Kwan, MHT, Breen, J, Bowden, M et al. (7 more authors) (2021) Continuous Flow Chiral Amine Racemization Applied to Continuously Recirculating Dynamic Diastereomeric Crystallizations. Journal of Organic Chemistry (JOC), 86 (3). pp. 2458-2473. ISSN 0022-3263
Abstract
A new, dynamic diastereomeric crystallization method has been developed, in which the mother liquors are continuously separated, racemized over a fixed-bed catalyst, and recirculated to the crystallizer in a resolution–racemization–recycle (R3) process. Separating the racemization from crystallization overcomes problems of using catalysts in situ, that suffer conflicting sets of conditions, inhibition, and separation. Continuous racemization has been achieved through the covalent attachment of [IrCp*I2]2 SCRAM catalyst to Wang resin solid support to give a fixed-bed catalyst. One tertiary and a variety of secondary optically enriched amines have been racemized efficiently, with residence times compatible with the crystallization (2.25–30 min). The catalyst demonstrates lower turnover (TOF) than the homogeneous analogue but with reuse shows a long lifetime (e.g., 40 recycles, 190 h) giving acceptable turnover number (TON) (up to 4907). The slow release of methylamine during racemization of N-methyl amines was found to inactivate the catalyst, which could be partially reactivated using hydroiodic acid. Dynamic crystallization is achieved in the R3 process through the continual removal of the more soluble diastereomer and supply of the less soluble one. The solubility of the diastereomers was determined, and the difference correlates to the rate of resolution but is also affected by the rates of racemization, crystal growth, and dissolution. A variety of cyclic and acyclic amine salts were resolved using mandelic acid (MA) and ditoluoyl tartaric acid (DTTA) with higher resolvability (S = yield × d.e.) than the simple diastereomeric crystallization alone. Comparing resolvabilities, resolutions were 1.6–44 times more effective with the R3 process than batch, though one case was worse. Further investigation of this revealed an unusual thermodynamic switching behavior: rac-N-methylphenethylamine was initially resolved as an (S,S)-bis-alkylammonium tartrate crystal but over time became the equivalent (R,S) salt. Thermal, mixing, concentration, stoichiometry, and seeding conditions were all found to affect the onset of the switching behavior which is only associated with difunctional resolving reagents.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Authors. Published by American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) |
Funding Information: | Funder Grant number Innovate UK fka Technology Strategy Board (TSB) EP/K504154/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 07 Jan 2021 13:41 |
Last Modified: | 25 Jun 2023 22:32 |
Status: | Published |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/acs.joc.0c02617 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:169321 |