Experimental Organic Chemistry, 3rd Edition

The definitive guide to the principles and practice of experimental organic chemistry - fully updated and now featuring more than 100 experiments The latest edition of this popular guide to experimental organic chemistry takes students from their first day in the laboratory right through to complex research procedures. All sections have been updated to reflect new techniques, equipment and technologies, and the text has been revised with an even sharper focus on practical skills and procedures. The first half of the book is devoted to safe laboratory practice as well as purification and analytical techniques; particularly spectroscopic analysis. The second half contains step-by-step experimental procedures, each one illustrating a basic principle, or important reaction type. Tried and tested over almost three decades, over 100 validated experiments are graded according to their complexity and all are chosen to highlight important chemical transformations and to teach key experimental skills. New sections cover updated health and safety guidelines, additional spectroscopic techniques, electronic notebooks and record keeping, and techniques, such as semi-automated chromatography and enabling technologies such as the use of microwave and flow chemistry. New experiments include transition metal-catalysed cross-coupling, organocatalysis, asymmetric synthesis, flow chemistry, and microwave-assisted synthesis. Key aspects of this third edition include: Detailed descriptions of the correct use of common apparatus used in the organic laboratory Outlines of practical skills that all chemistry students must learn Highlights of aspects of health and safety in the laboratory, both in the first section and throughout the experimental procedures Four new sections reflecting advances in techniques and technologies, from electronic databases and information retrieval to semi-automated chromatography More than 100 validated experiments of graded complexity from introductory to research level A user-friendly experiment directory An instructor manual and PowerPoint slides of the figures in the book available on a companion website A comprehensive guide to contemporary organic chemistry laboratory principles, procedures, protocols, tools and techniques, Experimental Organic Chemistry, Third Edition is both an essential laboratory textbook for students of chemistry at all levels, and a handy bench reference for experienced chemists. Table of Contents List of Tables List of Illustrations Experimental Organic Chemistry About the authors Preface to the third edition About the companion website Part 1 Laboratory practice 1 Safety in the chemical laboratory 1.1 Essential rules for laboratory safety ALWAYS NEVER 1.1.1 Laboratory safety procedures 1.1.2 Eye protection 1.1.3 Dress 1.1.4 Equipment and apparatus 1.1.5 Handling chemicals 1.1.6 Spills 1.2 Hazardous chemicals 1.2.1 Flammable reagents 1.2.2 Explosive reagents 1.2.3 Oxidizers 1.2.4 Corrosive reagents 1.2.5 Harmful and toxic reagents 1.2.6 Suspected carcinogens 1.3.2 Water‐soluble waste 1.3.3 Organic solvents 1.4 Accident procedures 1.4.1 Fire 1.4.2 Burning chemicals 1.4.3 Burning clothing 1.4.4 Burns 1.4.5 Chemicals in the eye 1.4.6 Cuts 1.4.7 Poisoning Further reading 2 Glassware and equipment in the laboratory 2.1 Glass equipment 2.1.1 Cleaning and drying glassware 2.2 Hardware 2.3 Heating 2.3.1 Heating baths Water and steam baths Oil baths and their relatives 2.3.2 Electric heating mantles 2.3.3 Stirrer/hotplates 2.3.4 Hot‐air gun 2.3.5 Microwave reactors 2.4 Stirring 2.4.1 Magnetic stirrers 2.4.2 Mechanical stirrers 2.5 Vacuum pumps 2.5.1 Water aspirators Using a water aspirator Water traps 2.5.2 Diaphragm pumps 2.5.3 Oil immersion rotary vacuum pumps Pressure measurement Air‐leak stopcocks Cold traps Isolation stopcocks Operation of the rotary vacuum pump Evacuating the system Releasing the vacuum Ballasting the pump 2.6 The rotary evaporator 2.6.1 The apparatus 2.6.2 Correct use of the rotary evaporator 2.7 Catalytic hydrogenation 2.7.1 Hydrogenation procedure 2.7.2 Flow Hydrogenation Further reading 2.8 Ozonolysis 2.8.1 The apparatus 2.8.2 Ozonolysis procedure Further reading 2.9 Irradiation 2.9.1 The photochemical reactor 2.9.2 Internal irradiation with a medium‐pressure mercury vapour lamp Further reading 2.10 Compressed gases 2.10.1 Safe handling of gas cylinders Gas pressure Size and weight of cylinders Identification of contents Cylinders containing liquefied gas 2.10.2 The diaphragm regulator Attaching the pressure regulator to the cylinder Further reading 3 Organic reactions: From starting materials to pure organic product 3.1 Handling chemicals 3.1.1 Safe handling of chemicals 3.1.2 Measuring and transferring chemicals Solids Liquids 3.1.3 Filtration Gravity filtration Hot filtration Suction filtration 3.1.4 Air‐ and moisture‐sensitive compounds: syringe techniques Drying the apparatus Drying the solvents Providing an inert atmosphere Dispensing and transferring air‐sensitive reagents Running the reaction Further reading 3.2 The reaction 3.2.1 Assembling the apparatus Stirring Stirring with addition Stirring with addition under an inert atmosphere Heating Heating with stirring Heating with addition Heating and stirring with addition under an inert atmosphere Continuous removal of water Addition of gases Reactions in liquid ammonia 3.2.2 Temperature control 3.2.3 Following the progress of a reaction 3.2.4 Reaction work‐up (isolation of the product) How to use a separatory funnel Preparing the separatory funnel Transferring liquids to the separatory funnel Shaking out Separating the layers Troubleshooting Mixture is so dark that the interface is not visible Mixture is clear but the interface is not visible Only a single layer is visible Insoluble material is visible at the interface Emulsions No product is isolated after evaporation of the organic layer 3.3 Purification of organic compounds 3.3.1 Extraction Aqueous–organic extraction Choice of extraction solvent Acid–base–neutral extraction Isolation and purification of a neutral organic compound Isolation and purification of an acidic organic compound Isolation and purification of a basic organic compound Extraction of solids Further reading 3.3.2 Solution drying 3.3.3 Crystallization Crystallization of organic compounds Why are the crystals pure? Dissolution Filtration Crystallization and what to do if no crystals are formed Collecting the crystals Drying the crystals Special crystallization techniques Crystallization of very small quantities Fractional crystallization Crystals for X‐ray crystallography Further reading 3.3.4 Drying solids 3.3.5 Distillation Theoretical aspects Simple distillation Distilling solvents Fractional distillation Distillation under reduced pressure Short‐path distillation Steam distillation Sublimation 3.3.6 Chromatography Adsorption chromatography – a general introduction The support or stationary phase Elution solvents Further reading Thin‐layer chromatography The TLC plate Micro‐pipettes Spotting the plate with sample The developing tank Developing the plate Visualizing the developed plate Retention factor (Rf) Streaks, crescents and other strangely shaped spots Further reading Gravity column chromatography The equipment Choosing the solvent system Packing the column Loading the sample Eluting the column Disposal of the adsorbent ‘Flash’ column chromatography The equipment The adsorbent and solvent systems Packing the column Loading the sample and eluting the column Disposal of the silica Further reading ‘Dry flash’ column chromatography The equipment Choosing the solvent system Packing the column Loading the sample and eluting the column Disposal of the silica Prepacked columns Further reading High‐performance liquid chromatography The equipment Practical points for HPLC use Further reading Gas chromatography (gas–liquid chromatography) The carrier gas Packed columns and supports Stationary phase in packed‐column GC Capillary columns The oven Detector and response factors Sample preparation Derivatization of involatile or polar compounds Introducing the sample onto the column Common problems Co‐injection as an indication of identity Further reading Qualitative analysis of organic compounds 4.1 Purity 4.1.1 Why bother to analyse compounds? 4.1.2 Laboratory safety 4.1.3 Criteria of purity Melting point Melting point range Mixed melting point as a means of preliminary identification Experimental procedures for recording melting points Capillary tube method Heated block method Calibration of the melting point apparatus – the ‘corrected melting point’ Boiling point Azeotropes or constant boiling point mixtures Boiling point determination Small‐scale determination of boiling point Quoting bath temperatures in short‐path distillations Specific rotation Further reading 4.1.4 Chromatography: the problems of purity and identity versus homogeneity and a few hints The vexed problems of absolute proof of purity and identity using chromatography Variation of TLC solvent systems or GC temperature programmes Variation of stationary phases Use of different visualizing agents in TLC 4.1.5 Conclusion 4.2 Determination of structure using chemical methods 4.2.1 Qualitative analysis Preliminary observation of general physical characteristics Purification and determination of physical constants 5 Spectroscopic analysis of organic compounds 5.1 Absorption spectroscopy 5.2 Infrared spectroscopy 5.2.1 The spectrometer 5.2.2 Preparing the sample 5.2.3 Running the spectrum In situ IR spectroscopy 5.2.4 Interpreting the spectrum Initial deductions More detailed analysis The 4000–2500 cm−1 region O–H (Appendix 2, Table A3) N–H (Appendix 2, Table A4) C–H (Appendix 2, Table A5) The 2500–1900 cm−1 region C≡C (Appendix 2, Table A6) C≡N (Appendix 2, Table A6) The 1900–1500 cm−1 region C═O (Appendix 2, Table A7) C═C (Appendix 2, Table A8) The fingerprint region Further reading 5.3 Nuclear magnetic resonance spectroscopy 5.3.1 Preparing the sample 5.3.2 Obtaining the spectrum 5.3.3 Interpreting the spectrum Main features Measuring chemical shifts The meaning of chemical shifts Measuring peak intensities The origin of coupling Measuring coupling constants Typical coupling patterns Coupling and chemical structure Failure of the first‐order approximation Working with 1H NMR 5.3.4 13C NMR 5.3.5 DEPT 5.3.6 Further features of NMR Chemical exchange? Other useful techniques Advanced techniques Nuclear Overhauser effect Correlation spectroscopy (COSY) HMQC/HSQC HMBC NOESY Further reading Introductory theory Proton NMR Carbon NMR Data tables Practical techniques Shift reagents Exchanging systems Advanced techniques 5.4 Ultraviolet spectroscopy 5.4.1 The instrument 5.4.2 Preparing the sample Cells Concentration Solvent Making up the sample 5.4.3 Running the spectrum 5.4.4 Interpreting the spectrum Further reading 5.5 Mass spectrometry 5.5.1 The instrument The ionization source The mass analyser The detector Additional techniques 5.5.2 Preparing the sample Avoiding contamination 5.5.3 Running the spectrum Sample submission Recording and calibrating spectra 5.5.4 Interpretation of spectra Isotopes The molecular ion The nitrogen rule Common fragmentation pathways High‐resolution mass measurement Further reading Further experimental aspects Mass spectrometry 6 Keeping records: The laboratory notebook and chemical literature 6.1 The laboratory notebook 6.1.1 Style and layout 6.1.2 The e‐notebook 6.1.3 Reporting spectroscopic and microanalytical data Infrared spectra Nuclear magnetic resonance spectra Mass spectra Ultraviolet spectra 6.1.4 Elemental analysis 6.1.5 Calculating yields 6.1.6 Data sheets 6.1.7 References 6.2 The research report Further reading 6.3 The chemical literature 6.3.1 Primary literature 6.3.2 Review literature 6.3.3 Major reference works 6.3.4 Conclusion Further reading Part 2 Experimental procedures Introduction List of experiments Experiments that can be taken in sequence Experiments that can be used to compare directly different techniques for undertaking a reaction Experiments that illustrate particular techniques 7 Functional group interconversions 7.1 Simple transformations Experiment 1 Preparation of 3‐methyl‐1‐butyl ethanoate (isoamyl acetate) (pear essence) Procedure Problems Experiment 2 Preparation of s‐butyl but‐2‐enoate (s‐butyl crotonate) Procedure Problems Experiment 3 Preparation of N‐methylcyclohexanecarboxamide Procedure Problems Further reading Experiment 4 Protection of ketones as ethylene acetals (1,3‐dioxolanes) Procedure Problems Further reading Experiment 5 Preparation of (E)‐benzaldoxime Procedure Problems Further reading Experiment 6 Preparation of 4‐bromoaniline (p‐bromoaniline) Procedure 1 Preparation of N‐phenylethanamide (acetanilide) 2 Preparation of N ‐(4‐bromophenyl)ethanamide (p‐bromoacetanilide) 3 Preparation of 4‐bromoaniline Problems 7.2 Reactions of alkenes Experiment 7 Stereospecific preparation of trans‐cyclohexane‐1,2‐diol via bromohydrin and epoxide formation Procedure 1 Preparation of cyclohexene oxide 2 Preparation of trans‐cyclohexane‐1,2‐diol Problems Further reading 7.2.1 Stereospecific syntheses of cis‐1,2‐diols from alkenes Experiment 8 Preparation of cis‐cyclohexane‐1,2‐diol by the Woodward method Procedure 1 Preparation of cis‐2‐acetoxycyclohexanol 2 Preparation of cis‐cyclohexane‐1,2‐diol Problems Further reading Experiment 9 Asymmetric dihydroxylation of trans‐1,2‐diphenylethene (trans‐stilbene) Procedure Problems Further reading Experiment 10 Preparation of ethyl (E)‐3‐methyl‐3‐phenylglycidate Procedure Problems Further reading Experiment 11 Peracid epoxidation of cholesterol: 3β‐hydroxy‐5α,6α‐epoxycholestane Experiment 11 Peracid epoxidation of cholesterol: 3β‐hydroxy‐5α,6α‐epoxycholestane Procedure Problems Further reading Experiment 12 The Sharpless epoxidation: asymmetric epoxidation of (E)‐3,7‐dimethyl‐2,6‐octadien‐1‐ol (geraniol) Experiment 12 The Sharpless epoxidation: asymmetric epoxidation of (E)‐3,7‐dimethyl‐2,6‐octadien‐1‐ol (geraniol) Procedure 1 Preparatory operations 2 Preparation of (2S,3S)‐epoxygeraniol Problems Further reading Experiment 13 Hydration of alkenes by hydroboration–oxidation: preparation of octan‐1‐ol from 1‐octene Procedure Problems Further reading Experiment 14 Preparation of 7‐trichloromethyl‐8‐bromo‐Δ1‐p‐menthane by free‐radical addition of bromotrichloromethane to β‐pinene Experiment 14 Preparation of 7‐trichloromethyl‐8‐bromo‐Δ1‐p‐menthane by free‐radical addition of bromotrichloromethane to β‐pinene Procedure Problems Further reading 7.3 Substitution Experiment 15 Preparation of 1‐iodobutane by SN2 displacement of bromide: the Finkelstein reaction Procedure Problems 7.3.1 Free‐radical substitution Experiment 16 Preparation of 4‐bromomethylbenzoic acid by radical substitution and conversion to 4‐methoxymethylbenzoic acid by nucleophilic substitution Procedure 1 Preparation of 4‐bromomethylbenzoic acid 2 Preparation of 4‐methoxymethylbenzoic acid (optional) Problems Further reading 7.4 Reduction 7.4.1 Reduction with hydride transfer reagents Experiment 17 Preparation of methyl diantilis Polymer‐supported reagents Procedure 1 Preparation of 3‐ethoxy‐4‐hydroxybenzyl alcohol 2 Preparation of methyl diantilis Problems Further reading Experiment 18 Reduction of benzophenone with sodium borohydride: preparation of diphenylmethanol Procedure Problems Further reading Experiment 19 Reduction of 4‐t‐butylcyclohexanone with sodium borohydride Procedure 1 Preparation of cis‐ and trans‐4‐t‐butylcyclohexanol 2 GC analysis Problems Further reading Experiment 20 Stereospecific reduction of benzoin with sodium borohydride: determination of the stereochemistry by 1H NMR spectroscopy Procedure 1 Preparation of 1,2‐diphenylethane‐1,2‐diol 2 Preparation of acetonide derivative (2,2‐dimethyl‐4,5‐diphenyl‐1,3‐dioxolane) Problems Further reading Experiment 21 Chemoselectivity in the reduction of 3‐nitroacetophenone Procedure 1 Reduction using tin and hydrochloric acid: 3‐aminoacetophenone Reduction using sodium borohydride: 1‐(3‐nitrophenyl)ethanol Problems Further reading Experiment 22 Reduction of diphenylacetic acid with lithium aluminium hydride Procedure Problems Further reading Experiment 23 Reduction of N‐methylcyclohexanecarboxamide with lithium aluminium hydride: N‐methylcyclohexylmethylamine Procedure Problems Further reading Experiment 24 Reduction of butyrolactone with diisobutylaluminium hydride and estimation by 1H NMR of the relative proportions of 4‐hydroxybutanal and its cyclic isomer, 2‐hydroxytetrahydrofuran, in the product mixture Procedure Problems Further reading 7.4.2 Reduction of aldehyde or ketone carbonyl groups to methylene groups Experiment 25 Wolff–Kishner reduction of propiophenone to n‐propylbenzene Procedure Problems Further reading Experiment 26 Preparation of ethylbenzene 1 Preparation of carbomethoxyhydrazone 2 Preparation of carbomethoxyhydrazone Problems Further reading 7.4.3 Catalytic hydrogenation Experiment 27 Preparation of Adams’ catalyst and the heterogeneous hydrogenation of cholesterol Procedure 1 Preparation of Adams’ catalyst 2 Hydrogenation of cholesterol Problems Further reading Experiment 28 Preparation of Wilkinson’s catalyst and its use in the selective homogeneous reduction of carvone to 7,8‐dihydrocarvone Procedure 1 Preparation of Wilkinson’s catalyst 2. Selective reduction of carvone Problems Further reading 7.4.4 Dissolving metal reduction Experiment 29 Birch reduction of 1,2‐dimethylbenzene (o‐xylene): 1,2‐dimethyl‐1,4‐cyclohexadiene Experiment 29 Birch reduction of 1,2‐dimethylbenzene (o‐xylene): 1,2‐dimethyl‐1,4‐cyclohexadiene Procedure Problems Further reading 7.4.5 Biological reduction Experiment 30 Reduction of ethyl 3‐oxobutanoate using baker’s yeast; asymmetric synthesis of (S)‐ethyl 3‐hydroxybutanoate Procedure Problems Further reading 7.5 Oxidation 7.5.1 Oxidation of alcohols Experiment 31 Oxidation of 2‐methylcyclohexanol to 2‐methylcyclohexanone using aqueous chromic acid Experiment 31 Oxidation of 2‐methylcyclohexanol to 2‐methylcyclohexanone using aqueous chromic acid Procedure Problems Further reading Experiment 32 Oxidation of menthol to menthone using aqueous chromic acid Procedure 1. Oxidation of (–)‐menthol 2. GC analysis Problems Further reading Experiment 33 Oxidation of 1‐heptanol to heptanal using pyridinium chlorochromate Procedure 1 Preparation of pyridinium chlorochromate (PCC) 1 2 Oxidation of 1‐heptanol with PCC Problem Further reading Experiment 34 Preparation of ‘active’ manganese dioxide and the oxidation of (E)‐3‐phenyl‐2‐propenol (cinnamyl alcohol) to (E)‐3‐phenyl‐2‐propenal (cinnamaldehyde) Procedure 1 Preparation of activated manganese dioxide on carbon 2 Preparation of (E)‐3‐phenyl‐2‐propenal (cinnamaldehyde) Problems Further reading Experiment 35 Organic supported reagents: oxidations with silver(I) carbonate on Celite® (Fetizon’s reagent) Procedure 1 Preparation of silver carbonate on Celite® (Fetizon’s reagent) 2 Oxidation of 2‐furanmethanol 3 Conversion of hexane‐1,6‐diol to caprolactone Problems Further reading 7.6 Rearrangements Experiment 36 Preparation of 2‐aminobenzoic acid (anthranilic acid) by Hofmann rearrangement of phthalimide Procedure Problems Further reading Experiment 37 Investigation into the stereoselectivity of the Beckmann rearrangement of the oxime derived from 4‐bromoacetophenone Procedure 1 Conversion of 4‐bromoacetophenone to the oxime 2 Beckmann rearrangement of the oxime 3 Hydrolysis of the amide Problems Further reading 8 Carbon–carbon bond‐forming reactions 8.1 Grignard and organolithium reagents Experiment 38 Grignard reagents: addition of phenylmagnesium bromide to ethyl 3‐oxobutanoate ethylene acetal Procedure 1 Preparation and reaction of the Grignard reagent 2 Hydrolysis of the acetal: 4,4‐diphenylbut‐3‐en‐2‐one (optional) Problems Further reading Experiment 39 Preparation of isophorone Procedure Problem Experiment 40 Conjugate addition of a Grignard reagent to s‐butyl but‐2‐enoate (s‐butyl crotonate): preparation and saponification of s‐butyl 3‐methylheptanoate Experiment 40 Conjugate addition of a Grignard reagent to s‐butyl but‐2‐enoate (s‐butyl crotonate): preparation and saponification of s‐butyl 3‐methylheptanoate Procedure FUME HOOD 1 Preparation of s‐butyl 3‐methylheptanoate Problems Further reading Experiment 41 Acetylide anions: preparation of ethyl phenylpropynoate (ethyl phenylpropiolate) Procedure FUME HOOD Problems Further reading Experiment 42 Generation and estimation of a solution of t‐butyllithium and preparation of the highly branched alcohol tri‐t‐butylcarbinol [3‐(1,1‐dimethyl)ethyl‐2,2,4,4‐tetramethylpentan‐3‐ol] Procedure FUME HOOD 1 Preparation of t‐butyllithium 2 Titration of t‐butyllithium solution 3 Preparation of tri‐t‐butylcarbinol Problems Further reading 8.2 Enolate anions 8.2.1 Additions of enolate anions to carbonyl compounds Further reading 8.2.2 The Knoevenagel reaction Experiment 43 Preparation of (E)‐3‐phenylpropenoic acid (cinnamic acid) Procedure FUME HOOD Problems Further reading Experiment 44 Condensation of benzaldehyde with acetone: the Claisen–Schmidt reaction Procedure FUME HOOD 1 Preparation of ( E )‐4‐phenylbut‐3‐en‐2‐one (benzylideneacetone) 2 Preparation of 1,5‐diphenyl‐( E,E )‐1,4‐pentadien‐3‐one (dibenzylideneacetone) Problems Further reading Experiment 45 Synthesis of 5,5‐dimethylcyclohexane‐1,3‐dione (dimedone) Procedure FUME HOOD Problems Experiment 46 Reactions of indole: the Mannich and Vilsmeier reactions Procedure FUME HOOD 1 Preparation of gramine 2 Preparation of indole‐3‐carboxaldehyde FUME HOOD Problems Further reading Experiment 47 Preparation of 3‐methylcyclohex‐2‐enone Procedure FUME HOOD Problems Further reading Experiment 48 Enamines: acetylation of cyclohexanone via its pyrrolidine enamine Procedure 1 Preparation of 2‐acetylcyclohexanone 2 Preparation of 7‐oxooctanoic acid (optional) Problems Experiment 49 Enol derivatives: preparation of the enol acetate, trimethylsilyl enol ether and pyrrolidine enamine of 2‐methylcyclohexanone Procedure 1 Preparation of the enol acetate of 2‐methylcyclohexanone 2 Preparation of the trimethylsilyl enol ether of 2‐methylcyclohexanone 3 Preparation of the pyrrolidine enamine of 2‐methylcyclohexanone Problems Further reading Experiment 50 Preparation of (R)‐warfarin Procedure Problems Further reading Experiment 51 Reductive alkylation of enones: 2‐(prop‐2‐enyl)‐3‐methylcyclohexanone Experiment 51 Reductive alkylation of enones: 2‐(prop‐2‐enyl)‐3‐methylcyclohexanone Procedure Problems Further reading Experiment 52 Lithium diisopropylamide as base: regioselectivity and stereoselectivity in enolate formation Procedure 1 Formation of lithium diisopropylamide 2 Deprotonation and chlorotrimethylsilane quench Problems Further reading Experiment 53 Dianions: aldol condensation of the dianion from ethyl 3‐oxobutanoate (ethyl acetoacetate) with benzophenone Experiment 53 Dianions: aldol condensation of the dianion from ethyl 3‐oxobutanoate (ethyl acetoacetate) with benzophenone Procedure Problems Further reading 8.3 Heteroatom‐stabilized carbanions 8.3.1 The Wittig reaction Further reading Experiment 54 Preparation of ( E )‐diphenylethene (stilbene) with ylid generation under phase transfer conditions Procedure Problems Further reading Experiment 55 Preparation of 4‐vinylbenzoic acid by a Wittig reaction in aqueous medium Procedure Preparation of 4‐carboxybenzyltriphenylphosphonium bromide Preparation of 4‐vinylbenzoic acid Problems Experiment 56 A Wittig reaction involving preparation and isolation of a stabilized ylid: conversion of 1‐bromobutyrolactone to α‐methylenebutyrolactone Procedure 1 Preparation of 1‐butyrolactonyltriphenylphosphonium bromide 2 Preparation and isolation of 1‐butyrolactonylidene triphenylphosphorane 3 Preparation of α‐methylenebutyrolactone Problems Further reading 8.3.2 The Horner–Wadsworth–Emmons reaction Experiment 57 Preparation of ( E,E )‐1,4‐diphenyl‐1,3‐butadiene Procedure 1 Preparation of diethyl benzylphosphonate Preparation of (E,E)‐1,4‐diphenyl‐1,3‐butadiene Problems Further reading 8.3.3 Sulfur ylids Experiment 58 Sulfur ylids: preparation of methylenecyclohexane oxide (1‐oxaspiro[2.5]octane) Experiment 58 Sulfur ylids: preparation of methylenecyclohexane oxide (1‐oxaspiro[2.5]octane) Procedure 1 Preparation of dimethylsulfoxonium methylide 2 Preparation of methylenecyclohexane oxide Problems Further reading 8.3.4 Umpolung of reactivity Experiment 59 Illustration of ‘umpolung’ in organic synthesis: synthesis of ethyl phenylpyruvate via alkylation of ethyl 1,3‐dithiane‐2‐carboxylate, followed by oxidative hydrolysis with N‐bromosuccinimide Procedure 1 Preparation of ethyl 2‐benzyl‐1,3‐dithiane‐2‐carboxylate 2 Preparation of ethyl phenylpyruvate Problems Further reading 8.4 Aromatic electrophilic substitution Experiment 60 Nitration of methyl benzoate Procedure Problems 8.4.1 The Friedel–Crafts reaction Experiment 61 4‐Bromobenzophenone by the Friedel–Crafts reaction Procedure Problem Experiment 62 Friedel–Crafts acetylation of ferrocene using different Lewis acid catalysts and identification of the products by 1H NMR spectroscopy Procedure 1 Boron trifluoride‐catalysed acetylation of ferrocene 2 Aluminium chloride‐catalysed acetylation of ferrocene Problems Further reading Experiment 63 Fries rearrangement of phenyl acetate: preparation of 2‐hydroxyacetophenone Experiment 63 Fries rearrangement of phenyl acetate: preparation of 2‐hydroxyacetophenone Procedure 1 Preparation of 2‐hydroxyacetophenone 2 Isolation of the 4‐hydroxyacetophenone (optional) Problems 8.5 Pericyclic reactions Experiment 64 Diels–Alder preparation of cis‐cyclohex‐4‐ene‐1,2‐dicarboxylic acid Experiment 64 Diels–Alder preparation of cis‐cyclohex‐4‐ene‐1,2‐dicarboxylic acid Procedure 1 Preparation of cis‐cyclohex‐4‐ene‐1,2‐dicarboxylic anhydride 2 Hydrolysis of initial anhydride adduct to cis‐cyclohex‐4‐ene‐1,2‐dicarboxylic acid Problems Experiment 65 Formation of a Diels–Alder adduct Procedure Problems Experiment 66 Preparation of 2,3‐dimethyl‐1,3‐butadiene and its Diels–Alder reaction with butenedioic anhydride (maleic anhydride) Procedure 1 Preparation of 2,3‐dimethyl‐1,3‐butadiene 2 Diels–Alder reaction Problems Experiment 67 Benzyne: Diels–Alder reaction with furan Procedure 1 Preparation of 1,4‐dihydronaphthalene‐1,4‐endoxide 2 Treatment of 1,4‐dihydronaphthalene‐1,4‐endoxide with acid (optional) Problems Further reading Experiment 68 [2 + 2]‐ Cycloaddition of cyclopentadiene to dichloroketene: 7,7‐dichlorobicyclo[3.2.0]hept‐2‐en‐6‐one Procedure 1 Preparation of cyclopentadiene from dicyclopentadiene 2 Preparation of 7,7‐dichlorobicyclo[3.2.0]hept‐2‐en‐6‐one 3 Preparation of bicyclo[3.2.0]hept‐2‐en‐6‐one (optional) Problems Further reading Experiment 69 Generation of dichlorocarbene and addition to styrene: preparation of (2,2‐dichlorocyclopropyl)benzene Procedure Problems Further reading Experiment 70 Claisen rearrangement of 2‐propenyloxybenzene (allyl phenyl ether): preparation and reactions of 2‐allylphenol Procedure 1 Preparation of allyl phenyl ether 2 Preparation of 2‐allylphenol 3 Treatment of 2‐allylphenol with KOH (optional) 4 Treatment of 2‐allylphenol with HBr (optional) Problems Further reading Experiment 71 Preparation of 3,5‐diphenylisoxazoline by a 1,3‐dipolar cycloaddition Procedure Problems Further reading 8.6 Metal‐mediated coupling reactions Experiment 72 Preparation of 2‐methyl‐4‐(4‐nitrophenyl)but‐3‐yn‐2‐ol Experiment 72 Preparation of 2‐methyl‐4‐(4‐nitrophenyl)but‐3‐yn‐2‐ol Procedure Problems Further reading Experiment 73 Preparation and use of a palladium catalyst suitable for application in a Suzuki– Miyaura cross‐coupling reaction Procedure 1 Preparation of palladium catalyst 2 Preparation of biphenyl‐4‐carboxylic acid Problems Further reading Experiment 74 Preparation of unsymmetrical biaryls by Suzuki–Miyaura cross‐coupling Procedure Problems Further reading Experiment 75 Preparation of diethyl cyclopent‐3‐ene‐1,1‐dicarboxylate Procedure Problem Further reading 9 Experiments using enabling technologies 9.1 Microwave chemistry Further reading Experiment 76 Preparation of 2‐amino‐4‐phenylthiazole Procedure Problems Experiment 77 Preparation of 5,6‐dimethyl‐3a,4,7,7a‐tetrahydroisobenzofuran‐1,3‐dione Experiment 77 Preparation of 5,6‐dimethyl‐3a,4,7,7a‐tetrahydroisobenzofuran‐1,3‐dione Procedure Problems Experiment 78 The Fischer indole synthesis: preparation of 1,2,3,4‐tetrahydrocarbazole Experiment 78 The Fischer indole synthesis: preparation of 1,2,3,4‐tetrahydrocarbazole Procedure Problems Further reading Experiment 79 Preparation of trans‐ethyl cinnamate [(E)‐ethyl 3‐phenylpropenoate] Experiment 79 Preparation of trans‐ethyl cinnamate [(E)‐ethyl 3‐phenylpropenoate] Procedure Problems Further reading 9.2 Flow chemistry 9.2.1 Equipment 9.2.2 Performing a reaction in flow Further reading Experiment 80 An introductory experiment using flow chemistry Procedure 1 Prepare the reagent reservoirs 2 Set up the flow unit 3 Performing the experiment Experiment 81 Preparation of propyl benzoate using flow chemistry Procedure 1 Prepare the reagent reservoirs 2 Set up the flow unit 3 Preparation of propyl benzoate 4 Product purification Problems Experiment 82 Preparation of diethyl cyclopent‐3‐ene‐1,1‐dicarboxylate using flow chemistry Procedure 1 Prepare the reagent reservoirs 2 Set up the flow unit 3 Preparation of diethyl cyclopent‐3‐ene‐1,1‐dicarboxylate 4 Product purification Problems Experiment 83 Preparation of biphenyl using flow chemistry Procedure 1 Prepare the reagent reservoirs 2 Set up the flow unit 3 Preparation of biphenyl 4 Product purification Problems 10 Projects 10.1 Natural product isolation and identification Experiment 84 Isolation of eugenol, the fragrant component of cloves, and lycopene, a colouring component of tomatoes Procedure 1 Isolation of eugenol 2 Isolation of lycopene Problems Experiment 85 Isolation and characterization of limonene, the major component of the essential oil of citrus fruit Procedure Problems Further reading Experiment 86 Isolation of caffeine from tea and theobromine from cocoa Procedure 1 Isolation of caffeine 2 Isolation of theobromine Problems Further reading 10.2 Project in organic synthesis Experiment 87 Preparation of and use of Jacobsen’s catalyst Procedure 1 Preparation and recrystallization of (R,R)‐(+)‐1,2‐diaminocyclohexane L‐tartrate 2 Preparation of (R,R)‐N,N′‐bis(3,5‐di‐t‐butylsalicylidene)‐1,2‐cyclohexanediamine 2 Preparation of (R,R)‐N,N′‐bis(3,5‐di‐t‐butylsalicylidene)‐1,2‐cyclohexanediamine 3 Preparation of [(R,R)‐N,N′‐bis(3,5‐di‐t‐butylsalicylidene)‐1,2‐cyclohexanediaminato(2–)]manganese(III) chloride (Jacobsen’s catalyst) 3 Preparation of [(R,R)‐N,N′‐bis(3,5‐di‐t‐butylsalicylidene)‐1,2‐cyclohexanediaminato(2–)]manganese(III) chloride (Jacobsen’s catalyst) 4 Preparation of 1,2‐dihydronaphthalene oxide Problems Further reading Experiment 88 Dyes: preparation and use of indigo Procedure 1 Preparation of indigo 2 Vat dying of cotton Problems Further reading Experiment 89 Synthesis of flavone Procedure 1 Preparation of 2‐benzoyloxyacetophenone 2 Preparation of 2‐hydroxydibenzoylmethane 3 Preparation of flavone Problems Further reading 10.2.1 Syntheses of pheromones Experiment 90 Insect pheromones: synthesis of (±)‐4‐methylheptan‐3‐ol and (±)‐4‐methylheptan‐3‐one Procedure 1 Preparation of 4‐methylheptan‐3‐ol 2 Preparation of 4‐methylheptan‐3‐one Problems Further reading Experiment 91 Insect pheromones: methyl 9‐oxodec‐2‐enoate, the queen bee pheromone Procedure 1 Preparation of 1‐methylcycloheptanol 2 Preparation of 1‐methylcycloheptene 3 Preparation of 7‐oxooctanal 4 Preparation of methyl 9‐oxodec‐2‐enoate (queen bee pheromone methyl ester) 5 Preparation of methyl (triphenylphosphoranylidene)acetate (optional) Problems Further reading Experiment 92 Synthesis of 6‐nitrosaccharin Procedure 1 Preparation f 4‐nitrotoluene‐2‐sulfonamide 2 Preparation of 6‐nitrosaccharin Problems Further reading 10.2.2 Macrocyclic compounds Experiment 93 Preparation of copper phthalocyanine Procedure Problems Further reading Experiment 94 Synthesis of tetraphenylporphin and its copper complex Procedure 1 Preparation of meso‐tetraphenylporphin 2 Preparation of TPP copper complex [5,10,15,20‐tetraphenyl porphyrinatocopper(II)] Problems Further reading 10.2.3 Chemiluminescence Experi Title Page -- Copyright Page -- Contents -- About the authors -- Preface to the third edition -- About the companion website -- Part 1 Laboratory practice -- Chapter 1 Safety in the chemical laboratory -- 1.1 Essential rules for laboratory safety -- 1.2 Hazardous chemicals -- 1.3 Disposal of hazardous waste -- 1.4 Accident procedures -- Chapter 2 Glassware and equipment in the laboratory -- 2.1 Glass equipment -- 2.2 Hardware -- 2.3 Heating -- 2.4 Stirring -- 2.5 Vacuum pumps -- 2.6 The rotary evaporator -- 2.7 Catalytic hydrogenation -- 2.8 Ozonolysis -- 2.9 Irradiation -- 2.10 Compressed gases -- Chapter 3 Organic reactions: From starting materials to pure organic product -- 3.1 Handling chemicals -- 3.2 The reaction -- 3.3 Purification of organic compounds -- Chapter 4 Qualitative analysis of organic compounds -- 4.1 Purity -- 4.2 Determination of structure using chemical methods -- Chapter 5 Spectroscopic analysis of organic compounds -- 5.1 Absorption spectroscopy -- 5.2 Infrared spectroscopy -- 5.3 Nuclear magnetic resonance spectroscopy -- 5.4 Ultraviolet spectroscopy -- 5.5 Mass spectrometry -- Chapter 6 Keeping records: The laboratory notebook and chemical literature -- 6.1 The laboratory notebook -- 6.2 The research report -- 6.3 The chemical literature -- Part 2 Experimental procedures -- Introduction -- List of experiments -- Experiments that can be taken in sequence -- Experiments that can be used to compare directly different techniques for undertaking a reaction -- Experiments that illustrate particular techniques -- Chapter 7 Functional group interconversions -- 7.1 Simple transformations -- 7.2 Reactions of alkenes -- 7.3 Substitution -- 7.4 Reduction -- 7.5 Oxidation -- 7.6 Rearrangements -- Chapter 8 Carbon-carbon bond-forming reactions -- 8.1 Grignard and organolithium reagents -- 8.2 Enolate anions