Downloaded from orbit.dtu.dk on: Sep 26, 2021 Structural characterization of chiral molecules using vibrational circular dichroism spectroscopy Lassen, Peter Rygaard Publication date: 2006 Document Version Publisher's PDF, also known as Version of record Link back to DTU Orbit Citation (APA): Lassen, P. R. (2006). Structural characterization of chiral molecules using vibrational circular dichroism spectroscopy. Technical University of Denmark. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal 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. Peter Rygaard Lassen Structural Characterization of Chiral Molecules Using Vibrational Circular Dichroism Spectroscopy Ph.D. Thesis, July 2006 Quantum Protein Centre Department of Physics Technical University of Denmark DK-2800 Lyngby, Denmark Supervisors: Professor Henrik Bohra Associate Professor Lars Hemmingsena,b Associate Professor Per-Ola Norrbyc aQuantum Protein Centre, Department of Physics, Technical University of Denmark bDepartment of Natural Sciences, The Royal Veterinary and Agricultural University cDepartment of Chemistry, Technical University of Denmark c 2006 Peter Rygaard Lassen, M.Sc.E. Typeset in LATEX2ε Printed in Denmark by Vester Kopi, DTU, Lyngby Available online at http://hjem.get2net.dk/c971779/phd.pdf This thesis includes published papers reproduced with permission All trademarks are the properties of their respective owners Revised version “Saglighed er godt nok, men lidt salighed er ikke at foragte.” -Klaus Rifbjerg Cover illustration: Four of the molecular structures investigated during this project: Ginkgolide B, nyasol, curcuphenol dimer, and a rhenium(V) complex. Preface This thesis is submitted as part of the requirements for obtaining the Ph.D. degree from the Technical University of Denmark (DTU). The work presented here has been carried out from August 2003 to July 2006 at the Department of Physics, DTU, under supervision of Prof. Henrik Bohr and Assoc. Prof. Lars Hemmingsen (now Department of Natural Sciences, The Royal Veterinary and Agricultural University), as well as Assoc. Prof. Per-Ola Norrby, Department of Chemistry, DTU. A Ph.D. grant from DTU has sponsored the project. Some of this work has been published, and these papers are included as appendices, along with two preliminary manuscripts. Part of this work was carried out at the Department of Chemistry at Syracuse University, Syracuse, New York, where I had the opportunity to spend two semesters (fall of 2004 and spring 2005) in the world’s leading FT-VCD group, supervised by Professors Laurence A. Nafie and Teresa B. Freedman. Outline of the Thesis Chapter 1 introduces the fundamental concept of chirality and some research areas where it is significant. Chapter 2 reviews the theoretical and experimental methods used in this project. Chapter 3 describes some studies of small or medium-sized organic molecules, followed by larger metal complexes and myoglobin in Chapter 4. The appendices include a list of abbreviations and some Unix scripts written during the project. An English and Danish abstract is also given. Finally, a number of papers and manuscripts are attached. Acknowledgments I would like to thank my supervisors: Henrik Bohr for his enthusiasm, en- couragement and entertainment; Lars Hemmingsen for his clear-sightedness, overview and useful suggestions; Per-Ola Norrby for his chemical intuition and for classes on computational chemistry and spectroscopic methods. During my time at DTU, I have enjoyed sharing my office with two post- docs, Peter W. Thulstrup and later Niels H. Andersen. I thank them for their company, co-operation and discussions we had. I also appreciate Tobias M. Johansen for taking care of the computer cluster, Assoc. Prof. Karl J. Jalkanen for introducing me to VCD, and Assoc. Prof. Salim Abdali for providing the contact with Syracuse University. i Special thanks go to Professors Larry Nafie, Tess Freedman and Dr. Xiaolin Cao at Syracuse University (SU) for having me in their lab, where I also enjoyed the opportunity to work with two nice Ph.D. students, Yanan He and Rosina Lombardi. Dr. Tim Korter is acknowledged for instrument time on his FT-IR spectrometer. When project supervisor Lars Hemmingsen moved to The Royal Veterinary and Agricultural University during my stay abroad, a desk was provided for me by the Bioinorganic group at the Department of Natural Sciences. Ithankall of them for their hospitality and for sharing their expertise during my frequent visits. Finally, I wish to thank all the other co-workers, fellow students and friends both in Denmark and Syracuse, whose company I have enjoyed during my Ph.D. work. Kgs. Lyngby, July 2006 Peter Rygaard Lassen ii Contents Preface i 1 Introduction 1 1.1 Chirality ................................ 1 1.1.1 FormsofChirality ...................... 1 1.1.2 SymmetryBreaking ..................... 2 1.2 OutlineofVCDDevelopment . 3 1.3 ApplicationsofVCDinDrugDevelopment . 4 1.4 BioinorganicChemistryinNature . 4 2 Methods 7 2.1 TheoreticalMethods ......................... 7 2.1.1 MolecularMechanics. 7 2.1.2 QuantumMechanics .. .. .. .. .. .. 8 2.1.3 DensityFunctionalTheory . 9 2.1.4 Functionals .......................... 10 2.1.5 BasisSets ........................... 10 2.2 OpticalSpectroscopy . 12 2.2.1 ElectronicSpectra. 13 2.2.2 VibrationalSpectra . 14 2.2.3 CircularDichroismSpectroscopy . 16 2.3 TheoryofIRandVCD ........................ 17 2.3.1 Resonance-EnhancedVCD . 19 2.3.2 ProcessingCalculatedResults. 22 2.4 VCDInstrumentation. 23 2.4.1 Dispersive vs. Fourier Transform Instruments . 24 2.4.2 PolarizationModulation. 24 2.4.3 Detection............................ 25 3 SmallOrganicMoleculesandPharmaceuticals 27 3.1 Introduction: TheLessonFromThalidomide . 27 3.2 Methyl-Substituted Phenyloxiranes . 28 3.2.1 TheoreticalandExperimentalMethods . 28 3.2.2 ResultsandDiscussion. 29 3.3 Nyasol ................................. 34 3.3.1 ConformationalAnalysisandDFTCalculations . 34 iii 3.3.2 ResultsandDiscussion. 35 3.4 CurcuphenolDimer.......................... 40 3.4.1 TheoreticalModelCompound . 40 3.4.2 ExperimentalandCalculatedSpectra . 42 3.5 GinkgolideB.............................. 45 3.5.1 TheoreticalandExperimentalMethods . 46 3.5.2 ResultsandDiscussion. 46 3.6 Summary................................ 49 4 Transition Metal Complexes and Metalloproteins 51 4.1 Introduction .............................. 51 4.2 Rhenium(V)Complexes . 52 4.2.1 TheoreticalandExperimentalMethods . 52 4.2.2 Conformers and IR/VCDSpectra.............. 54 4.2.3 HigherresolutionIRspectra . 60 4.3 ChiralSchiff-BaseComplexes .................... 64 4.3.1 Co(II)saldiphenylComplex . 65 4.3.2 Co(II)salbinaphtylComplex. 70 4.4 MyoglobinandLigands . 73 4.4.1 ExperimentalMethods. 73 4.4.2 ComputationalModelStructures . 75 4.4.3 ResultsandDiscussion. 76 4.5 Summary................................ 87 5 Concluding Remarks 89 Bibliography 91 Index 99 A List of Abbreviations 101 B Unix Scripts 103 B.1 g03energies.bash .. .. .. .. .. .. .. .. 104 B.2 g03toCSV.bash............................. 104 B.3 plotCSV.bash.............................. 106 B.4 g03toFrq.bash ............................. 107 B.5 annotateIR.bash . .. .. .. .. .. .. .. .. 109 B.6 annotateVCD.bash . 110 C Abstract 111 D Dansk resumé 113 E Included Papers 115 iv List of Figures 1.1 Structureofhistidine ......................... 2 1.2 Manganesecatalyststructure . 5 1.3 Periodictableoftheelements . 6 2.1 Molecular mechanics structural deformations . ... 7 2.2 Visibleelectromagneticspectrum . 13 2.3 The Morse potential vs. harmonic approximation . .. 15 2.4 Shapesofthed-orbitals. 19 2.5 Octahedralligandfieldsplittingofd-orbitals . .... 20 2.6 Tetrahedral ligand field splitting of d-orbitals . ..... 20 2.7 Square planarligandfieldsplitting of d-orbitals . .... 21 2.8 Schematicofaphotoelasticmodulator . 25 2.9 Effectofaphotoelasticmodulator. 25 3.1 Methylphenyloxiranes: Three chemical structures . .... 28 3.2 Methylphenyloxiranes: DFT optimized geometries . ... 30 3.3 α-methylphenyloxirane: IR/VCDspectra ............. 31 3.4 cis-β-methylphenyloxirane: IR/VCDspectra. 32 3.5 trans-β-methylphenyloxirane: IR/VCDspectra . .. .. 33 3.6 Nyasol:Chemicalstructure . 34 3.7 Nyasol:DFToptimizedgeometry. 35 3.8 Nyasol: Calculated IR/VCDspectra................. 36 3.9 Nyasol: Observed vs. calculated IR/VCDspectra . 38 3.10 Nyasol: Calculated IR/VCDspectrawithsolvent . 39 3.11 Curcuphenol andits dimer: Chemicalstructures . ... 40 3.12 Curcuphenoldimer: DFToptimizedgeometry . 41 3.13 Curcuphenol dimer: A truncated model structure . .. 41 3.14 Curcuphenol dimer model: DFT optimized geometry . 41 3.15 Curcuphenol and its dimers: Experimental IR/VCDspectra . 43 3.16 Curcuphenol dimer: Experimental IR/VCD spectra vs. model . 44 3.17 Ginkgolides:Chemicalstructure . 45 3.18 GinkgolideB:DFToptimizedgeometry . 47 3.19 Ginkgolide B: Comparison of IR/VCDspectra.