Stereochemistry: A Three-Dimensional Insight

Stereochemistry
Copyright
Contents
About the authors
Foreword
Preface
1 Basic concepts of structure and stereochemistry
	1.1 Introduction
	1.2 A brief history
	1.3 Molecular geometry
		1.3.1 Van der Waals’ radius
		1.3.2 Bond length
		1.3.3 Bond angle
		1.3.4 Dihedral angle
	1.4 Isomers
		1.4.1 Conformational isomers
		1.4.2 Configuration and configurational isomers
	1.5 Projection formulae
		1.5.1 Fischer projection
		1.5.2 Newman projection
		1.5.3 Sawhorse projection
		1.5.4 Inter-conversion of Fischer projection to Newman projection or Sawhorse projection
		1.5.5 Flying wedge/zig-zag projection formula
		1.5.6 Inter-conversion of Fischer projection and zig-zag projection
	1.6 Summary
	Questions and Problems
	References
2 Symmetry and point groups
	2.1 Introduction
	2.2 Symmetry elements and symmetry operations
		2.2.1 Simple or proper axis of symmetry (Cn) and proper rotational operations (Cnk)
		2.2.2 Plane of symmetry (σ) – Operation of reflection (σ)
		2.2.3 Centre of symmetry (i) operation of inversion (i)
		2.2.4 Alternating or rotation-reflection axis of symmetry (Sn)
	2.3 Point groups and their classification
		2.3.1 Linear molecules with high symmetry (Special group)
		2.3.2 Nonlinear molecules with high symmetry and molecules with Platonic group structures
		2.3.3 Nonlinear molecules with high Cn axis (without platonic group molecules)
		2.3.4 Nonlinear molecules with absence of Cn, axis n≥2
	2.4 The chiral compounds and the difference between asymmetry and dissymmetry
	2.5 Symmetry number (σ)
		2.5.1 Practical method to assign the point group of given organic compound
	2.6 Summary
	Questions and Problems
	References
3 Elements of chirality and chiral stereoisomerism
	3.1 Introduction
	3.2 Molecules with central chirality
		3.2.1 Configurational descriptors for molecules with central chirality
			3.2.1.1 The D-L system
			3.2.1.2 The R/S system
	3.3 Molecules with two or more chiral centres
		3.3.1 Constitutionally unsymmetrical chiral molecules
			3.3.1.1 Erythro and Threo
			3.3.1.2 Pref and Parf
			3.3.1.3 Like (l) and unlike (u)
			3.3.1.4 Anti and Syn notations
			3.3.1.5 Brewster’s system
		3.3.2 Stereoisomerism in constitutionally symmetrical chiral molecules
		3.3.3 Stereoisomerism in cyclic molecules
	3.4 Molecules with the presence of chiral axis
		3.4.1 Assignment of configurational descriptors to molecules with presence of chiral axis
		3.4.2 Allenes
		3.4.3 Alkylidene cycloalkanes/Hemispiranes
		3.4.4 Spiranes
		3.4.5 Atropisomerism
		3.4.6 Atropisomerism of biaryls, restricted rotation around sp2-sp2, C–C bond
		3.4.7 Assignment of configurational descriptors to chiral biphenyls
		3.4.8 Bridged biphenyls
	3.5 Planar Chirality
		3.5.1 Assignment of configurational descriptor to molecules with chiral plane
		3.5.2 Cyclophanes and ansa compounds
		3.5.3 Trans-Cyclooctene
		3.5.4 Chiral ferrocenes
	3.6 Helicity
	3.7 Cyclostereoisomerism
	3.8 Summary
	Questions and Problems
	References
4 Chiroptical properties: Origin and applications
	4.1 Introduction
	4.2 Optical activity
		4.2.1 Origin of the optical activity
		4.2.2 Circular Birefringence
		4.2.3 Dissymmetric compounds and optical activity
		4.2.4 Circular dichroism
	4.3 Optical rotatory dispersion curves (ORD)
		4.3.1 Cotton effect curves
		4.3.2 The Cotton effect circular dichroism and optical rotatory dispersion curves
		4.3.3 Applications of the plain optical rotatory dispersion curves
		4.3.4 Applications of the Cotton effect optical rotatory dispersion/circular dichroism curves
		4.3.5 Empirical and semiempirical rules for conformational and configurational studies
	4.4 The axial α-haloketone rule and its applications
	4.5 Octant rule
		4.5.1 Applications of the octant rule
	4.6 Inherently symmetric or inherently dissymmetric optically active chromophores
	4.7 Helicity rules for inherently chiral chromophores
		4.7.1 α, β-Unsaturated ketone or enone
		4.7.2 1,3-Conjugated dienes
		4.7.3 Biaryls
		4.7.4 Helicenes
	4.8 Lowe’s rule for allenes
	4.9 Exciton coupling and dibenzoate chirality rule
	4.10 Summary
	Questions and Problems
	References
5 Configurational analysis
	5.1 Introduction
	5.2 Methods for the determination of absolute configuration
		5.2.1 Basic terminology of resonant X-ray scattering
		5.2.2 Determination of absolute configuration using resonant X-ray scattering
		5.2.3 Determination of absolute configuration by use of crystalline sponge-X-ray diffraction method
		5.2.4 Crystal morphological changes for assignment of absolute configuration
		5.2.5 Determination of absolute configuration using chiroptical methods
	5.3 Correlative methods for determination of configurations
		5.3.1 Chemical correlative methods of determination of configurations
			5.3.1.1 Correlation of configuration without affecting the bonds to the chiral centre
			5.3.1.2 Method of diastereoisomers
			5.3.1.3 Correlation of configuration via use of concerted reactions and reactions with known stereochemical outcome
			5.3.1.4 Correlation of configuration using predictable symmetry properties
		5.3.2 Correlative methods based on comparison of optical rotations
			5.3.2.1 Rule of shift
			5.3.2.2 Rule of optical superposition
			5.3.2.3 Hudson’s rule of isorotation
			5.3.2.4 Mills’ rule
		5.3.3 Quasi-racemate formation between two different molecules
		5.3.4 NMR Methods
			5.3.4.1 Use of CSA for the assignment of absolute configuration
			5.3.4.2 Use of CDA for the assignment of absolute configuration
			5.3.4.3 Use of CSR for the assignment of absolute configuration
	5.4 Assignment of configuration based on asymmetric synthesis
		5.4.1 Cram’s Rule
		5.4.2 Prelog’s rule
		5.4.3 Sharpless asymmetric epoxidation
	5.5 Horeau’s method of assignment of configuration based on kinetic resolution
	5.6 ‘Stand-alone’ methods for determination of configuration
		5.6.1 Assignment of configuration to an alkylidenecycloalkane via stereoselective synthesis
		5.6.2 Assignment of absolute configuration to (-)-trans-cyclooctene
		5.6.3 Determination of absolute configuration of allenes
			5.6.3.1 Use of stereoselective (concerted) reaction for assignment of configuration
			5.6.3.2 Conversion of an enantiomer of allene to compound of known configuration
		5.6.4 Assignment of absolute configuration to a spiro compound
		5.6.5 Assignment of absolute configuration to a biphenyl derivative
	5.7 Methods to distinguish between configurations of diastereoisomers
		5.7.1 Auwer’s Skita Rule
		5.7.2 UV-vis spectroscopy
		5.7.3 IR Spectroscopy
		5.7.4 X-ray diffraction studies
		5.7.5 NMR Spectroscopy
			5.7.5.1 Chemical shifts
			5.7.5.2 Coupling constant
			5.7.5.3 NOESY experiments
	5.8 Chemical method
	5.9 Summary
	Questions and Problems
	References
6 Racemates: Properties and methods of resolution
	6.1 Introduction: Properties of enantiomers and racemates
		6.1.1 Melting point phase diagrams
		6.1.2 Crystal shape/morphology
		6.1.3 Density of racemic modifications in solid state
		6.1.4 Solubility behaviour of racemic modifications
		6.1.5 IR spectroscopy
		6.1.6 NMR Spectroscopy
		6.1.7 X-ray diffraction studies
		6.1.8 Chromatographic behaviour
		6.1.9 Vapour Pressure
	6.2 Resolution of racemates
		6.2.1 Resolution of racemic modification exhibiting conglomerate behaviour: Spontaneous crystallisation
		6.2.2 Formation of diastereomeric salts or compounds followed by preferential crystallisation
		6.2.3 Resolution though formation of diastereomeric complexes
		6.2.4 Chromatographic resolutions
		6.2.5 Resolution of racemates via equilibrium asymmetric transformation
		6.2.6 Kinetic Resolutions of racemates
		6.2.7 Dynamic Kinetic Resolutions
	6.3 Racemisation processes
		6.3.1 Formation of a resonance stabilized carbanions
		6.3.2 Involvement of tautomeric species
		6.3.3 Racemisations involving a stable carbocation intermediate
		6.3.4 Racemisations involving a stable carbon-free radical intermediate
		6.3.5 Opposite reactions occurring simultaneously
		6.3.6 Racemisation encountered in DKR
		6.3.7 Rotation around single bond
	6.4 Summary
	Questions and Problems
	References
7 Conformation of acyclic molecules
	7.1 Introduction
	7.2 Conformation
		7.2.1 Torsional strain
		7.2.2 Notations for torsion angle, the Klyne–Prelog method
	7.3 Estimating strain energy
		7.3.1 Cause of the potential energy barriers
	7.4 Study of conformations due to rotation about sp3–sp3 single bond
		7.4.1 Rotations around C–C bond
			7.4.1.1 Conformations of ethane
			7.4.1.2 Conformations of propane
			7.4.1.3 Conformations of n-butane
			7.4.1.4 Branched alkanes
		7.4.2 Alkanes with polar substituents
		7.4.3 Rotation around C–N single bond
		7.4.4 Rotation around C–P single bond
		7.4.5 Rotation around C–O single bond
		7.4.6 Conformations due to rotation around sp3–sp2 single bond
		7.4.7 Conformations due to rotation around sp2–sp2 single bond
	7.5 Spectral/analytical/theoretical means of internal rotation studies
		7.5.1 Molecular mechanics and quantum mechanical approaches to estimate energies of molecules in different arrangements
		7.5.2 Dipole moment
		7.5.3 Use of NMR and ESR techniques
		7.5.4 Microwave spectroscopy
		7.5.5 Electron diffraction studies
		7.5.6 X-ray diffraction studies
		7.5.7 Infrared and Raman spectroscopy
	7.6 Conformation and chemical reactivity
		7.6.1 Curtin–Hammett principle
		7.6.2 Effect of conformation on kinetic and/or stereochemical outcome of chemical reactions
			7.6.2.1 Stereoselective 1,2-elimination reactions
			7.6.2.2 Pyrolytic eliminations
			7.6.2.3 Neighbouring Group Participation reaction
	7.7 Summary
	Questions and Problems
	References
8 Conformations of cyclic, fused and bridged ring molecules
	8.1 Introduction
	8.2 Cyclohexane conformations
		8.2.1 The chair conformation
		8.2.2 Ring inversion in cyclohexane
		8.2.3 Nonchair conformations of cyclohexane
			8.2.3.1 Monosubstituted cyclohexanes
		8.2.4 Cyclohexane derivatives with two or more substituents
			8.2.4.1 1,1-disubstituted cyclohexanes
			8.2.4.2 Non-geminal disubstituted cyclohexane derivatives
			8.2.4.3 1,2-dimethylcyclohexanes
			8.2.4.4 1,3-dimethyl cyclohexanes
			8.2.4.5 1,4-dimethyl cyclohexanes
			8.2.4.6 Conformational peculiarities exhibited by some di-substituted cyclohexanes
	8.3 Cyclohexanone conformational analysis
	8.4 Alkylidenecyclohexane conformation
	8.5 Cyclohexene conformation
	8.6 Cyclopropane conformation
	8.7 Cyclobutane conformations
	8.8 Normal ring compounds
		8.8.1 Cyclopentane conformation
		8.8.2 Cycloheptane conformation
	8.9 Medium-sized carbocycles
		8.9.1 Cyclooctane conformations
		8.9.2 Cyclononane conformations
		8.9.3 Cyclodecane conformations
	8.10 Large ring carbocycles
	8.11 Size and conformation-based trends in alicyclic compounds
		8.11.1 Accommodation of anti butane unit
		8.11.2 Accommodation of trans double bond
		8.11.3 Transannular effects
		8.11.4 I-strain concept
	8.12 Components of heterocyclic rings conformations
		8.12.1 Ring Inversion barriers in heterocycles
		8.12.2 Pyramidal inversion
		8.12.3 Anomeric effect
		8.12.4 Intramolecular hydrogen bonding
		8.12.5 1,3-Syn-axial interactions
	8.13 Fused ring compounds
		8.13.1 Decalins or bicyclo[4.4.0]decane
		8.13.2 Cis-decalin
			8.13.2.1 Geometry
			8.13.2.2 Symmetry properties
			8.13.2.3 Entropy
			8.13.2.4 Enthalpy
			8.13.2.5 Ring inversion barrier
		8.13.3 Trans-decalin
			8.13.3.1 Geometry
			8.13.3.2 Symmetry properties
			8.13.3.3 Entropy
			8.13.3.4 Enthalpy
			8.13.3.5 Ring-inversion
	8.14 Introduction of angular methyl groups in cis and -trans-decalins
	8.15 The octahydronaphthalene or octalins
	8.16 Bicyclo[4.3.0]nonane or hydrindane
	8.17 Bicyclo[3.3.0]octane or octahydropentalene
	8.18 Fused polycyclic compounds
		8.18.1 Perhydrophenanthrene
		8.18.2 Perhydroanthracenes
		8.18.3 Steroids stereochemistry
	8.19 Bridged-ring compounds
		8.19.1 Bicyclo[1.1.1]pentane
		8.19.2 Bicyclo[2.1.1]hexane
		8.19.3 Bicyclo[2.2.1]heptane
		8.19.4 Bicyclo[2.2.2]octane
		8.19.5 Bicyclo[3.2.1]octane
		8.19.6 Bicyclo[3.3.1]nonane
		8.19.7 Tricyclo[1.1.1.0]pentane or [1.1.1]propellane
		8.19.8 Adamantane or tricyclo[3.3.1.13,7]decane
		8.19.9 The bicyclo[2.2.1]heptyl and bicyclo[2.2.2]octyl systems and their contribution to nonclassical carbocation concept
		8.19.10 Bredt’s rule
	8.20 Conformation and chemical reactivity of cyclic compounds
		8.20.1 Reactions influenced by steric effects
		8.20.2 Systems where equatorially substituted conformer reacts faster
		8.20.3 Systems where axially substituted conformer reacts faster
		8.20.4 Reactions where stereo-electronic effects operate
			8.20.4.1 E2 reactions
			8.20.4.2 Pyrolytic ‘syn’ eliminations
			8.20.4.3 Grob’s fragmentation
		8.20.5 Molecular Rearrangements
			8.20.5.1 Rearrangements of 2-aminocyclohexanol derivatives
			8.20.5.2 Epoxide ring formation
			8.20.5.3 Furst-Plattner rule and the epoxide ring opening
			8.20.5.4 Electrophilic addition to the cyclohexene
	8.21 Summary
	Questions and Problems
	References
9 Prochirality
	9.1 Introduction
	9.2 Topicity, the relationship between two or more homomorphic ligands and faces
		9.2.1 Homotopic ligands and faces
			9.2.1.1 Substitution/addition criteria
			9.2.1.2 Symmetry criteria
			9.2.2.1 Stereoheterotopic ligands and faces
				9.2.2.1.1 Enantiotopic ligands and faces
					9.2.2.1.1.1 Substitution/addition criteria
					9.2.2.1.1.2 Symmetry criteria
				9.2.2.1.2 Diastereotopic ligands and faces
					9.2.2.1.2.1 Substitution/addition criteria
					9.2.2.1.2.2 Symmetry criteria
	9.3 Nomenclature system for stereoheterotopic ligands
		9.3.1 Stereodescriptors for enantiotopic ligands
		9.3.2 Diastereotopic ligands at pro-pseudoasymmetric centre
		9.3.3 Stereodescriptors for diastereotopic ligands
		9.3.4 Enantiotopic ligands in molecules with pro-chiral axis
		9.3.5 Enantiotopic ligands in molecules with pro-chiral plane
		9.3.6 Stereo-heterotopic ligands in molecules with pro-stereogenic units other than pro-chiral units
		9.3.7 Stereodescriptors for enantiotopic faces
		9.3.8 Stereodescriptors for diastereotopic faces
	9.4 Discrimination/recognition of stereo-heterotopic ligands and faces by bio-catalysts
	9.5 Discrimination/recognition of stereo-heterotopic ligands and faces by chiral chemical reagents/catalysts
	9.6 Recognition of stereo-heterotopic ligands by NMR
	9.7 Summary
	Questions and Problems
	References
10 Diastereomeric transition states and stereoselectivity
	10.1 Introduction
	10.2 Stereoselective processes
		10.2.1 Stereospecific reactions
		10.2.2 Asymmetric synthesis
		10.2.3 Steric and conformational effects in stereoselective processes
	10.3 The Asymmetric Aldol condensation reaction
		10.3.1 Substrate-controlled Aldol reactions
		10.3.2 Chiral reagent (enolate) controlled Aldol reactions
		10.3.3 Double stereo-differentiation
	10.4 Sharpless epoxidation
	10.5 Jacobsen-Katsuki epoxidation
	10.6 Asymmetric dihydroxylation (AD)
	10.7 Asymmetric Aminohydroxylation (AA)
	10.8 Enantioselective reduction of pro-chiral carbonyl compounds
		10.8.1 Chiral LiAlH4 reagents
		10.8.2 Enantioselective reduction of prochiral ketones using BINAL-H
		10.8.3 Chiral Borane reagents for enantioselective reductions of prochiral ketones
		10.8.4 Enantioselective reductions of functionalised carbonyl compounds using Ru-BINAP catalyst
	10.9 Homogeneous asymmetric catalytic reductions of prochiral alkene derivatives
	10.10 Allylamine to enamine asymmetric isomerisation
	10.11 Enantioselective reduction of C=N moiety via chiral cyclic hydrazone, synthesis of α-amino acids
	10.12 Asymmetric Diels-Alder reaction
		10.12.1 Chiral dienophiles for asymmetric Diels-Alder reaction
		10.12.2 Chiral dienes for asymmetric Diels-Alder reaction
		10.12.3 Chiral catalysts in asymmetric Diels-Alder reactions
	10.13 Chiral organo-catalysis
	10.14 Summary
	Questions and Problems
	References
	Further Reading
11 Chiral analytical chemistry
	11.1 Introduction
	11.2 Chiral analysis terminology
	11.3 Chiroptical methods for determination of enantiomer composition
	11.4 NMR for determination of enantiomer composition
		11.4.1 Chiral derivatising agents for determination of enantiomer composition
		11.4.2 Chiral solvating agents for determination of enantiomer composition
		11.4.3 Chiral shift reagents for determination of enantiomer composition
	11.5 Chromatographic techniques for determination of enantiomer composition
		11.5.1 Chiral derivatising agents for the indirect gas chromatography method
		11.5.2 Chiral derivatising agents for the indirect high-performance liquid chromatography method
		11.5.3 Use of chiral stationary phase (CSP) for determination of enantiomer composition
		11.5.4 Use of chiral mobile phase for determination of enantiomer composition
	11.6 Use of capillary electrophoresis for determination of enantiomer composition
	11.7 Enantiomer recognition and evaluation of chiral sensors
		11.7.1 Basics of chiral recognition and optical responses
		11.7.2 Ultraviolet spectroscopy–based chirality sensor
		11.7.3 Fluorescence spectroscopy–based chirality sensor
		11.7.4 Circular dichroism (CD) spectroscopy–based chirality sensor
		11.7.5 Determination of host-guest stoichiometry
		11.7.6 Determination of binding constant
		11.7.7 Benesi–Hildebrand method
		11.7.8 Stern–Volmer method
	11.8 Summary
	Questions and Problems
	References
12 Pericyclic reactions
	12.1 Introduction
	12.2 The atomic orbitals and the molecular orbitals
	12.3 The conservation of symmetry approach or the correlation diagram approach
		12.3.1 Correlation diagram method for electrocyclic reactions
		12.3.2 Correlation diagram for the cyclo-addition reactions
	12.4 The frontier molecular orbitals approach
		12.4.1 Application of FMO approach to cyclo-addition reactions
			12.4.1.1 The (4n+2) π electron cyclo-addition reactions
			12.4.1.2 The 4n π electron cyclo-addition reactions
		12.4.2 The FMO approach for the electrocyclic reactions
		12.4.3 The application of FMO approach to sigmatropic rearrangements
			12.4.3.1 Rearrangements involving the H-shift
			12.4.3.2 Rearrangements involving the C-shift
				12.4.3.2.1 [1,3]-Carbon migrations
				12.4.3.2.2 [1,5]-Carbon migrations
	12.5 The rates of Diels-Alder reactions
	12.6 Role of coefficients on selectivity
	12.7 1,3-Dipolar cycloaddition reactions
	12.8 Summary
	Questions and Problems
	References
Solutions and keys to the problems
	Chapter 1: Basic concepts of structure and stereochemistry
	Chapter 2: Symmetry and point groups
	Chapter 3: Elements of chirality and chiral stereoisomerism
	Chapter 4: Chiroptical properties: origin and applications
	Chapter 5: Configurational analysis
	Chapter 6: Racemates: properties and methods of resolution
	Chapter 7: Conformation of acyclic molecules
	Chapter 8: Conformations of cyclic, fused and bridged ring molecules
	Chapter 9: Prochirality
	Chapter 10: Diastereomeric transition states and stereoselectivity
	Chapter 11: Chiral analytical chemistry
	Chapter 12: Pericyclic reactions
Index