title: 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 small-molecule construction based on building blocks, largely because of 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, which has hindered efforts to address the 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 than the latter, and involves a rate-limiting attack by a hydroxide at a MIDA carbonyl carbon. The alternative 'neutral' hydrolysis does not require an exogenous acid or 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 by18O incorporation. Whether hydrolysis is 'fast' or 'slow' is dictated by the pH, the water activity and the mass-transfer rates between phases. These findings stand to enable, in a rational way, an even more effective and widespread utilization of MIDA boronates in synthesis.
authors: EaStCHEM, School of Chemistry, University of Edinburgh, Edinburgh, EH9 3FJ, UK.
authors: Jorge A
authors: JA
authors: Gonzalez
authors: Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, USA.
authors: O Maduka
authors: OM
authors: Ogba
authors: Department of Chemistry, University of Illinois, 454 RAL, Box 52-5 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors: Gregory F
authors: GF
authors: Morehouse
authors: Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, USA.
authors: Nicholas
authors: N
authors: Rosson
authors: Department of Chemistry and Biochemistry, University of California, Los Angeles, 607 Charles E. Young Drive East, Los Angeles, California 90095-1569, USA.
authors: Kendall N
authors: KN
authors: Houk
authors: School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UK.
authors: Andrew G
authors: AG
authors: Leach
authors: Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, USA.
authors: Paul H-Y
authors: PH
authors: Cheong
authors: Department of Chemistry, University of Illinois, 454 RAL, Box 52-5 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors: Martin D
authors: MD
authors: Burke
authors: EaStCHEM, School of Chemistry, University of Edinburgh, Edinburgh, EH9 3FJ, UK.
authors: Guy C
authors: 0000-0003-2128-6864
authors: GC
authors: Lloyd-Jones
mesh_terms: D001897:Boronic Acids / Q000737:chemistry* / Q000378:metabolism; D006868:Hydrolysis; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D010103:Oxygen Isotopes / Q000737:chemistry; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D001897:Boronic Acids; D010103:Oxygen Isotopes; C000615259:Oxygen-18; D014867:Water