Stereochemistry by Dr. Dorian Didier Office: F 3.080 [email protected] Lab: F 2.064 Dorian Didier Research Group DidierResearchGroup 1 0 Table of contents by D. Didier (LMU) 1 Introduction, definitions and reminders 2 Preparation of optically active molecules 3 Diastereoselective reactions 4 Enantioselective reactions 2 0 Table of contents by D. Didier (LMU) 1 Introduction, definitions and reminders 2 Preparation of optically active molecules 3 Diastereoselective reactions 4 Enantioselective reactions 3 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals 1.2 Isomerism 1.3 Definitions and reminders 1.4 Chirality 1.5 Absolute configurations 4 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals Steric vs. electronic effects Nonbonding interactions (Van der Waals repulsion) between Steric effects substituents within a molecule or between reacting molecules The effect of bond and through-space polarization by Electronic effects heteroatom substituents on reaction rates and selectivities Example: 1,4-addition Tet. 2000, 7715 (Yakura) Electronic effect: Steric effect: coordination repulsion 5 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals Stereoelectronic effects Stereoelectronic Geometrical constraints placed upon ground and transition effects states by orbital overlap considerations Anomeric effect s*(C-O) DG° = +0.6 kcal.mol-1 nO (filled sp3) DG° = -0.6 kcal.mol-1 6 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals Hybridization 1 x s + 3 x p 1 x s + 2 x p 1 x s + 1 x p s p p p s p p p s p p p sp3 sp3 sp3 sp3 sp2 sp2 sp2 p sp sp p p sp3 p p sp2 sp2 sp sp sp3 sp2 p sp3 sp3 tetrahedral planar linear 3 2 1 sp sp sp or sp 7 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals Resulting geometry sp3 sp2 sp 8 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals Orbital orientation s bonds p bonds antibonding s* p* bonding s p Nat. 2001, 539 (Weinhold) staggered eclipsed conformation s*C-H conformation LUMO sC-H s*C-H sC-H HOMO LUMO HOMO 9 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals study case: N2F2 LUMO LUMO HOMO HOMO s*N-F s*N-F nN nN s*N-F s*N-F Lone pair delocalization HOMO-LUMO appears to override delocalization is stronger electron-electron and in the cis isomer due dipole-dipole repulsion to better orbital overlap in the stabilization of nN nN the cis isomer the cis isomer is favored by 3 kcal/ mol at 25 °C 10 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals SN2 The Nu–C–X bonding interaction is that of a 3-center, 4-electron bond (3c4e). ∗ The frontier orbitals which are involved are the nonbonding orbital from Nu as well as σC–X and σ C–X 3c4e model Inversion Retention E LUMO s*C-X n HOMO N nN s*C-X HOMO LUMO s C-X Overlap from this Constructive overlap geometry results in no between Nu & σ* C–X net bonding interaction11 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals E2 synperiplanar antiperiplanar s C-H s*C-X s C-H s*C-X HOMO LUMO HOMO LUMO The interaction between s C-H and s*C-X leads to a conformation with H and X being trans-antiperiplanar 12 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals electrophilic trapping inversion retention ACIE 2002, 717 (Basu) ACIE 2018, 5516 (Knochel) 13 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism – reminder Isomers are structures that possess the same chemical formula Isomers same connectivity? NO YES Constitutional Stereoisomers isomers 14 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Stereoisomerism Form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms, but differ in the three-dimensional orientations of their atoms in space Stereoisomers Through Through bond rotation bond cleavage Configurational Conformers isomers 15 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Conformers Natta Sägebock Newman projection projection projection eclipsed conformation E (kcal.mol-1) 3 0 j () 0 60 120 staggered conformation 16 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism n-butane E (kcal.mol-1) 4.5 3.6 gauche-conformation 0.9 0 dihedral angle 180° 120° 60° 0° (H3C-C-C-CH3) anti-conformation 17 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Conformers chair boat conformation conformation E (kcal.mol-1) half-chair 11 7 5.5 twisted-boat 0 18 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Relevance Important to understand Felkin-Anh models eclipsed staggered Important to understand Zimmermann-Traxler models chair 1 chair 2 19 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism hydrazine N2H4 The nonbonding lone pair orbitals in the gauche isomer should be destabilizing due to electron-electron repulsion. s s N-H s n *N-H *N-H anti- N conformation E s*N-H Hydrazine can exist in LUMO either gauche or anti conformations (relative to lone pairs) nN gauche- HOMO conformation s N-H 20 HOMO 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism hydrogen peroxide H2O2 Major stabilizing interaction is the delocalization of O-lone pairs into the C–H antibonding orbitals. There are no such stabilizing interactions in the anti-conformation while there are 2 in the gauche conformation. anti- E conformation H2O2 can exist in either s*O-H gauche or anti LUMO conformations (relative s*O-H to H atoms) n nO O HOMO gauche- conformation 21 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Esters – (E) or (Z)? ? (E)-conformation (Z)-conformation 22 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Esters – (E) or (Z)? ? (E)-conformation (Z)-conformation E (kcal.mol-1) 1 s*C-O 10-12 s*C-R LUMO LUMO nO HOMO nO HOMO 2-3 1 nO – s*C-O nO – s*C-R overlap overlap 1 σ*C–O is a better acceptor than σ*C-R (where R is a carbon substituent). Therefore the (E) conformation is stabilized by this interaction. 23 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Destabilizing effects eclipsed staggered repulsive interaction between πC-C & σC-H πC-C πC-C -1 E (kcal.mol ) σC-H σC-H 2 σC-H σC-H σC-H σC-H 0 JACS 1985, 5035 (Wiberg) JACS 1987, 6591 (Houk) 24 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Allylic systems 1-butene E (kcal.mol-1) 1.32 0.49 0 j 25 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Allylic systems 2-propen-1-ol E (kcal.mol-1) 2 1.18 0.37 0 j 26 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Allylic systems 2-methyl-1-butene E (kcal.mol-1) 2.68 1.39 0.06 0 j 27 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Allylic systems 2-methyl-2-propen-1-ol E (kcal.mol-1) 2.01 1.16 0.21 0 j 28 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Allylic systems (Z)-2-pentene E (kcal.mol-1) 3.88 0.56 0 29 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Allylic systems (Z)-2-buten-1-ol E (kcal.mol-1) 1.44 0.86 0 30 1 Introduction, definitions and reminders by D. Didier (LMU) 1.3 Definitions Asymmetric synthesis Preparation of chiral molecules Point in a molecule bearing different substituents, Stereocenter such that interchanging any two of them or stereogenic center leads to a stereoisomer Molecule that possesses a non-superposable Chiral molecule mirror image 31 1 Introduction, definitions and reminders by D. Didier (LMU) 1.3 Definitions Configurational isomers are the molecules mirror images? NO YES Diasteoisomers Enantiomers 32 1 Introduction, definitions and reminders by D. Didier (LMU) 1.3 Definitions Mixture containing equal quantities of Racemic mixture both enantiomers Mixture containing different quantities of Enantioenriched mixture two enantiomers Enantiopure compound Mixture containing only one enantiomer 33 1 Introduction, definitions and reminders by D. Didier (LMU) 1.3 Definitions Enantiomeric excess Value representing the excess of one (ee) enantiomer over the second one n[(R)-A] – n[(S)-A] ee = 100 · 62% ee n[(R)-A] + n[(S)-A] n[(R)-A] er = er = 81:19 n[(S)-A] enantiomeric ratio Diastereomeric ratio (dr) dr = 93:7 dr = 95:3:1:1 34 1 Introduction, definitions and reminders by D. Didier (LMU) 1.3 Definitions A reaction that selectively leads to one or a series Stereoselectivite reaction of stereoisomers, disfavoring the other ones. This can be a result of competitive interactions. A reaction in which the stereochemical outcome is Stereospecific reaction guided by the mechanism. It requires a particular (specific) arrangement of the atoms (or functional groups) for the reaction to proceed. Stereospecific does not mean that only one stereoisomer is obtained. If a reaction gives only one diastereoisomer, it is fully diastereoselective.