University of Groningen Conglomerates surface in new resolution strategies van der Meijden, Maarten Willem 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: 2012 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): van der Meijden, M. W. (2012). Conglomerates surface in new resolution strategies. Groningen: s.n. 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: 21-04-2019
Conglomerates Surface in New Resolution Strategies Maarten W. Van der Meijden
The cover picture shows the columns of the Universitat Autònoma de Barcelona. Photograph by Claudia C. Delgado Simão This research project, named Resolve, was financially supported by the European commission (Seventh Framework Program NMP4-SL-2008-214340) Thesis printed by Wöhrmann print service, the Netherlands
Conglomerates Surface in New Resolution Strategies Proefschrift ter verkrijging van het doctoraat in de Wiskunde en Natuurwetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. E. Sterken, in het openbaar te verdedigen op vrijdag 12 oktober 2012 om 12.45 uur door Maarten Willem van der Meijden geboren op 7 september 1980 te Harderwijk
Promotor : Prof. dr. ir. A.J. Minnaard Copromotor : Prof. dr. R.M. Kellogg Beoordelingscommissie : Prof. dr. S. De Feyter Prof. dr. J.C. Hummelen Prof. dr. A.P.H.J. Schenning ISBN: 978-90-367-5731-7 (printed version) ISBN: 978-90-367-5732-4 (electronic version)
For experience relates to the past and the present whereas hope is the militant anticipation of the future Eduardo Frei Montalva Latin America: the hopeful option Voor Femmie, Hjalmar en Malin
Abbreviations: AFM Anicyphos Boc Brocyphos BSE Chlocyphos DBU DCB DCE DDQ DMF DMPU DMSO GC HOPG HPLC Josiphos Atomic force microscopy ortho-methoxyphencyphos tert-butoxycarbonyl para-bromo phencyphos Backscattered electrons ortho-chlorophencyphos 1,8-diazabicyclo[5.4.0]undec-7-ene 1,2-dichlorobenzene dichloroethane 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone N,N-dimethylformamide 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone dimethylsulfoxide Gas chromatography Highly ordered pyrolytic graphite High pressure liquid chromatography ferrocene ligand with the general structure: PR 2 2 R 1 2P Fe 2
LEED µcp MEK Low-energy electron diffraction micro contact printing 2-butanone M-mix Mandalic acid mix, mixture of mandelic acid, p-methylmandelic acid and p- bromomandelic acid NMO NMR PDMS N-Methylmorpholine N-oxide Nuclear magnetic resonance (spectroscopy) polydimethylsiloxane Phencyphos 2-hydroxy-5,5-dimethyl-4-phenyl-1,3,2-dioxaphosphinane 2-oxide P-Mix PMPP RAIRS SAM SE SEM S-Phos STM TCB THP TIPS TMA UHV XPS phosphoric acid mix, mixture of phencyphos, chlocyphos and anicyphos para-methyl phencyphos Reflection absorption infra red spectroscopy Self-assembled monolayers Secondary electrons Scanning electron microscopy 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl Scanning tunneling microscopy 1,2,4-trichlorobenzene Tetrahydropyranyl triisopropylsilyl Trimesic acid, 1,3,5-benzenetricarboxylic acid Ultra high vacuum X-ray photoelectron spectroscope 3
Contents Abbreviations: 2 Chapter 1 Introduction 9 1.1 What is chirality? 10 1.2 Chirality around us 10 1.3 Chirality in medicine 13 1.4 Chirality in the laboratory 14 1.5 Separation of enantiomers or diastereomers 18 1.6 Diastereomeric salt formation 20 1.7 Dutch resolution 21 1.8 Resolution on a surface 22 1.9 Aim and outline of the thesis 27 Chapter 2 Deracemization from academic novelty to practical application 31 2.1 Introduction 32 2.2 Background 33 2.2.1 Resolutions and deracemizations 33 2.2.2 Theory with deracemization 36 2.3 Clopidogrel 39 2.3.1 Background and introduction 39 2.3.2 Synthesis of and screening of a suitable conglomerate 40 4
2.3.3. Comparison of the two methods for attrition enhanced deracemization 42 2.4 Summary and Conclusions 45 2.5 Experimental Section 46 Chapter 3 Functionalization of resolving agents for their attachment to surfaces 51 3.1 Introduction 52 3.1.1 Self-assembled monolayers (SAMs) 52 3.1.2 Micro Contact Printing (μcp) 53 3.1.3 Analysis of the Surfaces 54 3.2 Design and synthesis of functionalized resolving agents 57 3.2.1 Introduction 57 3.2.2 The Synthesis of Brocyphos 4 57 3.2.3 Kumada Strategy 59 3.2.4 Preparation of vinylphencyphos 8 60 3.2.5 Bromomethylphencyphos 9 as a useful intermediate 61 3.2.6 Benzylderivatives of phencyphos 64 3.2.7 Copper-free click strategy 67 3.2.8 Suzuki-strategy 70 3.2.9 Sonogashira strategy 78 3.2.10 Heck strategies 80 3.2.11 Grubbs-strategy 83 3.3 The application of functionalized resolving agents (in collaboration with Dr. Magalí Lingenfelder, Angela Bejarano and Prof. David Amabilino of the ICMAB). 84 5
3.3.1 Introduction 84 3.3.2 Crystallization on surfaces with thiol 14 89 3.4 Summary and Conclusions 93 3.5 Experimental Section 93 Chapter 4 Functionalized Helicenes Towards a designable conglomerate? 103 4.1 Introduction 104 4.1.1 History of helicenes 104 4.2 synthesis of aminohexahelicene 108 4.2.1 De Koning strategy 108 4.2.2 Fürstner cycloisomerisation route; the first steps 108 4.2.3 Synthesis of boronic acid 25 (upper part) 110 4.2.4 Synthesis of bromoenol 26 (lower part) 112 4.2.5 Suzuki coupling of boron compound 25 and bromo aldehyde 26 114 4.3.6 Conversion to final product 116 4.3 Resolution of aminohelicene 23 118 4.4 STM-analysis 125 4.4.1 Introduction on STM analysis of aminohelicene 23 125 4.4.2 STM on HOPG at the liquid solid interface 125 4.4.3 STM on Au(111) at the liquid solid interface 127 4.4.4 STM on Cu(100) under UHV 131 4.5 computer modeling 134 4.6 Summary and Conclusions 136 4.7 Experimental Section 136 6
4.8 Supplementary data 142 Chapter 5 An acid functionalized helicene The long and winding road 149 5.1 Introduction 150 5.2 Synthetic strategies towards 7-carboxyhexahelicene 150 5.2.1 Adapted aminohelicene route 150 5.2.2 Double Suzuki strategies using acid functionalized alkynes 155 5.2.3 Double Suzuki strategy using Stobbe condensation 157 5.2.3 Phenanthrenecarboxylic ester routes 158 5.2.4 Michael addition route 160 5.2.5 Dihalide double Suzuki reaction 162 5.2.6 Methylphenanthrene routes 167 5.3 Summary and Conclusions 173 5.4 Experimental Section 173 Chapter 6 Outlookfor thefuture 183 6.1 Deracemizations 184 6.2 Functionalized resolving agents for resolutions on a surface 184 6.3 Helicenes 185 Chapter 7 Nederlandse samenvatting 189 7.1 Chiraliteit 190 7.2 Dit onderzoek 191 7
7.3 Dit proefschrift 193 Dankwoord 197 8