Harnessing polarisation transfer to indazole and imidazole through signal amplification by reversible exchange to improve their NMR detectability

Abstract

The signal amplification by reversible exchange (SABRE) approach has been used to hyperpolarise the substrates indazole and imidazole in the presence of the co‐ligand acetonitrile through the action of the precataysts [IrCl(COD)(IMes)] and [IrCl(COD)(SIMes)]. 2H‐labelled forms of these catalysts were also examined. Our comparison of the two precatalysts [IrCl(COD)(IMes)] and [IrCl(COD)(SIMes)], coupled with 2H labelling of the N‐heterocyclic carbene and associated relaxation and polarisation field variation studies, demonstrates the critical and collective role these parameters play in controlling the efficiency of signal amplification by reversible exchange. Ultimately, with imidazole, a 700‐fold1H signal gain per proton is produced at 400 MHz, whilst for indazole, a 90‐fold increase per proton is achieved. The co‐ligand acetonitrile proved to optimally exhibit a 190‐fold signal gain per proton in these measurements, with the associated studies revealing the importance the substrate plays in controlling this value. Copyright © 2017 The Authors. Magnetic Resonance in Chemistry published by John Wiley & Sons Ltd.

Signal Amplification by Reversible Exchange (SABRE): From Discovery to Diagnosis

“…[17] Thei dentity of the NHC ligand can also be modified to vary the lifetime of the active complex. [20] Thus far,n oq uantifiable correlation between the steric and electronic properties of the NHC ligands and polarization levels has been established;h owever, aromatic NHC ligands typically show improved performance. [18] Despite there being over 10 commercially available NHC ligands for the SABRE polarization of pyridine, [18,19] to date [IrCl(COD)(IMes)] remains the most impressive mediator of polarization transfer.T his optimum activity is common across ar ange of heterocyclic motifs, although rare examples exist for which this is not the case.…”

“…[37] Substituted pyridyl substrates have proved to be particularly efficacious to SABRE and 1 Hp olarization levels of up to 50 %h ave been reported. [33] More complex substrates have also been shown to be amenable to SABRE with molecules with multiple ligation modes [20,38] and anumber of biologically significant molecules such as nicotinamide, [33] vitamin B 3 , [39] adenosine, [40] and the tuberculosis drug isoniazid showing good signal gains. [35,41] It has also been shown that polarization efficiency is decreased if no 4 J HH coupling is present in the active catalyst and asmaller 5/6 J HH coupling has to be utilized instead.…”

“…[18] Despite there being over 10 commercially available NHC ligands for the SABRE polarization of pyridine, [18,19] to date [IrCl(COD)(IMes)] remains the most impressive mediator of polarization transfer.T his optimum activity is common across ar ange of heterocyclic motifs, although rare examples exist for which this is not the case. [20] Thus far,n oq uantifiable correlation between the steric and electronic properties of the NHC ligands and polarization levels has been established;h owever, aromatic NHC ligands typically show improved performance. [19] This reflects the complexity of the SABRE transfer step,although recently the p-accepting ability parameter [21] has been shown to offer better insight into how the NHC ligand influences the rate of pyridine exchange.…”

Using 2H labelling to improve the NMR detectability of pyridine and its derivatives by SABRE

“…As the rates of ligand exchange are relatively fast, substantial hyperpolarization levels can be produced in just a few seconds. SABRE has been demonstrated for a wide range of substrates which include pyridine and its derivatives, pyrazines, imidazoles, pyrazoles, pyridazines, pyrimidines, amino acids, diazirines, and acetonitrile . It hyperpolarizes not only their 1 H nuclei but the wide array of heteronuclei that they contain …”

Hyperpolarized NMR Spectroscopy: d‐DNP, PHIP, and SABRE Techniques

“…[120] Importantly,S ABRE technique allows to hyperpolarized different 13 Ca nd 15 Nm olecules simultaneously. [182] Aw ide range of nitrogen-based heterocycles, [96,114,[121][122][123] diazirines, [116] sulfur heterocycles, [124] and drug molecules [125] have been hyperpolarized by using the SABRE technique, and these compounds could potentially become suitable molecular probes for hypoxia, [115,118,126] pH sensing, [127] and other processes [128,129] in vivo, although no in vivo application has yet been demonstrated( largely because SABRE has only been widely adopted within the past few years). [63]…”