Fine-tuning the efficiency of para-hydrogen-induced hyperpolarization by rational N-heterocyclic carbene design

Abstract

Iridium N-heterocyclic carbene (NHC) complexes catalyse the para-hydrogen-induced hyperpolarization process, Signal Amplification by Reversible Exchange (SABRE). This process transfers the latent magnetism of para-hydrogen into a substrate, without changing its chemical identity, to dramatically improve its nuclear magnetic resonance (NMR) detectability. By synthesizing and examining over 30 NHC containing complexes, here we rationalize the key characteristics of efficient SABRE catalysis prior to using appropriate catalyst-substrate combinations to quantify the substrate’s NMR detectability. These optimizations deliver polarizations of 63% for 1H nuclei in methyl 4,6-d2-nicotinate, 25% for 13C nuclei in a 13C2-diphenylpyridazine and 43% for the 15N nucleus of pyridine-15N. These high detectability levels compare favourably with the 0.0005% 1H value harnessed by a routine 1.5 T clinical MRI system. As signal strength scales with the square of the number of observations, these low cost innovations offer remarkable improvements in detectability threshold that offer routes to significantly reduce measurement time.

Simulating Non‐linear Chemical and Physical (CAP) Dynamics of Signal Amplification By Reversible Exchange (SABRE)

“…The “SABRE formula” was the first attempt to explicitly include the chemical reaction, relaxation, and polarization transfer in a single analytical formula. An important conclusion from this study was that the polarization is proportional to the relaxation time T 1 of the bound substrate and dihydrogen (in the SABRE complex); soon after, this was confirmed experimentally …”

Relayed hyperpolarization from para-hydrogen improves the NMR detectability of alcohols

“…Co-ligands have therefore been employed to reduce spin-dilution and oen provide improved signal gains. 43,51 For SABRE-Relay, we propose that it is not only the total signal enhancement of the carrier amine but the efficiency of constructive proton exchange between the amine and the alcohol that is important. To probe these two effects a number of dry samples were prepared that contained increasing concentrations of d 7 -BnNH 2 and alcohol relative to the [IrCl(COD)(IMes)] pre-catalyst.…”

“…First, it is well established that the lifetime of active catalyst is instrumental in controlling SABRE polarization transfer efficiency. 35 There are a number of methods for controlling this parameter including ligand design 42,43 and temperature variation. The optimal catalyst lifetime is related to the size of its hydride-hydride and hydridesubstrate scalar coupling constants.…”

The Detection and Reactivity of Silanols and Silanes Using Hyperpolarized 29Si Nuclear Magnetic Resonance

“…After SABRE‐Relay transfer, an improved silanol signal gain of 92±4‐fold was observed (Figure B). Modification of the steric and electronic properties of the NHC ligand has also been shown to modulate the ligand dissociation rates and thereby lead to better SABRE enhancement . The rate of equatorial BnNH 2 dissociation from [Ir(H) 2 (IMes)(BnNH 2 ‐d 7 ) 3 ]Cl is 3.33 s −1 and therefore lower than predicted to be optimal .…”

“… Catalyst effects on the SABRE‐Relay polarization of T t BOS. A) Structures of catalysts and their buried volumes (% V bur ) . B) SABRE‐Relay signal enhancements using [IrCl(COD)(NHC)] (5 m m ), BnNH 2 ‐ d 7 (50 m m ), and T t BOS (50 m m ) in CD 2 Cl 2 (0.6 mL), 3 bar p‐H 2 for 10 s at 70 G. C) Δ G ≠298 values for BnNH 2 (solid) and hydride (hashed) ligand dissociation from the active catalysts of type [Ir(H) 2 (NHC)(BnNH 2 ) 3 ]Cl.…”