NMR/MRI SIGNAL ENHANCEMENT BY REVERSIBLE EXCHANGE (SABRE) AND HETEROGENEOUS SABRE (HET-SABRE)

Author

Fan Shi, Southern Illinois University CarbondaleFollow

Date of Award

5-1-2015

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

Goodson, Boyd

Abstract

Signal Amplification by Reversible Exchange, or SABRE, is a type of PHIP (ParaHydrogen Induced Polarization) pioneered by Duckett, Green, and co-workers where an organometallic catalyst is used to co-locate parahydrogen (pH2) and a molecular substrate to be hyperpolarized. Like traditional PHIP, SABRE is of interest because it is cost-effective, potentially continuous, scalable, and rapid (achieving polarization enhancement in seconds). However unlike traditional PHIP, SABRE does not require permanent alteration of the substrate to hyperpolarize it. In addition to achieving 1H polarizations of several percent, SABRE in microTesla fields has enabled the creation of ~10% polarization for heteronuclear (15N) spins. I will discuss on a series of novel catalysts that I developed in my Ph.D program. Firstly of all, a heterogeneous SABRE ("HET-SABRE") catalyst where catalytic moieties were tethered to solid supports. Although NMR enhancements were modest (5), this initial work showed the feasibility of the approach. Next, two types of nanoscale catalysts were created to explore SABRE at the interface between heterogeneous and homogeneous conditions. Nanoparticle and polymer comb variants were synthesized by covalently tethering Ir-based catalysts to support materials comprised of TiO2/PMAA (poly methacrylic acid) and PVP (polyvinyl pyridine), respectively, and characterized by AAS, NMR, and DLS. Following pH2 delivery to mixtures containing one type of "nano-SABRE" catalyst, a target substrate, and ethanol, up to ~(-)40-fold and ~(-)7-fold 1H NMR signal enhancements were observed for pyridine using the nanoparticle and polymer comb catalysts, respectively, following transfer to high field (9.4 T). These enhancements appear to result from intact particles and not from any catalyst molecules leaching from their supports. Unlike the case with homogeneous SABRE catalysts, high-field (in situ) SABRE effects were generally not observed with the nanoscale catalysts. The potential for separation and reuse of such catalyst particles is also demonstrated. Besides the effort on green chemistry of SABRE catalyst, I have been investigating the preparation of different variants of the "standard" SABRE catalyst--[IrCl(COD)(IMes)] (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene; COD=cyclooctadiene)]--for performing SABRE in otherwise "pure" aqueous environments. Because of the poor aqueous solubility of SABRE catalysts, previous promising efforts have used co-solvents to achieve SABRE in aqueous/organic mixtures. However, I have found that the chemical changes that accompany this catalyst's activation also endow it with water solubility. Complete removal of the organic solvent following activation and subsequent re-constitution of the activated structure in deuterated water allowed up to ~(-)33-fold 1H signal enhancements to be obtained for nicotinamide. Additionally, I have investigated chemical alteration of the structure of the pre-activated catalyst to endow greater water solubility. PEGylation of the aromatic carbine moiety provided much greater aqueous solubility, but while SABRE-active in organic solutions, the catalyst lost activity in >50% water (an effect under ongoing study). As an alternative approach, synthesis of a di-Ir complex precursor where the COD rings have been replaced by CODDA (1,2-dihydroxy-3,7-cyclooctadiene) permits creation of a water-soluble catalyst [IrCl(CODDA)IMes] that enables aqueous SABRE in a single step without need for any organic co-solvent; the potential utility of the catalyst is demonstrated with the ~(-)32-fold enhancement of 1H signals of pyridine in water with only 1 atm of pH2. Taken together, these results support the utility of rational design for improving SABRE and HET-SABRE for applications varying from fundamental studies of catalysis to biomedical imaging. In the following, I also investigate different aspects of how catalyst structure can affect resulting SABRE enhancements, including the interplay of catalyst structure and temperature for optimal SABRE, as well as the confounding effects on catalyst activation. Results from the "standard" Ir SABRE catalyst (1)--[IrCl(COD)(IMes)] (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene; COD=cyclooctadiene)]--are compared with those obtained with variants respectively created by synthetically replacing the -Cl moiety with 4-amino-pyridine (4AP, 2), (diphenylphosphino)ethylamine (DPPA, 3), triphenyl phosphine (TPP, 4), and tribenzyl phosphine (TBP, 5); a sixth variant (6) was serendipitously created by an alternate synthetic route for (1) that appears to result in a polymorph according to x-ray crystallography. Studies of activation rate found that (4) and (5) activated the fastest under pH2 exposure (~20 s, an order of magnitude faster than (1)); activation rate was inversely correlated with SABRE enhancement, with peak 1H polarization enhancement ( ranging from only ~(-)44 for (4) to nearly ~(-)1900 for (1) (or PH~6%) for pyridine at 9.4 T, and ~(-)240 for nicotinamide. Although (1) gave the overall highest  values as expected, other catalysts gave rise to better SABRE performance in other temperature regimes: Optimal temperatures varied significantly, e.g. ~273 K for (2) to ~310-320 K for (1); the optimal temperature for (6) was considerably lower (<273 K) than that for (1), despite the apparent structural similarity. Taken together, these results show that full optimization of SABRE enhancement for a given experiment (with respect to substrate, target nucleus, etc.) may require systematic variation of parameters including catalyst ligand choice and temperature (to modulate binding affinities and off rates with respect to relevant spin-spin couplings), in addition to pH2 partial pressure, flow rate, and magnetic field. Finally, some research on an ssNMR will be represented, to show the potential application of ssNMR on the coating detection.