Absolute Configuration Determination
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II. Stereochemistry 5
B.Sc.(H) Chemistry Semester - II Core Course - III (CC-III) Organic Chemistry - I II. Stereochemistry 5. Physical and Chemical Properties of Stereoisomers Dr. Rajeev Ranjan University Department of Chemistry Dr. Shyama Prasad Mukherjee University, Ranchi 1 Syllabus & Coverage Syllabus II Stereochemistry: Fischer Projection, Newmann and Sawhorse Projection formulae and their interconversions. Geometrical isomerism: cis–trans and syn-anti isomerism, E/Z notations with Cahn Ingold and Prelog (CIP) rules for determining absolute configuration. Optical Isomerism: Optical Activity, Specific Rotation, Chirality/Asymmetry, Enantiomers, Molecules with two or more chiral-centres, Distereoisomers, Meso structures, Racemic mixture. Resolution of Racemic mixtures. Relative and absolute configuration: D/L and R/S designations. Coverage: 1. Types of Isomers : Comparing Structures 2. Optical Activity 3. Racemic Mixtures : Separation of Racemic Mixtures 4. Enantiomeric Excess and Optical Purity 5. Relative and Absolute Configuration 6. Physical and Chemical Properties of Stereoisomers 2 Stereochemistry Types of Isomers Dr. Rajeev Ranjan 3 Stereochemistry Determining the Relationship Between Two Non-Identical Molecules Dr. Rajeev Ranjan 4 Stereochemistry Comparing Structures: Are the structures connected the same? yes no Are they mirror images? Constitutional Isomers yes no Enantiomers Enantiomers Is there a plane of symmetry? All chiral centers will be opposite between them. yes no Meso Diastereomers superimposable Dr. Rajeev Ranjan 5 Stereochemistry Optical Activity: • The chemical and physical properties of two enantiomers are identical except in their interaction with chiral substances. • The physical property that differs is the behavior when subjected to plane-polarized light ( this physical property is often called an optical property). • Plane-polarized (polarized) light is light that has an electric vector that oscillates in a single plane. -
Enantiomers & Diastereomers
Chapter 5 Stereochemistry Chiral Molecules Ch. 5 - 1 1. Chirality & Stereochemistry An object is achiral (not chiral) if the object and its mirror image are identical Ch. 5 - 2 A chiral object is one that cannot be superposed on its mirror image Ch. 5 - 3 1A. The Biological Significance of Chirality Chiral molecules are molecules that cannot be superimposable with their mirror images O O ● One enantiomer NH causes birth defects, N O the other cures morning sickness O Thalidomide Ch. 5 - 4 HO NH HO OMe Tretoquinol OMe OMe ● One enantiomer is a bronchodilator, the other inhibits platelet aggregation Ch. 5 - 5 66% of all drugs in development are chiral, 51% are being studied as a single enantiomer Of the $475 billion in world-wide sales of formulated pharmaceutical products in 2008, $205 billion was attributable to single enantiomer drugs Ch. 5 - 6 2. Isomerisom: Constitutional Isomers & Stereoisomers 2A. Constitutional Isomers Isomers: different compounds that have the same molecular formula ● Constitutional isomers: isomers that have the same molecular formula but different connectivity – their atoms are connected in a different order Ch. 5 - 7 Examples Molecular Constitutional Formula Isomers C4H10 and Butane 2-Methylpropane Cl Cl C3H7Cl and 1-Chloropropane 2-Chloropropane Ch. 5 - 8 Examples Molecular Constitutional Formula Isomers CH O CH C H O OH and 3 3 2 6 Ethanol Methoxymethane O OCH and 3 C H O OH 4 8 2 O Butanoic acid Methyl propanoate Ch. 5 - 9 2B. Stereoisomers Stereoisomers are NOT constitutional isomers Stereoisomers have their atoms connected in the same sequence but they differ in the arrangement of their atoms in space. -
Unit 3 – Stereochemistry
Stereochemistry Stereochemistry refers to the 3-dimensional properties and reactions of molecules. It has its own language and terms that need to be learned in order to fully communicate and understand the concepts. New vocabulary and concepts Handedness Chirality Fischer Projections Depicting Asymmetric Carbons (R) and (S) Nomenclature Enantiomers Diastereomers Optical Activity Stereochemistry Isomers: Different compounds that have the same molecular formula (composition) but different connectivity. Two classes: - Structural (constitutional) isomers: same molecular formula but different bonding sequence - Stereoisomers: same molecular formula, same bonding sequence, but different arrangement in space. Handedness…..Chirality Handedness” right glove doesn’t fit the left hand. Superimposable: A term that describes the ability to precisely overlap one object over another. Only identical objects are superposable, everything else is non-superposable superimposable nonsuperimposable Chiral molecules & Chirality Center Chemical substances can be handed, and they are called chiral. Chiral Molecules: are molecules that are nonsuperimposable on their mirror image. A carbon atom that is bonded to four chiral carbon atom different groups is called chairal carbon atom or stereocenter (asymmetric carbon atom). It is sp3 carbon and labeled with a strict. Achiral: A molecule is achiral if it is superimposable on its mirror image H H Cl Cl Practices on Asymmetric Carbons Example: Identify all asymmetric carbons present in the following compounds. Br Br H OH H H CH2CH3 H C *C C C H Br CH3 * H H H H H H H H H3C Br CH3 * * OH * CH CHCOOH* 3 * * * Fischer Projections: ➢ It is a two-dimensional representation of a three-dimensional organic molecule by projection. -
Chapter 4: Stereochemistry Introduction to Stereochemistry
Chapter 4: Stereochemistry Introduction To Stereochemistry Consider two of the compounds we produced while finding all the isomers of C7H16: CH3 CH3 2-methylhexane 3-methylhexane Me Me Me C Me H Bu Bu Me Me 2-methylhexane H H mirror Me rotate Bu Me H 2-methylhexame is superimposable with its mirror image Introduction To Stereochemistry Consider two of the compounds we produced while finding all the isomers of C7H16: CH3 CH3 2-methylhexane 3-methylhexane H C Et Et Me Pr Pr 3-methylhexane Me Me H H mirror Et rotate H Me Pr 2-methylhexame is superimposable with its mirror image Introduction To Stereochemistry Consider two of the compounds we produced while finding all the isomers of C7H16: CH3 CH3 2-methylhexane 3-methylhexane .Compounds that are not superimposable with their mirror image are called chiral (in Greek, chiral means "handed") 3-methylhexane is a chiral molecule. .Compounds that are superimposable with their mirror image are called achiral. 2-methylhexane is an achiral molecule. .An atom (usually carbon) with 4 different substituents is called a stereogenic center or stereocenter. Enantiomers Et Et Pr Pr Me CH3 Me H H 3-methylhexane mirror enantiomers Et Et Pr Pr Me Me Me H H Me H H Two compounds that are non-superimposable mirror images (the two "hands") are called enantiomers. Introduction To Stereochemistry Structural (constitutional) Isomers - Compounds of the same molecular formula with different connectivity (structure, constitution) 2-methylpentane 3-methylpentane Conformational Isomers - Compounds of the same structure that differ in rotation around one or more single bonds Me Me H H H Me H H H H Me H Configurational Isomers or Stereoisomers - Compounds of the same structure that differ in one or more aspects of stereochemistry (how groups are oriented in space - enantiomers or diastereomers) We need a a way to describe the stereochemistry! Me H H Me 3-methylhexane 3-methylhexane The CIP System Revisited 1. -
Kinetic Modeling of Chiral Amplification and Enantioselectivity Reversal in Asymmetric Reactions
J. Mex. Chem. Soc. 2007, 51(2), 117-121 Article © 2007, Sociedad Química de México ISSN 1870-249X Kinetic Modeling of Chiral Amplification and Enantioselectivity Reversal in Asymmetric Reactions Jesús Rivera Islas and Thomas Buhse* Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Colonia Chamilpa, 62209 Cuernavaca, Morelos, México. Tel/Fax: +52-7773297997, e-mail: [email protected]. Recibido el 30 de marzo de 2007; aceptado el 18 de mayo de 2007 Abstract: Nonlinear effects in asymmetric synthesis and the occa- Resumen: Los efectos no lineales en síntesis asimétrica y la inver- sionally observed reversal of the enantioselectivity of the employed sión de la enantioselectividad del catalizador empleado son evaluados catalyst are evaluated by a generalized kinetic approach. A non-auto- a través de un modelado cinético generalizado. Un sistema reactivo catalytic and an autocatalytic reaction system are considered as two autocatalítico y otro no autocatalítico son considerados como dos different prototype scenarios. It is predicted that during the course of escenarios prototipos diferentes. Se predice que durante el curso de la enantioselectivity reversal in the non-autocatalytic system a gradual inversión de la enantioselectividad en el sistema no autocatalítico transition between both optically active states under loss of chiral ocurre una transición gradual entre los dos estados óptimamente acti- amplification occurs while in the autocatalytic system a sharp transi- vos donde la amplificación quiral decae mientras en el sistema auto- tion under retention of chiral amplification is observed. catalítico ocurre una transición abrupta observándose la retención de Keywords: Asymmetric synthesis, chiral amplification, nonlinear la amplificación quiral. -
Catalytic Asymmetric Synthesis
Catalytic Asymmetric Synthesis Dr Alan Armstrong Rm 313 (RCS1), ext. 45876; [email protected] 7 lectures Recommended texts: “Catalytic Asymmetric Synthesis, 2nd edition”, ed. I Ojima, Wiley-VCH, 2000 (or 1st ed., 1993, which contains most of the lecture material) “Asymmetric Synthesis”, G Procter, Oxford, 1996 Aims of course: To give students an understanding of the basic principles of asymmetric catalysis, and to demonstrate these in the context of state-of-the-art catalytic asymmetric processes for C-C bond formation and redox processes. Course objectives: At the end of this course you should be able to: • Recognise the types of functional groups which can be prepared by catalytic asymmetric methods discussed in the course; • Use this knowledge in planning the synthesis of enantiomerically enriched compounds from given prochiral starting materials; • Outline the scope and limitations of any methods you propose, with respect to parameters such as turnover, substrate and functional group tolerance, availability of catalysts and/or ligands etc Course content (by lecture, approximately): 1. Introduction and general principles of asymmetric catalysis. Oxidation of functionalised olefins: asymmetric epoxidation of allylic alcohols and enones 2. Oxidation of unfunctionalised olefins: epoxidation, dihydroxylation and aminohydroxylation. 3. Reduction of olefins: asymmetric hydrogenation. 4. Reduction of ketones and imines 5. Asymmetric C-C bond formation: nucleophilic attack on carbonyls, imines and enones 6. Asymmetric transition metal catalysis in C-C bond forming reactions (cross-couplings, Heck reactions, allylic substitution, carbenoid reactions) 7. Chiral Lewis acid catalysis (aldol reactions, cycloadditions, Mannich reactions, allylations) 1 Catalytic Asymmetric Synthesis - Lecture 1 Background and general principles • Why asymmetric synthesis? The need to prepare pharmaceuticals and other fine chemicals as single enantiomers drives the field of asymmetric synthesis. -
Nonlinear Effects in Asymmetric Catalysis: a Personal Account Henri B
888 ACCOUNT Nonlinear Effects in Asymmetric Catalysis: A Personal Account Henri B. Kagan Laboratoire de Synthèse Asymétrique (ESA 8075), Institut de Chimie Moleculaire d’Orsay, Université Paris-Sud, 91405 Orsay, France Fax+33-1-69-15-46-80; E-mail: [email protected] Received 7 April 2001 Dedicated to Professor R. Noyori for his fundamental contributions to organic chemistry and asymmetric catalysis. of diastereomeric aggregate formation). Uskokovic et al. Abstract: The discovery of nonlinear effects (NLE) is recalled, and the main features of NLE are described. The origin of the nonlinear discovered that the nmr spectrum of dihydroquinine race- effects is discussed. The asymmetric amplification is especially mic or enantiopure are not identical, because of diastereo- 14 considered. The concept on nonlinear effects has been extended to meric solute-solute interactions. Horeau and Guetté pseudo-enantiomeric catalysts, to chiral reagents and to kinetic res- discussed in details in 1974 the diastereomeric interac- olution. The use of NLE as a mechanistic tool is underlined. tions in solution between enantiomers.15 In 1976 Wynberg Key words: asymmetric amplification, asymmetric catalysis, and Feringa demonstrated that some diastereoselective re- asymmetric depletion, asymmetric synthesis, chiral auxiliary, non- actions can give a different stereochemical outcome if the linear effects substrates are not enantiomerically pure.16 The authors called this effect “antipodal interaction effect”, it is relat- ed to non-bonded interactions. 1 Introduction In 1985 I was invited by Prof. Agami to give a seminar in Université Paris VI. After my lecture I discussed with This article does not intend to detail the area of nonlinear Prof. -
Enantiomeric Resolution and Absolute Configuration of a Chiral Δ-Lactam
molecules Article Enantiomeric Resolution and Absolute Configuration of a Chiral δ-Lactam, Useful Intermediate for the Synthesis of Bioactive Compounds 1, 1, 1 1 Roberta Listro y, Giacomo Rossino y, Serena Della Volpe , Rita Stabile , Massimo Boiocchi 2 , Lorenzo Malavasi 3, Daniela Rossi 1,* and Simona Collina 1 1 Department of Drug Sciences, University of Pavia, via Taramelli 12, 27100 Pavia, Italy; [email protected] (R.L.); [email protected] (G.R.); [email protected] (S.D.V.); [email protected] (R.S.); [email protected] (S.C.) 2 Centro Grandi Strumenti, University of Pavia, via Bassi 21, 27100 Pavia, Italy; [email protected] 3 Department of Chemistry, University of Pavia, via Taramelli 12, 27100 Pavia, Italy; [email protected] * Correspondence: [email protected] These authors contributed equally to this work. y Academic Editor: Józef Drabowicz Received: 2 December 2020; Accepted: 18 December 2020; Published: 19 December 2020 Abstract: During the past several years, the frequency of discovery of new molecular entities based on γ- or δ-lactam scaffolds has increased continuously. Most of them are characterized by the presence of at least one chiral center. Herein, we present the preparation, isolation and the absolute configuration assignment of enantiomeric 2-(4-bromophenyl)-1-isobutyl-6-oxopiperidin-3-carboxylic acid (trans-1). For the preparation of racemic trans-1, the Castagnoli-Cushman reaction was employed. (Semi)-preparative enantioselective HPLC allowed to obtain enantiomerically pure trans-1 whose absolute configuration was assigned by X-ray diffractometry. Compound (+)-(2R,3R)-1 represents a reference compound for the configurational study of structurally related lactams. -
Catalytic Enantioselective Desymmetrization of Meso
Catalytic Enantioselective Desymmetrization of Meso Compounds in Total Synthesis of Natural Products: Towards an Economy of Chiral Reagents Jérémy Mérad, Mathieu Candy, Jean-Marc Pons, Cyril Bressy To cite this version: Jérémy Mérad, Mathieu Candy, Jean-Marc Pons, Cyril Bressy. Catalytic Enantioselective Desym- metrization of Meso Compounds in Total Synthesis of Natural Products: Towards an Economy of Chiral Reagents. SYNTHESIS, Georg Thieme Verlag, 2017, 49 (09), pp.1938-1954. 10.1055/s-0036- 1589493. hal-01687264 HAL Id: hal-01687264 https://hal.archives-ouvertes.fr/hal-01687264 Submitted on 18 Jan 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2017, 49, 1938–1954 1938 short review Syn thesis J. Merad et al. Short Review Catalytic Enantioselective Desymmetrization of Meso Compounds in Total Synthesis of Natural Products: Towards an Economy of Chiral ReaGents OH Jérémy Merad1 HO O Me Mathieu Candy O O Me O Jean-Marc Pons O ( )8 O ( )9 N H H H H Cyril Bressy* MeO Me HO OH -
Absolute Configuration Some Definitions
Absolute Structure Absolute Configuration Some definitions • Absolute Configuration -> spatial arrangement of the atoms for a chiral molecule (R/S, P/M or D/L assignment). • Absolute Structure -> spatial arrangement of atoms in a noncentrosymmetric crystal structure (unit-cell, space group) • Chiral molecules Molecules that cannot be superimposed with their mirror image • Two mirror images of a chiral molecule are called enantiomers, they are optical isomers • Determination of absolute configuration -> handness of the molecule Origin of chirality • Asymmetric carbon atoms (R/S) • Axial chirality R-Binol S-Binol • Chiral Propeller Arrangement (P/M or / ) Helicenes In the solid state • Chiral molecules can crystallize as an enantiopure bulk sample or as a racemic mixture. • For enantiopure crystals Space group restriction: Only 65 space groups allowed for chiral molecules: No Inversion Center / No Mirror / No Glide Plane These include 11 pairs of eniantomorph space groups (screw axes of opposite handedness) eg: P41/P43 or P61/P65 Space Group Restrictions 85 % Racemic mixture In the solid state • 1) Conglomerate: a mixture of well-resolved crystals of both enantiomers Chiral space group Individual crystals have an optical activity 5-10 % • 2) Racemates: One type of crystal containing the two enantiommers in a well defined stoechiometry. No optical activity Usually centrosymmetric space group 90-95 % Conglomerate Racemates Racemic mixture In the solid state • 3) Inversion twin : twinned crystals of both enantiomers Chiral space group • 4) -
1 Fundamentals of the Stereochemistry of Organophosphorus Compounds
1 1 Fundamentals of the Stereochemistry of Organophosphorus Compounds 1.1 Historical Background Natural processes are subordinate to geometrodynamics – the theory describing physical objects, geometrical spacetime, and associated phenomena completely in terms of geometry, and her elder sister – symmetry. Symmetry/asymmetry is one of the basic concepts in modern natural science [1]. Research into this field began in the Middle Ages, when the birefringent properties of calcite were discovered. In 1669, Bartholinus observed the double refractive properties of the calcite Iceland spar. Later, in 1801, the mineralogist Haui found that quartz crystals are enantiomorphic, representing mirror images of one another. In 1815, another French naturalist J.-B. Biot discovered that certain chemical compounds rotate the plane of a beam of polarized light [2]. Biot constructed the first polarimeter and he also discovered that many natural compounds exhibit optical activity, that is, they rotate the plane of circularly polarized light. Studying crystals under a microscope, Biot discovered two types of crystals. The sample consisting of crystals of one type turned polarized light clockwise and that from another type in the opposite direction. A mixture of the two types of crystals had a neutral effect on polar- ized light. The nature of this property remained a mystery until 1848, when Louis Pasteur proposed that it had a molecular basis originating from some form of dissymmetry [3]. Pasteur separated the left and right hemihedral crystals of the sodium-ammonium salt of D,L-tartaric acid under a microscope, and connected the opposite optical activity to the mirror image of these crystals. Pasteur termed the mixture creating polarization as dissymetric and the phenomenon as dissymmetry (asymmetry). -
Distinction of Enantiomers by NMR
REVIEWS Disinction of enantiomers by NMR spectroscopy using chiral orienting media Burkhard Luy Abstract | NMR spectroscopy is a very important analytical tool in modern organic and inorganic chemistry. Next to the identification of molecules and their structure determination, it is also used for the distinction of enantiomers and the measurement of enantiomeric purity. This article gives a brief review of the techniques being developed for enantiomeric differentiation by virtue of chiral alignment media and their induction of enantiomerically dependent anisotropic NMR parameters like residual dipolar couplings. An overview of existing chiral alignment media, a brief introduction into the basic theory and measurement of the various anisotropic parameters, and several example applications are given. 1. Introduction valuable compounds one doesn’t necessarily want to NMR spectroscopy is one of the most important irreversibly modify the substance. analytical tools in modern organic and inorganic Another possibility for the distinction of chemistry as it is the only tool that allows the enantiomers is the orientation of the molecule of determination of molecular structures at atomic interest in a so-called chiral alignment medium. resolution in solution. It is used to identify the In this case, the molecule is partially aligned constitution, conformation and configuration and anisotropic NMR parameters like residual of countless molecules every day. However, the quadrupolar couplings, residual dipolar couplings magnetic field used for the induction of the Zeeman and residual chemical shift anisotropy can be splitting is per se achiral so that enantiomers measured2–4. As the orientation in a chiral have identical properties and therefore identical alignment medium is different for the two NMR spectra.