Reaction Mechanism Summary 2024 - V
Reaction Mechanisms Summary
2024
Based on the notes and slides of Prof. T.Kudernack and S. Otto. The
chapters 7,8, 9, 10, 11, and 15 of the book Modern Physical Organic
Chemistry by Eric V. Anslyn and Dennis A. Dougherty.
1
,Reaction Mechanism Summary 2024 - V
Table of Content
Chapter 7.3 Hammond postulate .............................................................................................7
Chapter 8: Experiments related to thermodynamics and kinetics ..............................................8
8.1 Isotope effect .................................................................................................................8
8.1.2 Origin of the primary kinetic isotope effect ................................................................9
8.1.3 Origin of secondary kinetic isotope effect ............................................................... 11
8.1.4 Equilibrium isotope effect (also known as thermodynamic IE) ................................. 13
8.1.5 Tunneling............................................................................................................... 14
8.1.6 Solvent isotope effect......................................................................................... 14
8.1.7 Heavy isotope effect .............................................................................................. 15
8.2 Substituent effect .................................................................................................. 15
8.3 Hammett plots ............................................................................................................. 17
8.3.2 Rho (ρ)................................................................................................................... 18
8.3.4 Deviation from Linearity ......................................................................................... 20
8.3.5 Separating Resonance from Induction. ................................................................... 21
8.4 Other Linear Free Energy Relationships ......................................................................... 22
8.4.1 Steric and Polar effects – Taft parameters ............................................................... 22
8.4.2 Grunwald-Weinstein plots —Solvent effects ........................................................... 23
8.4.3 Schleyer adaptation ............................................................................................... 23
8.4.5 Swain-Scott Parameters – Nucleophilicity parameters ............................................ 23
8.4.6 Edward and Ritchies correlations ........................................................................... 23
8.8 Miscellaneous experiments for studying mechanisms ................................................... 24
Chapter 9.3 Bronsted acid-base catalysis ........................................................................... 26
9.3.1 Specific catalysis ................................................................................................... 26
9.3.2 General Catalysis .................................................................................................. 27
9.3.5 Bronsted catalysis law ........................................................................................... 29
9.3.6 Libido rule ............................................................................................................. 30
Appendix 5: pushing electrons ............................................................................................... 30
Chapter 10: Mechanisms of reactions involving additions or/and eliminations ..................... 32
10.1 Predicting Organic Reactivity ...................................................................................... 33
1. Electrostatics ........................................................................................................ 33
2. Nucleophile-electrophile interactions .................................................................... 33
3. Lewis acid-Lewis base interactions ........................................................................ 34
4. Orbital interactions ................................................................................................ 34
Addition reactions ............................................................................................................. 35
10.2 Hydration of carbonyl compounds .............................................................................. 35
2
,Reaction Mechanism Summary 2024 - V
10.2.1 Acid-Base Catalysis ............................................................................................. 35
7.8.2 More O’Ferrall Jencks Plot ...................................................................................... 37
10.3 Electrophilic Addition of Water to Alkenes and Alkynes: Hydration ........................... 38
10.3.3 Regiochemistry .................................................................................................... 38
10.3.4 Electrophilic hydration of alkynes ......................................................................... 39
10.4 Electrophilic addition of hydrogen halides to alkenes ................................................... 39
10.4.3 Electrophilic addition of hydrogen halides of alkynes............................................. 41
10.5 Electrophilic addition of halogens to alkenes .......................................................... 41
10.5.5 Electrophilic addition of halogens to alkynes ........................................................ 42
10.6 Hydroboration of alkenes............................................................................................ 43
10.7 Epoxidation ................................................................................................................ 43
10.8 Nucleophilic addition to carbonyl compounds ............................................................ 44
10.8.5 Orbital considerations.......................................................................................... 45
10.8.7 Stereochemistry .................................................................................................. 46
10.9 Nucleophilic Additions to Olefins ................................................................................ 47
10.9.3 Regiochemistry of Addition ................................................................................... 47
10.9.4 Baldwin’s Rules ................................................................................................... 47
10.10 Radical additions to unsaturated systems ................................................................. 48
10.11 Carbene addition .................................................................................................. 51
10.11.2 Carbene Generation ........................................................................................... 51
10.12 Elimination to form carbonyls or “carbonyl-like” intermediates .................................. 52
10.12.4 Stereoelectronic effects ..................................................................................... 54
10.13 Elimination to give alkenes ........................................................................................ 55
10.13.3 Contrasting Elimination vs Substitution .............................................................. 56
10.13.4 Elimination, unimolecular, conjugate base (E1cB) ............................................... 56
10.3.7 Regiochemistry of eliminations............................................................................. 58
10.13.8 Stereochemistry of Elimination ........................................................................... 59
10.13.9 Dehydration ....................................................................................................... 61
10.13.10 Thermal eliminations Ei (intramolecular) ........................................................... 61
10.14 Eliminations from radical intermediates .................................................................... 61
10.15 The addition of nitrogen nucleophiles to carbonyl structures, Followed by elimination 62
10.15.2 Acid-Base Catalysis........................................................................................... 63
10.16 The addition of carbon nucleophiles, followed by elimination – Wittig reaction ........... 63
10.17 Acyl transfer ...................................................................................................... 64
10.17.2 Isotope Scrambling ............................................................................................ 65
10.17.3 Site of cleavage for acyl transfer in esters ............................................................ 65
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, Reaction Mechanism Summary 2024 - V
10.18 Electrophilic Aromatic substitution ..................................................................... 67
10.18.4 Regiochemistry and relative rates of aromatic substitution .................................. 68
10.9 Nucleophilic aromatic substitution (SNAr).................................................................... 68
10.20 Reactions involving Benzyne ..................................................................................... 69
10.20.3 Substituent effect .............................................................................................. 69
Chapter 11 ............................................................................................................................ 71
11.1 Tauromerization ......................................................................................................... 71
11.1.3 Catalysis of enolizations ...................................................................................... 71
11.1.4 Kinetic vs Thermodynamic Control in Enolate and Enol Formation ......................... 72
11. 2 α -Halogenation ......................................................................................................... 72
11.3 Alkylation ................................................................................................................... 72
11.4 The Aldol reaction....................................................................................................... 72
11.5 Nucleophilic Aliphatic Substitution Reactions ............................................................. 73
11.5.2 Kinetics ............................................................................................................... 73
11.5.3 Competition between elimination and substitution ............................................... 74
11.5.4 Stereochemistry .................................................................................................. 74
11.5.6 Solvent effects ..................................................................................................... 75
11.5.7 Isotope effects ..................................................................................................... 76
11.5.12 Carbocation rearrangements.............................................................................. 78
11.5.13 Anchimeric assistance ....................................................................................... 79
11.5.15 Carbocation stabilization ................................................................................... 79
11.8 Migration to electrophilic carbons ............................................................................... 80
11.8.1 Pinacol rearrangement ......................................................................................... 80
11.8.2 Benzilic acid rearrangements (EXAM probably)...................................................... 80
11.9 Migrations to electrophilic heteroatom ................................................................... 81
11.9.1 Beckmann rearrangements .................................................................................. 81
11.9.2 Hofmann rearrangements .................................................................................... 82
11.9.3 Schmidt rearrangement ....................................................................................... 82
11.9.4 Baeyer-Villiger Oxidation ...................................................................................... 82
Chapter 15 Pericyclic Reactions .......................................................................................... 83
15.2.1 Orbital symmetry diagrams .................................................................................. 85
15.2.3 Frontier Molecular Orbital (FMO) theory ................................................................ 87
15.2.4 Aromatic transition state theory............................................................................ 88
15.2.5 Generalized Orbital symmetry rule ....................................................................... 89
15.3 Cycloaddition ............................................................................................................. 91
15.3.1 An allowed Geometry for [2+2] cycloadditions ...................................................... 91
4
Reaction Mechanisms Summary
2024
Based on the notes and slides of Prof. T.Kudernack and S. Otto. The
chapters 7,8, 9, 10, 11, and 15 of the book Modern Physical Organic
Chemistry by Eric V. Anslyn and Dennis A. Dougherty.
1
,Reaction Mechanism Summary 2024 - V
Table of Content
Chapter 7.3 Hammond postulate .............................................................................................7
Chapter 8: Experiments related to thermodynamics and kinetics ..............................................8
8.1 Isotope effect .................................................................................................................8
8.1.2 Origin of the primary kinetic isotope effect ................................................................9
8.1.3 Origin of secondary kinetic isotope effect ............................................................... 11
8.1.4 Equilibrium isotope effect (also known as thermodynamic IE) ................................. 13
8.1.5 Tunneling............................................................................................................... 14
8.1.6 Solvent isotope effect......................................................................................... 14
8.1.7 Heavy isotope effect .............................................................................................. 15
8.2 Substituent effect .................................................................................................. 15
8.3 Hammett plots ............................................................................................................. 17
8.3.2 Rho (ρ)................................................................................................................... 18
8.3.4 Deviation from Linearity ......................................................................................... 20
8.3.5 Separating Resonance from Induction. ................................................................... 21
8.4 Other Linear Free Energy Relationships ......................................................................... 22
8.4.1 Steric and Polar effects – Taft parameters ............................................................... 22
8.4.2 Grunwald-Weinstein plots —Solvent effects ........................................................... 23
8.4.3 Schleyer adaptation ............................................................................................... 23
8.4.5 Swain-Scott Parameters – Nucleophilicity parameters ............................................ 23
8.4.6 Edward and Ritchies correlations ........................................................................... 23
8.8 Miscellaneous experiments for studying mechanisms ................................................... 24
Chapter 9.3 Bronsted acid-base catalysis ........................................................................... 26
9.3.1 Specific catalysis ................................................................................................... 26
9.3.2 General Catalysis .................................................................................................. 27
9.3.5 Bronsted catalysis law ........................................................................................... 29
9.3.6 Libido rule ............................................................................................................. 30
Appendix 5: pushing electrons ............................................................................................... 30
Chapter 10: Mechanisms of reactions involving additions or/and eliminations ..................... 32
10.1 Predicting Organic Reactivity ...................................................................................... 33
1. Electrostatics ........................................................................................................ 33
2. Nucleophile-electrophile interactions .................................................................... 33
3. Lewis acid-Lewis base interactions ........................................................................ 34
4. Orbital interactions ................................................................................................ 34
Addition reactions ............................................................................................................. 35
10.2 Hydration of carbonyl compounds .............................................................................. 35
2
,Reaction Mechanism Summary 2024 - V
10.2.1 Acid-Base Catalysis ............................................................................................. 35
7.8.2 More O’Ferrall Jencks Plot ...................................................................................... 37
10.3 Electrophilic Addition of Water to Alkenes and Alkynes: Hydration ........................... 38
10.3.3 Regiochemistry .................................................................................................... 38
10.3.4 Electrophilic hydration of alkynes ......................................................................... 39
10.4 Electrophilic addition of hydrogen halides to alkenes ................................................... 39
10.4.3 Electrophilic addition of hydrogen halides of alkynes............................................. 41
10.5 Electrophilic addition of halogens to alkenes .......................................................... 41
10.5.5 Electrophilic addition of halogens to alkynes ........................................................ 42
10.6 Hydroboration of alkenes............................................................................................ 43
10.7 Epoxidation ................................................................................................................ 43
10.8 Nucleophilic addition to carbonyl compounds ............................................................ 44
10.8.5 Orbital considerations.......................................................................................... 45
10.8.7 Stereochemistry .................................................................................................. 46
10.9 Nucleophilic Additions to Olefins ................................................................................ 47
10.9.3 Regiochemistry of Addition ................................................................................... 47
10.9.4 Baldwin’s Rules ................................................................................................... 47
10.10 Radical additions to unsaturated systems ................................................................. 48
10.11 Carbene addition .................................................................................................. 51
10.11.2 Carbene Generation ........................................................................................... 51
10.12 Elimination to form carbonyls or “carbonyl-like” intermediates .................................. 52
10.12.4 Stereoelectronic effects ..................................................................................... 54
10.13 Elimination to give alkenes ........................................................................................ 55
10.13.3 Contrasting Elimination vs Substitution .............................................................. 56
10.13.4 Elimination, unimolecular, conjugate base (E1cB) ............................................... 56
10.3.7 Regiochemistry of eliminations............................................................................. 58
10.13.8 Stereochemistry of Elimination ........................................................................... 59
10.13.9 Dehydration ....................................................................................................... 61
10.13.10 Thermal eliminations Ei (intramolecular) ........................................................... 61
10.14 Eliminations from radical intermediates .................................................................... 61
10.15 The addition of nitrogen nucleophiles to carbonyl structures, Followed by elimination 62
10.15.2 Acid-Base Catalysis........................................................................................... 63
10.16 The addition of carbon nucleophiles, followed by elimination – Wittig reaction ........... 63
10.17 Acyl transfer ...................................................................................................... 64
10.17.2 Isotope Scrambling ............................................................................................ 65
10.17.3 Site of cleavage for acyl transfer in esters ............................................................ 65
3
, Reaction Mechanism Summary 2024 - V
10.18 Electrophilic Aromatic substitution ..................................................................... 67
10.18.4 Regiochemistry and relative rates of aromatic substitution .................................. 68
10.9 Nucleophilic aromatic substitution (SNAr).................................................................... 68
10.20 Reactions involving Benzyne ..................................................................................... 69
10.20.3 Substituent effect .............................................................................................. 69
Chapter 11 ............................................................................................................................ 71
11.1 Tauromerization ......................................................................................................... 71
11.1.3 Catalysis of enolizations ...................................................................................... 71
11.1.4 Kinetic vs Thermodynamic Control in Enolate and Enol Formation ......................... 72
11. 2 α -Halogenation ......................................................................................................... 72
11.3 Alkylation ................................................................................................................... 72
11.4 The Aldol reaction....................................................................................................... 72
11.5 Nucleophilic Aliphatic Substitution Reactions ............................................................. 73
11.5.2 Kinetics ............................................................................................................... 73
11.5.3 Competition between elimination and substitution ............................................... 74
11.5.4 Stereochemistry .................................................................................................. 74
11.5.6 Solvent effects ..................................................................................................... 75
11.5.7 Isotope effects ..................................................................................................... 76
11.5.12 Carbocation rearrangements.............................................................................. 78
11.5.13 Anchimeric assistance ....................................................................................... 79
11.5.15 Carbocation stabilization ................................................................................... 79
11.8 Migration to electrophilic carbons ............................................................................... 80
11.8.1 Pinacol rearrangement ......................................................................................... 80
11.8.2 Benzilic acid rearrangements (EXAM probably)...................................................... 80
11.9 Migrations to electrophilic heteroatom ................................................................... 81
11.9.1 Beckmann rearrangements .................................................................................. 81
11.9.2 Hofmann rearrangements .................................................................................... 82
11.9.3 Schmidt rearrangement ....................................................................................... 82
11.9.4 Baeyer-Villiger Oxidation ...................................................................................... 82
Chapter 15 Pericyclic Reactions .......................................................................................... 83
15.2.1 Orbital symmetry diagrams .................................................................................. 85
15.2.3 Frontier Molecular Orbital (FMO) theory ................................................................ 87
15.2.4 Aromatic transition state theory............................................................................ 88
15.2.5 Generalized Orbital symmetry rule ....................................................................... 89
15.3 Cycloaddition ............................................................................................................. 91
15.3.1 An allowed Geometry for [2+2] cycloadditions ...................................................... 91
4
