MIDA boronates are hydrolysed fast and slow by two different mechanisms

Abstract

MIDA boronates (N-methylimidodiacetic boronic acid esters) serve as an increasingly general platform for building-block-based small molecule construction, largely due to the dramatic and general rate differences with which they are hydrolysed under various basic conditions. Yet the mechanistic underpinnings of these rate differences have remained unclear, hindering efforts to address current limitations of this chemistry. Here we show that there are two distinct mechanisms for this hydrolysis: one is base-mediated and the other neutral. The former can proceed more than three orders of magnitude faster, and involves rate-limiting attack at a MIDA carbonyl carbon by hydroxide. The alternative ‘neutral’ hydrolysis does not require an exogenous acid/base and involves rate-limiting B-N bond cleavage by a small water cluster, (H2O)n. The two mechanisms can operate in parallel, and their relative rates are readily quantified by 18O incorporation. Whether hydrolysis is ‘fast’ or ‘slow’ is dictated by the pH, the water activity (aw), and mass-transfer rates between phases. These findings stand to rationally enable even more effective and widespread utilisation of MIDA boronates in synthesis.

Towards the generalized iterative synthesis of small molecules

“…Deprotection can proceed through two different mechanisms: (1) under strong aqueous base, rate-limiting attack of hydroxide on the carbonyl carbon, or (2) under weakly basic or neutral aqueous conditions, slower rate-limiting attack of water on the boron-nitrogen bond. 137 This mechanistic divergence is consistent with extensive reaction kinetics, kinetic isotope effects, 18 O labelling, and computational data. In-situ slow release of MIDA boronates has been advantageous for many reactions including couplings of unstable heteroarylboronates, 138,139 polymerization reactions, 140–141 asymmetric methodologies, 142 the synthesis of organic photovoltaics, 143 and a one-pot homologation of boronic acids.…”

Chemoselective oxidation of aryl organoboron systems enabled by boronic acid-selective phase transfer

“…30,31 In the oxidative system this was not particularly problematic, since the rate of oxidation was rapid. However, this has clear implications for transition metal catalysis using organoboron species under basic biphasic reaction conditions ( e.g.…”

Elucidating the Role of the Boronic Esters in the Suzuki–Miyaura Reaction: Structural, Kinetic, and Computational Investigations

“…These masked reagents are presumed to work by slowly revealing the corresponding boronic acid by hydrolysis under typical aqueous basic reaction conditions. Recent investigations by Lloyd-Jones et al have shown that in certain cases such as trifluoroboronate salts 12 as well as MIDA boronates 13 a hydrolysis step is required prior to the transmetalation event.…”