrile was restrained to be approximately isotropic. For structure 5, data collection stopped prematurely leading to slightly low data coverage.

Field dependent polarisation transfer studies
Scheme S1: As illustrated in the manuscript, the hydride ligand symmetry is broken towards all the ligands bound to the metal and consequently hyperpolarisation transfer proceeds widely with the complex.
In order to complete the field dependent polarisation transfer studies that are described, a flow system was employed that enabled a solution containing the catalyst (in this case complex 3 or 4) and the ligand (pyridine or acetonitrile) to be polarised using parahydrogen. This took place within a reaction chamber that was located outside the main NMR magnet. This solution was then transferred into the Bruker Avance III series 400 MHz spectrometer for interrogation in an NMR flow probe. Once interrogated, the solution could be returned to the polarising chamber and this process repeated as required. A coil surrounded the reaction chamber such that a magnetic field could be generated in the z direction. This coil was designed to produce static specified DC fields in the range of 0 to 150 G.

Parahydrogen enables the NMR characterisation
The reaction chamber contained a solution comprising the Ir-complex (5 mM), ligand for polarization (5 -20 fold excess) and 3 mL d 4 -methanol. Parahydrogen, prepared by cooling hydrogen gas over charcoal in a copper block at 30 K, was than bubbled through the solution at the pressure of 3 bar for 6 s. After this point the sample is moved from the polarizer into the NMR probe for observation. It is then returned to the polarizer where it can be repolarized prior to this process being repeated. The solution was then allowed to settle for 1 s before a single scan 1 H NMR spectrum was collected.
The following figures highlight the effect of the magnetic field on the observed polarisation transfer from parahydrogen. Figure S4: Field dependence profile of the signal enhancement seen for the meta protons of pyridine when 1, 2, 3c and 4c are used as the catalyst 3 mL of 5.5mM d 4 -methanol solution of the complex, 20 fold excess of pyridine.

Only Parahydrogen Spectroscopy
Only parahydrogen spectroscopy (OPSY) is a gradient-based PHIP-NMR method. The pulse sequence discriminates between the multiple quantum coherence I x S x term produced from parahydrogen-derived nuclei, and the single quantum I x term generated in a normal thermal equilibrium experiment. 7 OPSY may be chosen to select either double or zero quantum coherence pathways to produce observable magnetization. In the Fig. S5 we see the hydride region of a 1 scan OPSYdq spectrum recorded using flow system after 10 s of bubbling of p-H2 through the d 4 -methanol solution containing 3a and 0.1 eq. pyridine.

Polarization transfer to heteronuclei
In the presence of p-H 2 , it is also possible to see polarization transfer to the 31 P centre of the bound PPh 3 ligand. For example, when the corresponding signal for 3a was examined in this way, a 31 P signal enhancement of 30 fold was determined, as shown in the Figure S6.

Synthesis of [Ir(H) 2 (NCMe) 2 (IMes)(PPh 3 )]BF 4 (3a)
: 0.5 g (0.72 mmol) of 2 was dissolved in 75 mL dry acetone. To this solution 0.19 g (0.72 mmol) of PPh 3 and 0.1 mL of dry acetonitrile (3 equivalents) was added. The color of the solution turned from magenta to red during this process. H 2 was then bubbled through the solution for 4 hours. Slowly a bright yellow solution was formed. The solvent was removed by vacuum and the resulting precipitate was washed with cold diethyl-ether (2 x 5 mL). The yield was 0.55 g (83 %) of a beige powder.

Synthesis of [Ir(H) 2 (py) 2 (IMes)(PPh 3 )]BF 4 (3b)
. This complex was synthesized in an analogous way to that described above for 3a although instead of adding NCMe, 3 equivalents of pyridine was used. The yield was 0.53 g (80%) of a beige powder.

Synthesis of [Ir(H) 2 (NCMe)(py)(IMes)(PPh 3 )]BF 4 (3c)
. 0.0485 g (0.065 mmol) 2 was dissolved in 10 mL dry acetone. To this orange solution 7 L acetonitrile (2 equivalent) and 11 L pyridine (2 equivalent) was added. A red solution is formed, and into this solution 0.0169 g (0.065 mmol) of PPh 3 was added. H 2 was then bubbled through this solution for 4 hours. During this period the solution became bright yellow. The solvent was removed by vacuum. Complex 3c was isolated in the form of a beige powder after washing the remaining sticky product with diethyl-ether (2 x 2 mL). Yield 0.115 g (74 %).