ABOUT THE COURSE: Molecular rearrangements in organic synthesis involve the transformation of the structure of a molecule by the movement of atoms or groups of atoms within the molecule. These rearrangements play a crucial role in the synthesis of organic compounds, allowing chemists to create complex structures from simpler starting materials. Molecular rearrangements can be classified into various types, and they are often named based on the specific changes occurring in the molecule such as 1,2-metallate rearrangement, Cope Rearrangement, Claisen Rearrangement, Wagner-Meerwein Rearrangement, Pinacol Rearrangement, Beckmann Rearrangement, Fries Rearrangement, Baeyer-Villiger Oxidation and so on. This is aprivileged tool towards chemists and biochemists providing access to control the structure-reactivity relationship.INTENDED AUDIENCE:Students of BSMS/BSc/MS/MSc and PhD can benefit from this course.PREREQUISITES: Basic Concept of Organic ChemistryINDUSTRY SUPPORT:Syngenta Goa, PI Industries Jaipur, TCG life science Kolkata, Merck India Pvt. Ltd. Zoetis India Pvt. Ltd and other chemical industry across India and around the world
Molecular Rearrangements and Reactive Intermediates in Organic Synthesis
Indian Institute of Technology, Kharagpur and NPTEL via Swayam
Overview
Syllabus
Week 1:Introduction to reactive intermediates such as carbocation, carbanion, carbene, nitrene, and free radicals;Carbocation: stability of carbocations, classification, and their stability comparison, carbocation generation, various carbocationic rearrangements including Wagner-Meerwein Rearrangement, Pinacol-pinacolone rearrangement, Beckman rearrangement,
Week 2:Carbanion: Structure, stability, and Molecular rearrangements using carbanions as the reactive intermediate. Claisen Rearrangement: -Ireland-Claisen, Johnson-Claisen, Eschenmoser-claisen, Overmann- Claisen with mechanism, example and application [2,3] Wittig rearrangement, [1,2] Wittig rearrangement, Stevens rearrangement, Sommelet–Hauser rearrangement, Benzilic acid rearrangement, Favorskii Rearrangement, Neber Rearrangement, Smiles rearrangement, Payne Rearrangement, Baker–Venkataraman rearrangement, Ramberg-Bäcklund Reaction etc.
Week 3:Carbene: history, definition, characteristic, different types of carbene, molecular orbital diagram of different carbene, singlet carbene, triplet carbene, persistent carbene, metallocarbene, various methods forgeneration of carbene: via fragmentation reaction-1) from diazo compounds, 2) from tosylhydrazone, 3) from ketene, 4) from the three-membered strained ring, 5) from strained alkene; via α-elimination, various reactions of carbene: addition reaction, insertion reaction, cyclopropanation, Name reactions: Simmons-Smith reaction, Bamford-Steven’s reaction, Shapiro reaction, Wolff rearrangement, alkene metathesis.
Week 4:Nitrene: Structure, stability, synthesis, and the transformations using Nitrenes. Curtius Rearrangement, Lossen Rearrangement, Schmidt Reaction, etc.
Week 5:Radicals: Definition, history, various radical formation methods: abstraction, addition, elimination. radical analyzation method: ESR, radicals stability and reactivity, various reactions of radical: HBr addition, chlorination, fluorination and iodination of alkanes/alkenes, radical chain reactions. Regiochemistry of HBr addition, carbon-carbon bond formation using radicals, nucleophilic vs electrophilic radicals, intramolecular vs intermolecular radical reactions, radical polymerization, and application of free radicals.
Week 6:Molecular rearrangements using free radicals. Different examples of molecular rearrangement using free radicals.Different photoreactions using free radical; Barton Nitrite Photolysis Reaction, Barton Decarboxylation, Barton-McCombie Deoxygenation, Hunsdiecker Reaction, Birch Reduction, Chain Walking in Polymerization, Norrish Type I and Type II , Electron transfer reaction: Kolbe electrolysis, radical coupling reactions, aromatic substitution reaction using free radical; Sandmeyer reaction
Week 7:Benzyne: Structural features, comparison study with acetylene and benzene, methods of benzyne generation: Deprotonation of aryl halide using strong base, metal halogen exchange and elimination, from anthranilic acid, fragmentation, Kobayashi and Hosoya methods of aryne generation, activation by cesiumcarbonate, Different types of reaction using benzyne intermediate like pericyclic reaction, arylation reaction, insertion reaction, metal-catalyzed reaction, molecular rearrangements and multicomponent reaction.
Week 8:Reactive intermediates of Si-based reagents towards organic synthesis: The nature of silicon bonding, Comparison between carbon and silicon, Alpha and beta effect of silicon, Nucleophilic substitution at silicon, Silicon-based protection of alcohol, TMS-OTf, TMS-CN, Alkynyl silanes in protection and activation, Ipso substitution of aryl silanes, Reactivity of vinylsilanes, Allyl silanes as nucleophiles, hydrosilylation, Hiyama coupling, The Peterson elimination, Brook rearrangement. Silyl-Heck coupling, Silyl-Negishi coupling.
Week 9:Reactive intermediates of P-/S- towards the organic synthesis.Sulfur:Sulfur ylide chemistry, Sulfur-stabilized anions, Julia Olefination, Addition Reactions with Electrophilic Sulfur and Selenium Reagents, Rearrangement of Allylic Sulfoxides, Pummerer rearrangement, Swern oxidation, Bamford-Stevens reaction, Barton radical decarboxylation reaction, Chugaev elimination reaction, Corey-Chaykovsky epoxidation and cyclopropanation, Corey-Kim oxidation, Kornblum oxidation, Mislow-Evans rearrangement, Ramberg-Bäcklund rearrangement, Smith-Tietze multicomponent dithiane linchpin coupling.Phosphorous:Appel reaction, Mitsunobu reaction, Arbuzov reaction, Wittig reaction, Horner–Wadsworth–Emmons reaction, E vs Z olefin, aza-Wittig reaction, Corey-Fuchs alkyne synthesis, Corey-Nicolaou macrolactonization, Corey-Winter olefination, Seyferth-Gilbert homologation, Staudinger reaction, Vilsmeier-Haack formylation.
Week 10:Organoboron: Reactive intermediates using boron and some basic transformations. Hydroboration, oxidation, Cross-coupling reaction, radical transformations. Molecular rearrangements using organoborons. 1,2-metallate rearrangement, Matteson homologation, Aggarwal homologation, Zweifel olefination, Boron-Wittig reaction.
Week 11 & 12:Various organometallic reagents such as organolithium: basic concepts, reactivity, basicity, nucleophilicity characters, chelation property, structures in various solvent, reactivity in different solvent, M.O- diagram, generation, deprotonation, transmetallation, metal-halogen exchange, various reactions, direct lithiation, formation of aldehyde, ortho-lithiation, umpulong effect, asymmetric synthesis; Grignard: definition, mechanism, structure, different types of Grignard reagent, synthesis; organozinc: synthesis, structure, reactivity, synthetic method, activated Zn- powder, Rieke- Zn, transmetallation, halogen Zn- exchange, different reaction, the reactivity of diethyl zinc, Negishi coupling, Reformatsky reaction, Blaise reaction, Simon-smith reactions; Organo Copper reagent: Gilmann’s reagent, synthesis, example, comparison with Grignard reagent.
Week 2:Carbanion: Structure, stability, and Molecular rearrangements using carbanions as the reactive intermediate. Claisen Rearrangement: -Ireland-Claisen, Johnson-Claisen, Eschenmoser-claisen, Overmann- Claisen with mechanism, example and application [2,3] Wittig rearrangement, [1,2] Wittig rearrangement, Stevens rearrangement, Sommelet–Hauser rearrangement, Benzilic acid rearrangement, Favorskii Rearrangement, Neber Rearrangement, Smiles rearrangement, Payne Rearrangement, Baker–Venkataraman rearrangement, Ramberg-Bäcklund Reaction etc.
Week 3:Carbene: history, definition, characteristic, different types of carbene, molecular orbital diagram of different carbene, singlet carbene, triplet carbene, persistent carbene, metallocarbene, various methods forgeneration of carbene: via fragmentation reaction-1) from diazo compounds, 2) from tosylhydrazone, 3) from ketene, 4) from the three-membered strained ring, 5) from strained alkene; via α-elimination, various reactions of carbene: addition reaction, insertion reaction, cyclopropanation, Name reactions: Simmons-Smith reaction, Bamford-Steven’s reaction, Shapiro reaction, Wolff rearrangement, alkene metathesis.
Week 4:Nitrene: Structure, stability, synthesis, and the transformations using Nitrenes. Curtius Rearrangement, Lossen Rearrangement, Schmidt Reaction, etc.
Week 5:Radicals: Definition, history, various radical formation methods: abstraction, addition, elimination. radical analyzation method: ESR, radicals stability and reactivity, various reactions of radical: HBr addition, chlorination, fluorination and iodination of alkanes/alkenes, radical chain reactions. Regiochemistry of HBr addition, carbon-carbon bond formation using radicals, nucleophilic vs electrophilic radicals, intramolecular vs intermolecular radical reactions, radical polymerization, and application of free radicals.
Week 6:Molecular rearrangements using free radicals. Different examples of molecular rearrangement using free radicals.Different photoreactions using free radical; Barton Nitrite Photolysis Reaction, Barton Decarboxylation, Barton-McCombie Deoxygenation, Hunsdiecker Reaction, Birch Reduction, Chain Walking in Polymerization, Norrish Type I and Type II , Electron transfer reaction: Kolbe electrolysis, radical coupling reactions, aromatic substitution reaction using free radical; Sandmeyer reaction
Week 7:Benzyne: Structural features, comparison study with acetylene and benzene, methods of benzyne generation: Deprotonation of aryl halide using strong base, metal halogen exchange and elimination, from anthranilic acid, fragmentation, Kobayashi and Hosoya methods of aryne generation, activation by cesiumcarbonate, Different types of reaction using benzyne intermediate like pericyclic reaction, arylation reaction, insertion reaction, metal-catalyzed reaction, molecular rearrangements and multicomponent reaction.
Week 8:Reactive intermediates of Si-based reagents towards organic synthesis: The nature of silicon bonding, Comparison between carbon and silicon, Alpha and beta effect of silicon, Nucleophilic substitution at silicon, Silicon-based protection of alcohol, TMS-OTf, TMS-CN, Alkynyl silanes in protection and activation, Ipso substitution of aryl silanes, Reactivity of vinylsilanes, Allyl silanes as nucleophiles, hydrosilylation, Hiyama coupling, The Peterson elimination, Brook rearrangement. Silyl-Heck coupling, Silyl-Negishi coupling.
Week 9:Reactive intermediates of P-/S- towards the organic synthesis.Sulfur:Sulfur ylide chemistry, Sulfur-stabilized anions, Julia Olefination, Addition Reactions with Electrophilic Sulfur and Selenium Reagents, Rearrangement of Allylic Sulfoxides, Pummerer rearrangement, Swern oxidation, Bamford-Stevens reaction, Barton radical decarboxylation reaction, Chugaev elimination reaction, Corey-Chaykovsky epoxidation and cyclopropanation, Corey-Kim oxidation, Kornblum oxidation, Mislow-Evans rearrangement, Ramberg-Bäcklund rearrangement, Smith-Tietze multicomponent dithiane linchpin coupling.Phosphorous:Appel reaction, Mitsunobu reaction, Arbuzov reaction, Wittig reaction, Horner–Wadsworth–Emmons reaction, E vs Z olefin, aza-Wittig reaction, Corey-Fuchs alkyne synthesis, Corey-Nicolaou macrolactonization, Corey-Winter olefination, Seyferth-Gilbert homologation, Staudinger reaction, Vilsmeier-Haack formylation.
Week 10:Organoboron: Reactive intermediates using boron and some basic transformations. Hydroboration, oxidation, Cross-coupling reaction, radical transformations. Molecular rearrangements using organoborons. 1,2-metallate rearrangement, Matteson homologation, Aggarwal homologation, Zweifel olefination, Boron-Wittig reaction.
Week 11 & 12:Various organometallic reagents such as organolithium: basic concepts, reactivity, basicity, nucleophilicity characters, chelation property, structures in various solvent, reactivity in different solvent, M.O- diagram, generation, deprotonation, transmetallation, metal-halogen exchange, various reactions, direct lithiation, formation of aldehyde, ortho-lithiation, umpulong effect, asymmetric synthesis; Grignard: definition, mechanism, structure, different types of Grignard reagent, synthesis; organozinc: synthesis, structure, reactivity, synthetic method, activated Zn- powder, Rieke- Zn, transmetallation, halogen Zn- exchange, different reaction, the reactivity of diethyl zinc, Negishi coupling, Reformatsky reaction, Blaise reaction, Simon-smith reactions; Organo Copper reagent: Gilmann’s reagent, synthesis, example, comparison with Grignard reagent.
Taught by
Prof. Santanu Panda
