Optimization of Grignard Addition to Esters: Kinetic and Mechanistic Study of Model Phthalide Using Flow Chemistry
Name
Optimization_of_Grignard_Addition_to_Esters.pdf
Description
Accepted version
Size
838.85 KB
Format
Adobe PDF
Checksum (MD5)
ac6697a59c7ba6ff667460e27908a0dc
Author(s)
Pedersen, Michael J
Born, Stephen
Neuenschwander, Ulrich
Skovby, Tommy
Mealy, Michael J
Kiil, Søren
Dam-Johansen, Kim
Jensen, Klavs F
Date Issued
2018
Journal
Industrial and Engineering Chemistry Research
Publisher
American Chemical Society (ACS)
Version
Author's final manuscript
Abstract
© 2018 American Chemical Society. The kinetics of sequential addition of a distinct Grignard species onto a lactone is studied by flow chemistry. The experimental data are shown to be consistent with a kinetic model based on four reaction steps, reaction of ester to magnesium hemiacetal, rearrangement to ketone (forward and backward), and reaction of ketone to tertiary alcohol upon quenching. The experimental derived reaction mechanism is supported by ab initio molecular computations, and the predicted activation energy is in good agreement with the experimental observations. The Grignard reaction follows a substrate-independent, reductive [2 + 2] cycloaddition of the Meisenheimer/Casper type. Moreover, the rearrangement equilibrium between magnesium hemiacetal and ketone is characterized and found to be feasible. Monoaddition of the ester carbonyl group is demonstrated for fluorophenylmagnesium bromide but at reaction conditions at -40 °C with several hours of residence time. Working under cryogenic temperature conditions is essential to realizing monoaddition of the ester carbonyl group with Grignard reagents.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
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DOI of Published Version
https://doi.org/10.1021/ACS.IECR.8B00564
