Transannular interactions in medium-ring carbocycles: Theoretical and experimental investigations Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften im Fachbereich Chemie der Universität Duisburg-Essen vorgelegt von Parveen Choudhary Mohr Chandigarh, India 2006 This work was carried out between January 2004 and July 2006 at the Fachbereich Chemie, Universität Duisburg-Essen, Germany. The systems discussed in chapter 7 (section 7.2) and 10 (section 10.2) have been studied using Gamess under supervision of Prof. Dr. Harjinder Singh, Dr. Tej Vir Singh and Dr. Paloth Venugopalan at Panjab University, Chandigarh, India. Ph.D. Advisor: Prof. Dr. Paul Rademacher Referee: Prof. Dr. Dr. h.c. Reiner Sustmann Date of the oral examination and defense of the Ph.D. thesis: 25-10-2006 For Andreas and my family Acknowledgments During my research work I have been accompanied and supported by many people directly or indirectly. Today, I am very pleased to express my gratitude to all of them. First and foremost I would like to express my sincere gratitude and thanks to my advisor Prof. Dr. Paul Rademacher at the Universität Duisburg-Essen for his valuable advice, guidance and constant encouragements throughout this research work. His editorial advice was essential to the completion of this dissertation and has given me insights on the workings of scientific research in general. Moreover, I am especially thankful to him for providing me the opportunity to work at Universität Duisbürg- Essen and carry out this research work. Special thanks are due to Prof. Dr. Dr. h. c. Reiner Sustmann for providing generous support and opportunity to attend and discuss my research work in his research group seminars. I would also like to give my thanks to Prof. Dr. Harjinder Singh, Dr. Tej Vir Singh and Dr. Paloth Venugopalan for the guidance and support during my stay in Panjab University. I am greatful that they have given me opportunity to work in a project under their supervision. The lessons learnt under their guidance remained helpful to me in both personal and professional life. I would like to extend my thanks to Prof. Dr. Georg Jansen for numerous stimulating discussions and fruitful suggestions. I would also like to thank Dr. Hans -Gert Korth for his constructive comments and valuable suggestions. For X-ray diffraction analyses I would like to thank Prof. Dr. Roland Boese and Mr. Dieter Bläser. Of course I should not forget to mention Dr. Torsten Schaller and Mr. Heinz Bandmann for recording NMR spectra and Mr. Werner Karow and Winfried van Hoof for mass spectra. I would like to thank Dr. Holger Gollan for his support regarding running Gaussian jobs in the computing centre. I would like to thank Prof. Dr. Sustmann and Mr. Wilhelm Sicking for allowing me to use the program Pergra. Special thanks are due to Mr. Sicking for his generous help regarding computer related problems. Last years spent in Essen have been a wonderful experience because of the nice, sociable and helpful colleagues. I would like to take this opportunity to thank all my colleagues for their whole hearted help and Dr. Ursula Maria Lottermoser for her support in initial days of my stay in Essen. I would also like to thank my friends some of them living thousands miles away but who have been always helpful and motivating. I have no words to express my deep sense of gratitude to my parents for providing me unconditional support throughout my studies. The motivation and invaluable support of my family in the stressful professional and personal stages has proved a great support for me. The unquestioning faith of my family in me remained a stablising force in all the decisions made until now. I would like to thank my family in-laws especially parents who have tried their best to make me feel comfortable in the family irrespective of wide cultural differences. The chain of my gratitude would be definitely incomplete if I would forget to thank my husband Dr. Andreas Mohr for his love and patience during the Ph.D. period. He has shown complete understanding towards my personal and professional difficulties and tried hard to remove them. He has been a constant support and motivation throughout my research especially during hard days of thesis writing. In the end I would like to dedicate my thesis to Andreas and my family. Table of Contents Chapter Page 1 Introduction--------------------------------------------------------------------------------------- 1 1.1 Biological importance--------------------------------------------------------------------- 1 1.2 Transannular interactions---------------------------------------------------------------- 2 1.3 Methods to study transannular interactions---------------------------------------- 3 2 Presentation of the problem ------------------------------------------------------------------ 5 3 An introduction to computational methods--------------------------------------------- 14 3.1 Methods used in calculations---------------------------------------------------------- 14 3.2 Molecular mechanics methods -------------------------------------------------------- 15 3.3 Semi-empirical methods ---------------------------------------------------------------- 15 3.4 Ab-initio molecular orbital methods ------------------------------------------------ 15 3.5 Density functional methods------------------------------------------------------------ 16 3.6 Conformational analysis ---------------------------------------------------------------- 16 3.7 Methods used for molecular orbital properties calculation ------------------- 18 3.8 Software ------------------------------------------------------------------------------------- 20 4 Synthesis and characterisation of model compounds 1 – 3 ------------------------- 21 5 Solvent effects on transannular interactions in model compounds 1 – 3 ------- 27 6 Nucleophilic addition reaction: Hemiacetal formation ------------------------------ 39 6.1 Bonding and interactions --------------------------------------------------------------- 42 6.2 Transition-state calculations ----------------------------------------------------------- 46 7 Hydroxy-ketone – hemiacetal rearrangement: Theoretical mechanistic study 49 7.1 Introduction--------------------------------------------------------------------------------- 49 7.2 Results for model compound 1 -------------------------------------------------------- 50 7.2.1 Structural features---------------------------------------------------------------------- 51 7.2.2 Bonding and interactions------------------------------------------------------------- 56 7.2.3 Reaction energies----------------------------------------------------------------------- 58 7.2.4 Transition-state calculations --------------------------------------------------------- 61 7.2.5 Thermodynamic analysis------------------------------------------------------------- 63 7.2.6 Solvent mediated calculations for the tautomeric equilibrium (1 1a)64 7.3 Results for model compound 2 -------------------------------------------------------- 66 7.3.1 Structural features---------------------------------------------------------------------- 66 7.3.2 Bonding and interactions------------------------------------------------------------- 67 7.3.3 Reaction energies----------------------------------------------------------------------- 70 7.3.4 Transition-state calculation ---------------------------------------------------------- 72 7.3.5 Thermodynamic analysis------------------------------------------------------------- 73 7.3.6 Solvent mediated calculations for the tautomeric equilibrium (2 2a)73 7.4 Results for model compound 3 -------------------------------------------------------- 75 7.4.1 Structural features---------------------------------------------------------------------- 75 7.4.2 Bonding and interactions------------------------------------------------------------- 77 7.4.3 Reaction energies----------------------------------------------------------------------- 78 7.4.4 Transition-state calculations --------------------------------------------------------- 79 7.4.5 Thermodynamic analysis------------------------------------------------------------- 80 7.4.6 Solvent mediated calculations for the tautomeric equilibrium (3 3a)81 7.5 Results for model compound 4 -------------------------------------------------------- 82 7.5.1 Structural features---------------------------------------------------------------------- 82 7.5.2 Bonding and interactions------------------------------------------------------------- 84 7.5.3 Reaction energies----------------------------------------------------------------------- 85 7.5.4 Transition-state calculations --------------------------------------------------------- 86 7.5.5 Thermodynamic analysis------------------------------------------------------------- 87 7.5.6 Solvent mediated calculations for the tautomeric equilibrium (4 4a)88 7.6 Results for model compound 5 -------------------------------------------------------- 89 7.6.1 Structural features---------------------------------------------------------------------- 89 7.6.2 Bonding and interactions------------------------------------------------------------- 91 7.6.3 Reaction energies----------------------------------------------------------------------- 93 7.6.4 Transition-state calculations --------------------------------------------------------- 93 7.6.5 Thermodynamic analysis------------------------------------------------------------- 96 7.6.6 Solvent mediated calculations for the tautomeric equilibrium (5 5a)97 7.7 Discussion-----------------------------------------------------------------------------------