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Microscale Organic Laboratory with Multistep and Multiscale Syntheses T H I R D E D I T I O N
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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
11
13
13
CHAPTER 2 SAFETY
5
XXV
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
44
44
47
48
50
50
53
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
364
370
376 378 379
380 382 384
388
392
396
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
530
536 538
543
548
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
644
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653
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656
657
657
658
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669
671
676
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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