Real-Time High-Sensitivity Reaction Monitoring of Important Nitrogen-Cycle Synthons by ¹⁵N Hyperpolarized Nuclear Magnetic Resonance

Abstract

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-d 2 coligand. We harness long 15N spin-order lifetimes to probe in situ reactivity out to 3 × T 1. In the case of NO2 – (T 1 17.7 s at 9.4 T), we monitor PhNH2 diazotization in acidic solution. The resulting diazonium salt (15N-T 1 38 s) forms within 30 s, and its subsequent reaction with NaN3 leads to the detection of hyperpolarized PhN3 (T 1 192 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 (T 1 < 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 + (T 1 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.

Real-time reaction monitoring of Azide-Alkyne cycloadditions us-ing benchtop NMR-based Signal Amplification by Reversible Ex-change (SABRE)

“…A recent study on SPAAC by Ducket's group has revealed that 15 N isotope phenyl azide (Ph- 15 N 3 ) contained long T1 values enabling strong hyperpolarization when reacting with BCN. 49 It is claimed that this data depicts the successful examination of SPAAC reactions, as it con rms the possibility to show 15 N signals for the phenyl azide and the triazole, simultaneously. Another study presents the hyperpolarization of triazole containing antifungal drugs and, thus, deducing detailed hyperpolarization mechanisms for both 1 H and 15 N nuclei.…”

“…They also have the additional bene t of attenuating the effect of relaxation. 49 Signal enhancement is effective for non-deuterated triazole derivatives (Figure S5). Compared with Methanol, DMSO can penetrate biological membranes, such as human skin, affecting the lipid structure and causing bilayer breaks.…”

“…Owing to the associated interest and importance, SABRE-based experiments on SPAAC using 15 N-containing synthons was recently performed, focusing on 15 N nuclei within the structure. 49 However, SABRE can also deliver to various structural components combined with 1 H, 42-44 13 C, 24,45,46 and 15 N 47,48 NMR signals; therefore, there is the possibility of observing a wider range of hyperpolarization by also focusing on other NMR-active nuclei.…”

Spin Hyperpolarization in Modern Magnetic Resonance

“…887 In another study, SABRE was employed to monitor chemical synthesis of methyl 2-(nicotinamide) acetate, 888 providing signal enhancements over 130-fold with 50%enriched p-H 2 . Most recently, SABRE was utilized 889 to produce high levels of 15 N hyperpolarization of a range of important nitrogen-containing synthons, such as NO 2 − , PhCH 2 NH 2 , ND 3 , NaN 3 , and NO 3 − , all exhibiting sufficiently long T 1n times to permit detection of hyperpolarized products and intermediates upon their chemical transformations to a range of potentially useful nitrogen-rich products.…”

NMR methods for the analysis of mixtures

“…SABRE is also being used for reaction monitoring applications. 126–128 This was illustrated by Halse, Duckett and co-workers, who monitored the activation of the SABRE catalyst and proton-deuterium exchange in a SABRE hyperpolarised substrate. 126 This was achieved with single-shot measurement of hyperpolarisation lifetimes for several protons in the substrates, which reflect both the extent of catalyst activation and the degree of substrate deuteration.…”