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-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.