Dynamic Stereochemistry of Chiral Axes. Design and Synthesis of Stable Atropisomers
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Alma Mater Studiorum – Università di Bologna DOTTORATO DI RICERCA IN Chimica Ciclo XXX Settore Concorsuale: 03/C1 Settore Scientifico Disciplinare: CHIM/06 Dynamic stereochemistry of chiral axes. Design and synthesis of stable atropisomers. Presentata da: Luca Prati Coordinatore Dottorato Supervisore Prof. Aldo Roda Prof. Andrea Mazzanti Co-supervisore Dr. Michele Mancinelli Esame finale anno 2018 Abstract In organic chemistry, dynamic processes involving the conformational exchange are ubiquitous phenomena that occur even in the simplest molecule. The study of the preferential disposition of functional groups and the definition of new interaction is therefore, of vital importance in order to foresee the spatial shape of organic molecules. In the following work, this has been accomplished by: first, an in silico DFT analysis of the conformers, second an experimental evaluation of the relative stability of the predicted conformers using the Dynamic-NMR, Dynamic-HPLC, and kinetic studies, and last the assessment of the potential absolute configuration by mean Electronic Circular Dichroism spectroscopy. The work herein reported finally aim to define the border between unstable conformations and stable ones (configurations). This border has been explored from both sides: 1) the stereodynamic side, that includes low energy process where the stereochemistry is not stable due to a low energy barrier. In this context are analysed molecules displaying long range interactions where only conformational changes are considered; 2) the stereostable side, where the energy barrier between conformers is high enough to generate distinct molecules. In this framework, the design and the synthesis of stereogenic axes in scaffold that cannot bear conventional stereogenic centre are reported. This work gives a well-rounded view of the conformational analysis of organic molecules providing new insight in the interaction within stereolabile conformations as well as the generation of new stereostable conformers by the insertion of steric demanding groups. Chirality is in the eyes of the beholder. Contents 1 INTRODUCTION 1 1.1 CHIRALITY 1 1.2 NOMENCLATURE AND CLASSIFICATION 2 1.3 STEREOCHEMICAL DESCRIPTORS 6 1.4 SYMMETRY AND TIME SCALE: DYNAMIC STEREOCHEMISTRY 6 1.5 DYNAMIC STEREOCHEMISTRY AND CHIRAL AXES 8 1.6 DYNAMIC STEREOCHEMISTRY AND CHIRAL PROPELLERS 18 REFERENCES 20 2 DYNAMIC STEREOCHEMISTRY ANALYSIS AND METHODOLOGIES 23 2.1 DYNAMIC NUCLEAR MAGNETIC RESONANCE (D-NMR) 23 2.2 DYNAMIC HIGH PERFORMANCE LIQUID CHROMATOGRAPHY (D-HPLC) 27 2.3 KINETIC STUDIES 29 2.4 THEORETICAL MODELS 31 2.4.1 DENSITY FUNCTIONAL THEORY 32 2.4.2 TRANSITION STATES 34 2.5 ELECTRONIC CIRCULAR DICHROISM: CONFIGURATION AND CONFORMATION ANALYSIS 36 2.5.1 EXCITON COUPLING 39 2.5.2 QUANTUM-MECHANICAL CALCULATIONS. 41 REFERENCES 42 3 AIM OF THE RESEARCH 45 4 DYNAMIC STEREOCHEMISTRY AND CONFORMATIONAL ANALYSIS 47 4.1 LONG-RANGE BONDING/NONBONDING INTERACTIONS: A DONOR−ACCEPTOR RESONANCE STUDIED BY DYNAMIC NMR 47 4.2 NEW AZO-DECORATED N-PYRROLIDINYLTHIAZOLES: SYNTHESIS, PROPERTIES AND AN UNEXPECTED REMOTE SUBSTITUENT EFFECT TRANSMISSION. 55 4.3 COMPUTATIONAL AND D-NMR ANALYSIS OF THE CONFORMATIONAL ISOMERS AND STEREODYNAMICS OF SECONDARY 2,2′-BISANILIDES 59 REFERENCES 71 5 CHASE FOR NEW ATROPISOMERS 73 5.1 CONFORMATIONAL ANALYSIS AND ABSOLUTE CONFIGURATION OF AXIALLY CHIRAL 1-ARYL AND 1,3-DIARYL- XANTHINES. 73 5.2 TETRASUBSTITUTED CYCLOPENTADIENONES AS SUITABLE ENANTIOPURE LIGANDS WITH AXIAL CHIRALITY. 88 REFERENCES 103 6 APPENDIX 105 6.1 STUDY OF 1,8 NAPHTHALENE DERIVATIVES AS SENSORS FOR NUCLEOBASES AND CHIRAL PRIMARY AMINE 105 6.1.1 NUCLEOBASES SENSING 105 6.1.2 CHIRAL PRIMARY AMINE SENSING 108 REFERENCES 110 7 EXPERIMENTAL SECTION 111 7.1 LONG-RANGE BONDING/NONBONDING INTERACTIONS: A DONOR−ACCEPTOR RESONANCE STUDIED BY DYNAMIC NMR 111 7.1.1 SYNTHETICAL PROCEDURE 111 7.1.2 DYNAMIC NMR 121 7.2 NEW AZO-DECORATED N-PYRROLIDINYLTHIAZOLES: SYNTHESIS, PROPERTIES AND AN UNEXPECTED REMOTE SUBSTITUENT EFFECT TRANSMISSION 128 7.2.1 DYNAMIC NMR 128 7.3 COMPUTATIONAL AND DNMR ANALYSIS OF THE CONFORMATIONAL ISOMERS AND STEREODYNAMICS OF SECONDARY 2,2′-BISANILIDES 129 7.3.1 SYNTHETICAL PROCEDURE 130 7.4 CONFORMATIONAL ANALYSIS AND ABSOLUTE CONFIGURATION OF AXIALLY CHIRAL 1-ARYL AND 1,3-DIARYL- XANTHINES 136 7.4.1 KINETIC STUDIES 137 7.4.2 SYNTHETIC PROCEDURES 145 7.4.3 ASSIGNMENT OF ABSOLUTE CONFIGURATION 159 7.5 TETRASUBSTITUTED CYCLOPENTADIENONES AS SUITABLE ENANTIOPURE LIGANDS WITH AXIAL CHIRALITY 166 7.5.1 SYNTHETIC PROCEDURE 167 Chapter 1 - Introduction 1 Introduction 1.1 Chirality Chirality is a pervading property of the universe. It is a feature of nature spanning from the living being to the inanimate world of light and elementary particles.1 In chemistry, in particular it is followed the definition provided by IUPAC: “The geometric property of a rigid object (or spatial arrangement of points or atoms) of being non-superimposable on its mirror image; such an object has no symmetry elements of the second kind (a mirror plane, = S1, a centre of inversion, i = S2, a rotation-reflection axis, S2n). If the object is superimposable on its mirror image the object is described as being achiral.”2 This definition is particularly true at molecular level in which chirality allows the generations of enantiomers that are mirror images one of the other but not superimposable. While in an achiral environment an enantiomeric couple has the same chemical and physical properties, in a chiral one they can display striking different behaviour. This effect is magnified in the living beings, where there is a high concentration of chiral elements (from the helix of the double strand of the DNA to the L- amino acid abundance), and is displayed a high sensitivity towards the interaction with single enantiomers. On this regards, fragrance and drugs can well exemplify the susceptibility of the biological systems towards chiral object. For instance, limonene ((±)-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene) exists as S and R enantiomers that interact differently with our body and respectively each enantiomer are responsible for the scent of lemon and orange (Figure 1.1.1a). Unfortunately, the importance of chirality in synthetic drugs was taken much more into consideration when negative side effects showed up. Thalidomide was a drug prescribed to pregnant women in the 1960s as anti-nausea. While the R enantiomer was active to alleviate nausea, its mirror image, the S enantiomer was a teratogen agent. Undisclosed the side effects, the drug was approved as a mixture 50:50 of the R and the S enantiomer (racemic) and it has caused hundreds of cases of severe birth defects3 (Figure 1.1.1b). Since then, the stereochemical behaviour of biologically active compound has gained increasingly attention and many sophisticated ways of enantioselective synthesis were designed. Moreover, once the globally and health related importance of chirality and its wide range of applicability was realised, researchers have focused their attention in study new type of molecular chirality in which it is explored the limits to determine the non ”superimposability” of a molecule with its mirror image. 1 Dynamic stereochemistry of chiral axes. Design and synthesis of stable atropisomers. Figure 1.1.1 Structure of chiral biological active molecules 1.2 Nomenclature and classification Due to the different activity of enantiomers it is of crucial importance to discriminate them in a chemical system. Although this detection may appear trivial it is not always straightforward to define the chirality of a chemical object. Therefore, it is important to have in mind how to detect and classify the chiral systems. Taking as example two compounds with the same molecular formula they are considered constitutional isomers if they do not have the same connectivity between the atoms (as in 2-nitro and 3-nitro toluene). On the contrary, stereoisomers display the same connectivity but differs in the disposition of atoms in the space. It is noteworthy that are formally considered stereoisomers also the different disposition resulting from the rotation around a single bond, as the four stereoisomers conceivable for the n-butane (Figure 1.2.1). CH3 CH3 H H HH HH H CH3 CH3 H CH3 H CH H CH H H CH3 3 3 CH3 H CH3 H H H I - anti II - gauche III - eclipsed IV – partially eclipsed Figure 1.2.1 Stereoisomers determined by the rotation around a single bond of n-butane A stereoisomer that are non-superimposable with its mirror image is called enantiomer otherwise it is identified as diastereoisomer. The geometrical conditions requested for a chemical system to have its mirror image non-superimposable with itself identify chirality in that system. These conditions 2 Chapter 1 - Introduction can be described as a lack of some symmetry element2 (mirror plane and/or centre of inversion) and can be achieved in chemical system by the presence of a stereogenic units (Figure 1.2.2). Two compounds with the same molecular formula NO Same YES Constitutional Isomers connectivity Stereoisomers ? Stereogenic Chiral center Chiral axis Topological - Asymmetric - Hindered rotation Helicity - Knots, rotaxanes, units quaternary center - about single bonds - concatenanes - Double bond stereoisomers cis/trans (Z/E) Are mirror NO Diastereoisomers images ? YES Achiral forms YES Are super- NO (meso) imposable? Enantiomers Figure 1.2.2 Classification of chiral molecules A stereogenic centre is the most common among the stereogenic units and it is identified by a single atom that carries four different substituents (Figure 1.2.3a). Chiral axes, instead, are identified by stereoisomers that can be interconverted by rotation about single bonds with a rotational barrier high enough to avoid interconversion at room temperature (Figure 1.2.3b).4 Such enantiomers, where the rotational barrier is higher than 24-25 kcal/mol, are called atropisomers. Figure 1.2.3 a) Chiral molecule displaying chiral centre. b) Chiral molecule displaying chiral axes Stereogenic units such as chiral axes and helicity identify enantiomers that are topologically equivalent, where is it possible to interconvert the two without crossing or breaking bonds.