Hyperpolarisation of weakly binding N-heterocycles using signal amplification by reversible exchange

Signal Amplification by Reversible Exchange (SABRE) is a catalytic method for improving the detection of molecules by magnetic resonance spectroscopy. It achieves this by simultaneously binding the target substrate (sub) and para-hydrogen to a metal centre. To date, sterically large substrates are relatively inaccessible to SABRE due to their weak binding leading to catalyst destabilisation. We overcome this problem here through a simple co-ligand strategy that allows the hyperpolarisation of a range of weakly binding and sterically encumbered N-heterocycles. The resulting ¹H NMR signal size is increased by up to 1400 times relative to their more usual Boltzmann controlled levels at 400 MHz. Hence, a significant reduction in scan time is achieved. The SABRE catalyst in these systems takes the form IrX(H)₂(NHC)(sulfoxide)(sub)] where X = Cl, Br or I. These complexes are shown to undergo very rapid ligand exchange and lower temperatures dramatically improve the efficiency of these SABRE catalysts.

The scope of the hyperpolarisation method Signal Amplification by Reversible Exchange (SABRE) is dramatically expanded through the use of co-ligands to substrates that weakly interact with the active cataylst.

Hyperpolarised magnetic resonance is receiving increasing attention from both the analytical science and medical communities due to its ability to create signals that are many orders of magnitude higher than those normally detected under Boltzmann control.^1–6 The time and cost benefits associated with this improvement have propelled this area of research forward over the past few decades. Two of the most prominent techniques used to create hyperpolarisation are dissolution Dynamic Nuclear Polarisation (d-DNP) and Para-Hydrogen Induced Polarisation (PHIP),^7,8 which derive their non-Boltzmann spin energy level populations from interactions with unpaired electrons and para-hydrogen (p-H₂, the singlet spin isomer of hydrogen), respectively. Both of these methods have been reviewed in detail.^3–5,9,10Signal Amplification by Reversible Exchange (SABRE) is a PHIP method that does not involve the chemical incorporation of p-H₂ into the target substrate.^11,12 Instead, under SABRE, spin order transfer proceeds catalytically through the temporary formation of a scalar coupling network between p-H₂ derived hydride ligands and the substrate''s nuclei whilst they are located in a transient metal complex. The most common catalysts are of the type Ir(H)₂(NHC)(sub)₃]Cl (where NHC = N-heterocyclic carbene and sub = the substrate of interest, Fig. 1a),^13,14 although other variants are known.^15–17 For SABRE to be accomplished, the target substrate must be able to reversibly ligate to the metal centre and this limits the methods applicability; although several routes to overcome this have been reported.^18–20 Recently, the use of bidentate ancillary ligands such as NHC-phenolates¹⁶ and phosphine-oxazoles²¹ has been shown to expand the applicability of SABRE for a variety of different ligands and solvents (Fig. 1b). For example, use of the PHOX ligand (PHOX = (2-diphenylphosphanyl)phenyl-4,5-dihydrooxazole) gives ¹H NMR signal gains of up to 132-fold for 2-picoline; a substrate previously shown to be unpolarised under classic SABRE conditions.²²Open in a separate windowFig. 1Development of the SABRE method for hyperpolarisation of a range of substrates.The use of co-ligands to stabilise the active SABRE catalyst has proven successful for substrates that weakly associate to the catalyst (Fig. 1c). Of particular note is the hyperpolarisation of sodium 1,2]-¹³C₂-pyruvate²³ and sodium ¹³C-acetate²⁴ which could be used as in vivo metabolic probes. The importance of co-ligands in breaking the chemical symmetry of the SABRE catalyst is also well established and co-ligands such as acetonitrile,²⁵ sulfoxides,^23,26 1-methyl-1,2,3-triazole²⁷ and substrate isotopologues²⁸ have been employed.We report here on the use of co-ligands to allow the NMR hyperpolarisation of weakly binding N-heterocyclic derived substrates with functionality in the ortho-position that have proven to be routinely inaccessible to the SABRE technique (Fig. 1d). ¹H signal gains of up to 1442 ± 84-fold were obtained for some of these substituted pyridines at 9.4 T and the expansion of this approach to ¹³C and ¹⁵N detection and other N-heterocyclic motifs is also exemplified.