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Xiaoping Sun. Organic Mechanisms
Table of Contents
List of Tables
List of Illustrations
Guide
Pages
ORGANIC MECHANISMS. Reactions, Methodology, and Biological Applications
PREFACE
FIRST EDITION PREFACE
ABOUT THE COMPANION WEBSITE
1 FUNDAMENTAL PRINCIPLES. 1.1 REACTION MECHANISMS AND THEIR IMPORTANCE
1.2 ELEMENTARY (CONCERTED) AND STEPWISE REACTIONS
1.3 MOLECULARITY
1.3.1 Unimolecular Reactions
1.3.2 Bimolecular Reactions
1.4 KINETICS. 1.4.1 Rate‐Laws for Elementary (Concerted) Reactions
Unimolecular reactions
Bimolecular reactions
1.4.2 Reactive Intermediates and the Steady‐State Assumption
1.4.3 Rate‐Laws for Stepwise Reactions
1.5 THERMODYNAMICS. 1.5.1 Enthalpy, Entropy, and Free Energy
1.5.2 Reversible and Irreversible Reactions
1.5.3 Chemical Equilibrium
1.6 THE TRANSITION STATE. 1.6.1 The Transition State and Activation Energy
1.6.2 The Hammond Postulate
1.6.3 The Bell–Evans–Polanyi Principle
1.7 ELECTRONIC EFFECTS AND HAMMETT EQUATION. 1.7.1 Electronic Effects of Substituents
1.7.2 Hammett Equation
1.8 THE MOLECULAR ORBITAL THEORY. 1.8.1 Formation of Molecular Orbitals from Atomic Orbitals
1.8.2 Molecular Orbital Diagrams
1.8.3 Resonance Stabilization
1.8.4 Frontier Molecular Orbitals
1.9 ELECTROPHILES/NUCLEOPHILES VERSUS ACIDS/BASES
1.9.1 Common Electrophiles
1.9.2 Common Nucleophiles
1.10 ISOTOPE LABELING
1.11 ENZYMES: BIOLOGICAL CATALYSTS
1.12 THE GREEN CHEMISTRY METHODOLOGY
PROBLEMS
REFERENCES
2 THE ALIPHATIC C─H BOND FUNCTIONALIZATION
2.1 ALKYL RADICALS: BONDING AND THEIR RELATIVE STABILITY
2.2 RADICAL HALOGENATIONS OF THE C─H BONDS ON SP3‐HYBRIDIZED CARBONS: MECHANISM AND NATURE OF THE TRANSITION STATES. Mechanism
The transition states
Multiple halogenations
2.3 ENERGETICS OF THE RADICAL HALOGENATIONS OF ALKANES AND THEIR REGIOSELECTIVITY
2.3.1 Energy Profiles for Radical Halogenation Reactions of Alkanes
2.3.2 Regioselectivity for Radical Halogenation Reactions. Simple alkanes
Hydrocarbons containing an unsaturated group
2.4 KINETICS OF RADICAL HALOGENATIONS OF ALKANES. 2.4.1 Alkanes
2.4.2 Hydrocarbons Containing an Unsaturated Group
2.5 RADICAL INITIATORS
2.5.1 Azobisisobutyonitrile (AIBN)
2.5.2 Dibenzol Peroxide
2.6 TRANSITION‐METAL‐COMPOUNDS CATALYZED ALKANE C─H BOND ACTIVATION AND FUNCTIONALIZATION. 2.6.1 The C─H Bond Activation via Agostic Bond
2.6.2 Mechanisms for the C─H Bond Oxidative Functionalization
2.7 SUPERACIDS CATALYZED ALKANE C─H BOND ACTIVATION AND FUNCTIONALIZATION
2.8 NITRATION OF THE ALIPHATIC C─H BONDS VIA THE NITRONIUM NO2+ ION
2.9 PHOTOCHEMICAL AND THERMAL C─H BOND ACTIVATION BY THE OXIDATIVE URANYL UO22+(VI) CATION
2.10 ENZYME CATALYZED ALKANE C─H BOND ACTIVATION AND FUNCTIONALIZATION: BIOCHEMICAL METHODS
1.8.3 PROBLEMS
REFERENCES
3 FUNCTIONALIZATION OF THE ALKENE C=C BOND BY ELECTROPHILIC ADDITIONS
3.1 MARKOVNIKOV ADDITIONS VIA INTERMEDIATE CARBOCATIONS. 3.1.1 Protonation of the Alkene C=C π Bond by Strong Acids to form Carbocations
3.1.2 Additions of Hydrogen Halides (HCl, HBr, and HI) to Alkenes: Mechanism, Regiochemistry, and Stereochemistry
Mechanism and regiochemistry
Stereochemistry
3.1.3 Acid and Transition‐Metal Catalyzed Hydration of Alkenes and Its Applications. Acid catalyzed hydration
Mercury(II) catalyzed hydration
3.1.4 Acid Catalyzed Additions of Alcohols to Alkenes
3.1.5 Special Electrophilic Additions of the Alkene C=C Bond: Mechanistic and Synthetic Aspects. Reactions with carboxylic acids
Lewis‐acid catalyzed electrophilic addition to alkenes
Additions of carbocations
3.1.6 Electrophilic Addition to the C≡C Triple Bond via a Vinyl Cation Intermediate
3.2 ELECTROPHILIC ADDITION OF HYDROGEN HALIDES TO CONJUGATED DIENES
3.3 NON‐MARKOVNIKOV RADICAL ADDITION
3.4 HYDROBORATION: CONCERTED, NON‐MARKOVNIKOV syn‐ADDITION. 3.4.1 Diborane (B2H6): Structure and Properties
3.4.2 Concerted, Non‐Markovnikov syn‐Addition of Borane (BH3) to the Alkene C=C Bond: Mechanism, Regiochemistry, and Stereochemistry
Mechanism and regiochemistry
Stereochemistry
3.4.3 Synthesis of Special Hydroborating Reagents
3.4.4 Reactions of Alkenes with Special Hydroborating Reagents: Regiochemistry, Stereochemistry, and Their Applications in Chemical Synthesis
3.5 TRANSITION‐METAL CATALYZED HYDROGENATION OF THE ALKENE C=C BOND (syn‐ADDITION)
3.5.1 Mechanism and Stereochemistry
3.5.2 Synthetic Applications. Hydrogenation of unsaturated carbonyl compounds
Hydrogenation of alkynes
Hydrogenation of dienes
3.5.3 Biochemically Related Applications: Hydrogenated Fats (Oils)
3.6 HALOGENATION OF THE ALKENE C=C BOND (ANTI‐ADDITION): MECHANISM AND ITS STEREOCHEMISTRY
Mechanism
Stereochemistry
Halogenations in nucleophilic solvents
PROBLEMS
REFERENCES
4 FUNCTIONALIZATION OF THE ALKENE C=C BOND BY CYCLOADDITION REACTIONS
4.1 CYCLOADDITION OF THE ALKENE C=C BOND TO FORM THREE‐MEMBERED RINGS
4.1.1 Epoxidation
4.1.2 Cycloadditions via Carbenes and Related Species. Dichlorocarbene (CCl2)
Diphenylcarbene (CPh2)
Carbenoids
4.2 CYCLOADDITIONS TO FORM FOUR‐MEMBERED RINGS
4.3 DIELS–ALDER CYCLOADDITIONS OF THE ALKENE CC BOND TO FORM SIX‐MEMBERED RINGS
4.3.1 Frontier Molecular Orbital Interactions
4.3.2 Substituent Effects. Reaction rates
Regiochemistry
4.3.3 Other Diels–Alder Reactions. Formation of bicyclic molecules
Cycloaddition of the C=N bond to conjugated dienes
Cycloaddition of 2,3‐dicyano‐p‐benzoquinone to 1,3‐cyclopentadiene
Cycloaddition of larger alkenes
Cyclohexene derivatives
Synthetic application by intramolecular Diels–Alder cycloaddition
4.4 1,3‐DIPOLAR CYCLOADDITIONS OF THE C=C AND OTHER MULTIPLE BONDS TO FORM FIVE‐MEMBERED RINGS. 4.4.1 Oxidation of Alkenes by Ozone (O3) and Osmium Tetraoxide (OsO4) via Cycloadditions
4.4.2 Cycloadditions of Nitrogen‐Containing 1,3‐Dipoles to Alkenes. Diazoalkanes
4.4.3 Cycloadditions of the Dithionitronium (NS2+) Ion to Alkenes, Alkynes, and Nitriles: Making CNS‐Containing Aromatic Heterocycles
Cycloadditions with alkenes
Cycloadditions with alkynes and nitriles
Kinetics
4.5 OTHER PERICYCLIC REACTIONS
4.5.1 Conjugated Trienes
4.5.2 The Cope Rearrangement
4.5.3 Conjugate Dienes
4.5.4 The 4π‐Cycloaddition Between the N=N Bonds
4.5.5 The 4π‐Cycloaddition of Buckminsterfullerene C60
4.6 DIELS–ALDER CYCLOADDITIONS IN WATER: THE GREEN CHEMISTRY METHODS
4.7 BIOLOGICAL APPLICATIONS. 4.7.1 Photochemical Synthesis of Vitamin D2 via a Cyclic Transition State
4.7.2 Ribosome‐Catalyzed Peptidyl Transfer via a Cyclic Transition State: Biosynthesis of Proteins
PROBLEMS
REFERENCES
5 THE AROMATIC C─H BOND FUNCTIONALIZATION AND RELATED REACTIONS
5.1 AROMATIC NITRATION: ALL REACTION INTERMEDIATES AND FULL MECHANISM FOR THE AROMATIC C─H BOND SUBSTITUTION BY NITRONIUM (NO2+) AND RELATED ELECTROPHILES
5.1.1 Charge‐Transfer Complex [ArH, NO2+] Between Arene and Nitronium
5.1.2 Ion‐Radical Pair [ArH+˙, NO2˙]
5.1.3 Arenium [Ar(H)NO2]+ Ion
5.1.4 Full Mechanism for Aromatic Nitration
5.2 MECHANISMS AND SYNTHETIC UTILITY FOR AROMATIC C─H BOND SUBSTITUTIONS BY OTHER RELATED ELECTROPHILES. The dithionitronium NS2+ ion
The Cl2SO+–−AlCl3 (thionyl chloride—aluminum chloride) zwitterionic adduct
The p‐CH3C6H4SO2Cl–AlCl3 (p‐toluenesulfonyl chloride–aluminum chloride) zwitterionic adduct
Unexpected ring‐opening in the acylium ion (–C≡O+)
5.3 THE IRON (III) CATALYZED ELECTROPHILIC AROMATIC C─H BOND SUBSTITUTION
EAS reactions with aldehydes
EAS reactions with alcohols
3.3 EAS reactions with alkenes
FeCl 3‐catalyzed EAS reaction of chlorobenzene with SOCl2
5.4 THE ELECTROPHILIC AROMATIC C─H BOND SUBSTITUTION REACTIONS VIA SN1 and SN2 MECHANISMS
5.4.1 Reactions Involving SN1 Steps. Friedel–Crafts alkylation reactions
Other reactions
5.4.2 Reactions Involving SN2 Steps
5.5 SUBSTITUENT EFFECTS ON THE ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS
5.5.1 Ortho ‐ and para‐Directors
5.5.2 Meta ‐Directors
5.6 ISOMERIZATIONS EFFECTED BY THE ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS
5.7 ELECTROPHILIC SUBSTITUTION REACTIONS ON THE AROMATIC CARBON─METAL BONDS: MECHANISMS AND SYNTHETIC APPLICATIONS
5.7.1 Aryl Grignard and Aryllithium Compounds
5.7.2 Ortho ‐Metallation‐Directing Groups (o‐MDGs): Mechanism and Synthetic Applications
5.8 NUCLEOPHILIC AROMATIC SUBSTITUTION VIA A BENZYNE (ARYNE) INTERMEDIATE: FUNCTIONAL GROUP TRANSFORMATIONS ON AROMATIC RINGS
5.9 NUCLEOPHILIC AROMATIC SUBSTITUTION VIA AN ANIONIC MEISENHEIMER COMPLEX
5.10 BIOLOGICAL APPLICATIONS OF FUNCTIONALIZED AROMATIC COMPOUNDS
PROBLEMS
REFERENCES
6 NUCLEOPHILIC SUBSTITUTIONS ON SP3‐HYBRIDIZED CARBONS: FUNCTIONAL GROUP TRANSFORMATIONS
6.1 NUCLEOPHILIC SUBSTITUTION ON MONO‐FUNCTIONALIZED SP3‐HYBRIDIZED CARBON
6.2 FUNCTIONAL GROUPS WHICH ARE GOOD AND POOR LEAVING GROUPS
6.3 GOOD AND POOR NUCLEOPHILES
6.4 SN2 REACTIONS: KINETICS, MECHANISM, AND STEREOCHEMISTRY
6.4.1 Mechanism and Stereochemistry for SN2 Reactions
6.4.2 Steric Hindrance on SN2 Reactions
6.4.3 Effect of Nucleophiles
6.4.4 Solvent Effect
6.4.5 Effect of Unsaturated Groups Attached to the Functionalized Electrophilic Carbon
6.5 ANALYSIS OF THE SN2 MECHANISM USING SYMMETRY RULES AND MOLECULAR ORBITAL THEORY
6.5.1 The SN2 Reactions of Methyl and Primary Haloalkanes RCH2X (X = Cl, Br, or I; R = H or an Alkyl Group)
6.5.2 Reactivity of Dichloromethane CH2Cl2
6.6 SN1 REACTIONS: KINETICS, MECHANISM, AND PRODUCT DEVELOPMENT
6.6.1 The SN1 Mechanism and Rate Law
6.6.2 Solvent Effect
6.6.3 Effects of Carbocation Stability and Quality of Leaving Group on the SN1 Rates
6.6.4 Product Development for SN1 Reactions
6.7 COMPETITIONS BETWEEN SN1 AND SN2 REACTIONS
6.8 SOME USEFUL SN1 AND SN2 REACTIONS: MECHANISMS AND SYNTHETIC PERSPECTIVES
6.8.1 Nucleophilic Substitution Reactions Effected by Carbon Nucleophiles
6.8.2 Synthesis of Primary Amines
6.8.3 Synthetic Utility of Triphenylphosphine: A Strong Phosphorus Nucleophile
6.8.4 Neighboring Group‐Assisted SN1 Reactions
6.8.5 Nucleophilic Substitution Reactions of Alcohols Catalyzed by Solid Bronsted Acids: A Green Chemistry Approach
6.9 BIOLOGICAL APPLICATIONS OF NUCLEOPHILIC SUBSTITUTION REACTIONS. 6.9.1 Biomedical Applications
6.9.2 Glycoside Hydrolases: Enzymes Catalyzing Hydrolytic Cleavage of the Glycosidic Bonds by the SN2‐Like Reactions
6.9.3 Biosynthesis Involving Nucleophilic Substitution Reactions
6.9.4 An Enzyme‐Catalyzed Nucleophilic Substitution of an Haloalkane
PROBLEMS
REFERENCES
7 ELIMINATIONS
7.1 E2 ELIMINATION: BIMOLECULAR β‐ELIMINATION OF H/LG AND ITS REGIOCHEMISTRY AND STEREOCHEMISTRY. 7.1.1 Mechanism and Regiochemistry
7.1.2 E2 Eliminations of Functionalized Cycloalkanes
7.1.3 Stereochemistry
7.2 ANALYSIS OF THE E2 MECHANISM USING SYMMETRY RULES AND MOLECULAR ORBITAL THEORY. 7.2.1 Chain‐Like Haloalkanes
7.2.2 Halocyclohexane
7.2.3 Quantitative Theoretical Studies of E2 Reactions
7.3 BASICITY VERSUS NUCLEOPHILICITY FOR VARIOUS ANIONS
7.4 COMPETITION OF E2 AND SN2 REACTIONS
7.5 E1 ELIMINATION: STEPWISE β‐ELIMINATION OF H/LG VIA AN INTERMEDIATE CARBOCATION AND ITS RATE‐LAW. 7.5.1 Mechanism and Rate Law
7.5.2 E1 Dehydration of Alcohols
7.6 ENERGY PROFILES FOR E1 REACTIONS. 7.6.1 The Bell–Evans–Polanyi Principle
7.6.2 The E1 Dehydration of Alcohols (ROH)
7.6.3 The E1 Dehydrohalogenation of Haloalkanes (RX, X = Cl, Br, or I)
7.7 THE E1 ELIMINATION OF ETHERS
7.8 INTRAMOLECULAR (UNIMOLECULAR) ELIMINATIONS VIA CYCLIC TRANSITION STATES. 7.8.1 Concerted, syn‐Elimination of Esters
7.8.2 Selenoxide Elimination
7.8.3 Silyloxide Elimination
7.8.4 Unimolecular β‐Elimination of Hydrogen Halide from Haloalkanes
7.9 MECHANISMS FOR REDUCTIVE ELIMINATION OF LG1/LG2 (TWO FUNCTIONAL GROUPS) ON ADJACENT CARBONS
7.10 THE α‐ELIMINATION GIVING A CARBENE: A MECHANISTIC ANALYSIS USING SYMMETRY RULES AND MOLECULAR ORBITAL THEORY
7.10.1 The Bimolecular α‐Elimination of Trichloromethane (CHCl3) Giving Dichlorocarbene (CCl2)
7.10.2 Formation of a Carbene by Unimolecular α‐Elimination of a Haloalkane and the Subsequent Rearrangement to an Alkene via a C─H (C─D) Bond Elimination
7.11 E1cb ELIMINATION
7.12 BIOLOGICAL APPLICATIONS: ENZYME‐CATALYZED BIOLOGICAL ELIMINATION REACTIONS. 7.12.1 The Enzyme‐Catalyzed β‐Oxidation of Fatty Acyl Coenzyme A
7.12.2 Elimination Reactions Involved in Biosynthesis
PROBLEMS
REFERENCES
8 NUCLEOPHILIC ADDITIONS AND SUBSTITUTIONS ON CARBONYL GROUPS
8.1 NUCLEOPHILIC ADDITIONS AND SUBSTITUTIONS OF CARBONYL COMPOUNDS
8.2 NUCLEOPHILIC ADDITIONS OF ALDEHYDES AND KETONES AND THEIR BIOLOGICAL APPLICATIONS
8.2.1 Acid and Base Catalyzed Hydration of Aldehydes and Ketones
8.2.2 Acid Catalyzed Nucleophilic Additions of Alcohols to Aldehydes and Ketones
8.2.3 Biological Applications: Cyclic Structures of Carbohydrates
8.2.4 Addition of Sulfur Nucleophile to Aldehydes
8.2.5 Nucleophilic Addition of Amines to Ketones and Aldehydes
Biological application
8.2.6 Nucleophilic Additions of Hydride Donors to Aldehydes and Ketones: Organic Reductions and Mechanisms
8.3 BIOLOGICAL HYDRIDE DONORS NAD(P)H AND FADH2
8.4 ACTIVATION OF CARBOXYLIC ACIDS VIA NUCLEOPHILIC SUBSTITUTIONS ON THE CARBONYL CARBONS
8.4.1 Reactions of Carboxylic Acids with Thionyl Chloride
8.4.2 Esterification Reactions, Synthetic Applications, and Green Chemistry Methods
8.4.3 Formation of Anhydrides
8.4.4 Nucleophilic Addition with Alkyllithium
8.5 NUCLEOPHILIC SUBSTITUTIONS OF ACYL DERIVATIVES AND THEIR BIOLOGICAL APPLICATIONS. 8.5.1 Nucleophilic Substitutions of Acyl Chlorides and Anhydrides
8.5.2 Hydrolysis and Other Nucleophilic Substitutions of Esters
8.5.3 Biodiesel Synthesis and Reaction Mechanism
8.5.4 Biological Applications: Mechanisms of Serine‐Type Hydrolases
8.6 REDUCTION OF ACYL DERIVATIVES BY HYDRIDE DONORS
8.7 KINETICS OF THE NUCLEOPHILIC ADDITION AND SUBSTITUTION OF ACYL DERIVATIVES
PROBLEMS
REFERENCES
9 REACTIVITY OF THE α‐HYDROGEN TO CARBONYL GROUPS. 9.1 FORMATION OF ENOLATES AND THEIR NUCLEOPHILICITY. 9.1.1 Formation of Enolates. Acidity of the α‐hydrogen
Formation of enolates
Lithium enolates
Enol
9.1.2 Molecular Orbitals and Nucleophilicity of Enolates
9.2 ALKYLATION OF CARBONYL COMPOUNDS (ALDEHYDES, KETONES, AND ESTERS) VIA ENOLATES AND HYDRAZONES. 9.2.1 Alkylation via Enolates
9.2.2 Alkylation via Hydrazones and Enamines
9.3 ALDOL REACTIONS. 9.3.1 Mechanism and Synthetic Utility. General situation
Aldol reaction and condensation of aldehydes and ketones
Crossed aldol reactions
Intramolecular aldol reactions
Other aldol reactions
9.3.2 Stereoselectivity (S)‐Proline catalyzed aldol reaction
Reactions of Boc‐imines
Aldol reactions of ester enolates
9.3.3 Other Synthetic Applications. 1,4‐Addition of enolate
Robinson ring annulations
9.4 ACYLATION REACTIONS OF ESTERS VIA ENOLATES: MECHANISM AND SYNTHETIC UTILITY
9.5 BIOLOGICAL APPLICATIONS: ROLES OF ENOLATES IN METABOLIC PROCESSES IN LIVING ORGANISMS
9.5.1 The Citric Acid Cycle and Mechanism for Citrate Synthase
9.5.2 Ketogenesis and Thiolase. Ketogenesis
PROBLEMS
REFERENCES
10 REARRANGEMENTS. 10.1 MAJOR TYPES OF REARRANGEMENTS
10.2 REARRANGEMENT OF CARBOCATIONS: 1,2‐SHIFT
10.2.1 1,2‐Shifts in Carbocations Produced from Acyclic Molecules
10.2.2 1,2‐Shifts in Carbocations Produced from Cyclic Molecules—Ring Expansion
10.2.3 Resonance Stabilization of Carbocation—Pinacol Rearrangement
10.2.4 In vivo Cascade Carbocation Rearrangements: Biological Significance
10.2.5 Acid Catalyzed 1,2‐Shift in Epoxides
10.2.6 Anion Initiated 1,2‐Shift
10.3 NEIGHBORING LEAVING GROUP FACILITATED 1,2‐REARRANGEMENT
10.3.1 Beckmann Rearrangement
10.3.2 Hofmann Rearrangement
10.3.3 Baeyer–Villiger Oxidation (Rearrangement)
10.3.4 Acid Catalyzed Rearrangement of Organic Peroxides
10.4 CARBENE REARRANGEMENT: 1,2‐REARRANGEMENT OF HYDROGEN FACILITATED BY A LONE PAIR OF ELECTRONS
10.5 CLAISEN REARRANGEMENT
10.6 CLAISEN REARRANGEMENT IN WATER: THE GREEN CHEMISTRY METHODS
10.7 PHOTOCHEMICAL ISOMERIZATION OF ALKENES AND ITS BIOLOGICAL APPLICATIONS
10.7.1 Photochemical Isomerization
10.7.2 Biological Relevance
10.8 REARRANGEMENT OF CARBON–NITROGEN–SULFUR CONTAINING HETEROCYCLES
PROBLEMS
REFERENCES
INDEX
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