Microscale Organic Laboratory with Multistep and Multiscale Syntheses T H I R D E D I T I O N

.- na . • • . • • ' . • - • • • • • • • > ' , }

Dana W. Mayo Charles Weston Pickard Research Professor of Chemistry Bowdoin College

Ronald M. Pike Professor of Chemistry, Emeritus Merrimack College

Peter K. Trumper Professor of Chemistry University of Southern Maine

John Wiley *L Sons, Inc. New York Chichester Brisbane Toronto Singapore

Contents

General Ruies for the Microscaie Laboratory The Organic Chemistry Laboratory

3

4 CHAPTER 1

INTRODUCTION l

Making the Laboratory a Safer Place

Nature of Hazards Reduction of Risks Precautionary Measures

Thinking about the Risks in Using Chemicals

Storage of Chemicals Disposal of Chemicals Material Safety Data Sheets Estimating the Risks from Vapors Hood Use Concluding Thoughts

5 6 6 7 7 8 8 8

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CHAPTER 2 SAFETY

5

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XXVi Contents

CHAPTER 3 INTRODUCTION TO MICROSCALE ORGANIC LABORATORY EQUIPMENT AND TECHNIQUES 15

Microglassware Equipment Standard Experimental Apparatus

Heating and Stirring Arrangements Reflux Apparatus Distillation Apparatus Moisture-Protected Reaction Apparatus Specialized Pieces of Equipment

Microscale Laws Rules of the Trade for Handling Organic Materials at the

Microscale Level Rules for Working with Liquids at the Microscale Level Rules for Working with Solids at the Microscale Level

The Laboratory Notebook Example of a Laboratory Notebook Entry Calculation of Yields

17 19 19 24 26 29 32 34

34 34 37 38 39 41

CHAPTER 4 DETERMINATION OF PHYSICAL PROPERTIES 43

LIQUIDS Ultramicro-Boiling Point Density

Refractive Index SOLIDS Melting Points Mixture Melting Points

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47

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CHAPTER 5 DEVELOPMENT OF MICROSCALE TECHNIQUES 55

TECHNIQUE 1 Microscale Separation of Liquid Mixtures by Preparative Gas Chromatography 56

Introduction 56 Procedure for Preparative Collection 60

TECHNIQUE 2 Semimicroscale Distillation 61 Introduction 61

Distillation Theory 61 Technique 2A Simple Distillation at the Microscale Level 65 Technique 2B Fractional Distillation at the Semimicroscale

Level 68 TECHNIQUE 3 Steam Distillation 71 Theory 71 TECHNIQUE 4 Solvent Extraction 73 Solubility 73 Partition Coefficient 76 Extraction 78

Solid-Liquid Extraction 78 Liquid—Liquid Extraction 80

Contents xxvii

Separatory Funnel Extraction 82 Continuous Liquid-Liquid Extraction 83 Drying of the Wet Organic Layer 86 Separation of Acids and Bases 87

Salting Out 88 Solid-Phase Extraction 88 TECHNIQUE 5 Crystallization 90 Procedure 91 Simple Crystallization 92 Filtration Techniques 93

Use of the Hirsch Funnel 93 Craig Tube Crystallizations 95

Recrystallization Pipet 96 TECHNIQUE 6 Chromatography 97

Technique 6A Column, High-Performance Liquid, and Thin-Layer Chromatography 97

Column Chromatography 98 Packing the Column 99 Sample Application 100 Elution of the Column 100 Fraction Collection 100 Flash Chromatography 101

Thin-Layer Chromatography 103 High-Performance Liquid Chromatography 105

Technique 6B Concentration of Solutions 106 Distillation 106 Evaporation with Nitrogen Gas 107 Removal of Solvent Under Reduced Pressure 107 TECHNIQUE 7 Collection and Control of Gaseous Products 109 TECHNIQUE 8 Measurement Of Specific Rotation 111 Optical Rotation Theory 111 The Polarimeter 113 TECHNIQUE 9 Sublimation 116 Sublimation Theory 116

Introduction EXPERIMENT [1] Measurement of Physical Properties EXPERIMENT [2] The Separation of a 25 ^L Mixture of Heptanol

(bp 153 °C) and Cydohexanol (bp 160 °C) by Gas Chromatography

EXPERIMENT [3] Distillation Experiment [3A] Simple Distillation at the Semimicroscale

Level: Separation of Ethyl Acetate from trans-i,2-Dibenzoylethylene

Experiment [3B] Fractional Semimicroscale Distillation: Separation of Hexane and Toluene

119 121

126 132

133

136

CHAPTER 6 MICROSCALE ORGANIC

LABORATORY EXPERIMENTS 119

XXVÜi Contents

Experiment [3C] Fractional Semimicroscale Distillation: Separation of 2-Methylpentane and Cyclohexane Using a Spinning Band Column 139

Experiment [3D] Fractional Semimicroscale Distillation: The Separation of 2-Methylpentane and Cyclohexane Using a Spinning Band in a Hickman-Hinkle Still 142

EXPERIMENT [4] Solvent Extraction 144 Experiment [4A] Determination of a Partition Coefficient for

the System Benzoic Acid, Methylene Chloride, and Water 144 Experiment [4B] Solvent Extraction I: The System; Benzoic

Acid, Methylene Chloride, and 10% Sodium Bicarbonate Solution; An Example of Acid-Base Extraction Techniques 150

Experiment [4C] Solvent Extraction II: A Three Component Mixture; An Example of the Separation of an Acid, a Base, and a Neutral Substance 151

EXPERIMENT [5] Reduction of Ketones Using a Metal Hydride Reagent: Cyclohexanol and eis- and frans-4-tert-Butylcyclohexanol 155

Experiment [5A] Cyclohexanol 158 Experiment [5B] eis- and trans-4-tert-Butylcyclohexanol 163

EXPERIMENT [6] Photochemical Isomerization of an Alkene: c/s-1,2-Dibenzoylethylene 169

Experiment [6A] Purification of frans-1,2-Dibenzoylethylene 172 Experiment [6B] Isomerization of an Alkene: Thin-Layer

Chromatographie Analysis 173 Experiment [6C] Isomerization of an Alkene: Nuclear

Magnetic Resonance Analysis 177 EXPERIMENT [7] The Cannizzaro Reaction with

4-Chlorobenzaldehyde: 4-Chlorobenzoic Acid and 4-ChlorobenzyI Alcohol 180

EXPERIMENT [8] The Esterification Reaction: Ethyl Laurate, Isopentyl Acetate, and the Ilse of Acidic Resins 190

Experiment [8A] Ethyl Laurate 202 Experiment [8B] Isopentyl Acetate 203

Semimicroscale Preparation

Experiment [8C] Esterification by Acidic Resins 207 Semimicroscale Preparations

EXPERIMENT [9] The EI Elimination Reaction: Dehydration of 2-Butanol to Yieid 1-Butene, frans-2-Butene, and c/s-2-Butene 210

EXPERIMENT [10] The E2 Elimination Reaction: Dehydrohaiogenation of 2-Bromobutane to Yield 1-Butene, frans-2-Butene, and c/s-2-Butene 219

EXPERIMENT [11] The Isolation of Natural Products 226 Experiment [ I IA] Isolation and Characterization of an

Optically Active Natural Product: Usnic Acid 226 Experiment [IIB] Isolation and Characterization of a Natural

Product: Caffeine and Caffeine 5-Nitrosalicylate 232 Experiment [ 11C] Isolation of a Natural Product by Steam

Distillation: Cinnamaldehyde from Cinnamon 241 EXPERIMENT [12] Reductive Catalytic Hydrogenation of an

Alkene: Octane 246

EXPERIMENT [13] Hydroboration-Oxidation of an Alkene: Octanol 252

EXPERIMENT [ 14] Diels-Alder Reaction: 4-Cyclohexene-c/s-l,2-dicarboxyIic Acid Anhydride 260

Optional Semimicroscale Preparation

EXPERIMENT [15] Diels-Alder Reaction: 9,10-Dihydroanthracene-9,10-a,/3-sucdnic Acid Anhydride 272

Optional Semimicroscale and Macroseale Preparations EXPERIMENT [16] Grignard Reaction with a Ketone:

Triphenylmethanol 277 EXPERIMENT [ 17] Grignard Reaction with an Aldehyde:

4-Methyl-3-heptanol 286 EXPERIMENT [18] The Perkin Reaction: Condensation of

Rhodanine with an Aromatic Aldehyde to Yield o-Chlorobenzylidene Rhodanine 292

Optional Semimicroscale Preparation EXPERIMENT [19] Alkene Preparation by the Wittig Reaction:

(f)-Stilbene; 1 -MethyIene-4-ferf-butylcyclohexane; and fr«uis-9-(2-Phenylethenyl)anthracene 297

Experiment [ 19A] (£)-Stilbene by the "Instant Ylide" Method 302 Experiment [19B] (£)-Stilbene by the Homer-Wadsworth-

Emmons Reaction 305 Experiment [ 19C] Methylene-4-rerf-butylcyclohexane 307 Experiment [ 19D] frans-9-(2-Phenylethenyl)anthracene 309

EXPERIMENT [20] Aldo! Reaction: Dibenzalacetone 313 Optional Semimicroscale Preparation

EXPERIMENT [21 ] Quantitative Analysis of Grignard Reagents: 1 -Methylbutylmagnesium Bromide and Phenylmagnesium Bromide 321

Part 1 1 -Methylbutylmagnesium Bromide 323 Part 2 Phenylmagnesium Bromide 324

EXPERIMENT [22] Williamson Synthesis of Ethers: Propyl p-Tolyl Ether and Methyl p-Ethylphenyl Ether 325

Experiment [22A] Propyl p-Tolyl Ether 327 Optional Macroseale Preparation

Experiment [22B] Methyl p-Ethylphenyl Ether 331 Optional Semimicroscale and Macroseale Preparations

EXPERIMENT [23] Amide Synthesis: Acetanilide and JV,iV'-Diacetyl-1,4-phenylenediamine 339

Experiment [23A] Acetanilide 342 Optional Semimicroscale Preparation

Experiment [23B] N,N'-Diacetyl-1,4-phenylenediamine 344

EXPERIMENT [24] Imide Synthesis: N-Phenylmaleimide 347

Experiment [24A] Maleanilic Acid 349 Experiment [24B] N-Phenylmaleimide 351

EXPERIMENT [25] Synthesis of Cyclic Carboxylic Acid Anhydrides: Succinic Anhydride and Phthalic Anhydride 353

Experiment [25A] Succinic Anhydride 355 Experiment [25B] Phthalic Anhydride 356

EXPERIMENT [26] Diazonium Coupling Reaction: Methyl Red 358

Contents

EXPERIMENT [27] Friedel-Crafts Acylation: Acetylferrocene and Diacetylferrocene

EXPERIMENT [28] Halogenation: Electrophilic Aromatic Substitution to Yield 4-Bromoacetaniiide

EXPERIMENT [29] Nitration: 2,5-Dichloronitrobenzene; N,N' -Diacety!-2,3-dinitro-1,4-phenylenediamine; 5-Nitrosalicylic Acid; and 2- and 4-Nitrophenol

Semimicroscale Preparation of Anhydrous Nitric Acid Experiment [29A] 2,5-Dichloronitrobenzene Experiment [29B] A/,N'-Diacetyl-2,3-dinitro-1,4-

phenylenediamine Experiment [29C] 5-Nitrosalicylic Acid Experiment [29D] 2- and 4-Nitrophenol

EXPERIMENT [30] Nucleophilic Aromatic Substitution: 2,4-Dinitrophenyithiocyanate

EXPERIMENT [31 ] Halogenation Using JV-Bromosucdnimide: 9-Bromoanthracene

EXPERIMENT [32] Hypochlorite Oxidation of an Alcohol: Cyclohexanone

EXPERIMENT [33] Chromium Trioxide-Resin Oxidation of an Alcohol: 9-Fluorenone; Conversion to the 2,4-Dinitrophenylhydrazone 400

Experiment [33A] 9-Fluorenone 402 Experiment [33B] 9-Fluorenone 2,4-Dinitrophenylhydrazone 403

EXPERIMENT [34] Hypochlorite Oxidation of Methyl Ketones by the Haloform Reaction: Benzoic Acid and p-Methoxybenzoic Acid 405

Experiment [34A] Benzoic Acid 407

Experiment [34B] p-Methoxybenzoic Acid 408 Optional Semimicroscale Preparation

EXPERIMENT [35] Photochemical Isomerization: c/s-Azobenzene 411

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376 378 379

380 382 384

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CHAFTER 7 ADVANCED MICROSCALE ORGANIC LABORATORY EXPERIMENTS 415

Introduction 415

EXPERIMENT [ladv] Diborane Reductions: Thioxanthene and Xanthene 416

Experiment [ 1 Aadv] Thioxanthene 419 Experiment [ 1 Badv] Xanthene 420

EXPERIMENT [2adv] Heterocyclic Ring Synthesis: Benzimidazole 425 EXPERIMENT [3adv] Heterocyclic Ring Synthesis:

4-Hydroxycoumarin and Dicoumarol 428 Experiment [3Aadv] 4-Hydroxycoumarin 431 Experiment [3Badv] Dicoumarol 433

EXPERIMENT [4adv] Grignard and Aryl Halide Cross-Coupling Reaction: l-Methyl-2-(methyl-d3)-benzene 435

EXPERIMENT [5adv] Oxidative Coupling of 2-Naphthol: l,i '-BI-2 Naphthol 442

EXPERIMENT [6adv] Beckmann Rearrangement: Benzanilide 446

Contents XXXI

EXPERIMENT [7adv] Preparation of an Enol Acetate: ChoIesta~3,5-dien-3-ol Acetate 453

Introduction 459 CHAPTER 8 SEQUENCE A The Synthesis of Hexaphenylbenzene 462 SEQUENTIAL SYNTHESES:

Experiment [Ala] The Benzoin Condensation of T H E T R A N S I T I O N F R O M Benzaldehyde: Benzoin 468 MACRO TO MICRO

Semimicroscale Preparation and Optional Microscale Preparations

Experiment [A2a] Copper(II) Ion Oxidation of Benzoin: Benzil 473 Semimicroscale Preparation and Optional Microscale Preparation

Experiment [A3a] Tetraphenylcyclopentadienone 478 Optional Microscale Preparation

Experiment [AIb] (£)-Stilbene 482 Semimicroscale Preparation

Experiment [A2b] Bromination of (E)-Stilbene: meso-Stilbene Dibromide 485

Semimicroscale Preparation and Optional Macroseale and Microscale Preparations

Experiment [A3b] Dehydrohalogenation of meso-Stilbene Dibromide: Diphenylacetylene 490

Semimicroscale Preparation and Optional Macroseale and Microscale Preparations

Experiment [A4ab] Hexaphenylbenzene 494 SEQUENCE B The Stepwise Synthesis of Nylon-6,6 497

Experiment [B1 ] Oxidation of Cyclohexanol: Adipic Acid 499 Macroseale Preparation

Experiment [B2] Preparation of an Acid Chloride: Adipoyl Chloride 502

Semimicroscale Preparation Experiment [B3] Preparation of a Polyamide: Nylon-6,6 505

SEQUENCE C The Synthesis of Sulfanilamide 507 Experiment [C1 ] Acetylation of Aniline:

2,2,2-Trifluoroacetanilide 508 Semimicroscale Preparation

Experiment [C2] Chlorosulfonation of 2,2,2-Trifluoroacetanilide: p-(Trifluoroacetamido)benzenesulfonyl Chloride 512

Semimicroscale Preparation Experiment [C3] Preparation of an Arene Sulfonamide:

Sulfanilamide 515 Semimicroscale Preparation

SEQUENCE D The Synthesis of 2 -Bromostyrene 518 Experiment [DI ] The Verley-Doebner Modifcation of the

Knoevenagel Reaction: frans-Cinnamic Acid 521 Semimicroscale Preparation

Experiment [D2] Bromination of frans-Cinnamic Acid: e/yf/7ro-2,3-Dibromo-3-phenylpropanoic Acid 525

Semimicroscale Preparation

XXXII Contents

Experiment [D3] An Elimination Reacton with e/yf/iro-2,3-Dibromo-3-phenylpropanoic Acid: 2'-Bromostyrene

Semimicroscale Preparation SEQUENCE E The Synthesis of Piperonylonitrile from Piperonyl

Alcohol Experiment [El] Piperonal

Macroseale Preparation and Optional Microscale Preparations

Experiment [E2] Piperonal 0-(2,4-Dinitrophenyl)oxime Semimicroscale Preparation and Optional Microscale Preparation

Experiment [E3] Piperonylonitrile SEQUENCE F Introduction of Photochromism: The Synthesis of a

Photochromic Imine 553 Experiment [Fl] An Aldol Reaction: frar?s-4-Nitrochalcone 557

Semimicroscale Preparation

Experiment [F2] e/yf/7ro-2,3-Dibromo-3-(4-nitrophenyl)propiophenone 562

Semimicroscale Preparation

Experiment [F3] rrans-2-(4-Nitrophenyl)-3-benzoylaziridine 568 Semimicroscale Preparation

Experiment [F4] A Photochromic lmine: 2-exo-6-exo-2,4-Diphenyl-6-(4-nitrophenyl)-1,3-diazabicyclo[3.1.0]hex-3-ene 576

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536 538

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CHAPTER 9 SPECTROSCOPIC IDENTIFICATION OF ORGANIC COMPOUNDS 585

INTRODUCTION TO INFRARED SPECTROSCOPY 585 Molecular Energy 587 Molecular Vibrations 587

Quantized Vibrational Energy 589 Selection Rules 590

The Case of Water 591 The Case of Carbon Dioxide 591

Vibrational Coupling 592

Coupled Oscillators 592 Second-Order Coupling 593

INTRODUCTION TO GROUP FREQUENCIES: Interpretation of Infrared Spectra 594

Group Frequencies of the Hydrocarbons 594 Characteristic Group Frequencies of Alkanes 594 Characteristic Group Frequencies of Alkenes 599 Characteristic Group Frequencies of Alkynes 602 Characteristic Group Frequencies of Arenes 603 Group Frequencies of the Phenyl Group 603

Factors Affecting Carbonyl Group Frequencies 606 Mass Effects 606 Geometrie Effects 607 Electronic Effects (Resonance and Inductive) 607 Interaction Effects 609

Contents XXXIII

Characteristic Frequencies of Functional Groups 613

Strategies for Interpreting lnfrared Spectra 629 INFRARED SPECTROSCOPY: Instrumentation and Sample Handling 630 Instrumentation 631 Sample Handling in the lnfrared 634

Liquid Samples 634 Solution Spectra and Spectra of Materials Boiling Below 100°C 635 Solid Samples 635

NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY: Introduction to Nuclear Magnetic Resonance 644

Nuclear Spin

Instrumentation

Chemical Shift

Spin-Spin Coupling

Intensities

Second-Order Effects

INTERPRETATION OF 'H NMR SPECTRA

'H Chemical Shifts

Spin-Spin Coupling

Geminal Coupling

Vicinal Coupling

Long-Range Coupling

Examples of Complex, Yet First-Order, Coupling

Ethyl Vinyl Ether

Allyl Acetate ,3C NMR SPECTROSCOPY

TWO-DIMENSIONAL NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY

NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY SAMPLING

ULTRAVIOLET-VISIBLE SPECTROSCOPY: Introduction to Absorption Spectroscopy

UV-VS Spectroscopy

Applications to Organic Molecules

Instrumentation

Sample Preparation

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ORGANIC QUALITATIVE ANALYSIS 693 CHAPTER 1 0 Preliminary Tests 695 QUALITATIVE Separation of Impurites 698 IDENTIFICATION OF Detection of Elements Other Than Carbon, Hydrogen, and Oxygen 698 ORGANIC C O M P O U N D S Solubility Characteristics 702 693 The Classification Tests 704 PREPARATION OF DERIVATIVES 718

Carboxylic Acids 718 Alcohols 720 Aldehydes and Ketones 721

xxxiv Contents

Amines 722 Acid Chlorides and Anhydrides 723 Aromatic Hydrocarbons 724 Nitriles 724 Phenols 724 Aliphatic Hydrocarbons, Halogenated Hydrocarbons, Amides, Nitro

Compounds, Ethers, and Esters 725

APPENDIX A

TABLES OF DERIVATIVES 729

APPENDIX B CHAFTERS 6, 7 AND 8: EXPERIMENTS CLASSIFIED BY MECHANISM 743

GLOSSARY 751

INDEX 755