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

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 spinorder lifetimes to probe in situ reactivity out to 3 x 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.

Automated summary

In this study, we demonstrate how signal amplification by reversible exchange hyperpolarization of 15N-containing synthons can be used to study their reactivity. By using a range of spin-polarization transfer catalysts, we successfully probe various in situ reactions and develop simple methods for the preparation of hyperpolarized substances. This work is of significant importance for the synthesis of future hyperpolarized pharmaceuticals.