A four week undergraduate group mini-project that introduces upper-division undergraduate students to sustainable synthesis, reaction optimization, and quantitative NMR spectroscopy is described. Students work as a team to optimize the stereoselective reduction of substituted cyclohexanones using polymethylhydrosiloxane (PMHS). Through a scaffolded progression, the project emphasizes research-led practice with student autonomy and cooperative learning while also addressing sustainability goals by replacing traditional hydride reagents with a safer, greener alternative. Students prepare an assessed individual research report that were subjected to a thematic analysis that reveals students' growing awareness of green chemistry considerations, including solvent selection and waste metrics. Evaluation of student feedback over four cohorts demonstrates high levels of project engagement with students reporting increased confidence in experimental design and appreciation for the real-world challenges of chemical research. The project offers a flexible and replicable model for embedding sustainability, autonomy, and authentic research experiences into the undergraduate chemistry curriculum.

The neutral catalysts [IrCl(H)2(NHC)(substrate)2] or [IrCl(H)2(NHC)(substrate)(sulfoxide)] are used to transfer polarization from para hydrogen (pH2) to 3,5-dichloropyridine and 3,5-dibromopyridine substrates. This is achieved in a rapid, reversible, and low-cost process that relies on ligand exchange within the active catalyst. Notably, the sulfoxide-containing catalyst systems produced NMR signal enhancements between 1 and 2 orders of magnitude larger than its unmodified counterpart. Consequently, this signal amplification by reversible exchange hyperpolarization method can boost the 1H, 13C, and 15N nuclear magnetic resonance (NMR) signal intensities by factors up to 4350, 1550, and 46,600, respectively (14.0, 1.3, and 15.4% polarization). In this paper, NMR and X-ray crystallography are used to map the evolution of catalytically important species and provide mechanistic rational for catalytic efficiency. Furthermore, applications in spontaneous radiofrequency amplification by stimulated emission and NMR reaction monitoring are also shown.

PURPOSE:Enabling drug tracking (distribution/specific pathways) with magnetic resonance spectroscopy requires manipulation (via hyperpolarization) of spin state populations and targets with sufficiently long magnetic lifetimes to give the largest possible window of observation. Here, we demonstrate how the proton resonances of a group of thienopyridazines (with known anticancer properties), can be amplified using the para-hydrogen (p-H2 ) based signal amplification by reversible exchange (SABRE) hyperpolarization technique. METHODS:Thienopyridazine isomers, including a 2 H version, were synthesized in house. Iridium-based catalysts dissolved in a methanol-d4 solvent facilitated polarization transfer from p-H2 gas to the target thienopyridazines. Subsequent SABRE 1 H responses of hyperpolarized thienopyridazines were completed (400 MHz NMR). Pseudo-singlet state approaches were deployed to extend magnetic state lifetimes. Proof of principle spectral-spatial images were acquired across a range of field strengths (7T-9.4T MRI). RESULTS:1 H-NMR signal enhancements of -10,130-fold at 9.4T (~33% polarization) were achieved on thieno[2,3-d]pyridazine (T[2,3-d]P), using SABRE under optimal mixing/field transfer conditions. 1 H T1 lifetimes for the thienopyridazines were ~18-50 s. Long-lived state approaches extended the magnetic lifetime of target proton sites in T[2,3-d]P from an average of 25-40 seconds. Enhanced in vitro imaging (spatial and chemical shift based) of target T[2,3-d]P was demonstrated. CONCLUSION:Here, we demonstrate the power of SABRE to deliver a fast and cost-effective route to hyperpolarization of important chemical motifs of anticancer agents. The SABRE approach outlined here lays the foundations for realizing continuous flow, hyperpolarized tracking of drug delivery/pathways.

Here, we show how signal amplification by reversible exchange hyperpolarization of a range of 15N-containing synthons can be used to enable studies of their reactivity by 15N nuclear magnetic resonance (NO2- (28% polarization), ND3 (3%), PhCH2NH2 (5%), NaN3 (3%), and NO3- (0.1%)). A range of iridium-based spin-polarization transfer catalysts are used, which for NO2- work optimally as an amino-derived carbene-containing complex with a DMAP-d2 coligand. We harness long 15N spin-order lifetimes to probe in situ reactivity out to 3 × T1. In the case of NO2- (T1 17.7 s at 9.4 T), we monitor PhNH2 diazotization in acidic solution. The resulting diazonium salt (15N-T1 38 s) forms within 30 s, and its subsequent reaction with NaN3 leads to the detection of hyperpolarized PhN3 (T1 192 s) in a second step via the formation of an identified cyclic pentazole intermediate. The role of PhN3 and NaN3 in copper-free click chemistry is exemplified for hyperpolarized triazole (T1 < 10 s) formation when they react with a strained alkyne. We also demonstrate simple routes to hyperpolarized N2 in addition to showing how utilization of 15N-polarized PhCH2NH2 enables the probing of amidation, sulfonamidation, and imine formation. Hyperpolarized ND3 is used to probe imine and ND4+ (T1 33.6 s) formation. Furthermore, for NO2-, we also demonstrate how the 15N-magnetic resonance imaging monitoring of biphasic catalysis confirms the successful preparation of an aqueous bolus of hyperpolarized 15NO2- in seconds with 8% polarization. Hence, we create a versatile tool to probe organic transformations that has significant relevance for the synthesis of future hyperpolarized pharmaceuticals.

Abstract Utility of the pyridazine motif is growing in popularity as pharmaceutical and agrochemical agents. The detection and structural characterisation of such materials is therefore imperative for the successful development of new products. Signal amplification by reversible exchange (SABRE) offers a route to dramatically improve the sensitivity of magnetic resonance methods, and we apply it here to the rapid and cost‐effective hyperpolarisation of substituted pyridazines. The 33 substrates investigated cover a range of steric and electronic properties and their capacity to perform highly effective SABRE is assessed. We find the method to be tolerant to a broad range of electron donating and withdrawing groups; however, good sensitivity is evident when steric bulk is added to the 3‐ and 6‐positions of the pyridazine ring. We optimise the method by reference to a disubstituted ester that yields signal gains of >9000‐fold at 9.4 T (>28% spin polarisation).

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.

AbstractSilanols and silanes are key precursors and intermediates for the synthesis of silicon‐based materials. While their characterization and quantification by 29Si NMR spectroscopy has received significant attention, it is a technique that is limited by the low natural abundance of 29Si and its low sensitivity. Here, we describe a method using p‐H2 to hyperpolarize 29Si. The observed signal enhancements, approaching 3000‐fold at 11.7 T, would take many days of measurement for comparable results under Boltzmann conditions. The resulting signals were exploited to monitor the rapid reaction of tris(tert‐butoxy)silanol with triflic anhydride in a T1‐corrected process that allows for rapid quantification. These results demonstrate a novel route to quantify dynamic processes and intermediates in the synthesis of silicon materials.

Signal amplification by reversible exchange (SABRE) is a hyperpolarization technique that uses a metal complex to catalytically transfer magnetization from parahydrogen to molecules of interest. SABRE is used here to monitor the decarboxylation of sodium pyruvate-1,2-[13C2] at a 15 mM concentration to form ethanoic acid and CO2 upon reaction with hydrogen peroxide (150 mM). The rate constant of this reaction is determined by hyperpolarized 13C SABRE-NMR spectroscopy as 0.056 ± 0.003 dm3 mol-1 s-1 at 298 K and is comparable to that determined from thermal 1H NMR (k = 0.050 ± 0.003 dm3 mol-1 s-1) and UV measurements (k = 0.053 ± 0.001 dm3 mol-1 s-1). The hyperpolarized reaction intermediate 2-hydroperoxy-2-hydroxypropanoate is detected in a single scan hyperpolarized 13C NMR spectrum. This work highlights how SABRE hyperpolarization can be used as a tool for the precise monitoring of chemical transformations by hyperpolarized NMR spectroscopy.

Signal Amplification by Reversible Exchange (SABRE) is an inexpensive and simple hyperpolarization technique that is capable of boosting nuclear magnetic resonance sensitivity by several orders of magnitude. It utilizes the reversible binding of para -hydrogen, as hydride ligands, and a substrate of interest to a metal catalyst to allow for polarization transfer from para -hydrogen into substrate nuclear spins. While the resulting nuclear spin populations can be dramatically larger than those normally created, their lifetime sets a strict upper limit on the experimental timeframe. Consequently, short nuclear spin lifetimes are a challenge for hyperpolarized metabolic imaging. In this report, we demonstrate how both hyperpolarization and long nuclear spin lifetime can be simultaneously achieved in nitrogen-15 containing deriva-tives of pyridazine and phthalazine by SABRE. These substrates were chosen to reflect two distinct classes of 15 N 2 -coupled species that differ according to their chemical symmetry and thereby achieve different nuclear spin lifetimes. The pyridazine derivative proves to exhibit a signal lifetime of ∼ 2.5 min and can be produced with a signal enhancement of ∼ 2700. In contrast, while the phthalazine derivative yields a superior 15 000-fold 15 N signal enhancement at 11.7 T, it has a much shorter signal lifetime.

Hyperpolarisation techniques such as signal amplification by reversible exchange (SABRE) can deliver NMR signals several orders of magnitude larger than those derived under Boltzmann conditions. SABRE is able to catalytically transfer latent magnetisation from para-hydrogen to a substrate in reversible exchange via temporary associations with an iridium complex. SABRE has recently been applied to the hyperpolarisation of pyruvate, a substrate often used in many in vivo MRI studies. In this work, we seek to optimise the pyruvate-13C2 signal gains delivered through SABRE by fine tuning the properties of the active polarisation transfer catalyst. We present a detailed study of the effects of varying the carbene and sulfoxide ligands on the formation and behaviour of the active [Ir(H)2(η2-pyruvate)(sulfoxide)(NHC)] catalyst to produce a rationale for achieving high pyruvate signal gains in a cheap and refreshable manner. This optimisation approach allows us to achieve signal enhancements of 2140 and 2125-fold for the 1-13C and 2-13C sites respectively of sodium pyruvate-1,2-[13C2].

To prepare the way for using the isotopically labelled SABRE hyperpolarized 4,6-d2-nicotinamide as an MRI agent in humans we have performed an in-vivo study to measure its pharmacokinetics in the plasma of healthy rats after intravenous and oral administration. Male Han Wistar rats were dosed with either 4,6-d2-nicotinamide or the corresponding control, non-labelled nicotinamide, and plasma samples were obtained at eight time points for up to 24 h after administration. Pharmacokinetic parameters were determined from agent concentration-versus-time data for both 4,6-d2-nicotinamide and nicotinamide. 4,6-d2-Nicotinamide proved to be well tolerated regardless of route of administration at the concentrations used (20, 80 and 120 mg/kg). Pharmacokinetic parameters were similar after oral and intravenous administration and similar to those obtained for nicotinamide. Analysis of nicotinamide plasma concentrations after dosing 4,6-d2-nicotinamide intravenously demonstrates a reversible exchange of endogenous nicotinamide by this labelled agent over the time-course of our assays. Supported by a large body of evidence for the safety of nicotinamide when dosed orally in humans, we conclude that 4,6-d2-nicotinamide can also be safely administered intravenously, which will provide significant benefit when using this agent for planned imaging studies in humans.

The monosaccharides glucose and fructose are rapidly detected and quantified by13C NMR in conjunction with the hyperpolarisation method signal amplification by reversible exchange-relay.

NMR signal strength improvements delivered through hyperpolarisation via para-hydrogen enable the facile detection of alcohols.

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 1 H nuclei in methyl 4,6- d 2 -nicotinate, 25% for 13 C nuclei in a 13 C 2 -diphenylpyridazine and 43% for the 15 N nucleus of pyridine- 15 N. These high detectability levels compare favourably with the 0.0005% 1 H 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.

The asymmetric lithiation-trapping of six-membered N-Boc heterocycles using s-BuLi and two different Alexakis diamines is reported. These readily available ligands outperform the current 'best-in-class' sparteine-type diamines in the lithiation and benzophenone trapping of N-Boc piperazines and the lithiation-cyclisation-trapping of N-Boc-4-chloropiperidine. In situ IR spectroscopy has been used to optimise lithiation times and to discover previously unknown subtleties regarding the lithiation step.

The hyperpolarization technique, Signal Amplification by Reversible Exchange (SABRE), has the potential to improve clinical diagnosis by making molecular magnetic resonance imaging in vivo a reality. Essential to this goal is the ability to produce a biocompatible bolus for administration. We seek here to determine how the identity of the catalyst and substrate affects the cytotoxicity by in vitro study, in addition to reporting how the use of biocompatible solvent mixtures influence the polarization transfer efficiency. By illustrating this across five catalysts and 8 substrates, we are able to identify routes to produce a bolus with minimal cytotoxic effects.

By introducing a range of 2H labels into pyridine and the para‐substituted agents, methyl isonicotinate and isonicotinamide, we significantly improve their NMR detectability in conjunction with the signal amplification by reversible exchange process. We describe how the rates of T1 relaxation for the remaining 1H nuclei are increased and show how this leads to a concomitant increase in the level of 1H and 13C hyperpolarization that can ultimately be detected.

Para hydrogen is used to give efficient NMR detection of array of amines, amides, alcohols, carboxylates, carbonates, and phosphates.

Signal amplification by reversible exchange (SABRE) turns typically weak magnetic resonance responses into strong signals making previously impractical measurements possible. This technique has gained significant popularity because of its speed and simplicity. This Minireview tracks the development of SABRE from the initial hyperpolarization of pyridine in 2009 to the point in which 50 % 1 H polarization levels have been achieved in a di-deuterio-nicotinate, a key step in the pathway to potential clinical use. Simple routes to highly efficient 15 N hyperpolarization and the creation of hyperpolarized long-lived magnetic states are illustrated. To conclude, we describe how the recently reported SABRE-RELAY approach offers a route for parahydrogen to hyperpolarize a much wider array of molecular scaffolds, such as amides, alcohols, carboxylic acids, and phosphates, than was previously thought possible. We predict that collectively these developments ensure that SABRE will significantly impact on both chemical analysis and the diagnosis of disease in the future.