University of Groningen Resolutions of racemates by crystallization Leeman, Michel Sebastiaan IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2009 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Leeman, M. S. (2009). Resolutions of racemates by crystallization: additives and attrition. University of Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 23-09-2021 Resolutions of Racemates by Crystallization Additives and Attrition Michel S. Leeman The cover picture shows backlit quartz form Tequisquiapan, Queretaro, Mexico, downloaded from: http://www.sxc.hu/photo/702163. This research project, named Ultimate Chiral Technology (UCT), was financially supported by Syncom B.V., Samenwerkingsverband Noord-Nederland (Cooperation Northern Netherlands) and the European Fund for Regional Development (EFRO) RIJKSUNIVERSITEIT GRONINGEN Resolutions of Racemates by Crystallization Additives and Attrition Proefschrift ter verkrijging van het doctoraat in de Wiskunde en Natuurwetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op vrijdag 20 november 2009 om 16:15 uur door Michel Sebastiaan Leeman geboren op 9 augustus 1978 te Emmen Promotores Prof. dr. ir. A.J. Minnaard Prof. dr. R.M. Kellogg Beoordelingscommissie: Prof. dr. J.G. de Vries Prof. dr. E. Vlieg Prof. dr. G. Coquerel ISBN: 978-90-367-3843-9 (printed version) ISBN: 978-90-367-3842-2 (electronic version) The most exciting phrase to hear in science, the one that heralds new discoveries, is not 'Eureka!' but 'That's funny ...' Isaac Asimov (1920 - 1992) Opgedragen aan Anita Contents CHAPTER 1 INTRODUCTION ........................................................................................ 1 1.1 History .................................................................................................................... 2 1.2 Optically Pure Compounds in Our Daily Life ........................................................ 6 1.3 Calculations ............................................................................................................ 9 1.4 Methods for the Preparation of Optically Pure Compounds................................. 10 1.4.1 Chiral Pool ...................................................................................................... 10 1.4.2 Prochiral Substrates ........................................................................................ 12 1.4.2.1 Chiral Auxiliary .................................................................................................... 12 1.4.2.2 Biocatalysis ........................................................................................................... 12 1.4.2.3 Chemocatalysis ..................................................................................................... 13 1.4.3 Resolution of Racemates ................................................................................ 14 1.4.3.1 Chromatographic Resolution ................................................................................ 14 1.4.3.2 Kinetic Resolution ................................................................................................ 15 1.4.3.3 Direct Crystallization, ........................................................................................... 16 1.4.3.4 Resolution by Diastereomeric Salt Formation, ..................................................... 18 1.5 Dutch Resolution .................................................................................................. 20 1.6 Aim and Outline of This Thesis ........................................................................... 22 1.7 References ............................................................................................................ 23 CHAPTER 2 RESOLUTION BY CRYSTALLIZATION ............................................. 31 2.1 Introduction .......................................................................................................... 32 2.2 Crystal Growth from Solution .............................................................................. 32 2.2.1 Primary Nucleation ......................................................................................... 32 2.2.2 Polymorphism ................................................................................................. 34 2.2.2.1 (Dis)appearing Polymorphs .................................................................................. 36 2.2.2.2 Polymorphism in Chocolate .................................................................................. 36 2.2.3 Nucleation Inhibition ...................................................................................... 37 2.2.4 Crystal Growth and Habit Modifiers .............................................................. 39 2.3 Phase Diagrams: a Necessary Evil on the Path to Salvation/Solvation ................ 40 2.3.1 Construction of a Ternary Phase Diagram ...................................................... 41 2.3.2 Conglomerates, Racemic Compounds and Solid Solutionsc .......................... 43 2.3.2.1 Finding Conglomerates ......................................................................................... 44 2.3.3 Phase Diagrams and Diastereomers ................................................................ 45 2.3.4 End Solid Solutions, Solvates and Hydrates ................................................... 46 2.3.5 Binary versus Ternary Phase Diagrams, ......................................................... 47 2.4 References ............................................................................................................ 48 CHAPTER 3 RESOLUTION OF RACEMATES BY DIASTEREOMERIC SALT FORMATION WITH THE AID OF NUCLEATION INHIBITORS. .......................... 53 3.1 Introduction .......................................................................................................... 54 3.2 Resolution with Optically Pure Mandelic Acid .................................................... 55 3.2.1 Screening for Possible Candidates .................................................................. 55 3.2.2 Nucleation Inhibitors Based on the Resolving Agent ..................................... 58 3.2.3 Nucleation Inhibitors Based on the Racemate ................................................ 62 3.2.4 Nucleation Inhibition in Ternary Phase Diagrams .......................................... 66 3.2.5 Upscaling of the Resolution ............................................................................ 69 3.3 Pope-Peachey and Nucleation Inhibitors .............................................................. 71 3.4 Experimental Section ........................................................................................... 74 3.5 References ............................................................................................................ 84 CHAPTER 4 THE EFFECT OF ADDITIVES ................................................................ 89 4.1 Introduction .......................................................................................................... 90 4.2 Resolution of (±)-PEA with DBTA ...................................................................... 90 4.3 Resolution of (±)-PEA with TA ........................................................................... 93 4.4 Dissolution by Abrasive Grinding ........................................................................ 97 4.4.1 Dissolution of Diastereomers in Saturated Mixtures ...................................... 97 4.4.2 Dissolution of Enantiomers in Saturated Mixtures ....................................... 102 4.5 Simultaneous Resolution with Cyclic Phosphoric Acids ................................... 103 4.5.1 Phencyphos ................................................................................................... 104 4.5.2 Anicyphos and Chlocyphos .......................................................................... 106 4.6 Experimental Section ......................................................................................... 108 4.7 References .......................................................................................................... 113 CHAPTER 5 DERACEMIZATION BY ABRASIVE GRINDING ............................. 117 5.1 Introduction ........................................................................................................ 118 5.2 Racemizable Conglomerate ................................................................................ 119 5.3 Deracemization by Abrasive Grinding ............................................................... 120 5.4 Deracemization by Sonication