Harnessing asymmetric N-heterocyclic carbene ligands to optimise SABRE hyperpolarisation

The catalytic signal amplification by reversible exchange process is used widely to improve the magnetic resonance detectability of small molecules by hyperpolarisation.

Macquarie University, Sydney, Australia.. Mass spectra were acquired using a Thermo LTQ Orbitrap XL located in the Bioanalytical Mass Spectrometry Facility (BMSF) in UNSW. M is defined as the molecular weight of the compound of interest or cationic fragment for cationic metal complexes.

General Procedure for preparation of NMR samples for SABRE analysis
SABRE experiments were conducted either in a 5 mm NMR tubes fitted with Young's valves (Method 1) or an automated polarizer (Method 2).

Method 1
NMR samples were prepared in 5 mm NMR tubes fitted with Young's valves. Samples were degassed three times on a high vacuum Schlenk line whilst immersing the solution in a dry CO 2 /acetone slush bath prior to p-H 2 (3 bar) addition. Typical procedures for reactions with pyridine, 3,4-lutidine and 3,5-lutidine are described. NMR characterisation data was collected using a range of 1D and 2D methods that include nOe, COSY and HMQC procedures. In a typical experiment, the iridium complex, [Ir(NHC)CODCl] (1a-1e) (5 mM), and five equivalents of either pyridine, 3,4-lutidine or 3,5-lutidine (25 mM) were dissolved in methanol-d 4 (0.6 ml). The bright yellow mixture was degassed and parahydrogen at a pressure of 3 bar was added. When the samples were analysed at 298K, samples were then shaken for 10 s at 65 G of the NMR spectrometer before rapidly transported into the magnet for NMR measurements. When the samples were analysed at 313K, the samples were first placed in a water bath at 313K for 3 minutes. The samples were then quickly shaken for 10 s at 65G of the NMR spectrometer before rapidly transported into the magnet, which was previously heated to 313K for NMR measurements.
The solvent, catalyst and substrate were placed in a glass enclosed tube with two side arms (mixing chamber). The mixing chamber was placed in a tuneable copper coil (0-140 G) situated in a magnetic field, All magnitudes of the magnetic field in which polarization transfer occurs are stated without correction for this local field. The system is entirely automated -the liquid and gas flow from the mixing chamber are computer controlled via the pulse program. The mixing chamber was heated within by an external circulating heated water pump to 313K. Parahydrogen was introduced continuously through an external parahydrogen generator into the mixing chamber to activate the catalyst. Nitrogen gas was used to transfer the hyperpolarized solution from the mixing chamber to the NMR probe head for measurement. Before taking a measurement 1 H NMR measurement, the parahydrogen bubbling time into the mixture was set to be 10s. Before taking a measurement 13 C NMR measurement, the parahydrogen bubbling time into the mixture was set to be 30s. The transportation time was calibrated to 0.4 s. A further delay of 0.5 s was allowed for settling of the sample prior to signal acquisition.

General calculation for 1 H NMR enhancement factors
The 1 H NMR signal enhancement was calculated by using the following equation: ℎ = The reference spectrum, or the spectrum of the unpolarised sample was measured using the same hyperpolarised sample, were recorded after it had fully relaxed. The reference spectrum and the hyperpolarized spectrum were measured using the same acquisition, delay and receiver gain parameters. The raw integrals of the relevant resonances in the reference and the hyperpolarized spectra were used to determine the enhancement levels using the equation above. The results are not corrected for relaxation losses during the transfer time (0.9 s for flow measurements and ca. 4 s for NMR tube measurements) into the NMR magnet and hence reflect experimentally observed values.

General calculation for 13 C NMR enhancement factors
13 C enhancements were calculated by taking the raw integral of the 13 CD 3 OD peak observed from the solvent in the sample after equilibration inside the magnet for 1 minute. 13 CD 3 OD was present in each sample at a concentration of 24.6 M and the resulting SABRE hyperpolarized signal was then scaled according to the concentration of substrate in solution relative to the methanol signal to give the final enhancement value for 13 C. 7

Synthesis of MesIBn.Br
Mesityl imidazole (250 mg, 1.34 mmol) was dissolved in acetonitrile (20 mL). Benzyl bromide (248 mg, 1.45 mmol) was then added dropwise to the brown mixture. The mixture was stirred and heated at reflux overnight. The brown mixture was cooled to room temperature and the solvent was evaporated to give a dark brown oily residue. The crude product was dissolved in a small amount of methanol (3 mL) and diethyl ethyl (30 mL) was added to the mixture with stirring to give the product as a fluffy off-white solid.

Synthesis of MesIEtPh.Br
Mesityl imidazole (575 mg, 3.62 mmol) was dissolved in acetonitrile (20 mL). 2-Phenylethyl bromide (1000 mg, 5.43 mmol) was then added dropwise to the brown mixture. The mixture was stirred and heated at reflux overnight. The brown mixture was cooled to room temperature and the solvent was evaporated to give a dark brown oily residue. The crude product was dissolved in a small amount of methanol (3 mL) and diethyl ethyl (30 mL) was added to the mixture with stirring to give the product as a fluffy off-white solid.       combined and reduced in volume to ca. 10 mL. The solution was cooled in the freezer overnight to give 1e as yellow needle-like crystals.         .05 ***288 K k diss =3.55 ± 0.03 s -1 , total enhancement = 3200. It should be note that the k diss rates correspond to the rate constant for the loss of one of the two axial ligands.      Figure 4S. Intensity of the indicated protons of 3,5-lutidine as a function of polarisation transfer field over the range 0 G to 140 G, in steps of 10 G. Magnetic field / G Total 13C enhancement / a.u. Figure 6S. Polarization transfer field profile for the indicated 13 C NMR signals of 3,4-lutidine achieved when using complex 1d.      C27 13(7) 24(6) 26(4) 10(5) -6(4) 2(4) C32 13(7) 24(6) 26(4) 10(5) -6(4) 2(4)   C24 C25 C31 C32 38.0(12) C22 C21 C28 Ir1 -106.6(5)