Lewis Acid Coordination Redirects S‐Nitrosothiol Signaling Output

Abstract

S-Nitrosothiols (RSNOs) serve as air-stable reservoirs for nitric oxide in biology. While copper enzymes promote NO release from RSNOs by serving as Lewis acids for intramolecular electron-transfer, redox-innocent Lewis acids separate these two functions to reveal the effect of coordination on structure and reactivity. The synthetic Lewis acid B(C₆ F₅ )₃ coordinates to the RSNO oxygen atom, leading to profound changes in the RSNO electronic structure and reactivity. Although RSNOs possess relatively negative reduction potentials, B(C₆ F₅ )₃ coordination increases their reduction potential by over 1 V into the physiologically accessible +0.1 V vs. NHE. Outer-sphere chemical reduction gives the Lewis acid stabilized hyponitrite dianion trans-[LA-O-N=N-O-LA]^2- [LA=B(C₆ F₅ )₃ ], which releases N₂ O upon acidification. Mechanistic and computational studies support initial reduction to the [RSNO-B(C₆ F₅ )₃ ] radical anion, which is susceptible to N-N coupling prior to loss of RSSR.