Modifications and a mechanistic study of the Ley-Griffith oxidation, and generation of hydroxyl radicals in the gas phase

Abstract

The Ley-Griffith oxidation was published 30 years ago, and since then it has become one of the most commonly used alcohol to aldehyde or ketone oxidation methods used in both academic and industrial laboratories. Since its discovery, a number of modifications have been developed, but none that have superseded the original conditions. The discovery of an NMO·TPB salt, a nonhygroscopic NMO salt, lead us to develop a modulation of reactivity in the Ley-Griffith oxidation, limiting the reactivity to activated alcohols (allylic or benzylic). A number of other tetraphenylborate amine N-oxide salts were synthesised leading to the discovery of the second generation salt DABCOO·TPB, which gave increased yields and selectivity for activated alcohols; overall providing the avoidance of protecting groups when multiple diols are present within a molecule. TMEDAO2 was utilised in place of NMO in a different modification, leading to thedevelopment of a Ley-Griffith/Wittig tandem oxidation reaction. A new range of perruthenate catalysts were designed and developed, which show increased stability in the solid state under ambient conditions (i.e. bench stability), and identical activity as compare to the Ley-Griffith catalyst TPAP. X-ray crystal structures of organic soluble perruthenates have been obtained for the first time. There is little published data on the mechanism of the Ley-Griffith oxidation with literature proposals limited to the non-catalytic system (alcohol + TPAP). Consequently, there is limited information about the role of NMO, the exact catalytic species and why high conversion is often challenging. We addressed this aspect by analysing the Ley-Griffith oxidation (NMO + TPAP + alcohol) via both the organic oxidation reaction and the inorganic ruthenium species simultaneously. This was performed by analysing samples from the same reaction using UV-vis spectroscopy and, high resolution mass spectrometry (HRMS), gas chromatography mass spectrometry GCMS/UV-vis spectroscopy, GCMS/HRMS, electron paramagnetic resonance (EPR), UV-vis/EPR, 1H NMR, 99Ru NMR, cyclic voltammetry (CV) and spectroelectrochemistry. A rate law for the reaction was also generated via UV-vis spectroscopy. We discovered that the role of NMO is to rescue Ru(V), reoxidising it to perruthenate, but it also hydrogen bonds to water and the alcohol. The active catalyst appears to be perruthenate (TPAP), with no evidence for a dimmer or Ru(VI) catalyst leading to us to propose a catalytic cycle. Hydroxyl radicals have been generated in the gas phase via mass spectrometry fragmentation of 4- (hydroxymethyl)-N,N,N-trimethylbenzenaminium iodide. These results were confirmed via the use of deuterated alcohols and a range of similar benzyl alcohols. Two related esters were synthesised, and submitted to the same mass spectrometry conditions from which decarboxylation in the gas iii phase was observed. This is now being developed into a solution phase next generation Barton decarboxylation reaction.