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.
Gonzalez JA, Ogba OM, Morehouse GF, et al. MIDA boronates are hydrolysed fast and slow by two different mechanisms. Nat. Chem. 2016; 8:1067-1075. doi: 10.1038/nchem.2571