Applied Organic Chemistry E-Book

Surya K. De

• Herausgeber: Wiley-VCH GmbH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 876

Veröffentlichungsjahr: 2020

Beschreibung

An indispensable guide for all synthetic chemists who want to learn about the most relevant reactions and reagents employed to synthesize important heterocycles and drugs!

The synthesis of natural products, bioactive compounds, pharmaceuticals, and drugs is of fundamental interest in modern organic chemistry. New reagents and reaction methods towards these molecules are being constantly developed. By understanding the mechanisms involved and scope and limitations of each reaction applied, organic chemists can further improve existing reaction protocols and develop novel efficient synthetic routes towards frequently used drugs, such as Aspirin or Penicillin.

Applied Organic Chemistry provides a summary of important (name) reactions and reagents applied in modern organic chemistry and drug synthesis. It covers rearrangement, condensation, olefination, metathesis, aromatic electrophilic substitutions, Pd-catalyzed C-C bond forming reactions, multi-component reactions, as well as oxidations and reductions. Each chapter is clearly structured, providing valuable information on reaction details, step-by-step mechanism, experimental procedures, applications, and (patent) references. By providing mechanistic information and representative experimental procedures, this book is an indispensable guide for researchers and professionals in organic chemistry, natural product synthesis, pharmaceutical, and medicinal chemistry, as well as post-graduates preparing themselves for a job in the pharmaceutical industry.

• Hot Topic: Reviews important classes of organic reactions (incl. name reactions) and reagents in medicinal chemistry.
• Useful: Provides information on reaction details, common reagents, and functional group transformations used to synthesize natural products, bioactive compounds, drugs, and pharmaceuticals, e.g. Aspirin, Penicillin.
• Unique: For every reaction the mechanism is explained step by step, and representative experimental procedures are given, unlike most books in this area.
• User-friendly: Chapters are clearly structured making it easy for the reader to compare different reactions.

Applied Organic Chemistry is an indispensable guide for researchers and professionals in organic chemistry, natural product synthesis, pharmaceutical, and medicinal chemistry, as well as post-graduates preparing themselves for a job in the pharmaceutical industry.

Leseprobe

Table of Contents

Cover

Applied Organic Chemistry

Copyright

Preface

About the Book

About the Author

Acknowledgments

List of Abbreviations

References

List of Cooling Baths

Further Reading

1 Rearrangement Reactions

Baeyer–Villiger Oxidation or Rearrangement

Dakin Oxidation (Reaction)

Bamberger Rearrangement

Beckmann Rearrangement

Benzilic Acid Rearrangement

Baker–Venkataraman Rearrangement

Claisen Rearrangement

Eschenmoser–Claisen Rearrangement

Ireland–Claisen Rearrangement

Johnson–Claisen Rearrangement

Overman Rearrangement

Cope Rearrangement

Curtius Rearrangement

Demjanov Rearrangement

Tiffeneau–Demjanov Rearrangement

Fries Rearrangement

Favorskii Rearrangement

Fischer–Hepp Rearrangement

Hofmann Rearrangement (Hofmann degradation of amide)

Hofmann–Martius Rearrangement

Lossen Rearrangement

Orton Rearrangement

Pinacol–Pinacolone Rearrangement

Rupe Rearrangement/Meyer–Schuster Rearrangement

Schmidt Rearrangement or Schmidt Reaction

Wagner–Meerwein Rearrangement

Wolff Rearrangement

Arndt–Eistert Homologation or Synthesis

Zinin Rearrangement or Benzidine and Semidine Rearrangements

References

Dakin Oxidation or Reaction

Bamberger Rearrangement

Beckmann Rearrangement

Benzilic Acid Rearrangement

Baker–Venkataraman Rearrangement

Claisen Rearrangement/Eschenmoser–Claisen Rearrangement/Ireland–Claisen Rearrangement/Johnson–Claisen Rearrangement/Overman Rearrangement

Cope Rearrangement

Curtius Rearrangement

Demjanov Rearrangement

Tiffeneau–Demjanov Rearrangement

Fries Rearrangement

Favorskii Rearrangement

Fischer–Hepp Rearrangement

Hofmann Rearrangement (Hofmann Degradation of Amide)

Hofmann–Martius Rearrangement

Lossen Rearrangement

Orton Rearrangement

Pinacol–Pinacolone Rearrangement

Rupe Rearrangement/Meyer–Schuster Rearrangement

Schmidt Rearrangement or Schmidt Reaction

Wagner–Meerwein Rearrangement

Wolff Rearrangement

Arndt–Eistert Homologation or Synthesis

Zinin Rearrangement or Benzidine and Semidine Rearrangements

2 Condensation Reaction

Aldol Condensation Reaction

Mukaiyama Aldol Reaction

Evans Aldol Reaction

Henry Reaction

Benzoin Condensation

Claisen Condensation

Darzens Glycidic Ester Condensation

Dieckmann Condensation

Knoevenagel Condensation

Pechmann Condensation (synthesis of coumarin) (also called von Pechmann condensation)

Perkin Condensation or Reaction

Stobbe Condensation

References

Mukaiyama Aldol Reaction

Evans Aldol Reaction

Henry Reaction

Benzoin Condensation

Claisen Condensation

Darzens Glycidic Ester Condensation

Dieckmann Condensation

Knoevenagel Condensation

Pechmann Condensation

Perkin Condensation or Reaction

Stobbe Condensation

3 Olefination, Metathesis, and Epoxidation Reactions

Olefination

Horner–Wadsworth–Emmons Reaction

Julia–Lythgoe Olefination

Julia–Kocienski Olefination

Kauffmann Olefination

Peterson Olefination

Petasis Olefination

Tebbe Olefination

Wittig Reaction or Olefination

Metathesis

Asymmetric Epoxidation

Sharpless Asymmetric Aminohydroxylation

Woodward cis‐Dihydroxylation

Prévost trans‐Dihydroxylation Reaction

References

Horner–Wadsworth–Emmons Reaction

Julia–Lythgoe Olefination

Julia–Kocienski Olefination

Kauffmann Olefination

Peterson Olefination

Petasis Olefination

Tebbe Olefination

Wittig Reaction or Olefination

Metathesis

Sharpless Asymmetric Epoxidation

Jacobsen–Katsuki Asymmetric Epoxidation

Shi Asymmetric Epoxidation

Sharpless Asymmetric Dihydroxylation

Sharpless Asymmetric Aminohydroxylation

Woodward cis‐Dihydroxylation

Prévost trans‐Dihydroxylation Reaction

4 Miscellaneous Reactions

Alder‐Ene Reaction

Appel Reaction

Barton Decarboxylation

Barton Nitrite Photolysis (Barton nitrite ester reaction)

Brown Hydroboration

Bucherer Reaction

Chichibabin Reaction

Chugaev Elimination Reaction

Cannizzaro Reaction

Cope Elimination Reaction

Corey–Fuchs Reaction

Corey–Nicolaou Macrolactonization

Danheiser Annulation

Danheiser Benzannulation

Diels–Alder Reaction

Dutt–Wormall Reaction

Étard Reaction

Finkelstein Reaction

Fischer–Speier Esterification

Mukaiyama Esterification

Yamaguchi Esterification

Grignard Reaction

Gabriel Synthesis

Hell–Volhard–Zelinsky Reaction

Hofmann Elimination or Exhaustive Methylation

Hosomi–Sakurai Reaction

Huisgen Cycloaddition Reaction

Hunsdiecker Reaction

Keck Asymmetric Allylation

Thionation Reaction (Lawesson's Reagent)

Michael Addition or Reaction

Mitsunobu Reaction

Morita–Baylis–Hillman Reaction (Baylis–Hillman Reaction)

Nozaki–Hiyama–Kishi Reaction

Paterno–Büchi Reaction

Pauson–Khand Reaction

Reformatsky Reaction

Ritter Reaction

Robinson Annulation

Sandmeyer Reaction

Schotten–Baumann Reaction

Simmons–Smith Reaction

Stork Enamine Synthesis

Tishchenko Reaction

Ullmann Coupling or Biaryl Synthesis

Ullmann Biaryl Ether and Biaryl Amine Synthesis/Ullman Condensation

Weinreb Ketone Synthesis

Williamson Ether Synthesis

Wurtz Coupling or Reaction

Wurtz–Fittig Reaction

References

Appel Reaction

Barton Decarboxylation

Barton Nitrite Photolysis (Barton Nitrite Ester Reaction)

Brown Hydroboration

Bucherer Reaction

Chichibabin Reaction

Chugaev Elimination Reaction

Cannizzaro Reaction

Cope Elimination Reaction

Corey–Fuchs Reaction

Corey–Nicolaou Macrolactonization

Danheiser Annulation/Danheiser Benzannulation

Diels–Alder Reaction

Dutt–Wormall Reaction

Étard Reaction

Finkelstein Reaction

Fischer–Speier Esterification

Mukaiyama Esterification

Yamaguchi Esterification

Grignard Reaction

Gabriel Synthesis

Hell–Volhard–Zelinsky Reaction

Hofmann Elimination or Exhaustive Methylation

Hosomi–Sakurai Reaction

Huisgen Cycloaddition Reaction/Click Chemistry

Hunsdiecker Reaction

Keck Asymmetric Allylation

Thionation Reaction (Lawesson's Reagent)

Michael Addition or Reaction

Mitsunobu Reaction

Morita–Baylis–Hillman Reaction (Baylis–Hillman Reaction)

Nozaki–Hiyama–Kishi Reaction

Paterno–Büchi Reaction

Pauson–Khand Reaction

Reformatsky Reaction

Ritter Reaction

Robinson Annulation

Sandmeyer Reaction

Schotten–Baumann Reaction

Simmons–Smith Reaction

Stork Enamine Synthesis

Tishchenko Reaction

Ullmann Coupling or Biaryl Synthesis

Ullmann Biaryl Ether and Biaryl Amine Synthesis/Ullman Condensation

Weinreb Ketone Synthesis

Williamson Ether Synthesis

Wurtz Coupling or Reaction

Wurtz–Fittig Reaction

5 Aromatic Electrophilic Substitution Reactions

Bardhan–Sengupta Synthesis

Bogert–Cook Reaction or Synthesis of Phenanthrene

Friedel–Crafts Reaction

Gattermann Aldehyde Synthesis

Gattermann–Koch Aldehyde Synthesis

Haworth Reaction

Houben–Hoesch Reaction

Kolbe–Schmitt Reaction

Reimer–Tiemann Reaction

Vilsmeier–Haack Reaction

References

Bogert–Cook Reaction or Synthesis of Phenanthrene

Friedel–Crafts Reaction

Gattermann Aldehyde Synthesis

Gattermann–Koch Aldehyde Synthesis

Haworth Reaction

Houben–Hoesch Reaction

Kolbe–Schmitt Reaction

Reimer–Tiemann Reaction

Vilsmeier–Haack Reaction

6 Pd‐Catalyzed CC Bond‐Forming Reactions

Suzuki Coupling Reaction

Heck Coupling Reaction (Mizoroki–Heck Reaction)

Negishi Coupling Reaction

Stille Coupling Reaction (Migita–Kosugi–Stille Coupling Reaction)

Sonogashira Coupling Reaction

Kumada Cross‐Coupling

Hiyama Coupling Reaction

Liebeskind–Srogl Coupling Reaction

Fukuyama Coupling Reaction

Buchwald–Hartwig Coupling Reaction (Buchwald–Hartwig Amination)

Tsuji–Trost Allylation

References

Heck Coupling Reaction (Mizoroki–Heck Reaction)

Negishi Coupling Reaction

Stille Coupling Reaction (Migita–Kosugi–Stille Coupling Reaction)

Sonogashira Coupling Reaction

Kumada Cross‐Coupling

Hiyama Coupling Reaction

Liebeskind–Srogl Coupling Reaction

Fukuyama Coupling Reaction

Buchwald–Hartwig Coupling Reaction (Buchwald–Hartwig Amination)

Tsuji–Trost Allylation

7 Multicomponent Reaction

Biginelli Reaction (3‐Component Reaction [3‐CR])

Gewald Reaction (3‐Component Reaction [3‐CR])

Hantzsch Pyridine Synthesis

Mannich Reaction

Passerini Reaction (3‐Component Reaction [3‐CR])

Strecker Amino Acid Synthesis

Ugi Reaction (4‐Component Reaction [4‐CR])

Asinger Reaction (4‐Component Reaction [A‐4CR])

References

Gewald Reaction

Hantzsch Pyridine Synthesis

Mannich Reaction

Passerini Reaction

Strecker Amino Acid Synthesis

Ugi Reaction

Asinger Reaction

8 Oxidations and Reductions

Oxidation Reactions

Dess–Martin Oxidation

Jones Oxidation

Swern Oxidation

Pfitzner–Moffatt Oxidation

Tamao–Fleming Oxidation

Tamao–Kumada Oxidation

Oppenauer Oxidation

Riley Oxidation

Ley–Griffith Oxidation

Criegee Oxidation (Criegee Glycol Cleavage)

Criegee Ozonolysis

Reduction Reactions

Bouveault–Blanc Reduction

Clemmensen Reduction

Corey–Bakshi–Shibata Reduction (also known as Itsuno–Corey reduction)

Noyori Asymmetric Hydrogenation

Luche Reduction

Meerwein–Ponndorf–Verley Reduction

Mozingo Reduction

Rosenmund Reduction

Wolff–Kishner Reduction

References

Dess–Martin Oxidation

Jones Oxidation

Swern Oxidation

Pfitzner–Moffatt Oxidation

Tamao–Fleming Oxidation

Tamao–Kumada Oxidation

Oppenauer Oxidation

Riley Oxidation

Ley–Griffith Oxidation

Criegee Oxidation (Criegee Glycol Cleavage)

Criegee Ozonolysis

Birch Reduction

Bouveault–Blanc Reduction

Clemmensen Reduction

Corey–Bakshi–Shibata Reduction (also known as Itsuno–Corey Reduction)

Noyori Asymmetric Hydrogenation

Luche Reduction

Meerwein–Ponndorf–Verley Reduction

Mozingo Reduction

Rosenmund Reduction

Wolff–Kishner Reduction

9 Nomenclature and Application of Heterocyclic Compounds

The Hantzsch–Widman Nomenclature

Common Names

The Replacement Nomenclature

Application of Heterocyclic Compounds

Drugs for Oxirane Derivatives

Drugs for Aziridine Derivatives

Drugs for Azetidine Derivatives

Drugs for Oxetane Derivatives

Drugs for Furan Derivatives

Drugs for Thiophene Derivatives

Drugs for Pyrrole and Pyrrolidine Derivatives

Drugs for Imidazole, Imidazoline, and Imidazolidine Derivatives

Drugs for Triazole Derivatives

Drugs for Isoxazole Derivatives

Drugs for Thiazole Derivatives

Drugs for Pyridine Derivatives

Drugs for Pyrimidine Derivatives

Drugs for Pyrazine Derivatives

Drugs for Piperidine Derivatives

Drugs for Quinoline/Isoquinoline Derivatives

Drugs for Oxazole/Isoxazole/Thiazole/Thiadiazole Derivatives

Drugs for Chromane Derivatives

Drugs for Indole Derivatives

Drugs for Benzimidazole Derivatives

Drugs for Indazole Derivatives

Drugs for Azepin/Diazepine Derivatives

Drugs for Xanthine Derivatives

Drugs for Lactone Derivatives

Drugs for β‐Lactam Derivatives

References

10 Synthesis of Some Heterocyclic Compounds Using Named Reactions

Bartoli Indole Synthesis

Bischler–Napieralski Reaction

Combes Quinoline Synthesis

Conrad–Limpach Synthesis

Doebner–Miller Reaction

Feist–Benary Synthesis of Furan

Fischer Indole Synthesis

Friedländer Synthesis or Annulation

Knorr Pyrrole Synthesis

Madelung Indole Synthesis

Paal–Knorr Furan Synthesis

Paal–Knorr Pyrrole Synthesis

Pictet–Gams Isoquinoline Synthesis

Pictet–Spengler Reaction

Skraup Quinoline Synthesis

References

Bischler–Napieralski Reaction

Combes Quinoline Synthesis

Conrad–Limpach Synthesis

Doebner–Miller Reaction

Feist–Benary Synthesis of Furan

Fischer Indole Synthesis

Friedländer Synthesis or Annulation

Knorr Pyrrole Synthesis

Madelung Indole Synthesis

Paal–Knorr Furan Synthesis

Paal–Knorr Pyrrole Synthesis

Pictet–Gams Isoquinoline Synthesis

Pictet–Spengler Reaction

Skraup Quinoline Synthesis

11 Protection and Deprotection of Common Functional Groups

Amines

Alcohols

For 1,2‐Diols

For 1,3‐Diols

For Phenols

Protection and Deprotection for the Carboxylic Acid Group

Protection and Deprotection of Carbonyl Group

Protection and Deprotection of Terminal Alkyne

References

Alcohols

Protection and Deprotection for the Carboxylic Acid Group

Protection and Deprotection of Carbonyl Group

Protection for the Terminal Alkyne CH

12 Amino Acids and Peptides

Natural Amino Acids

Nonnatural Amino Acids

Solution‐Phase Peptide Synthesis

Solid‐Phase Peptide Synthesis

Cleavage Cocktail

Cleavage Cocktail A

Cleavage Cocktail B

Reagents and conditions

Covalent Peptides

Staple Peptides

Building Blocks for Stapled Peptides (Both L and D Analogs of Amino Acids Are Available)

References

13 Functional Group Transformation

Alcohol to Aldehyde

Secondary Alcohol to Ketone

Primary Alcohol to Carboxylic Acid

1,2‐Diol Oxidation

Alcohol to Fluoride [11,14,15]

Alcohol to Chloride

Alcohol to Bromide

Alcohol to Iodide [13]

Alcohol to Ester

Alcohol to Ether

Alcohol to Sulfonic Ester

Alcohol to Methylene

Alcohol to Azide

Azide to Amine

Aldehyde to Alcohol

Aldehyde to Carboxylic Acid

Aldehyde to Difluoro [14, 15]

Ketone to Alcohol

Ketone to Ester

Ketone to Difluoro [14,15]

Ketone to Methylene

Ketone to Thioketone

Acid (Carboxylic) to Ester

Acid to Amide

Acid to Ketone

Ester to Acid

Ester to Aldehyde

Ester to Alcohol

Ester to Ketone

Nitro to Amine

Alkene to Epoxide

Alkene to Alkane

Alkyne to Alkane

Alkyne to Alkene

Cyano to Carboxylic Acid

Cyano to Amine [16]

Cyano to Amide

Methyl Phenyl Ether to Phenol [17, 18]

Toluene to Benzyl Halides

Alkylbenzene to Benzoic Acid

Aromatic Amine to Azide

Aromatic Halide to Aldehyde [21]

Aromatic Halide to Benzoic Acid [22]

Thioether to Sulfoxide

Thioether to Sulfone

Thiol to Disulfide [23–25]

Unsymmetrical Disulfide

Reductive Amination

Amine to Urea and Thiourea

Urea Formation from Two Amines

References

14 Synthesis of Some Drug Molecules

References

15 Common Laboratory Methods

Acetylation of Alcohol (patent WO2013040068A2)

Deacetylation (patent WO2013040068A2)

Tosylation of Alcohol (patent US9399645B2)

Benzoylation of Alcohol (patent WO2019093776A1)

Pivaloylation of Alcohol (patent WO2019093776A1)

Silylation of Alcohol (patent WO1998008849A1)

Desilylation (patent WO1998008849A1)

Esterification (ester formation)

Ester Formation from Acid and Alcohol (patent US9399645B2)

Carboxylic Acid to Benzyl Ester (patent WO2019134765A1)

Hydrolysis (saponification) of Ester

Carboxylic Acid to Acid Chloride (patent US20070197544A1)

Acid Chloride to Amide (patent US20070197544A1)

Amide Bond Formation Using Carboxylic Acid and PBr3 (patent US20070197544A1)

Buchwald–Hartwig Amination (patent US20070197544A1)

Ester to Carboxylic Acid (patent WO2019134765A1)

Benzyl Ester to Carboxylic Acid (patent WO2019134765A1)

Boc‐ Protection of Amino Group (patent US20090054548A1)

Deprotection of Boc Group (patent US20090054548A1)

Sulfonation of Aromatic Compound (patent WO2002030878A1)

Nitration of Aromatic Compound (mild and noncorrosive conditions) (patent WO1994019310A1)

Nitration of Aromatic Compound (regular method)

Nitration of Aromatic Compound (regular method) (patent WO2016118450A1)

Reduction of Nitro Group (patent WO2018167800A1)

Reduction of Nitro Group by Hydrogenation (patent US6329380B1)

Reduction of Nitro Group Using Hydrazine Raney Nickel (patent US20070197544A1)

Reduction of Nitro Group Using Fe and NH4Cl (patent US20070197544A1)

Reduction of Ketone with NaBH4 (patent WO2013040068A2)

Reduction of Ester to Alcohol (patent US9399645B2)

Reduction of Ester to Alcohol with DIBAL‐H (patent WO2016037566A1)

Ester to Aldehyde (patent US20190337964A1)

Selective Oxidation of Primary Alcohol (patent WO2013040068A2)

Oxidation of Alcohol Using DMP

Oxidation of Primary Alcohol Using TEMPO (patent US10407378B2)

Benzylation of Phenol

Debenzylation by Hydrogenation (Patent WO1994028886A1)

Iodination of Aromatic Compound (patent US7951832B2)

Methylation of Phenol

Demethylation to Phenol (patent US6924310B2)

Bromide to O‐Benzyl (patent WO2019134765A1)

Tosylate to Fluoride (patent WO2019134765A1)

Iodide to Tosylate (patent WO2019134765A1)

Ozonolysis of Alkene (patent WO2013040068A2)

Asymmetric Dihydroxylation of Alkene (Sharpless Method) (WO2019093776A1)

Alcohol to Fluoride (WO2019134765A1)

Alcohol to Iodide (patent US9399645B2)

Alcohol to Bromide (patent WO2016037566A1)

Alcohol to Iodide via Tosylation (patent WO2016037566A1)

Alkene to Aldehyde (patent WO1998008849A1)

Amine to Azide via Diazotization (patent WO20030135050A1)

Azide to Amine (patent US6329380B1)

Reductive Amination (patent WO2005118525A1)

Asymmetric C‐Alkylation (patent WO2005118525A1)

Aldehyde to 1,1‐Difluoroalkane (WO2018167800A1)

Free Radical Reaction (patent WO2013040068A2)

Umpolung

Silylation of 1,3‐Dithiane (C‐Silylation) (Model reactions for education purpose only)

Alkylation on 2‐Diphenylmethyl‐1,3‐Dithiane

Deprotection of 1,3‐Dioxolane

Preparation of Grignard Reagent and Reaction with an Aldehyde

Alcohol to Bromide

Deprotection of 1,3‐Dithiane

16 Common Reagents in Organic Synthesis

Acetic Acid (CH

3

CO

2

H)

Acetic Anhydride

Acetyl Chloride

AlkylFluor

Aluminum Chloride (Aluminium Chloride; AlCl

3

)

Aluminum Isopropoxide (Aluminium Isopropoxide)

Ammonium Chloride (NH

4

Cl)

Ammonium Formate

Ascorbic Acid (Vitamin C) Sodium Salt (Sodium

L

‐Ascorbate)

9‐Azabicyclo[3.3.1]nonane

N

‐Oxyl, (2‐Azaadamantane‐

N

‐oxyl) (AZADO)

Azobisisobutyronitrile (AIBN)

[1,1′‐(Azodicarbonyl)dipiperidine] (ADDP)

Benzoyl Peroxide

[1,1′‐Bis(diphenylphosphino)ferrocene] palladium(II) dichloride, Pd(dppf)Cl

2

[Bis(triphenylphosphine)palladium(II) dichloride], Pd(Ph

3

P)

2

Cl

2

Bismuth Chloride (BiCl

3

)

(Bis(trifluoroacetoxy)iodo)benzene

9‐Borabicyclo[3.3.1]nonane (9‐BBN)

Boron Tribromide (BBr

3

)

Boron Trifluoride Diethyl Etherate (BF

3

‐OEt

2

)

Bromine (Br

2

)

N

‐Bromosaccharin (NBSa)

N

‐Bromosuccinimide (NBS)

Burgess Reagent [Methyl

N

‐(triethylammoniosulfonyl)carbamate]

tert

‐Butyldimethylsilyl Chloride (TBDMS‐Cl)

tert

‐Butyldimethylsilyl Trifluoromethanesulfonate (TBS‐OTf)

tert

‐Butyl Hydroperoxide (TBHP)

n

‐Butyllithium (

n

‐BuLi)

tert

‐Butyllithium

tert

‐Butyl Nitrite (TBN)

Carbon Tetrabromide (CBr

4

)

Carbonyldiimidazole (CDI)

Ceric Ammonium Nitrate (CAN; (NH

4

)

2

Ce(NO

3

)

6

)

Cesium Carbonate (Cs

2

CO

3

)

Cesium Fluoride (CsF)

Chloramine‐T,

N

‐chloro Tosylamide Sodium Salt

m

‐Chloroperbenzoic Acid (

m

‐CPBA)

N

‐Chlorosuccinimide (NCS)

Chromium Trioxide

Cobalt Chloride

Copper Iodide (CuI)

Dess–Martin Periodinane (DMP)

(Diacetoxyiodo)benzene (DAIB)

1,4‐Diazabicyclo[2.2.2]octane (DABCO)

1,8‐Diazabicyclo[5.4.0]undec‐7‐ene (DBU)

Diazomethane

Di‐

tert

‐butyl Azodicarboxylate (DBAD)

2,3‐Dichloro‐5,6‐dicyanobenzoquinone (DDQ)

N

,

N

′‐Dicyclohexylcarbodiimide (DCC)

Diethylaminosulfur Trifluoride (DAST)

Diethyl Azodicarboxylate (DEAD)

Diiodomethane (CH

2

I

2

)

Diisobutylaluminum Hydride (DIBAL‐H)

Diisopropylaminoborane

Diisopropyl Azodicarboxylate (DIAD)

N

,

N

‐Diisopropylethylamine (DIEA) (Hünig's Base)

4‐Dimethylaminopyridine (

N

,

N

′‐Dimethylaminopyridine) (DMAP)

Diphenylphosphoryl Azide (DPPA)

Di‐

tert

‐butyl Peroxide (DTBP)

Ethyl Chloroformate

1‐Ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide Hydrochloride (EDC·HCl)

Formic Acid

O

‐(7‐Azabenzotriazol‐1‐yl)‐

N

,

N

,

N

′,

N

′‐tetramethyluronium hexafluorophosphate (HATU)

Hexafluorophosphate Benzotriazole Tetramethyl Uronium (HBTU)

Hexamethylphosphoramide (HMPA)

Hydrazine (NH

2

NH

2

·H

2

O)

1‐Hydroxybenzotriazole (HOBt)

Hydrogen Peroxide

[Hydroxy(tosyloxy)iodo]benzene (HTIB) (Koser's Reagent)

Imidazole

Iodine (I

2

)

Iodobenzene Dichloride

N

‐Iodosuccinimide (NIS)

2‐Iodoxybenzoic Acid (IBX)

Iron(III) Nitrate Nonahydrate

Isoamyl Nitrite (Also Called Amyl Nitrite)

Isobutyl Chloroformate

Jones Reagent

Lawesson's Reagent

Lead Tetraacetate (Pd(OAc)4)

Lithium Aluminum Hydride (LiAlH

4

)

Lithium Diisopropylamide (LDA)

2,6‐Lutidine (2,6‐Dimethylpyridine)

Manganese Dioxide (MnO

2

)

Methanesulfonyl Chloride (Mesyl Chloride)

N

‐Methylmorpholine N‐oxide (NMO)

Nitrosobenzene

Osmium Tetroxide

Oxalyl Chloride

Oxone (Potassium Peroxymonosulfate)

Ozone (O

3

)

PhenoFluor Mix

Palladium on Calcium Carbonate (Pd/CaCO

3

)

Palladium on Carbon

Phenyltrimethylammonium Perbromide (PTAB) or Phenyltrimethylammonium Tribromide (PTT)

Phosphorus Oxychloride

Phosphorus Tribromide (PBr

3

)

Piperidine

Platinum on Carbon

Platinum(IV) Oxide

Potassium bis(trimethylsilyl)amide (KHMDS) (Potassium Hexamethyldisilazide)

Potassium

tert

‐Butoxide

Potassium Carbonate

Potassium Iodide

Potassium Permanganate

Potassium Sodium Tartrate Tetrahydrate (Rochelle's Salt)

Propylphosphonic Anhydride (T3P)

PyAOP

(Benzotriazol‐1‐yloxy)tripyrrolidinophosphonium Hexafluorophosphate (PyBOP)

Pyridine

Pyridinium Chlorochromate (PCC)

Pyridinium Dichromate (PDC)

Pyridinium p‐Toluenesulfonate (PPTS)

Raney Nickel

Ruthenium(III) Chloride (RuCl

3

)

Scandium(III) Trifluoromethanesulfonate (Scandium Triflate)

Selectfluor

Sodium Azide

Sodium Bis(trimethylsilyl)amide (NaHMDS)

Sodium Borohydride

Sodium Cyanoborohydride

Sodium Hydride (NaH)

Sodium Hypochlorite (Bleach)

Sodium Nitrite

Sodium Periodate

Sodium Sulfide (Na

2

S)

Sodium Triacetoxyborohydride (STAB)

Tetra‐

n

‐butylammonium Fluoride (TBAF)

Tetra‐

n

‐butylammonium Iodide (TBAI)

Tetrakis(triphenylphosphine)palladium(0) (Pd(Ph

3

P)

4

)

2,2,6,6‐Tetramethylpiperidin‐1‐yl)oxyl (TEMPO)

Tetrapropylammonium Perruthenate (TPAP)

Thionyl Chloride

Titanium(IV) Chloride

Titanium Isopropoxide

p

‐Toluenesulfonic Acid

Tributyltin Hydride

Triethylamine (TEA)

Triethyl Orthoformate

Trifluoroacetic Acid (TFA)

Trimethylsilyl Chloride (TMS‐Cl)

2‐(Trimethylsilyl)ethoxymethyl Chloride (SEM‐Cl)

Trimethylsilyl Cyanide (TMS‐CN)

Trimethylsilyl Diazomethane

Trimethylsilyl Iodide

Triphenylphosphine (Ph

3

P)

Triphosgene [bis(trichloromethyl) carbonate (BTC)]

Tris(dibenzylideneacetone)dipalladium(0)

Trityl Chloride (Triphenylmethyl Chloride)

Urea Hydrogen Peroxide (UHP)

Zinc (Zn)

Zinc Chloride

References

Further Reading

Appendix A: Appendix AList of Medicines (Partial) and Nutrients

Antibiotic (antibacterial agent)

Antiviral Medicines

Antifungal Medicines

Antimalarial Medicines

Antituberculosis Medicines

Medicines for Pain

Anticonvulsants Medication (antiepileptic drugs or as antiseizure drugs)

Anti‐infective Medicines (anthelminthics and antifilarials)

Medicines for Migraine

Antileprosy Medicines

Disinfectant and Antiseptics

Antidiabetic Medicines (diabetes medications)

Medicines for Anesthetics (anesthetics)

Antiallergics and Medicines for Anaphylaxis

Cardiovascular Medicines

Medicines for Gastrointestinal

Medicines for Mental and Behavioral Disorders

Medicine for Joint Paints

Medicines Affecting the Blood

Medicines for Cancer (antineoplastics)

Medicines for Parkinson's Disease

Medicines for Ear, Nose, and Throat

Medicines for the Respiratory Tract

Reproductive Health and Perinatal Care Medicines

Medicines for Dermatological (topical)

Antidotes in Poisonings

Vitamins

Other Nutrients

Medical Advice Disclaimer

Further Reading

Index

End User License Agreement

List of Tables

Chapter 9

Table 9.1 Type of heteroatom described by prefix.

Table 9.2 Ring size and nature of ring (saturation and unsaturation).

Chapter 12

Table 12.1 20 essential amino acids.

Table 12.2 Side‐chain protecting groups and deprotection conditions.

List of Illustrations

Chapter 12

Scheme 12.1 Modification of cysteine with (a) chloroacetamides and (b) acryl...

Guide

Cover Page

Title Page

Copyright

Preface

About the Book

About the Author

Acknowledgments

List of Abbreviations

Table of Contents

Begin Reading

1 List of Medicines (Partial) and Nutrients

Index

WILEY END USER LICENSE AGREEMENT

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Applied Organic Chemistry

Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry

Surya K. De

Volume 1

Copyright

Author

Dr. Surya K. De

Supra Sciences

San Diego, CA

United States

Cover Image:

© enot‐poloskun/Getty

All books published by Wiley‐VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

Library of Congress Card No.:

applied for

British Library Cataloguing‐in‐Publication Data

A catalogue record for this book is available from the British Library.

Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at <http://dnb.d-nb.de>.

© 2021 WILEY‐VCH GmbH, Boschstr. 12, 69469 Weinheim, Germany

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

Print ISBN: 978‐3‐527‐34785‐8

ePDF ISBN: 978‐3‐527‐82815‐9

ePub ISBN: 978‐3‐527‐82817‐3

oBook ISBN: 978‐3‐527‐82816‐6

Preface

Organic chemistry is a constantly developing and expanding field of science because of its infinite research and application possibilities. Clear understanding of organic chemistry concepts, including the mechanistic aspects of organic reactions, helps chemists design drug molecules with the power to save human lives.

This textbook is targeted to advanced undergraduates and postgraduate students in all areas of organic, bioorganic, pharmaceutical, and medicinal chemistry. Professional researchers may utilize it as a handbook due to its references to original literature, recent reviews, and application of named reactions and reagents frequently used in organic synthesis. This book also covers, step by step, the mechanism of selected reactions that are part of undergraduate and postgraduate curricula. The definition of each named reaction with its original reference(s), i.e. the first one or others if applicable, current reviews, and their applications (sourced from Journal of Medicinal Chemistry and others) are also included. Heterocyclic compounds have important biological activities, so the nomenclature and application of heterocyclic compounds have been summarized in Chapter 9. In addition, Chapter 12 presents preliminary concepts regarding solution‐phase and solid‐phase peptide syntheses. For synthetic stand points, common organic reagents and functional groups transformation are discussed in Chapters 13–16.

References included in this book are available on PubMed (https://www.ncbi.nlm.nih.gov/pubmed) or https://pubs.acs.org. The experimental procedure of each reaction can be found on Google Patents (http://patents.google.com).

I would like to express great thanks to Dr. Ramkrishna De (Vertex Pharmaceuticals) for reviewing the manuscript and providing valuable suggestions. Also, Dr. Maloy Kumar Parai provided some assistance in preparing the manuscript.

I would like to express great thanks to Wiley editors Dr. Anne Brennführer, Dr. Frank Weinreich, Ms. Katherine Wong, as well as their staffs Ms. Pinky Sathishkumar, Ms. Abisheka Santhoshini who helped me to complete this book.

Finally, I wish to thank my family members for their continual understanding and support.

I welcome and, in fact, earnestly request readers to notify me of any suggestions for improving this book.

Surya K. De

San Diego, CA, USAMarch 2020

About the Book

This book is unique in that it covers most reactions that are the syllabus of undergrascapduate and postgraduate students. The reaction mechanisms are shown in details with step‐by‐step explanation of the processes. Most of the reactions' applications and experimental procedures are also given. Professional researcher may utilize it as a handbook due to its references to original literature, recent reviews, and application of named reactions and reagents frequently used in organic synthesis.

About the Author

Surya K. De received his BS degree from Midnapore College and his PhD degree from Jadavpur University. His first book, Cancer & You: What Everyone Needs to Know About Cancer and Its Prevention, was published in 2018. He has published over 100 peer‐reviewed papers in reputed international journals, covering a broad array of specialized topics in science, and he holds 15 US patents for his inventions. Due to Dr. De's abundant research contributions in the areas of cancer, metabolic diseases, organic and medicinal chemistry, and neuroscience, he earned the distinction of Fellow of the Royal Society of Chemistry (London, UK) in 2010; he was subsequently awarded the status of Chartered Chemist in 2011. Furthermore, he is an elected alternate councilor in the American Chemical Society (San Diego section). Dr. De resides in San Diego, California, where he loves the scenic coastline and sunny skies.

Acknowledgments

The author would like to extend his gratitude to the original publishers for experimental procedures for granting permission to use in this book. The publishers include the American Chemical Society, Elsevier, the Royal Society of Chemistry, John Wiley & Sons, Wiley VCH‐Verlag, Thieme, and the Japan Institute of Heterocyclic Chemistry. I would like to thank all inventors for patent literatures cited in this book.

List of Abbreviations

Abbreviation

Name

Chemical structure

Å

Ångström

NA

Ac

Acetyl

Acac

Acetylacetonyl

AIBN

2,2′‐Azobisisobutyronitrile

Alloc

Allyloxycarbonyl

Aq

Aqueous

With water

Ar

Aryl

Substituted aromatic ring

9‐BBN

9‐Borabicyclo[3.3.1]nonane

BINAL‐H

2,2′‐Dihydroxy‐1,1′‐binaphthyl lithium aluminum hydride

BINAP

2,2′‐Bis(diphenylphosphino)‐1,1′‐binaphthyl

BINOL

1,1′‐Bi‐2,2′‐naphthol

BMS

Borane dimethyl sulfide complex

H

3

B • SMe

2

Abbreviation

Name

Chemical structure

Boc

tert

‐Butoxycarbonyl

BOM

Benzyloxymethyl

b.p.

Boiling point

NA

BPO

Benzoyl peroxide

Bn

Benzyl

br

Broad

NA

Bz

Benzoyl

n

‐Bu

n

‐Butyl

t

‐Bu

tert

‐Butyl

°C

Degree Celsius

NA

13

C NMR

Carbon NMR

NA

CAN

Ceric ammonium nitrate

(NH

4

)

2

Ce(NO

3

)

6

cat.

Catalytic

NA

Cbz (Z)

Benzyloxycarbonyl

conc.

Concentrated

NA

COSY

Correlation spectroscopy

NA

CDI

Carbonyldiimidazole

CSA

Camphorsulfonic acid

CTAB

Cetyltrimethylammonium bromide

Δ

Chemical shift in ppm

NA

d

Doublet

NA

DABCO

1,4‐Diazabicyclo[2.2.2]octane

Abbreviation

Name

Chemical structure

DAST

Diethylaminosulfur trifluoride

Dba

Dibenzylideneacetone

DBAD

Di‐

tert

‐butyl azodicarboxylate

DBU

1,8‐Diazabicyclo[5.4.0]undec‐7‐ene

DCC

N,N′

‐Dicyclohexylcarbodiimide

DCE

1,2‐Dichloroethane

DCM

Dichloromethane

CH

2

Cl

2

DCU

N,N′

‐Dicyclohexylurea

DDQ

2,3‐Dichloro‐5,6‐dicyano‐1,4‐benzoquinone

de

Diastereomeric excess

NA

DEAD

Diethyl azodicarboxylate

DET

Diethyl tartrate

DHP

3,4‐Dihydro‐2H‐pyran

(DHQ)

2

PHAL

Bis(dihydroquinino)phthalazine

Abbreviation

Name

Chemical structure

(DHQD)

2

‐PHAL

Bis(dihydroquinidino)phthalazine

DIAD

Diisopropyl azodicarboxylate

DAIB (DIB)

(Diacetoxyiodo)benzene

DIBAL‐H

Diisobutylaluminum hydride

DIC

Diisopropylcarbodiimide

DIEA (DIPEA)

Diisopropylethylamine

DIPT

Diisopropyl tartrate

DMA

N,N

‐Dimethylacetamide

DMAP

4‐

N,N

‐Dimethylaminopyridine

DME

1,2‐Dimethoxyethane

DMF

N,N

‐Dimethylformamide

DMP

Dess–Martin periodinane

Abbreviation

Name

Chemical structure

DMPS

Dimethylphenylsilyl

DMS

Dimethyl sulfide

DMSO

Dimethyl sulfoxide

DPPA

Diphenylphosphoryl azide

DPS (TBDPS)

tert

‐Butyldiphenylsilyl

DTT (DTE)

1,4‐Dithioerythritol

E1

Unimolecular elimination

NA

E2

Bimolecular elimination

NA

EDC (EDCI)

1‐Ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide

EDG

Electron‐donating group

NA

EDTA

Ethylenediaminetetraacetic acid

ee

Enantiomeric excess

NA

E

i

Intramolecular

syn

elimination

NA

Et

Ethyl

Equiv.

Equivalent

NA

EWG

Electron‐withdrawing group

NA

Fmoc

9‐Fluorenylmethoxycarbonyl

Fp

Flash point

NA

g

Grams

NA

GC

Gas chromatography

NA

h

Hour

NA

Abbreviation

Name

Chemical structure

HATU

O‐(7‐Azabenzotriazol‐1‐yl)‐N,N,N′,N′‐tetramethyluronium hexafluorophosphate

HBTU

H

exafluorophosphate

B

enzotriazole

T

etramethyl

U

ronium

HFIP

1,1,1,3,3,3‐Hexafluoro‐2‐propanol (hexafluoroisopropanol)

HMDS

1,1,1,3,3,3‐Hexamethyldisilazane

HMPA

Hexamethylphosphoric acid triamide (hexamethylphosphoramide)

HMPT

Hexamethylphosphorous triamide

HOAt

1‐Hydroxy‐7‐azabenzotriazole

HOBt

1‐Hydroxybenzotriazole

HOMO

Highest occupied molecular orbital

NA

HPLC

High‐performance liquid chromatography

NA

HTIB

[Hydroxy(tosyloxy)iodo]benzene

Hz

Hertz

NA

1

H NMR

Proton NMR

NA

HMBC

Heteronuclear multiple bond coherence

NA

Abbreviation

Name

Chemical structure

HSQC

Heteronuclear single quantum coherence

NA

IBX

o

‐Iodoxybenzoic acid

IPA

Isopropyl alcohol

IR

Infrared spectroscopy

NA

J

Coupling constant

NA

KHMDS

Potassium bis(trimethylsilyl)amide

L

Ligand

NA

LAH

Lithium aluminum hydride

LiAlH

4

LHMDS (LiHMDS)

Lithium bis(trimethylsilyl)amide

Liq.

Liquid

NA

LiTMP (LTMP)

Lithium 2,2,6,6‐tetramethylpiperidide

L.R.

Lawesson's reagent 2,4‐Bis(4‐methoxyphenyl)‐1,3,2,4‐dithiadiphos‐phetane‐2,4‐disulfide

L‐selectride

Lithium tri‐sec‐butylborohydride

LTA

Lead tetraacetate

Pb(OAc)

4

LUMO

Lowest unoccupied molecular orbital

NA

Lut

2,6‐Lutidine

m

Meta

NA

m

Multiplet

NA

Abbreviation

Name

Chemical structure

M

Moles/liter

NA

m

‐CPBA

meta‐Chloroperbenzoic acid

Me

Methyl

−−

CH

3

MEM

(2‐Methoxyethoxy)methyl

MIC

Methyl isocyanate

min

Minute

NA

mg

Milligrams

NA

ml

Milliliters

NA

Mol

Moles

NA

mmol

Millimoles

NA

μl

Microliters

NA

MOM

Methoxymethyl

m.p.

Melting point

NA

Ms

Mesyl (methanesulfonyl)

MS

Mass spectrometry

NA

MS

Molecular sieves

NA

MSA

Methanesulfonic acid

MSDS

Material safety data sheet

NA

MTBE

Methyl

ter

t‐butyl ether

MVK

Methyl vinyl ketone

Mv

Microwave

NA

n

Normal (e.g. unbranched alkyl chain)

NA

NaHMDS

Sodium bis(trimethylsilyl)amide Sodium hexamethyldisilazane

NBS

N

‐Bromosuccinimide

Abbreviation

Name

Chemical structure

NCS

N

‐Chlorosuccinimide

NIS

N

‐Iodosuccinimide

NMM

N

‐Methylmorpholine

NMO

N

‐Methylmorpholine oxide

NMP

N

‐Methyl‐2‐pyrrolidinone

NMR

Nuclear magnetic resonance

NA

NSAID

Nonsteroidal anti‐inflammatory drug

NA

Nuc/Nu

Nucleophile

NA

o

Ortho

NA

p

Para

NA

Pbf

2,2,4,6,7‐Pentamethyldihydrobenzofuran‐5‐sulfonyl

31

P NMR

Phosphorus NMR

NA

PBP

Pyridinium bromide perbromide

PCC

Pyridinium chlorochromate

PDC

Pyridinium dichromate

Abbreviation

Name

Chemical structure

Pd

2

(dba)

3

Tris(dibenzylideneacetone)dipalladium

Pd(dppf)Cl

2

[1,1′‐Bis(diphenylphosphino)ferrocene]dichloropalladium(II)

PdCl

2

(PPh

3

)

2

Bis(triphenylphosphine)palladium(II) dichloride

Pd(PPh

3

)

4

Tetrakis(triphenylphosphine)palladium(0)

(Ph

3

P)

4

Pd

PhI(OH)OTs

[Hydroxyl(tosyloxy)iodo]benzene

PEG

Polyethylene glycol

Ph

Phenyl

PHAL

Phthalazine

PIFA

Phenyliodonium bis(trifluoroacetate)

Piv

Pivaloyl

PMB

p

‐Methoxybenzyl

PMP

4‐Methoxyphenyl

Abbreviation

Name

Chemical structure

PNB

p

‐Nitrobenzyl

ppm

Parts per million

NA

PPTS

Pyridinium

p

‐toluenesulfonate

Pr

Propyl

P.T.

Proton transfer

NA

PTAB

Phenyltrimethylammonium perbromide

PTSA (TsOH)

p

‐Toluenesulfonic acid

r.t. (rt)

Room temperature

NA

R

f

Retention factor in chromatography

NA

ROM

Ring‐opening metathesis

NA

ROMP

Ring‐opening metathesis polymerization

NA

RB (Rose Bengal)

2,4,5,7‐Tetraiodo‐3′,4′,5′,6′‐tetrachlorofluorescein, disodium salt (a photosensitizer, dye)

s

Singlet

NA

SDS

Sodium dodecyl sulfate

Selectfluor

N

‐Chloromethyl‐

N

′‐fluorotriethylenediammonium bis(tetrafluoroborate)

SEM

2‐(Trimethylsilyl)ethoxymethyl

SET

Single‐electron transfer

NA

S

N

Ar

Nucleophilic substitution on an aromatic ring

NA

Abbreviation

Name

Chemical structure

S

N

1

Unimolecular nucleophilic substitution

NA

S

N

2

Bimolecular nucleophilic substitution

NA

SPB

Sodium perborate

NaBO

3

t

Triplet

NA

TBAB

Tetra‐

n

‐butylammonium bromide

TBAF

Tetra‐

n

‐butylammonium fluoride

TBAI

Tetra‐

n

‐butylammonium iodide

TBD

Triazabicyclodecene (1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene

TBDMS (TBS)

tert

‐Butyldimethylsilyl

TBDPS (BPS)

tert

‐Butyldiphenylsilyl

TBH

tert

‐Butyl hypochlorite

TBHP

tert

‐Butyl hydroperoxide

TBP

Tributylphosphine

TBTH

Tributyltin hydride

Abbreviation

Name

Chemical structure

TBTSP

tert

‐Butyl trimethylsilyl peroxide

TCCA

Trichloroisocyanuric acid

TCDI

Thiocarbonyldiimidazole

TCNE

Tetracyanoethylene

TCNQ

7,7,8,8‐Tetracyano‐

para

‐quinodimethane

TEA

Triethylamine

TEMPO

2,2,6,6‐Tetramethyl‐1‐piperidinyloxy free radical

Teoc

2‐(Trimethylsilyl)ethoxycarbonyl

TEP

Triethylphosphite

TES

Triethylsilyl

Tf

Trifluoromethanesulfonyl

TFA

Trifluoroacetic acid

TFAA

Trifluoroacetic anhydride

TFE

2,2,2‐Trifluoroethanol

TFMSA

Trifluoromethanesulfonic acid (triflic acid)

Abbreviation

Name

Chemical structure

THF

Tetrahydrofuran

THP

2‐Tetrahydropyranyl

TIPS

Triisopropylsilyl

TIPS

Triisopropylsilane

TMP

2,2,6,6‐Tetramethylpiperidine

TMS

Trimethylsilyl

TMSA

Trimethylsilyl azide

TMU

Tetramethylurea

TPAP

Tetra‐

n

‐propylammonium perruthenate

TPP

Triphenylphosphine

TPS

Triphenylsilane

Trt

Trityl (triphenylmethyl)

Abbreviation

Name

Chemical structure

T.S.

Transition state

NA

Ts (Tos)

p

‐Toluenesulfonyl

TTN

Thallium(III) trinitrate

Tl(NO

3

)

3

UHP

Urea–hydrogen peroxide complex

Z (Cbz)

Benzyloxycarbonyl

Polarity of Solvents

Common Solvents in Chemistry

Solvent

Formula

MW

Boiling point (°C)

Density (g/ml)

Solubility in water (g/100 g)

Dielectric constant

Acetic acid

C

2

H

4

O

2

60.052

118

1.044

Miscible

 6.20

Acetone

C

3

H

6

O

 58.078

 56

0.784

Miscible

21.01

Acetonitrile

C

2

H

3

N

 41.052

 81

0.785

Miscible

36.64

Benzene

C

6

H

6

 78.110

 80

0.876

0.18

 2.28

1‐Butanol

C

4

H

10

O

 74.120

117

0.809

6.3

17.8 

2‐Butanol

C

4

H

10

O

 74.120

 99

0.806

15

17.26

tert

‐Butanol

C

4

H

10

O

 74.12 

 82

0.788

Miscible

12.5 

2‐Butanone

C

4

H

8

O

 72.11 

 79

0.799

25.6

18.6 

Carbon disulfide

CS

2

 76.13 

 46

1.274

1.266

Carbon tetrachloride

CCl

4

153.82

 76

1.594

0.08

—

Chlorobenzene

C

6

H

5

Cl

112.56

131

1.105

0.05

 5.69

Chloroform

CHCl

3

119.38 

 61

1.478

0.79

 4.81

Cyclohexane

C

6

H

12

 84.16 

 80

0.773

0.005

 2.02

1,2‐Dichloroethane

C

2

H

4

Cl

2

 98.96 

 83

1.245

0.86

10.42

Diethylene glycol

C

4

H

10

O

3

106.12 

246

1.119

10

31.8 

Diethyl ether

C

4

H

10

O

 74.12 

 34

0.713

7.5

 4.26

Diglyme

C

6

H

14

O

3

134.17 

162

0.943

Miscible

 7.23

1,2‐Dimethoxyethane

C

4

H

10

O

2

 90.12 

 84

0.863

Miscible

 7.3 

N,N

‐Dimethylacetamide (DMA)

C

4

H

9

NO

 87.12 

165

0.937

Miscible

37.8 

N,N

‐Dimethylformamide (DMF)

C

3

H

7

NO

 73.09 

153

0.944

Miscible

38.24

Dimethyl sulfoxide (DMSO)

C

2

H

6

OS

 78.03 

189

1.092

25.3

47

1,4‐Dioxane

C

4

H

8

O

2

88.11

101

1.033

Miscible

 2.21

Ethanol

C

2

H

6

O

 46.01 

 78

0.786

Miscible

24.6 

Ethyl acetate

C

4

H

8

O2

 88.11 

 77

0.895

8.7

6

Ethylene glycol

C

2

H

6

O

2

62.07

195

1.115

Miscible

37.7 

Glycerine

C

3

H

8

O

3

 92.09 

290

1.261

Miscible

42.5 

Heptane

C

7

H

16

100.20 

 98

0.684

0.01

 1.92

Hexamethylphosphoramide (HMPA)

C

6

H

18

N

3

OP

179.20 

232

1.03

Miscible

31.3 

Hexamethylphosphorous triamide (HMPT)

C

6

H

18

N

3

P

163.20 

150

0.898

Miscible

Hexane

C

6

H

14

86.18

 69

0.659

0.001

 1.89

Methanol

CH

4

O

 32.04 

 65

0.791

Miscible

32.6 

Methyl

t

‐butyl ether (MTBE)

C

5

H

12

O

 88.15 

 55

0.741

5.1

Solvent

Formula

MW

Boiling point (°C)

Density (g/ml)

Solubility in water (g/100 g)

Dielectric constant

Methylene chloride

CH

2

Cl

2

84.93

 40

1.326

9.08

 1.6 

N

‐Methyl‐2‐pyrrolidinone (NMP)

C

5

H

9

NO

 99.13 

202

1.033

10

32

Nitromethane

CH

3

NO

2

61.04

101

1.382

9.5

35.9 

Pentane

C

5

H

12

 72.15 

 36

0.626

0.04

 1.84

Petroleum ether (ligroine)

—

30–60

0.656

—

—

1‐Propanol

C

3

H

8

O

60.10

 97

0.803

Miscible

20.1 

2‐Propanol (isopropyl alcohol)

C

3

H

8

O

 60.10 

 82

0.786

Miscible

18.3 

Pyridine

C

5

H

5

N

 79.10 

115

0.982

Miscible

12.3 

Tetrahydrofuran (THF)

C

4

H

8

O

 72.106

 65

0.883

Soluble

 7.52

Toluene

C

7

H

8

 92.14 

110

0.867

0.05

 2.38

Triethylamine

C

6

H

15

N

101.19 

 89

0.728

0.02

 2.4 

Trifluoroacetic acid

C

2

HFO

2

114.023

 72

1.489

Miscible

 8.55

2,2,2‐Trifluoroethanol

C

2

H

3

F

3

O

100.04 

 74

1.384

Miscible

 8.56

Water

H

2

O

 18.02 

100

0.998

—

78.54

Water heavy

D

2

O

 20.03 

101

1.107

Miscible

o

‐Xylene

C

8

H

10

106.17

144

0.897

Insoluble

 2.57

m

‐Xylene

C

8

H

10

106.17 

139

0.868

Insoluble

 2.37

p‐

Xylene

C

8

H

10

106.17 

138

0.861

Insoluble

 2.27

References

1. Professor Murov's Organic solvent table.

2. Vogel's Practical Organic Chemistry.

3. American Chemical Society, Organic Division.

List of Cooling Baths

Cooling agent

Organic solvent or inorganic salt

Temperature (°C)

Dry ice

1,4‐Dioxane

+12

Dry ice

Cyclohexane

+6

Dry ice

Benzene

+5

Dry ice

N,N

‐Dimethylformamide

+2

Ice

Water

0

Cooling agent

Organic solvent or inorganic salt

Temperature (°C)

Liquid N

2

Aniline

−

6

Liquid N

2

Ethylene glycol

−

10

Liquid N

2

Cycloheptane

−

12

Dry ice

Benzyl alcohol

−

15

Dry ice

Ethylene glycol

−

15

Dry ice

Tetrahydrofuran

−

22

Dry ice

Carbon tetrachloride

−

23

Dry ice

1,3‐Dichlorobenzene

−

25

Dry ice

o

‐Xylene

−

29

Liquid N

2

Bromobenzene

−

30

Dry ice

m

‐Toluidine

−

32

Dry ice

3‐Heptanone

−

38

Dry ice

Pyridine

−

42

Dry ice

Cyclohexanone

−

46

Dry ice

Acetonitrile

−

46

Dry ice

m

‐Xylene

−

47

Dry ice

Diethyl carbitol

−

52

Dry ice

n

‐Octane

−

56

Dry ice

Diisopropyl ether

−

60

Dry ice

Trichloroethylene

−

73

Dry ice

Isopropyl alcohol

−

77

Liquid N

2

Butyl acetate

−

77

Dry ice

Acetone

−

78

Liquid N

2

Isoamyl alcohol

−

79

Dry ice

Sulfur dioxide

−

82

Liquid N

2

Ethyl acetate

−

84

Liquid N

2

n

‐Butanol

−

89

Liquid N

2

Hexane

−

94

Liquid N

2

Acetone

−

94

Liquid N

2

Toluene

−

95

Liquid N

2

Methanol

−

98

Liquid N

2

Cyclohexene

−

104

Liquid N

2

Isooctane

−

107

Liquid N

2

Ethyl iodide

−

109

Liquid N

2

Carbon disulfide

−

110

Liquid N

2

Butyl bromide

−

112

Liquid N

2

Ethanol

−

116

Liquid N

2

Ethyl bromide

−

119

Cooling agent

Organic solvent or inorganic salt

Temperature (°C)

Liquid N

2

Acetaldehyde

−

124

Liquid N

2

Methylcyclohexane

−

126

Liquid N

2

1‐Propanol

−

127

Liquid N

2

n

‐Pentane

−

131

Liquid N

2

1,5‐Hexadiene

−

141

Liquid N

2

Isopentane

−

160

Liquid N

2

None

−

196

Liquid He

None

−

269

Dry ice is the solid form of carbon dioxide (CO2).

Ice is the frozen water.

Liquid N2 is the liquid state of nitrogen.

Liquid He is the liquid state of helium.

Further Reading

1 Rondeau, R.E. (1966).

J. Chem. Eng. Data

11: 124.

2 Phipps, A.M. and Hume, D.N. (1968).

J. Chem. Educ.

45: 664.

3 Lee, D.W. and Jensen, C.M. (2000).

J. Chem. Educ.

77: 629.

1Rearrangement Reactions

A rearrangement reaction is a board class of organic reactions in which an atom, ion, group of atoms, or chemical unit migrates from one atom to another atom in the same or different species, resulting in a structural isomer of the original molecule. Rearrangement reactions mostly involve breaking and/or making CC, CO, or CN bonds. The migration origin is the atom from which the group moves, and the migration terminus is the atom to which it migrates.

Baeyer–Villiger Oxidation or Rearrangement

The Baeyer–Villiger oxidation is an organic reaction that converts a ketone to an ester or a cyclic ketone to a lactone in the presence of hydrogen peroxide or peroxy acids [1]. The reaction was discovered in 1899 by Adolf von Baeyer and Victor Villiger. It is an intramolecular anionotropic rearrangement where an alkyl group migrates from the carbonyl carbon atom (migration origin) to an electron‐deficient oxygen atom (migration terminus). The most electron‐rich alkyl group (most substituted carbon) that is able to stabilize a positive charge migrates most readily. The migration order is as follows:

Tertiary alkyl > cyclohexyl > secondary alkyl > phenyl > primary alkyl > CH

3

 > H.

Several new catalysts including organics, inorganics, and enzymes have been developed for this reaction [2-76]. Amine or alkene functional groups are limitations, however, because of their easy and undesirable oxidation.

Mechanism

Step 1

: The oxygen atom of the ketone is protonated to form a carbenium ion.

Step 2

: Nucleophilic attacks by aperoxycarboxylate ion at electron‐deficient carbonyl carbon atom.

Step 3

: One of the alkyls on the ketone migrates to the oxygen of the peroxide group, while a carboxylic acid departs.

Step 4

: Deprotonation of the oxocarbenium ion produces the desired ester.

Application

Zoapatanol and testololactone (anticancer agent) were synthesized using Baeyer–Villiger oxidation reaction conditions. Total syntheses of several natural products such as 9‐epi‐pentalenic acid [40], (+)‐hippolachnin A, (+)‐gracilioether A, (−)‐gracilioether E, (−)‐gracilioether F [71], and salimabromide [76] have been accomplished utilizing this reaction.

Experimental Procedure (from patent US 5142093A)

Preparation of 4‐(2,4‐Difluorophenyl)‐phenyl 4‐nitrobenzoate

Sodium perborate tetrahydrate (1.5 g, 9.7 mmol) was added to a mixture of 4‐(2,4‐difluorophenyl)‐4‐nitro‐benzophenone (A) (1 g, 2.9 mmol) and trifluoroacetic acid (9 ml) at 20 °C under stirring and under nitrogen for 24 hours and then poured into a mixture of methylene chloride (10 ml) and water (10 ml). The organic phase was washed with an 8% aqueous solution of sodium bicarbonate. After drying with sodium sulfate and evaporation of the solvent under reduced pressure, a crude (1.03 g) containing a mixture of ester and ketone starting material in the ratio 98 : 2 from 19F NMR analysis was obtained. The amount of ester (B) (0.946 g, 91.9% yield) in the crude was determined by high‐performance liquid chromatography (HPLC) analysis. An analytical sample (0.89 g) of the crude was crystallized from ethyl acetate giving pure product (0.70 g).

Dakin Oxidation (Reaction)

Dakin reaction is a redox reaction used to convert an ortho‐ or para‐hydroxylated phenyl aldehyde or a ketone to a benzenediol with alkaline hydrogen peroxide. This reaction, which is named after British chemist Henry Drysdale Dakin, is closely related to Baeyer–Villiger oxidation [1-17].

Mechanism

Step 1

: Nucleophilic attack by a hydroperoxide anion to the electron‐deficient carbonyl carbon atom forms a tetrahedral intermediate.

Step 2

: Aryl esmigration, elimination of hydroxide, and formation of an aryl ester.

Step 3

: Nucleophilic addition of hydroxide to the ester carbonyl carbon atom forms a second tetrahedral intermediate.

Step 4

: The unstable tetrahedral intermediate collapses to eliminate a phenoxide and forms a carboxylic acid.

Step 5

: Proton transfers from carboxylic acid to phenoxide.

Application

Catecholamine, a neurotransmitter, and (±)‐fumimycin, a natural product [14], were synthesized by Dakin oxidation.

Experimental Procedure (from patent EP0591799B)

Preparation of Catechol (o‐Dihydroxybenzene)

6.1 g (0.05 mol) of salicylaldehyde (A) and 0.01 g (0.25 mol) of NaOH in 50 ml of acetonitrile were introduced and mixed with 17.2 g of a 11.8% strength (0.06 mol) of hydrogen peroxide aqueous solution and stirred at 50 °C for 48 hours. Any remaining peroxide was removed with a dilute sodium sulfite solution. The reaction mixture was then mixed with essigester, the organic phase separated, and aqueous phase was washed several times with essigester. Then the combined organic phases were dried and freed of solvent in vacuo to obtain 5.4 g, which was 1H NMR spectroscopy identified by a comparative sample as catechol (B). (Purity was determined by gas chromatography: 98%; yield 96% of theoretical.)

Bamberger Rearrangement

The Bamberger rearrangement is an organic reaction used to convert N‐phenylhydroxylamine to 4‐aminophenol in the presence of strong aqueous acid [1,2]. The reaction is named after German chemist Eugen Bamberger. Several new catalysts have been developed for the preparation of 4‐aminophenol from directly nitrobenzene [3-19].

Mechanism

Step 1

: Mono‐protonation of

N

‐phenylhydroxylamine.

Step 2

: Elimination of water and formation of carbocation via a nitrenium ion.

Step 3

: Nucleophilic attack by water at the carbocation.

Step 4

: Protonation and deprotonation.

Step 5

: Deprotonation and rearomatization.

Experimental Procedure (from patent CN102001954B)

Preparation of p‐Aminophenol from N‐Phenylhydroxylamine

In a 100 ml reactor, 0.5 mmol N‐phenylhydroxylamine (A) was added; in a 50 ml of water, the closed reactor with CO2 substituted three times and then charged with CO2; the reaction was heated at 100 °C; in CO2 pressure 8 MPa conditions, the reaction was stirred for one hour. The reaction mixture was extracted with ethyl acetate and washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed over silica gel to afford a pure product (B).

Beckmann Rearrangement

The Beckmann rearrangement, named after the German chemist Ernst Otto Beckmann, is a conversion of an oxime to an N‐substituted amide in the presence of acid catalyst [1]. The acid catalysts are used including HCl, H2SO4, PCl5, SOCl2, P2O5, tosyl chloride, SO3, BF3, etc. These catalysts require the excess amounts and produce a large amount of by‐products. Most recently, this reaction has been utilized by using a catalytic amount of new types of catalysts such as RuCl3, BiCl3, etc. [2-51].

Mechanism

Step 1

: Protonation of hydroxyl group and formation of a better leaving group

Step 2

: Migration of R

2

group

trans

or anti to the leaving group and loss of water group leading to formation of carbocation. This

trans

(1,2) shift predicts the regiochemistry for this reaction.

Step 3

: Water molecule attacks as a nucleophile with a lone pair of electrons to the carbocation.

Step 4

: Deprotonation.

Step 5

: Tautomerization affords an

N

‐substituted amide, the final product.

Application

The Beckmann rearrangement reaction is used for the synthesis of paracetamol (acetaminophen), benazepril, ceforanide, olanzapine, elantrine, prazepine, enprazepine, etazepine, and other medicines.

Experimental Procedure (general)

Synthesis of Acetanilide

A mixture of acetophenone oxime (135 mg, 1 mmol) and RuCl3 (100 mg) or any other catalyst in acetonitrile (10 ml) was refluxed until no starting material was left (thin‐layer chromatography [TLC] monitored). The solvent was removed by rotary evaporator, and the residue was purified over silica gel chromatography using 30% ethyl acetate in hexane to yield an acetanilide (m.p. 114 °C).

Preparation of Caprolactam (from patent US 3437655A)

In a 1 l reaction vessel equipped with a stirrer, a reflux cooler, and a gas inlet tube, 113 g of cyclohexanone oxime (A) (1 mol) was mixed with 200 ml of acetonitrile, after which 40 g of gaseous hydrogen chloride (1.1 mol) was introduced at room temperature. Subsequently the temperature was raised and maintained at 75 °C for two hours, after which the rearrangement was completed. After the acetonitrile had been removed by distillation, the reaction product was dissolved in water and the solution neutralized with sodium bicarbonate. The resulting solution, which was saturated with common salt, was extracted with benzene. After removal of the benzene, 81 g of product caprolactam (B) was obtained, 71% yield.

Benzilic Acid Rearrangement

The benzilic acid rearrangement reaction is an organic reaction used to convert 1,2‐diketones to 2‐hydroxycarboxylic acids using strong base (KOH or NaOH) and then acid work‐up [1]. Benzil reacts with base to give benzilic acid that bears the name of the reaction. The reaction works well with aromatic 1,2‐diketones. Aliphatic diketones with adjacent enolizable protons undergo aldol‐type condensation. The aryl groups with electron‐withdrawing groups work the best [2-17].

Cyclic diketones lead to form the ring contraction products.

Mechanism

Step 1

: Nucleophilic attack by hydroxide at the electron‐deficient carbonyl carbon atom.

Step 2

: Migration of phenyl group.

Step 3

: Proton transfer.

Step 4

: Acidic work‐up gives the desired product.

Application

The natural product preuisolactone A [16] has been synthesized using this reaction.

Experimental Procedure (from patent US20100249451B)

Synthesis of Benzilic Acid from Benzil

A mixture of benzil (0.1 mol) and Triton B (benzyltrimethylammonium hydroxide) (0.2 mol) was heated at 40 °C for two hours with stirring. The mixture was diluted with water and acidified with 10% hydrochloric acid up to pH 3. The solid was filtered and washed with water to obtain benzilic acid in 92% yield.

Baker–Venkataraman Rearrangement

The Baker–Venkataraman rearrangement is a base‐catalyzed acyl transfer reaction of aromatic ortho‐acyloxyketones to aromatic β‐diketones (1,3‐diketones) [1-3]. The reaction is named after chemists Wilson Baker and Krishnaswami Venkataraman. This reaction has a wide range of applications in organic and medicinal chemistry [4-23].

Mechanism

Step 1

: The hydroxide abstracts an α‐hydrogen atom to form an enolate.

Step 2

: The nucleophilic attacks by the enolate to the ester carbonyl to form a cyclic alkoxide.

Step 3

: Ring opening and transfer of the acyl group.

Step 4

: Protonation from acidic work‐up gives the desired product.

Application

Total syntheses of natural products including stigmatellin A [9,10], zapotin [14], houttuynoid B [19], glycosylflavone aciculatin [21], and dirchromone‐1 [23] have been accomplished utilizing this reaction.

Experimental Procedure (from patent CN105985306B)

Synthesis of 2,4‐Dimethoxyphenyl‐3‐(2‐hydroxy‐4,6‐dimethoxyphenyl)‐2‐propyl‐1,3‐dicarbonyl‐benzoate

NaH (53 mg, 2.20 mmol) and 400 mg (A) were placed into 20 ml of dry tetrahydrofuran (THF), and the reaction mixture was stirred at 75 °C until starting material disappeared. The reaction mixture was cooled to room temperature, immersed in 30 ml ice water, extracted three times with ethyl acetate, and washed with brine three times. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified over silica gel column chromatography (PE/EA 6 : 1) to give 330 mg of the product B as a white solid (yield 77%).

Claisen Rearrangement

The Claisen rearrangement is a [3,3]‐sigmatropic rearrangement of an allyl vinyl ether to form a γ,δ‐unsaturated carbonyl compound under heating or acidic conditions. The reaction is a concerted process where bonds are forming and breaking at the same time [1-31].

When 2,6‐positions are blocked, rearomatization cannot take place; there are no o‐H atoms. In this case the allyl group will first migrate to the o‐position, and then second migration will take place to the p‐position via tandem Claisen and Cope rearrangement.

Mechanism

This rearrangement is an exothermic, suprafacial, concerted, and pericylic reaction.

When large groups are in equatorial positions, the 1,3‐interaction is minimized. When large groups are in axial positions, the 1,3‐diaxial unfavorable interaction is maximized.

The aromatic Claisen rearrangement undergoes [3,3]‐sigmatropic rearrangement accompanied by a rearomatization.

Step 1

: [3,3]‐Sigmatropic rearrangement.

Step 2

: Rearomatization gives the desired product.

Application

Total syntheses of termicalcicolanone A [6], (+)‐flavisiamine F [12], schiglautone A [27], hemigossypol, gossypol [28], hybridaphniphylline B [29], (±)‐corymine [25], sanggenons C [21], (+)‐antroquinonol, (+)‐antroquinonol D [20],(−)‐teucvidin [13], (+)‐jasplakinolide [10], and many more have been achieved using this reaction.

Experimental Procedure (from patent WO2016004632A1)

To a 5 ml microwave vial fitted with a magnetic stirrer was charged with calcium bistriflimide (16 mg) and O‐allylguaiacol (A) (438 mg, 2.67 mmol). The vial was then sealed, and the resultant homogeneous mixture was stirred for two minutes at the temperature of 200 °C under an autogenous pressure and a microwave irradiation generated by the Biotage® microwave instrument. After cooling to room temperature, the resulting reaction mixture was analyzed by 1H NMR to determine the conversion ratio (100%) and isomeric composition [76% of ortho‐eugenol (B) and 24% of para‐eugenol (C)].

Eschenmoser–Claisen Rearrangement

When an allylic alcohol is heated in the presence of N,N‐dimethylacetamide dimethyl acetal to produce a γ,δ‐unsaturated amide, the reaction is known as the Eschenmoser–Claisen rearrangement [32,33].

Mechanism

Step 1

: The

N

,

N

‐dimethylacetamide dimethyl acetal releases one methoxide to form an iminium cation.

Step 2

: The alcohol attacks at the iminium.

Step 3

: Methoxide abstracts a proton.

Step 4

: Protonation.

Step 5

: Methoxide abstracts a proton from the methyl, and the intermediate releases a methanol to form a 1,5‐diene intermediate (ketene aminal).

Step 6