Microscale Organic
Laboratory
with Multistep and Multiscale Syntheses
THIRD
EDITION
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Dana W. Mayo
Ronald M. Pike
Peter K. Trumper
John Wiley *L Sons, Inc.
New York
Chichester
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Charles Weston Pickard
Research Professor of Chemistry
Bowdoin College
Professor of Chemistry, Emeritus
Merrimack College
Professor of Chemistry
University of Southern Maine
Brisbane
Toronto
Singapore
Contents
General Ruies for the Microscaie Laboratory
The Organic Chemistry Laboratory
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CHAPTER 1
4
INTRODUCTION
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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
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CHAPTER
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SAFETY
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CHAPTER
Contents
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INTRODUCTION TO
MICROSCALE ORGANIC
LABORATORY EQUIPMENT
AND TECHNIQUES
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CHAPTER 4
DETERMINATION OF
PHYSICAL PROPERTIES
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CHAPTER
5
DEVELOPMENT OF
MICROSCALE TECHNIQUES
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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
LIQUIDS
Ultramicro-Boiling Point
Density
Refractive Index
SOLIDS
Melting Points
Mixture Melting Points
TECHNIQUE 1 Microscale Separation of Liquid Mixtures by
Preparative Gas Chromatography
Introduction
Procedure for Preparative Collection
TECHNIQUE 2 Semimicroscale Distillation
Introduction
Distillation Theory
Technique 2A Simple Distillation at the Microscale Level
Technique 2B Fractional Distillation at the Semimicroscale
Level
TECHNIQUE 3 Steam Distillation
Theory
TECHNIQUE 4 Solvent Extraction
Solubility
Partition Coefficient
Extraction
Solid-Liquid Extraction
Liquid—Liquid Extraction
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Contents
Separatory Funnel Extraction
Continuous Liquid-Liquid Extraction
Drying of the Wet Organic Layer
Separation of Acids and Bases
Salting Out
Solid-Phase Extraction
TECHNIQUE 5 Crystallization
Procedure
Simple Crystallization
Filtration Techniques
Use of the Hirsch Funnel
Craig Tube Crystallizations
Recrystallization Pipet
TECHNIQUE 6 Chromatography
Technique 6A Column, High-Performance Liquid, and
Thin-Layer Chromatography
Column Chromatography
Packing the Column
Sample Application
Elution of the Column
Fraction Collection
Flash Chromatography
Thin-Layer Chromatography
High-Performance Liquid Chromatography
Technique 6B Concentration of Solutions
Distillation
Evaporation with Nitrogen Gas
Removal of Solvent Under Reduced Pressure
TECHNIQUE 7 Collection and Control of Gaseous Products
TECHNIQUE 8 Measurement Of Specific Rotation
Optical Rotation Theory
The Polarimeter
TECHNIQUE 9 Sublimation
Sublimation Theory
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
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CHAPTER
6
MICROSCALE ORGANIC
LABORATORY EXPERIMENTS
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Contents
Experiment [3C] Fractional Semimicroscale Distillation:
Separation of 2-Methylpentane and Cyclohexane Using a
Spinning Band Column
Experiment [3D] Fractional Semimicroscale Distillation: The
Separation of 2-Methylpentane and Cyclohexane Using a
Spinning Band in a Hickman-Hinkle Still
EXPERIMENT [4] Solvent Extraction
Experiment [4A] Determination of a Partition Coefficient for
the System Benzoic Acid, Methylene Chloride, and Water
Experiment [4B] Solvent Extraction I: The System; Benzoic
Acid, Methylene Chloride, and 10% Sodium Bicarbonate
Solution; An Example of Acid-Base Extraction Techniques
Experiment [4C] Solvent Extraction II: A Three Component
Mixture; An Example of the Separation of an Acid, a Base,
and a Neutral Substance
EXPERIMENT [5] Reduction of Ketones Using a Metal Hydride
Reagent: Cyclohexanol and eis- and
frans-4-tert-Butylcyclohexanol
Experiment [5A] Cyclohexanol
Experiment [5B] eis- and trans-4-tert-Butylcyclohexanol
EXPERIMENT [6] Photochemical Isomerization of an Alkene:
c/s-1,2-Dibenzoylethylene
Experiment [6A] Purification of frans-1,2-Dibenzoylethylene
Experiment [6B] Isomerization of an Alkene: Thin-Layer
Chromatographie Analysis
Experiment [6C] Isomerization of an Alkene: Nuclear
Magnetic Resonance Analysis
EXPERIMENT [7] The Cannizzaro Reaction with
4-Chlorobenzaldehyde: 4-Chlorobenzoic Acid and
4-ChlorobenzyI Alcohol
EXPERIMENT [8] The Esterification Reaction: Ethyl Laurate,
Isopentyl Acetate, and the Ilse of Acidic Resins
Experiment [8A] Ethyl Laurate
Experiment [8B] Isopentyl Acetate
Semimicroscale Preparation
Experiment [8C] Esterification by Acidic Resins
Semimicroscale Preparations
EXPERIMENT [9] The EI Elimination Reaction: Dehydration of
2-Butanol to Yieid 1-Butene, frans-2-Butene, and
c/s-2-Butene
EXPERIMENT [10] The E2 Elimination Reaction:
Dehydrohaiogenation of 2-Bromobutane to Yield
1-Butene, frans-2-Butene, and c/s-2-Butene
EXPERIMENT [11] The Isolation of Natural Products
Experiment [IIA] Isolation and Characterization of an
Optically Active Natural Product: Usnic Acid
Experiment [IIB] Isolation and Characterization of a Natural
Product: Caffeine and Caffeine 5-Nitrosalicylate
Experiment [ 11C] Isolation of a Natural Product by Steam
Distillation: Cinnamaldehyde from Cinnamon
EXPERIMENT [12] Reductive Catalytic Hydrogenation of an
Alkene: Octane
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EXPERIMENT [13] Hydroboration-Oxidation of an Alkene:
Octanol
EXPERIMENT [ 14] Diels-Alder Reaction:
4-Cyclohexene-c/s-l,2-dicarboxyIic Acid Anhydride
Optional Semimicroscale Preparation
EXPERIMENT [15] Diels-Alder Reaction:
9,10-Dihydroanthracene-9,10-a,/3-sucdnic Acid
Anhydride
Optional Semimicroscale and Macroseale Preparations
EXPERIMENT [16] Grignard Reaction with a Ketone:
Triphenylmethanol
EXPERIMENT [ 17] Grignard Reaction with an Aldehyde:
4-Methyl-3-heptanol
EXPERIMENT [18] The Perkin Reaction: Condensation of
Rhodanine with an Aromatic Aldehyde to Yield
o-Chlorobenzylidene Rhodanine
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
Experiment [ 19A] (£)-Stilbene by the "Instant Ylide" Method
Experiment [19B] (£)-Stilbene by the Homer-WadsworthEmmons Reaction
Experiment [ 19C] Methylene-4-rerf-butylcyclohexane
Experiment [ 19D] frans-9-(2-Phenylethenyl)anthracene
EXPERIMENT [20] Aldo! Reaction: Dibenzalacetone
Optional Semimicroscale Preparation
EXPERIMENT [21 ] Quantitative Analysis of Grignard Reagents:
1 -Methylbutylmagnesium Bromide and Phenylmagnesium
Bromide
Part 1 1 -Methylbutylmagnesium Bromide
Part 2 Phenylmagnesium Bromide
EXPERIMENT [22] Williamson Synthesis of Ethers: Propyl p-Tolyl
Ether and Methyl p-Ethylphenyl Ether
Experiment [22A] Propyl p-Tolyl Ether
Optional Macroseale Preparation
Experiment [22B] Methyl p-Ethylphenyl Ether
Optional Semimicroscale and Macroseale Preparations
EXPERIMENT [23] Amide Synthesis: Acetanilide and
JV,iV'-Diacetyl-1,4-phenylenediamine
Experiment [23A] Acetanilide
Optional Semimicroscale Preparation
Experiment [23B] N,N'-Diacetyl-1,4-phenylenediamine
EXPERIMENT [24] Imide Synthesis: N-Phenylmaleimide
Experiment [24A] Maleanilic Acid
Experiment [24B] N-Phenylmaleimide
EXPERIMENT [25] Synthesis of Cyclic Carboxylic Acid
Anhydrides: Succinic Anhydride and Phthalic Anhydride
Experiment [25A] Succinic Anhydride
Experiment [25B] Phthalic Anhydride
EXPERIMENT [26] Diazonium Coupling Reaction: Methyl Red
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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-1,4phenylenediamine
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
Experiment [33A] 9-Fluorenone
Experiment [33B] 9-Fluorenone 2,4-Dinitrophenylhydrazone
EXPERIMENT [34] Hypochlorite Oxidation of Methyl Ketones by
the Haloform Reaction: Benzoic Acid and
p-Methoxybenzoic Acid
Experiment [34A] Benzoic Acid
Experiment [34B] p-Methoxybenzoic Acid
Optional Semimicroscale Preparation
EXPERIMENT [35] Photochemical Isomerization: c/s-Azobenzene
CHAFTER
7
ADVANCED MICROSCALE
ORGANIC LABORATORY
EXPERIMENTS
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Introduction
EXPERIMENT [l a d v ] Diborane Reductions: Thioxanthene and
Xanthene
Experiment [ 1 Aadv] Thioxanthene
Experiment [ 1 Badv] Xanthene
EXPERIMENT [2 adv ] Heterocyclic Ring Synthesis: Benzimidazole
EXPERIMENT [3 adv ] Heterocyclic Ring Synthesis:
4-Hydroxycoumarin and Dicoumarol
Experiment [3Aadv] 4-Hydroxycoumarin
Experiment [3Badv] Dicoumarol
EXPERIMENT [4adv] Grignard and Aryl Halide Cross-Coupling
Reaction: l-Methyl-2-(methyl-d3)-benzene
EXPERIMENT [5adv] Oxidative Coupling of 2-Naphthol:
l,i'-BI-2 Naphthol
EXPERIMENT [6 adv ] Beckmann Rearrangement: Benzanilide
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EXPERIMENT [7 adv ] Preparation of an Enol Acetate:
ChoIesta~3,5-dien-3-ol Acetate
Introduction
SEQUENCE A The Synthesis of Hexaphenylbenzene
Experiment [Al a ] The Benzoin Condensation of
Benzaldehyde: Benzoin
Semimicroscale Preparation and Optional Microscale
Preparations
Experiment [A2a] Copper(II) Ion Oxidation of Benzoin: Benzil
Semimicroscale Preparation and Optional Microscale
Preparation
Experiment [A3a] Tetraphenylcyclopentadienone
Optional Microscale Preparation
Experiment [AI b ] (£)-Stilbene
Semimicroscale Preparation
Experiment [A2b] Bromination of (E)-Stilbene: meso-Stilbene
Dibromide
Semimicroscale Preparation and Optional Macroseale and
Microscale Preparations
Experiment [A3b] Dehydrohalogenation of meso-Stilbene
Dibromide: Diphenylacetylene
Semimicroscale Preparation and Optional Macroseale and
Microscale Preparations
Experiment [A4ab] Hexaphenylbenzene
SEQUENCE B The Stepwise Synthesis of Nylon-6,6
Experiment [B1 ] Oxidation of Cyclohexanol: Adipic Acid
Macroseale Preparation
Experiment [B2] Preparation of an Acid Chloride: Adipoyl
Chloride
Semimicroscale Preparation
Experiment [B3] Preparation of a Polyamide: Nylon-6,6
SEQUENCE C The Synthesis of Sulfanilamide
Experiment [C1 ] Acetylation of Aniline:
2,2,2-Trifluoroacetanilide
Semimicroscale Preparation
Experiment [C2] Chlorosulfonation of
2,2,2-Trifluoroacetanilide:
p-(Trifluoroacetamido)benzenesulfonyl Chloride
Semimicroscale Preparation
Experiment [C3] Preparation of an Arene Sulfonamide:
Sulfanilamide
Semimicroscale Preparation
SEQUENCE D The Synthesis of 2 -Bromostyrene
Experiment [DI ] The Verley-Doebner Modifcation of the
Knoevenagel Reaction: frans-Cinnamic Acid
Semimicroscale Preparation
Experiment [D2] Bromination of frans-Cinnamic Acid:
e/yf/7ro-2,3-Dibromo-3-phenylpropanoic Acid
Semimicroscale Preparation
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CHAPTER 8
S E Q U E N T I A L SYNTHESES:
THE TRANSITION FROM
MACRO TO MICRO
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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
Experiment [Fl] An Aldol Reaction: frar?s-4-Nitrochalcone
Semimicroscale Preparation
Experiment [F2] e/yf/7ro-2,3-Dibromo-3(4-nitrophenyl)propiophenone
Semimicroscale Preparation
Experiment [F3] rrans-2-(4-Nitrophenyl)-3-benzoylaziridine
Semimicroscale Preparation
Experiment [F4] A Photochromic lmine: 2-exo-6-exo-2,4Diphenyl-6-(4-nitrophenyl)-1,3-diazabicyclo[3.1.0]hex-3-ene
CHAPTER 9
SPECTROSCOPIC
IDENTIFICATION OF
ORGANIC COMPOUNDS
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INTRODUCTION TO INFRARED SPECTROSCOPY
Molecular Energy
Molecular Vibrations
Quantized Vibrational Energy
Selection Rules
The Case of Water
The Case of Carbon Dioxide
Vibrational Coupling
Coupled Oscillators
Second-Order Coupling
INTRODUCTION TO GROUP FREQUENCIES: Interpretation of
Infrared Spectra
Group Frequencies of the Hydrocarbons
Characteristic Group Frequencies of Alkanes
Characteristic Group Frequencies of Alkenes
Characteristic Group Frequencies of Alkynes
Characteristic Group Frequencies of Arenes
Group Frequencies of the Phenyl Group
Factors Affecting Carbonyl Group Frequencies
Mass Effects
Geometrie Effects
Electronic Effects (Resonance and Inductive)
Interaction Effects
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Characteristic Frequencies of Functional Groups
Strategies for Interpreting lnfrared Spectra
INFRARED SPECTROSCOPY: Instrumentation and Sample Handling
Instrumentation
Sample Handling in the lnfrared
Liquid Samples
Solution Spectra and Spectra of Materials Boiling Below 100°C
Solid Samples
NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY:
Introduction to Nuclear Magnetic Resonance
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Nuclear Spin
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Instrumentation
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Chemical Shift
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Spin-Spin Coupling
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Intensities
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Second-Order Effects
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INTERPRETATION OF 'H NMR SPECTRA
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'H Chemical Shifts
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Spin-Spin Coupling
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Geminal Coupling
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Vicinal Coupling
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Long-Range Coupling
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Examples of Complex, Yet First-Order, Coupling
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Ethyl Vinyl Ether
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Allyl Acetate
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C NMR SPECTROSCOPY
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TWO-DIMENSIONAL NUCLEAR MAGNETIC RESONANCE
SPECTROSCOPY
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NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY SAMPLING
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ULTRAVIOLET-VISIBLE SPECTROSCOPY: Introduction to
Absorption Spectroscopy
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UV-VS Spectroscopy
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Applications to Organic Molecules
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Instrumentation
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Sample Preparation
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ORGANIC QUALITATIVE ANALYSIS
Preliminary Tests
Separation of Impurites
Detection of Elements Other Than Carbon, Hydrogen, and Oxygen
Solubility Characteristics
The Classification Tests
PREPARATION OF DERIVATIVES
Carboxylic Acids
Alcohols
Aldehydes and Ketones
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CHAPTER 1 0
QUALITATIVE
IDENTIFICATION OF
ORGANIC C O M P O U N D S
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Contents
Amines
Acid Chlorides and Anhydrides
Aromatic Hydrocarbons
Nitriles
Phenols
Aliphatic Hydrocarbons, Halogenated Hydrocarbons, Amides, Nitro
Compounds, Ethers, and Esters
APPENDIX
A
TABLES OF DERIVATIVES
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APPENDIX B
CHAFTERS 6, 7 AND 8:
EXPERIMENTS CLASSIFIED
BY MECHANISM
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GLOSSARY
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INDEX
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