Xiaoping Sun - Organic Mechanisms

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2 TITLE PAGE

3 COPYRIGHT PAGE

4 PREFACE

5 FIRST EDITION PREFACE

6 ABOUT THE COMPANION WEBSITE

7 1 FUNDAMENTAL PRINCIPLES1.1 REACTION MECHANISMS AND THEIR IMPORTANCE 1.2 ELEMENTARY (CONCERTED) AND STEPWISE REACTIONS 1.3 MOLECULARITY 1.4 KINETICS 1.5 THERMODYNAMICS 1.6 THE TRANSITION STATE 1.7 ELECTRONIC EFFECTS AND HAMMETT EQUATION 1.8 THE MOLECULAR ORBITAL THEORY 1.9 ELECTROPHILES/NUCLEOPHILES VERSUS ACIDS/BASES 1.10 ISOTOPE LABELING 1.11 ENZYMES: BIOLOGICAL CATALYSTS 1.12 THE GREEN CHEMISTRY METHODOLOGY REFERENCES

8 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 SP 3‐HYBRIDIZED CARBONS: MECHANISM AND NATURE OF THE TRANSITION STATES 2.3 ENERGETICS OF THE RADICAL HALOGENATIONS OF ALKANES AND THEIR REGIOSELECTIVITY 2.4 KINETICS OF RADICAL HALOGENATIONS OF ALKANES 2.5 RADICAL INITIATORS 2.6 TRANSITION‐METAL‐COMPOUNDS CATALYZED ALKANE C─H BOND ACTIVATION AND FUNCTIONALIZATION 2.7 SUPERACIDS CATALYZED ALKANE C─H BOND ACTIVATION AND FUNCTIONALIZATION 2.8 NITRATION OF THE ALIPHATIC C─H BONDS VIA THE NITRONIUM NO 2 +ION 2.9 PHOTOCHEMICAL AND THERMAL C─H BOND ACTIVATION BY THE OXIDATIVE URANYL UO 2 2+(VI) CATION 2.10 ENZYME CATALYZED ALKANE C─H BOND ACTIVATION AND FUNCTIONALIZATION: BIOCHEMICAL METHODS REFERENCES

9 3 FUNCTIONALIZATION OF THE ALKENE C=C BOND BY ELECTROPHILIC ADDITIONS 3.1 MARKOVNIKOV ADDITIONS VIA INTERMEDIATE CARBOCATIONS 3.2 ELECTROPHILIC ADDITION OF HYDROGEN HALIDES TO CONJUGATED DIENES 3.3 NON‐MARKOVNIKOV RADICAL ADDITION 3.4 HYDROBORATION: CONCERTED, NON‐MARKOVNIKOV syn ‐ADDITION 3.5 TRANSITION‐METAL CATALYZED HYDROGENATION OF THE ALKENE C=C BOND ( syn ‐ADDITION) 3.6 HALOGENATION OF THE ALKENE C=C BOND (ANTI‐ADDITION): MECHANISM AND ITS STEREOCHEMISTRY REFERENCES

10 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 4.2 CYCLOADDITIONS TO FORM FOUR‐MEMBERED RINGS 4.3 DIELS–ALDER CYCLOADDITIONS OF THE ALKENE CC BOND TO FORM SIX‐MEMBERED RINGS 4.4 1,3‐DIPOLAR CYCLOADDITIONS OF THE C=C AND OTHER MULTIPLE BONDS TO FORM FIVE‐MEMBERED RINGS 4.5 OTHER PERICYCLIC REACTIONS 4.6 DIELS–ALDER CYCLOADDITIONS IN WATER: THE GREEN CHEMISTRY METHODS 4.7 BIOLOGICAL APPLICATIONS REFERENCES

11 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 (NO 2 +) AND RELATED ELECTROPHILES 5.2 MECHANISMS AND SYNTHETIC UTILITY FOR AROMATIC C─H BOND SUBSTITUTIONS BY OTHER RELATED ELECTROPHILES 5.3 THE IRON (III) CATALYZED ELECTROPHILIC AROMATIC C─H BOND SUBSTITUTION 5.4 THE ELECTROPHILIC AROMATIC C─H BOND SUBSTITUTION REACTIONS VIA S N1 and S N2 MECHANISMS 5.5 SUBSTITUENT EFFECTS ON THE ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS 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 5.8 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

12 6 NUCLEOPHILIC SUBSTITUTIONS ON SP 3‐HYBRIDIZED CARBONS 6.1 NUCLEOPHILIC SUBSTITUTION ON MONO‐FUNCTIONALIZED SP 3‐HYBRIDIZED CARBON 6.2 FUNCTIONAL GROUPS WHICH ARE GOOD AND POOR LEAVING GROUPS 6.3 GOOD AND POOR NUCLEOPHILES 6.4 S N2 REACTIONS: KINETICS, MECHANISM, AND STEREOCHEMISTRY 6.5 ANALYSIS OF THE S N2 MECHANISM USING SYMMETRY RULES AND MOLECULAR ORBITAL THEORY 6.6 S N1 REACTIONS: KINETICS, MECHANISM, AND PRODUCT DEVELOPMENT 6.7 COMPETITIONS BETWEEN S N1 AND S N2 REACTIONS 6.8 SOME USEFUL S N1 AND S N2 REACTIONS: MECHANISMS AND SYNTHETIC PERSPECTIVES 6.9 BIOLOGICAL APPLICATIONS OF NUCLEOPHILIC SUBSTITUTION REACTIONS PROBLEMS REFERENCES

13 7 ELIMINATIONS 7.1 E2 ELIMINATION: BIMOLECULAR β‐ELIMINATION OF H/LG AND ITS REGIOCHEMISTRY AND STEREOCHEMISTRY 7.2 ANALYSIS OF THE E2 MECHANISM USING SYMMETRY RULES AND MOLECULAR ORBITAL THEORY 7.3 BASICITY VERSUS NUCLEOPHILICITY FOR VARIOUS ANIONS 7.4 COMPETITION OF E2 AND S N2 REACTIONS 7.5 E1 ELIMINATION: STEPWISE β‐ELIMINATION OF H/LG VIA AN INTERMEDIATE CARBOCATION AND ITS RATE‐LAW 7.6 ENERGY PROFILES FOR E1 REACTIONS 7.7 THE E1 ELIMINATION OF ETHERS 7.8 INTRAMOLECULAR (UNIMOLECULAR) ELIMINATIONS VIA CYCLIC TRANSITION STATES 7.9 MECHANISMS FOR REDUCTIVE ELIMINATION OF LG 1/LG 2(TWO FUNCTIONAL GROUPS) ON ADJACENT CARBONS 7.10 THE α‐ELIMINATION GIVING A CARBENE: A MECHANISTIC ANALYSIS USING SYMMETRY RULES AND MOLECULAR ORBITAL THEORY 7.11 E1cb ELIMINATION 7.12 BIOLOGICAL APPLICATIONS: ENZYME‐CATALYZED BIOLOGICAL ELIMINATION REACTIONS REFERENCES

14 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 8.3 BIOLOGICAL HYDRIDE DONORS NAD(P)H AND FADH 2 8.4 ACTIVATION OF CARBOXYLIC ACIDS VIA NUCLEOPHILIC SUBSTITUTIONS ON THE CARBONYL CARBONS 8.5 NUCLEOPHILIC SUBSTITUTIONS OF ACYL DERIVATIVES AND THEIR BIOLOGICAL APPLICATIONS 8.6 REDUCTION OF ACYL DERIVATIVES BY HYDRIDE DONORS 8.7 KINETICS OF THE NUCLEOPHILIC ADDITION AND SUBSTITUTION OF ACYL DERIVATIVES PROBLEMS REFERENCES

15 9 REACTIVITY OF THE α‐HYDROGEN TO CARBONYL GROUPS9.1 FORMATION OF ENOLATES AND THEIR NUCLEOPHILICITY 9.2 ALKYLATION OF CARBONYL COMPOUNDS (ALDEHYDES, KETONES, AND ESTERS) VIA ENOLATES AND HYDRAZONES 9.3 ALDOL REACTIONS 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 REFERENCES

16 10 REARRANGEMENTS10.1 MAJOR TYPES OF REARRANGEMENTS 10.2 REARRANGEMENT OF CARBOCATIONS: 1,2‐SHIFT 10.3 NEIGHBORING LEAVING GROUP FACILITATED 1,2‐REARRANGEMENT 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 10.8 REARRANGEMENT OF CARBON–NITROGEN–SULFUR CONTAINING HETEROCYCLES PROBLEMS REFERENCES

17 INDEX

18 END USER LICENSE AGREEMENT

1 Chapter 2 TABLE 2.1 Regioselectivity of Radical Chlorination of 2‐Methylbutane TABLE 2.2 Regioselectivity of Radical Bromination of 2‐Methylbutane

2 Chapter 6TABLE 6.1 Quantitative Strengths of Various NucleophilesTABLE 6.2 Factors that Determine the Reaction Mechanisms: Competition Between SN2...

1 Chapter 1 FIGURE 1.1 Reaction profiles for a concerted S N2 reaction (a) and a stepwise... FIGURE 1.2 The changes in concentrations of the reactant (X), intermediate (... FIGURE 1.3 The effects of enthalpy and entropy on reversibility of the chemi... FIGURE 1.4 Early transition state (a) and late transition state (b). FIGURE 1.5 The S N2 reactions that proceed via (a) an early transition state ... FIGURE 1.6 The ρ constants for various reactions of substituted benzene... FIGURE 1.7 The shapes of the s and p orbitals in the three‐dimensional space... FIGURE 1.8 Formation of the hydrogen molecule (H 2) from two hydrogen (H) ato... FIGURE 1.9 Formation of the fluorine molecule (F 2) from two fluorine (F) ato... FIGURE 1.10 Formation of (a) the C=C π bond from two equivalent p orbitals a... FIGURE 1.11 Formation of conjugate π bonds from p orbitals in (a) the allyl ... FIGURE 1.12 Resonance stabilization of benzene. FIGURE 1.13 Possible resonance structures for the carbonyl (C=O) group. FIGURE 1.14 Resonance stabilization of the anolate anion. FIGURE 1.15 Possible resonance structures for (a) hydrogen chloride (HCl) an... FIGURE 1.16 Structure of different types of carbocations. FIGURE 1.17 (a) Overlap of a C─H bond of the methyl group in the ethyl catio... FIGURE 1.18 Reaction mechanism for acid‐catalyzed hydrolysis of the oxygen‐1... FIGURE 1.19 Energetics for C─H and C─D (deuterium) bonds. FIGURE 1.20 Reaction mechanism for nitration of benzene by acetyl nitrate. FIGURE 1.21 Acid–base catalysis for enzymatic reactions. (a) Uncatalyzed con... FIGURE 1.22 (a) Mechanism for the concerted reaction of H 2O and CO 2giving H... FIGURE 1.23 Comparison of energetics for the concerted and the enzyme (carbo... FIGURE 1.24 Hydrophobic effects on organic reactions. (a) The intermolecular...