Bispidine Derivatives

Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 161 Bispidine Derivatives Synthesis and Interactions with Lewis Acids LAURI TOOM ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6214 UPPSALA ISBN 91-554-6509-9 2006 urn:nbn:se:uu:diva-6735 ! " # $$% & '&( ) * ) ) +* *, -* . / *, - 0, $$%, , 1 * 2 . * 0. ", " , &%&, 3 , , 214 5&6((36%($565, 2 * * * * * ) 76 8 9 , ,&: ; < , -* * = * ) ) * * * ) . * * , -* * * ) )) . * . * 8 ) . * ) 0. , " * * .* * ) ** * 8 .** > * , " ) . * ) . * 8 * .** * ) , . * * ) * . * ** , -* ) * ) * * 8 * ?6 * 4 , 1 ;@6 < . * * * * * , = ) ;A 6 < * 9B;A 6 <+C%;D 6E<3: . , 4 ) ! " # ! "$ ! " % &'(! ! )*'&+,- ! F 0 - $$% 2114 &%(&6%&3 214 5&6((36%($565 ' ''' 6%7 ( ;* 'GG ,=,G H I ' ''' 6%7 (< List of Papers Included in this Thesis This thesis is based on the following papers, which are referred to in the text by their Roman numerals: I. Toom, L., Grennberg, H., Gogoll, A. Microwave-Assisted Raney Nickel Reduction of Bispidinone Thioketals to N,N’-Dialkyl- bispidines. Accepted for publication in Synthesis. II. Toom, L., Kütt, A., Kaljurand, I., Leito I., Ottosson, H., Grennberg, H., Gogoll, A. Substituent Effects on the Basicity of 3,7-Diaza- bicyclo[3.3.1]nonanes. Submitted to Journal of Organic Chemistry. III. Toom, L., Grennberg, H., Gogoll, A. Solution structure and dynamics of a sterically congested (ʌ-allyl)palladium complex. Submitted to Magnetic Resonance in Chemistry. IV. Gogoll, A., Toom, L., Grennberg, H. Ligand-Induced Formation II of an Adamantanoid Hexanuclear (ʌ-Allyl)Pd (ȝ3-Hydroxo) Cluster Stacked as Hydrogen-Bonded Double Strands. Angewandte Chemie International Edition 2005, 44, 4729-4731. Reprints are made with permission from the publishers. Reprint of paper I with permission from the publisher: Copyright 2006 Georg Thieme Verlag Stuttgart · New York. Contribution Report The author wishes to clarify his own contributions to the research presented in the present thesis. Paper I. Carried out the experimental work, documented and evaluated the results, and participated in writing of the manuscript. Paper II. Carried out the synthetic experimental work, the NMR studies, contributed to the interpretation of the results and to the writing of the manuscript. Established contact with the Estonian research group. Paper III. Carried out the synthetic experimental work, the NMR studies, contributed to the interpretation of the results and to the writing of the manuscript. Paper IV. Prepared the bispidine, proved reproducibility of the formation of cluster crystals, made contributions to the manuscript. The pKa measurements were carried out by MSc. Agnes Kütt, Dr. Ivari Kaljurand and Prof. Ivo Leito at the University of Tartu, Estonia. Computational studies presented in paper II were done by Dr. Henrik Ottosson at the Uppsala University. X-ray crystallographic analyses were done by Dr. Vratislav Langer at the Chalmers University of Technology. Contents 1 Introduction...............................................................................................7 1.1 Acid-Base Interactions .....................................................................8 1.2 Bidentate Lewis Bases as Ligands....................................................8 1.2.1 Bispidines for Structural Analysis...........................................10 1.2.2 Previous Structural Characterization Work with Bispidinones and Bispidines .........................................................................12 1.3 Aims of the Present Study ..............................................................14 2 Synthesis of Substituted Bispidines and Bispidinones ...........................15 2.1 Microwave-Assisted Preparation of N,N’-Dialkylbispidines from a Bispidinone Thioketal (I) .....................................................16 2.2 Synthesis of N,N’-Dibenzhydrylbispidine (II)..................................18 2.3 Synthesis of N,N’-Dibenzhydrylbispidinone (II)..............................20 3 Interactions with Brønsted Acids............................................................21 3.1 Protonation of Bispidines ...............................................................21 3.2 Protonation of Bispidinones ...........................................................24 3.3 Basicity of Bispidines and Bispidinones (II) ....................................25 3.3.1 Measured Basicity Values.......................................................25 3.3.2 Calculated pKa Values and Correlation with Measured pKa Values......................................................................................26 3.3.3 15N NMR Chemical Shifts.......................................................28 3.3.4 Structure-Property Relationship..............................................29 4 Transition Metal Complexes (III) .............................................................31 4.1 Conformation of a (ʌ-Allyl)Pd Complex, and Dynamics in Solution..........................................................................................31 4.2 A New Type of (ʌ-Allyl)Pd Cluster (IV) ..........................................35 5 Conclusions.............................................................................................37 6 Bispidinderivat: Syntes och interaktioner med Lewis-syror...................38 7 Acknowledgements.................................................................................40 8 References...............................................................................................41 Abbreviations B3LYP Becke’s 3 parameter hybrid functional using the Lee-Yang- Parr correlation functional Boc t-Butyloxycarbonyl CB Chair-boat CC Chair-chair DFT Density functional theory DMSO Dimethyl sulfoxide HPLC High-performance liquid chromatography IEF-PCM Integral-equation-formalism polarizable continuum model L Ligand M Metal MW Microwave assisted heating NMR Nuclear magnetic resonance NOE Nuclear Overhauser effect NPA Natural population analysis ORTEP Oak Ridge thermal ellipsoid plot PA Proton affinity Ref. Reference ROESY Rotating frame Overhauser effect spectroscopy r.t. Room temperature (20-25 °C) Ts Toluenesulfonyl UV-vis Ultraviolet-visible 1 Introduction One of the most important recent developments in modern chemistry is that the focus of research has been extended from studies of single molecules towards molecular interactions (Figure 1). The goal of this extension is to understand and mimic what is going on in the “real world” of biological systems (as opposed to the laboratory) and to develop, as well as utilize, large molecular systems with new or improved properties. This has grown into a very interdisciplinary field - supramolecular chemistry, bearing on organized entities that result from the association of two or more chemical species.1 To approach these goals we need to utilize the interactions between separate molecules. Several forces are involved in these intermolecular interactions, most importantly: x hydrogen bonding, x electrostatic interactions, x ʌ-ʌ stacking interactions, x van der Waals interactions. These are the fundamental interactions we can work with, and several of them are utilized in the work described in this thesis. Interacting molecules Isolated Solvated Molecules with forming new molecules molecules specific interactions structures Molecule as part Molecular aggregates, In gas phase Molecules of a complex, supramolecular or in vacuum in solution molecule binding chemistry to a receptor Figure 1. Increasing levels of complexity in the molecular world. 7 1.1 Acid-Base Interactions A concept that approaches some of these interactions is the acid-base theory. In its more general form it is described by the Lewis electronic theory of acids and bases, where an acid - defined to be any species that accepts lone pair electrons - is interacting with a Lewis base - any species that donates lone pair electrons.2 When dealing with organometallic chemistry, a Lewis base can also be named a ligand, i.e., a unit that can attach to a metal center to form an aggregate known as a complex. Ligand structures have a determinant effect on the complex structures, they can stabilize metal centers, influence the reactivity and selectivity of metal complexes and determine the mechanism and rate of a reaction. Stronger bonds between the metal center and the ligands reduce the abilities of the complexes to isomerize or to decompose. The degree of conformational freedom of the ligands is reduced some- what during complex formation, resulting in a higher order of the system. The two parts of the system are both forced into a smaller number of possible conformations, making structural characterization simpler. The Brønsted-Lowry theory deals with a narrower field of the same type - just proton abstraction and donation.3 Since the correlation between metal ion complex stability and ligand basicity is well established,4 Brønsted basicities are studied in the present thesis. Base strength is also related to hydrogen bonding, which is important in drug discovery. However, hydrogen bond acceptor strength (proton sharing) and basicity

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