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Science of Synthesis

Water in Organic Synthesis

Date of publication: February 8, 2012

b Georg Thieme Verlag KGStuttgart · New York

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Volume Editor S. Kobayashi

Authors D. A. AlonsoM. BenohoudA. ChandaS. ChevanceB. CornilsE. DinjusO. El-SepelgyJ. B. F. N. EngbertsV. V. FokinF. FringuelliK. GrelaF. HapiotY. HayashiI. T. Horv�thF. Jo�T. Katsuki

S. KobayashiA. KruseP. Le MauxG. MolteniC.-J. LiK. MaruokaN. MaseL. T. MikaJ. MlynarskiE. MonflierY. MoriC. N�jeraC. OgawaK. OshimaS. OttoM. Ouchi

O. PiermattiC. SamojłowiczM. SawamotoK. SchmidR. A. SheldonS. ShirakawaG. SimonneauxC. TorborgY. UozumiE. WiebusM. WoyciechowskaX. WuJ. XiaoH. YorimitsuL. Zhao

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Preface

Volume Editor�s Preface

Abstracts

Table of Contents

1 IntroductionS. Kobayashi

2 Structure and Properties of WaterS. Otto and J. B. F. N. Engberts

3 Aqueous Media: Reactions of C-C Multiple Bonds

3.1 Asymmetric Oxidation Reactions: Sulfoxidation, Epoxidation,Dihydroxylation, and AminohydroxylationT. Katsuki

3.2 Hydrogenation of Alkenes, Alkynes, Arenes, and HetarenesF. Jo�

3.3 Hydroformylation and Related ReactionsL. T. Mika and I. T. Horv�th

3.4 Conjugate Addition ReactionsN. Mase

3.5 Cyclopropanation ReactionsG. Simonneaux, P. Le Maux, and S. Chevance

3.6 Metathesis ReactionsC. Torborg, C. Samojłowicz, and K. Grela

4 Aqueous Media: Reactions of Carbonyl and Imino Groups

4.1 Reduction of Carbonyl and Imino GroupsX. Wu and J. Xiao

4.2 Alkylation, Allylation, and Benzylation of Carbonyl and Imino GroupsL. Zhao and C.-J. Li

4.3 Arylation, Vinylation, and Alkynylation of Carbonyl and Imino GroupsL. Zhao and C.-J. Li

4 Science of Synthesis Alert

4.4 Aldol ReactionM. Woyciechowska, O. El-Sepelgy, and J. Mlynarski

4.5 Mannich Reaction and Baylis–Hillman ReactionM. Benohoud and Y. Hayashi

5 Aqueous Media: Cyclization, Rearrangement, Substitution,Cross Coupling, Oxidation, and Other Reactions

5.1 Cycloaddition and Cyclization ReactionsG. Molteni

5.2 Pericyclic Rearrangements: Sigmatropic, Electrocyclic, and Ene ReactionsF. Fringuelli and O. Piermatti

5.3 Allylic and Aromatic Substitution ReactionsY. Uozumi

5.4 Cross-Coupling and Heck ReactionsD. A. Alonso and C. N�jera

5.5 Ring Opening of Epoxides and AziridinesC. Ogawa and S. Kobayashi

5.6 Asymmetric Æ-Functionalization of Carbonyl Compounds andAlkylation of EnolatesS. Shirakawa and K. Maruoka

5.7 Oxidation of Alcohols, Allylic and Benzylic Oxidation, Oxidation of SulfidesR. A. Sheldon

5.8 Free-Radical ReactionsH. Yorimitsu and K. Oshima

5.9 PolymerizationM. Ouchi and M. Sawamoto

6 Special Techniques with Water

6.1 Organic Synthesis “On Water”A. Chanda and V. V. Fokin

6.2 Sub- and Supercritical WaterA. Kruse and E. Dinjus

6.3 �-Cyclodextrin Chemistry in WaterF. Hapiot and E. Monflier

7 Industrial Application

Water in Organic Synthesis: Overview 5

7.1 HydroformylationE. Wiebus, K. Schmid, and B. Cornils

7.2 Industrial Applications Other than HydroformylationY. Mori and S. Kobayashi

8 Perspective: The New World of Organic Chemistry UsingWater as SolventS. Kobayashi

Keyword Index

Author Index

Abbreviations


Table of Contents

1 IntroductionS. Kobayashi

1 Introduction

1.1 Water-Compatible Lewis Acids

1.2 Lewis Acid–Surfactant Combined Catalysts for Organic Reactions in Water


2 Structure and Properties of Water

2.1 The Single Water Molecule

2.2 Liquid Water

2.3 Water as a Reaction Medium for Organic Synthesis

2.4 Thermodynamics of Hydration

2.5 Solvent Properties of Water

2.5.1 The Size of the Water Molecule

2.5.2 Polarizability

2.5.3 Solvent Polarity Indicators

2.5.4 Solvatochromic Solvent Parameters

2.5.5 The Solvatochromic Comparison Method: Linear Solvation Energy Relationships

2.5.6 Cohesive Energy Density

2.5.7 Internal Pressure

2.5.8 The Ionic Product of Water: Proton and Hydroxide Ion Mobilities

2.5.9 Water at High and Low Temperatures and Pressures

2.5.10 Water and Deuterium Oxide

2.6 Aqueous Electrolyte Solutions

2.6.1 Ionic Hydration: Hydration Numbers

2.6.2 Dynamics of Ion Hydration

2.7 Hydrophobic Effects

2.7.1 Hydrophobic Hydration

2.7.2 Hydrophobic Interactions

2.8 Organic Reactivity in Water

2.8.1 Catalysis in Water

2.8.2 Micellar Catalysis

Water in Organic Synthesis: Overview 7

2.8.3 Hydrophobic Effects on Reactivity: Initial-State versus Transition-State Effects

2.8.4 Effects of Additives on Reactivity in Water

2.8.4.1 Salt Effects

2.8.4.2 Cosolvent Effects

2.8.5 Reactions on Water

2.8.6 Reactions in Supercritical Water

2.8.7 Water as a Green Solvent

2.9 Epilogue

3 Aqueous Media: Reactions of C-C Multiple Bonds

3.1 Asymmetric Oxidation Reactions: Sulfoxidation, Epoxidation,Dihydroxylation, and AminohydroxylationT. Katsuki

3.1 Asymmetric Oxidation Reactions: Sulfoxidation, Epoxidation,Dihydroxylation, and Aminohydroxylation

3.1.1 Catalyst Tuning by Water

3.1.1.1 Enantioselective Oxidation of Sulfides Using a Water-ModifiedTitanium/Tartrate Catalyst

3.1.1.2 Asymmetric Aerobic Epoxidation Using a Water-BoundRuthenium–Salen Complex as Catalyst

3.1.2 Enantioselective Oxidation of Sulfides under Aqueous Conditions

3.1.2.1 Enantioselective Oxidation of Sulfides Using Chiral Metal–Schiff Base Catalysts

3.1.2.1.1 Vanadium-Catalyzed Oxidation

3.1.2.1.2 Iron-Catalyzed Oxidation

3.1.2.2 Enantioselective Oxidation of Sulfides Using Metallosalen andRelated Complexes as Catalysts

3.1.2.2.1 Manganese–Salen-Catalyzed Oxidation

3.1.2.2.2 Titanium–Salen-Catalyzed Oxidation

3.1.2.2.3 Aluminum–Salalen-Catalyzed Oxidation

3.1.2.3 Asymmetric Oxidation of Sulfides in Water

3.1.2.3.1 Platinum-Catalyzed Asymmetric Oxidation of Sulfides

3.1.2.3.2 Iron–Salan-Catalyzed Oxidation

3.1.3 Enantioselective Epoxidation

3.1.3.1 Asymmetric Epoxidation of Allylic Alcohols

3.1.3.1.1 Asymmetric Epoxidation of Allylic Alcohols under Aqueous Conditions


3.1.3.1.2 Asymmetric Epoxidation of Allylic Alcohols Using Aqueous Hydrogen Peroxide

3.1.3.2 Asymmetric Epoxidation of Unfunctionalized Alkenes

3.1.3.2.1 Metalloporphyrin-Catalyzed Enantioselective Epoxidation

3.1.3.2.2 Enantioselective Epoxidation Using Metal–Salen/Salalen/Salan Complexesas Catalyst

3.1.3.2.2.1 Bioinspired Enantioselective Epoxidation Using Manganese–Salalen orManganese–Salen Complexes as Catalyst

3.1.3.2.2.2 Enantioselective Epoxidation Using Titanium–Salalen orTitanium–Salan Complexes as Catalyst

3.1.3.2.3 Iron-Catalyzed Enantioselective Epoxidation

3.1.3.2.4 Ruthenium-Catalyzed Enantioselective Epoxidation

3.1.3.2.5 Platinum-Catalyzed Enantioselective Epoxidation

3.1.3.3 Enantioselective Epoxidation Using Organic Compounds as Catalysts

3.1.3.3.1 Chiral Ketone Catalyzed Enantioselective Epoxidation

3.1.3.3.2 Enantioselective Epoxidation of Electron-Deficient Alkenes Using Organocatalysts

3.1.3.3.2.1 Polyamino Acid Catalyzed Asymmetric Epoxidation

3.1.3.3.2.2 Phase-Transfer Catalyst Mediated Epoxidation

3.1.3.3.2.3 Amine-Catalyzed Asymmetric Epoxidation

3.1.4 Enantioselective Dihydroxylation

3.1.4.1 Osmium-Catalyzed Enantioselective Dihydroxylation

3.1.4.2 Iron-Catalyzed Enantioselective Dihydroxylation

3.1.5 Enantioselective Aminohydroxylation

3.1.6 Conclusions


3.2 Hydrogenation of Alkenes, Alkynes, Arenes, and Hetarenes

3.2.1 Catalysts and General Techniques for Hydrogenations in Water

3.2.2 Hydrogenation of Alkenes

3.2.2.1 Alkanes by Hydrogenation of Alkenes with Water-Soluble Analogues ofWilkinson�s Catalyst

3.2.2.1.1 Using Preprepared Rhodium(I)–Sulfonated Triphenylphosphine Catalysts

3.2.2.1.2 Using In Situ Prepared Rhodium(I)–Sulfonated Triphenylphosphine Catalysts

3.2.2.1.3 Using In Situ Prepared Rhodium(I) Catalysts in Microemulsions

3.2.2.2 Alkanes by Hydrogenation of Alkenes with Rhodium(I)-BasedCatalysts Attached to Proteins

3.2.2.3 Alkanes by Hydrogenation of Alkenes with Ruthenium(II) Catalysts

Water in Organic Synthesis: Table of Contents 9

3.2.2.4 Alkanes by Hydrogenation of Alkenes with Polymer-StabilizedColloidal Metal Catalysts

3.2.2.4.1 Using an In Situ Prepared Palladium–Poly(vinylpyrrolidone) Catalyst

3.2.2.4.2 Using a Preprepared Palladium–Poly(vinylpyrrolidone) Catalyst

3.2.2.5 Isotope Labeling by Hydrogenation in Water

3.2.3 Asymmetric Hydrogenation of Alkenes

3.2.3.1 Chiral Alkanes by Hydrogenation of Prochiral Alkenes Catalyzed byRhodium(I) Complexes

3.2.3.2 Chiral Alkanes by Hydrogenation of Prochiral Alkenes Catalyzed byRuthenium(II) Complexes

3.2.3.2.1 In Homogeneous Aqueous Solution with a Ruthenium(II)–Tetrasulfonated2,2¢-Bis(diphenylphosphino)-1,1¢-binaphthyl Catalyst

3.2.3.2.2 Alkanoic Acids by Hydrogenation of Alkenoic Acids witha Water-Soluble Chiral Ruthenium(II)–Bisphosphine Catalyst

3.2.4 Hydrogenation of Dienes

3.2.4.1 Alkenes by Selective Hydrogenation of Dienes with PotassiumPentacyanohydridocobaltate(III)

3.2.4.2 Alkenoic Acids by Selective Hydrogenation of Hexa-2,4-dienoic Acid witha Ruthenium(II)–Sulfonated Phosphine Catalyst

3.2.5 Hydrogenation of Polymers

3.2.5.1 Modified Elastomers by Hydrogenation of Polymers

3.2.6 Hydrogenation of Alkynes

3.2.6.1 Alkenes by Selective Hydrogenation of Alkynes

3.2.6.1.1 Hydrogenation of Pent-2-yne with Polymer-Stabilized Metal Colloids

3.2.6.1.2 Hydrogenation of Diphenylacetylene with a Ruthenium(II)–SulfonatedTriphenylphosphine Catalyst

3.2.7 Hydrogenation of Arenes and Hetarenes

3.2.7.1 Hydrogenation of Benzene Derivatives with a HomogeneousRuthenium-Based Catalyst

3.2.7.2 Hydrogenation of Aromatics with Stabilized Metal Nanoparticles

3.2.7.2.1 Arene Hydrogenation Catalyzed by Aqueous Solutions ofRhodium(III) Chloride Trihydrate and Aliquat 336

3.2.7.2.2 Arene Hydrogenation Catalyzed by Aqueous Solutions of Rhodium(III) Chlorideand N-Alkyl-N-(2-hydroxyethyl)-N,N-dimethylammonium Surfactants

3.2.7.2.3 Hydrogenation of Arenes with Poly(N-vinylpyrrolidone)-StabilizedRuthenium Nanoparticles

3.2.7.2.4 4-Propylcyclohexanols by Stereoselective Hydrogenation of4-Propylphenols (Lignin Degradation Model Compounds)

3.2.7.2.5 Hydrogenation of Hetarenes with Water-Soluble Ruthenium(II) Complexes



3.3 Hydroformylation and Related Reactions

3.3.1 Background to Hydroformylation and Related Reactions

3.3.2 Ligands for Hydroformylation in Aqueous Media

3.3.3 Hydroformylation in Aqueous Media

3.3.3.1 Hydroformylation of Higher Alkenes

3.3.3.2 Hydroformylation of Functionalized Alkenes

3.3.3.3 Asymmetric Hydroformylation Reactions

3.3.3.4 Laboratory Techniques

3.3.3.4.1 Biphasic Hydroformylation under Batch Conditions

3.3.3.4.2 Biphasic Hydroformylation under Continuous Conditions

3.3.4 Supported Aqueous-Phase Hydroformylation

3.3.5 Hydrocarboxylation in Aqueous Media


3.4 Conjugate Addition Reactions

3.4.1 C-H Bond Formation

3.4.1.1 Metal-Complex-Mediated Conjugate Reduction

3.4.1.2 Metal-Free Catalytic Conjugate Reduction of Enals

3.4.2 C-C Bond Formation

3.4.2.1 Addition of Alkyl Groups in C-C Bond Formation

3.4.2.1.1 Radical-Mediated Addition of Alkyl Groups

3.4.2.1.2 Metal-Complex-Mediated Addition of Alkyl Groups

3.4.2.1.3 Metal-Free Catalytic Addition of Alkyl Groups

3.4.2.2 Addition of Alkenyl and Aryl Groups in C-C Bond Formation

3.4.2.2.1 Catalyst-Free Addition of Aryl Groups

3.4.2.2.2 Metal-Complex-Catalyzed Addition of Alkenyl and Aryl Groups

3.4.2.2.2.1 Addition of Alkenyl and Aryl Groups to Carbonyl Compounds

3.4.2.2.2.2 Asymmetric Addition of Aryl Groups to Carbonyl Compounds

3.4.2.2.2.3 Addition of Indoles to Electron-Deficient Alkenes

3.4.2.2.3 Metal-Free Catalytic Addition of Aryl Groups

3.4.2.2.3.1 Brønsted Acid Catalyzed Addition of Indoles to Electron-Deficient Alkenes

3.4.2.2.3.2 Asymmetric Addition of Pyrroles and Indoles to Enals via Iminium Catalysis

3.4.2.3 Addition of Alkynyl Groups in C-C Bond Formation


3.4.2.3.1 Metal-Complex-Catalyzed Addition of Alkynyl Groups

3.4.2.4 Addition of Carbonyl Compounds in C-C Bond Formation

3.4.2.4.1 Catalyst-Free Addition of Carbonyl Compounds

3.4.2.4.2 Metal-Complex-Catalyzed Addition of Carbonyl Compounds to Enones

3.4.2.4.3 Metal-Free Catalytic Addition of Carbonyl Compounds

3.4.2.4.3.1 Addition of Carbonyl Compounds to Enals or Enones via Iminium Catalysis

3.4.2.4.3.2 Addition of Carbonyl Compounds to Æ,�-Unsaturated Esters via Enamine Catalysis

3.4.2.4.3.3 Addition of Carbonyl Compounds to Nitroalkenes via Enamine Catalysis

3.4.2.4.3.4 Addition of Carbonyl Compounds Using Other Metal-Free Catalysts

3.4.3 C-N Bond Formation

3.4.3.1 Catalyst-Free Addition in C-N Bond Formation

3.4.3.1.1 Addition of Amines to Enones

3.4.3.1.2 Addition of Amines to Æ,�-Unsaturated Carboxylic Acid Derivatives

3.4.3.1.3 Addition of Amines to Acrylonitrile

3.4.3.1.4 Addition of Amines to Nitro, Phosphonate, and Sulfonate Derivatives

3.4.3.2 Metal-Complex-Catalyzed Addition in C-N Bond Formation

3.4.3.3 Metal-Free Catalytic Addition in C-N Bond Formation

3.4.4 C-O Bond Formation

3.4.4.1 Metal-Free Catalytic Addition in C-O Bond Formation

3.4.4.1.1 Phosphine-Catalyzed Hydration

3.4.4.1.2 Asymmetric Addition of Alcohols to Enals via Iminium Catalysis

3.4.5 C-S and C-Se Bond Formation

3.4.5.1 Catalyst-Free Addition in C-S Bond Formation

3.4.5.1.1 Addition of Thiols to Enones and Quinones

3.4.5.1.2 Addition of Thiols to Æ,�-Unsaturated Carboxylic Acid Derivatives

3.4.5.1.3 Addition of Thiols to Acrylonitrile

3.4.5.1.4 Addition of Thiols to Nitroalkenes

3.4.5.2 Catalytic Addition in C-S Bond Formation

3.4.5.3 C-Se Bond Formation: Reaction of Zinc Selenolates


3.5 Cyclopropanation Reactions

3.5.1 Transition-Metal-Catalyzed Reaction of Diazo Compounds

3.5.1.1 Reaction Using Water-Soluble Catalysts

3.5.1.1.1 Using pybox–Ruthenium Catalysts


3.5.1.1.2 Using Metalloporphyrin Catalysts

3.5.1.2 Using Diazo Esters in Biphasic Media

3.5.1.3 In Situ Generation of the Diazo Reagent

3.5.2 Triphenylarsine-Catalyzed Cyclopropanation

3.5.3 Radical Reaction from Halogenated Compounds and Zinc Powder


3.6 Metathesis Reactions

3.6.1 Aqueous Alkene Metathesis Using Poorly Defined Catalytic Systems

3.6.1.1 Polymerization of 7-Oxabicyclo[2.2.1]hept-2-ene Derivatives

3.6.1.2 Polymerization of 7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate Derivatives

3.6.2 Aqueous Alkene Metathesis Using Water-Insoluble Well-Defined Catalysts

3.6.2.1 Applications in Homogeneous Aqueous Solutions

3.6.2.1.1 Ring-Closing Metathesis Using Ruthenium-Based Defined Catalysts inHomogeneous Water/Organic Solvent Mixtures

3.6.2.1.2 Cross Metathesis Using Ruthenium-Based Defined Catalysts inHomogeneous Water/Organic Solvent Mixtures

3.6.2.2 Applications in Water-Containing Heterogeneous Mixtures

3.6.2.2.1 Metathesis in the Presence of Water without a Cosolvent, Additives, or Surfactants

3.6.2.3 Metathesis in Aqueous Emulsions

3.6.2.3.1 Ring-Opening Metathesis Polymerization in Aqueous Emulsions

3.6.2.3.1.1 Ring-Opening Polymerization Using DodecyltrimethylammoniumBromide as a Surfactant

3.6.2.3.1.1.1 Polymerization of Bicyclo[2.2.1]hept-2-enes and 7-Oxa Derivatives

3.6.2.3.1.1.2 Polymerization of Bicyclo[2.2.1]hept-5-ene-2-carboxamides and 7-Oxa Derivatives

3.6.2.3.1.1.3 Polymerization of Vancomycin-Based Oligomers

3.6.2.3.1.2 Polymerization Using Sodium Dodecyl Sulfate as a Surfactant

3.6.2.3.1.2.1 Polymerization of Bicyclo[2.2.1]hept-2-ene

3.6.2.3.1.2.2 Polymerization of Cyclooctadiene and Cyclooctene

3.6.2.3.1.3 Polymerizations Using Acacia Gum as a Surfactant

3.6.2.3.2 Ring-Closing Metathesis and Cross Metathesis in Aqueous Emulsions

3.6.2.3.2.1 Ring-Closing Metathesis and Cross Metathesis in AqueousEmulsions Using Surfactants

3.6.2.3.2.1.1 Ring-Closing Metathesis of Diethyl 2,2-Diallylmalonate UsingSodium Dodecyl Sulfate


3.6.2.3.2.1.2 Homo-Cross Metathesis of Vancomycin Derivatives UsingDodecyltrimethylammonium Bromide

3.6.2.3.2.1.3 Cross Metathesis Using Polyoxyethanyl Æ-Tocopheryl Sebacate

3.6.2.3.2.1.4 Ring-Closing Metathesis Using Polyoxyethanyl Æ-Tocopheryl Sebacate

3.6.2.3.2.1.5 Ring-Closing Metathesis and Cross Metathesis in the Presence of Calix[n]arenes

3.6.2.3.2.2 Ring-Closing Metathesis and Cross Metathesis in Aqueous EmulsionsUsing Other Methods

3.6.2.3.2.2.1 Non-Water-Soluble Catalysts Embedded in Poly(dimethylsiloxane)

3.6.2.3.2.2.2 Ring-Closing Metathesis and Cross Metathesis Using Dendrimers

3.6.2.4 Applications of Water-Insoluble Catalysts for Protein Modification

3.6.2.4.1 Cross Metathesis with SBL-156Sac

3.6.2.4.2 Intramolecular Alkene Metathesis in O-Crotylserine Containing cpVenus-2TAG

3.6.3 Tagged Metathesis Catalysts

3.6.3.1 Catalysts Tagged to Hydrophilic Polymers

3.6.3.2 Small-Molecule Polar Catalysts

3.6.3.3 Applications in Heterogeneous Aqueous Media

4 Aqueous Media: Reactions of Carbonyl and Imino Groups

4.1 Reduction of Carbonyl and Imino GroupsX. Wu and J. Xiao

4.1 Reduction of Carbonyl and Imino Groups

4.1.1 Reduction of Carbonyl Groups

4.1.1.1 Hydrogenation of Carbonyl Groups

4.1.1.1.1 Nonasymmetric Hydrogenation of Aldehydes and Ketones

4.1.1.1.2 Hydrogenation of Carbon Dioxide

4.1.1.1.3 Asymmetric Hydrogenation of Ketones

4.1.1.2 Transfer Hydrogenation of Carbonyl Groups

4.1.1.2.1 Nonasymmetric Transfer Hydrogenation

4.1.1.2.2 Asymmetric Transfer Hydrogenation

4.1.1.2.2.1 Of Ketones with Molecular Catalysts

4.1.1.2.2.2 Of Ketones with Immobilized Catalysts

4.1.1.2.2.3 Of Ketones by Biomimetic Reduction

4.1.1.2.2.4 Of Functionalized Ketones

4.1.2 Reduction of Imino Groups

4.1.2.1 Hydrogenation of Imino Groups


4.1.2.1.1 Nonasymmetric Hydrogenation

4.1.2.1.2 Asymmetric Hydrogenation

4.1.2.2 Transfer Hydrogenation of Imino Groups

4.1.2.2.1 With Water-Soluble Catalysts

4.1.2.2.2 With Water-Insoluble Catalysts


4.2 Alkylation, Allylation, and Benzylation of Carbonyl and Imino Groups

4.2.1 Metal-Mediated Alkylation of Carbonyl and Imino Groups

4.2.1.1 Alkylation of Carbonyl Groups

4.2.1.1.1 Metal-Mediated Alkylation Reactions with Alkyl Halides

4.2.1.1.2 Metal-Mediated Reformatsky-Type Reactions

4.2.1.2 Alkylation of Imino Groups

4.2.2 Metal-Mediated Allylation of Carbonyl and Imino Groups

4.2.2.1 Allylation of Carbonyl Groups

4.2.2.1.1 Mediated by Zinc

4.2.2.1.2 Mediated by Tin

4.2.2.1.3 Mediated by Indium

4.2.2.1.4 Mediated by Other Metals

4.2.2.1.5 Regio- and Stereoselectivity

4.2.2.1.6 Asymmetric Allylation

4.2.2.2 Allylation of Imino Groups

4.2.3 Metal-Mediated Benzylation of Carbonyl and Imino Groups


4.3 Arylation, Vinylation, and Alkynylation of Carbonyl and Imino Groups

4.3.1 Arylation and Vinylation of Carbonyl and Imino Groups

4.3.1.1 Arylation and Vinylation of Aldehydes

4.3.1.2 Arylation and Vinylation of Imino Groups

4.3.1.2.1 Asymmetric Arylation of Imino Groups

4.3.2 Alkynylation of Carbonyl and Imino Groups

4.3.2.1 Alkynylation of Carbonyl Compounds

4.3.2.1.1 Alkynylation of Aldehydes


4.3.2.1.2 Alkynylation of Acid Chlorides

4.3.2.1.3 Alkynylation of Ketones

4.3.2.2 Alkynylation of Imino Groups

4.3.2.2.1 Alkynylation of Imines

4.3.2.2.2 Alkynylation of Iminium Ions

4.3.2.2.3 Alkynylation of Acylimines or Acyliminium Ions


4.4 Aldol Reaction

4.4.1 Indirect Catalytic Aldol Addition Reactions

4.4.1.1 Mukaiyama-Type Aldol Reactions

4.4.1.1.1 Application of Bis(4,5-dihydrooxazole) Ligands

4.4.1.1.2 Application of Crown Ether Type Ligands

4.4.1.1.3 Europium-Catalyzed Mukaiyama Aldol Reactions

4.4.1.1.4 Application of a Trost-Type Semicrown Ligand

4.4.1.1.5 Application of Iron(II) and Zinc(II) Complexes

4.4.1.1.6 Hydroxymethylation of Silyl Enol Ethers

4.4.2 Direct Catalytic Aldol Reactions

4.4.2.1 Enamine-Based Direct Aldol Reactions

4.4.2.1.1 Synthesis of 2-[Aryl(hydroxy)methyl]cycloalkanones

4.4.2.1.2 Synthesis of 4-Aryl-4-hydroxybutan-2-ones

4.4.2.1.3 Synthesis of syn-Æ-Methyl-�-hydroxy Ketones

4.4.2.1.4 Synthesis of Alcohols Containing a Quaternary Carbon Atom

4.4.2.1.5 Synthesis of 1,4-Dihydroxylated Ketones

4.4.2.1.6 Synthesis of syn-3,4-Dihydroxylated Ketones

4.4.2.1.7 Synthesis of 1,3,4-Trihydroxylated Ketones

4.4.2.1.8 Synthesis of 1,3-Dihydroxylated Compounds

4.4.2.1.9 Synthesis of Erythrose and Threose Derivatives

4.4.2.2 Direct Aldol Reactions Assisted by Chiral Metal Complexes

4.4.2.2.1 Synthesis of Hydroxymethyl Ketones



4.5 Mannich Reaction and Baylis–Hillman Reaction

4.5.1 Mannich Reaction

4.5.1.1 Reaction Catalyzed by Organometals

4.5.1.1.1 Lewis Acids

4.5.1.1.1.1 Reaction Using a Preformed Imine or a Preformed Enolate

4.5.1.1.1.2 One-Pot Three-Component Reaction

4.5.1.1.1.3 Stereoselective Methods

4.5.1.1.2 Lewis Bases

4.5.1.2 Reaction Catalyzed by Brønsted Acids or Bases

4.5.1.2.1 Brønsted Acids

4.5.1.2.2 Brønsted Bases

4.5.1.2.3 Enantioselective Methods

4.5.1.3 Chiral Amine Catalysis via an Enamine Intermediate

4.5.1.3.1 syn-Selective Mannich Reaction

4.5.1.3.2 anti-Selective Mannich Reaction

4.5.1.3.3 Application in Total Synthesis

4.5.1.4 Autocatalysis

4.5.1.5 Biocatalyzed Mannich Reaction

4.5.2 Baylis–Hillman Reaction

4.5.2.1 Stereoselective Baylis–Hillman Reaction

4.5.2.2 Biocatalyzed Baylis–Hillman Reaction

5 Aqueous Media: Cyclization, Rearrangement, Substitution,Cross Coupling, Oxidation, and Other Reactions


5.1 Cycloaddition and Cyclization Reactions

5.1.1 Cycloadditions

5.1.1.1 Diels–Alder Cycloadditions

5.1.1.1.1 Hetero-Diels–Alder Cycloadditions

5.1.1.1.2 Lewis Acid Catalyzed Diels–Alder Cycloadditions

5.1.1.2 1,3-Dipolar Cycloadditions

5.1.1.2.1 Nitrile Imine Cycloadditions


5.1.1.2.2 Nitrile Oxide Cycloadditions

5.1.1.2.3 Diazo Compound Cycloadditions

5.1.1.2.4 Azide Cycloadditions

5.1.1.2.5 Azomethine Ylide Cycloadditions

5.1.1.2.6 Nitrone Cycloadditions

5.1.2 Cyclization Reactions

5.1.2.1 Barbier-Type Cyclizations

5.1.2.2 Epoxide-Opening Cascade Cyclizations

5.1.2.3 Radical Cyclizations


5.2 Pericyclic Rearrangements: Sigmatropic, Electrocyclic, and Ene Reactions

5.2.1 Sigmatropic Rearrangement

5.2.1.1 Claisen Rearrangement

5.2.1.1.1 First Examples in Water

5.2.1.1.2 Rearrangement of Allyl Vinyl Ethers

5.2.1.1.3 Rearrangement of Allyl Aryl Ethers

5.2.1.1.4 Claisen Rearrangement Coupled with Other Reactions

5.2.1.1.5 Aza-Claisen Rearrangements

5.2.1.2 Cope Rearrangement

5.2.1.2.1 Rearrangement of Compounds Containing a Hydrophilic Group

5.2.1.2.2 Catalyzed Rearrangement

5.2.1.2.3 Aza-Cope Rearrangement

5.2.1.3 [1,5] Rearrangement

5.2.1.4 [2,3] Rearrangement

5.2.1.4.1 Rearrangement of Allyl Sulfoxides

5.2.1.4.2 Rearrangement of Sulfonium and Ammonium Ylides

5.2.2 Electrocyclic Rearrangement

5.2.2.1 4�-Electrocyclic Rearrangement

5.2.2.2 6�-Electrocyclic Rearrangement

5.2.3 Ene Reaction

5.2.3.1 Photoinduced Reaction

5.2.3.2 Aza-Ene Reaction

5.2.3.3 Ene-Like Reaction

5.2.3.4 Catalyzed Reactions



5.3 Allylic and Aromatic Substitution Reactions

5.3.1 Allylic Substitution

5.3.1.1 Palladium-Catalyzed Substitution

5.3.1.1.1 Using Water-Soluble Ligands

5.3.1.1.1.1 Substitution of Allylic Esters

5.3.1.1.1.1.1 Intermolecular Allylic Substitution

5.3.1.1.1.1.2 Intramolecular Allylic Substitution

5.3.1.1.1.2 Substitution of Allylic Alcohols

5.3.1.1.2 Using Amphiphilic Polymeric Ligands

5.3.1.1.3 Using Additives

5.3.1.1.4 Miscellaneous Metal-Catalyzed Systems

5.3.1.2 Metal-Mediated Substitution

5.3.1.3 Allylic Substitution with Calixarene Catalysts

5.3.1.4 Asymmetric Allylic Substitution

5.3.1.4.1 Substitution of Acyclic Allylic Systems

5.3.1.4.2 Substitution of Cyclic Allylic Systems

5.3.2 Aromatic Substitution

5.3.2.1 Electrophilic Aromatic Substitution

5.3.2.1.1 Electrophilic Substitution of Indoles

5.3.2.1.1.1 Synthesis of Bis(indolyl)methanes

5.3.2.1.1.2 Synthesis of 3-Substituted Indoles

5.3.2.1.1.2.1 Nucleophilic Addition of Indoles

5.3.2.1.1.2.2 Michael Addition of Indoles

5.3.2.1.2 Electrophilic Substitution of Benzenes

5.3.2.1.2.1 Indium-Catalyzed Aromatic Substitution

5.3.2.1.2.2 Sulfonic Acid Catalyzed Aromatic Substitution

5.3.2.2 Nucleophilic Aromatic Substitution

5.3.2.2.1 Intermolecular C-N and C-S Bond-Forming Substitution

5.3.2.2.2 Intramolecular C-N and C-S Bond-Forming Substitution



5.4 Cross-Coupling and Heck Reactions

5.4.1 Palladium-Catalyzed Coupling Reactions

5.4.1.1 C-C Bond-Forming Reactions

5.4.1.1.1 Mizoroki–Heck Reaction

5.4.1.1.1.1 Aqueous Ligand-Free Palladium-Catalyzed Heck Coupling

5.4.1.1.1.2 Aqueous Heck Coupling Catalyzed by Palladium–Nitrogen Complexes

5.4.1.1.1.3 Aqueous Palladium-Catalyzed Heck Coupling Employing HydrophobicPhosphine Ligands

5.4.1.1.1.4 Aqueous Palladium-Catalyzed Heck Couplings Employing HydrophilicPhosphine Ligands

5.4.1.1.1.5 Aqueous Palladacycle-Catalyzed Heck Coupling

5.4.1.1.1.6 Aqueous Heck Couplings Catalyzed by Supported Palladium Complexes

5.4.1.1.2 Suzuki–Miyaura Coupling

5.4.1.1.2.1 Aqueous Ligand-Free Palladium-Catalyzed Suzuki–Miyaura Coupling

5.4.1.1.2.2 Aqueous Suzuki–Miyaura Coupling Catalyzed by Palladium–Nitrogen Complexes

5.4.1.1.2.3 Aqueous Palladium-Catalyzed Suzuki–Miyaura Coupling EmployingHydrophobic Phosphine or N-Heterocyclic Carbene Ligands

5.4.1.1.2.4 Palladium-Catalyzed Suzuki–Miyaura Coupling Employing Hydrophilic Ligands

5.4.1.1.2.5 Aqueous Palladacycle-Catalyzed Suzuki–Miyaura Coupling

5.4.1.1.2.6 Aqueous Suzuki–Miyaura Couplings Catalyzed by Supported Palladium Complexes

5.4.1.1.3 Sonogashira Coupling

5.4.1.1.3.1 Aqueous Ligand-Free Palladium-Catalyzed Sonogashira Coupling

5.4.1.1.3.2 Aqueous Sonogashira Coupling Catalyzed by Palladium–Nitrogen Complexes

5.4.1.1.3.3 Aqueous Sonogashira Coupling Employing Hydrophobic Phosphine Ligands

5.4.1.1.3.4 Aqueous Sonogashira Coupling Catalyzed by Supported Palladium Complexes

5.4.1.1.4 Hiyama Coupling

5.4.1.1.4.1 Aqueous Ligand-Free Palladium-Catalyzed Hiyama Coupling

5.4.1.1.4.2 Aqueous Hiyama Coupling Catalyzed by Palladium–Nitrogen Complexes

5.4.1.1.4.3 Aqueous Hiyama Coupling Catalyzed by Palladium–Phosphine Complexes

5.4.1.1.4.4 Aqueous Oxime Palladacycle Catalyzed Hiyama Coupling

5.4.1.1.5 Kosugi–Migita–Stille Coupling

5.4.1.1.6 Ullmann-Type Coupling

5.4.1.1.7 Negishi Coupling

5.4.1.1.8 C-H Activation

5.4.1.1.9 Cyanation Reactions


5.4.1.2 Carbon-Heteroatom Bond-Forming Reactions

5.4.1.2.1 Buchwald–Hartwig Amination

5.4.2 Copper-Catalyzed Cross-Coupling Reactions

5.4.2.1 C-C Bond-Forming Reactions

5.4.2.1.1 Sonogashira–Hagihara Reaction

5.4.2.1.2 Cyanation Reactions

5.4.2.2 Carbon-Heteroatom Bond-Forming Reactions

5.4.2.2.1 Aqueous Copper-Catalyzed C-N Bond-Forming Reactions

5.4.2.2.2 Aqueous Copper-Catalyzed C-S Bond-Forming Reactions

5.4.2.2.3 Aqueous Copper-Catalyzed C-O Bond-Forming Reactions


5.5 Ring Opening of Epoxides and Aziridines

5.5.1 Ring-Opening Reactions of Epoxides

5.5.1.1 Epoxide Ring Opening with Oxygen Nucleophiles

5.5.1.1.1 Noncatalyzed Epoxide Ring Opening

5.5.1.1.2 Small Organic Molecule Catalyzed Epoxide Ring Opening

5.5.1.1.3 Metal-Catalyzed Epoxide Ring Opening

5.5.1.1.3.1 Using Zirconium(IV) Tetrakis(dodecyl sulfate)

5.5.1.1.3.2 Using Cobalt–Salen Complexes

5.5.1.1.3.3 Using Scandium–Chiral Bipyridine Complexes

5.5.1.2 Epoxide Ring Opening with Nitrogen Nucleophiles

5.5.1.2.1 Epoxide Ring Opening with Amines

5.5.1.2.1.1 Noncatalyzed Epoxide Ring Opening with Amines in Water

5.5.1.2.1.2 Small Organic Molecule Catalyzed Aminolysis

5.5.1.2.1.3 Metal-Catalyzed Aminolysis

5.5.1.2.1.4 Aminolysis Catalyzed by Chiral Lewis Acids

5.5.1.2.2 Epoxide Ring Opening with Azide

5.5.1.2.2.1 Metal-Catalyzed Azidolysis

5.5.1.2.2.1.1 Using Zirconium(IV) Tetrakis(dodecyl sulfate)

5.5.1.2.2.1.2 Using Copper(II) Nitrate

5.5.1.2.3 Epoxide Ring Opening with Other Nitrogen-Containing Nucleophiles

5.5.1.3 Epoxide Ring Opening with Thiols

5.5.1.3.1 Noncatalyzed Epoxide Ring Opening with Thiols

5.5.1.3.2 Metal-Catalyzed Epoxide Ring Opening with Thiols


5.5.1.3.2.1 Using Indium(III) Chloride

5.5.1.3.2.2 Using Scandium(III) Tris(dodecyl sulfate)

5.5.1.4 Epoxide Ring Opening with Carbon Nucleophiles

5.5.2 Ring-Opening Reactions of Aziridines

5.5.2.1 Aziridine Ring Opening with Oxygen Nucleophiles

5.5.2.1.1 Noncatalyzed Aziridine Ring Opening with Oxygen Nucleophiles

5.5.2.1.2 Aziridine Ring Opening with Oxygen Nucleophiles Promoted byTributylphosphine and Silica Gel

5.5.2.2 Aziridine Ring Opening with Nitrogen Nucleophiles

5.5.2.2.1 Noncatalyzed Aziridine Ring Opening with Nitrogen Nucleophiles

5.5.2.2.2 Small Organic Molecule Catalyzed Aziridine Ring Opening withNitrogen Nucleophiles

5.5.2.3 Aziridine Ring Opening with Sulfur Nucleophiles

5.6 Asymmetric Æ-Functionalization of Carbonyl Compounds andAlkylation of EnolatesS. Shirakawa and K. Maruoka

5.6 Asymmetric Æ-Functionalization of Carbonyl Compounds andAlkylation of Enolates

5.6.1 Asymmetric Alkylation

5.6.1.1 Asymmetric Benzylation of Glycine Derivatives for the Synthesis ofPhenylalanine Derivatives

5.6.1.1.1 Asymmetric Alkylation of Glycine Derivatives for the Synthesis ofÆ-Alkyl-Æ-amino Acids

5.6.1.2 Asymmetric Æ-Alkylation of Ketones

5.6.1.3 Asymmetric Alkylation of �-Keto Esters

5.6.1.4 Asymmetric Alkylation of Diaryloxazolidine-2,4-diones

5.6.1.5 Asymmetric Æ-Alkylation of Aldehydes with Alcohols

5.6.2 Asymmetric Alkenylation and Alkynylation

5.6.2.1 Asymmetric Alkenylation of �-Keto Esters

5.6.2.1.1 Asymmetric Alkynylation of �-Keto Esters

5.6.3 Asymmetric Oxidation

5.6.3.1 Asymmetric Æ-Hydroxylation of Ketones

5.6.3.2 Asymmetric Æ-Oxyamination of Aldehydes

5.6.4 Asymmetric Amination

5.6.4.1 Asymmetric Amination of �-Keto Esters

5.6.5 Asymmetric Fluorination

5.6.5.1 Asymmetric Fluorination of �-Keto Esters



5.7 Oxidation of Alcohols, Allylic and Benzylic Oxidation, Oxidation of Sulfides

5.7.1 Water-Soluble Ligands

5.7.2 Biomimetic Metalloporphyrins and Metallophthalocyanines

5.7.3 Enzymatic Oxidations: Oxidoreductases

5.7.4 Alcohol Oxidations in Aqueous Media

5.7.4.1 Tungsten(VI) Catalysts

5.7.4.2 Palladium–Diamine Complexes as Catalysts

5.7.4.3 Noble Metal Nanoparticles as Quasi-homogeneous Catalysts

5.7.4.4 Ruthenium and Manganese Catalysts

5.7.4.5 Organocatalysts: Hypervalent Iodine Compounds and Stable N-Oxyl Radicals

5.7.4.6 Enzymatic Oxidation of Alcohols

5.7.5 Benzylic and Allylic Oxidations in Water

5.7.5.1 Benzylic Oxidations

5.7.5.2 Allylic Oxidations

5.7.6 Sulfoxidations in Water

5.7.6.1 Tungsten- and Vanadium-Catalyzed Oxidations with Hydrogen Peroxide

5.7.6.2 Enantioselective Sulfoxidation with Enzymes

5.7.6.3 Flavins as Organocatalysts for Sulfoxidation

5.7.7 Concluding Remarks


5.8 Free-Radical Reactions

5.8.1 Reductive Processes

5.8.1.1 Reductions with Metal Hydrides

5.8.1.2 Reduction with Phosphinic Acid and Its Derivatives

5.8.1.3 Reductions with Trialkylboranes

5.8.1.3.1 With Trialkylborane–Water Complexes

5.8.1.3.2 Triethylborane-Mediated Radical Addition to a C=N Bond

5.8.1.4 Reduction with Inorganic Reducing Agents

5.8.2 Atom Transfer Processes

5.8.3 Fragmentation Processes



5.9 Polymerization

5.9.1 Living Radical Polymerization

5.9.1.1 Nitroxide-Mediated Polymerization

5.9.1.2 Metal-Catalyzed Living Radical Polymerization or Atom-Transfer RadicalPolymerization

5.9.1.3 Reversible Addition–Fragmentation Chain-Transfer Polymerization

5.9.2 Living Radical Suspension Polymerization

5.9.2.1 Iron-Catalyzed Living Radical Polymerization

5.9.2.2 Copper-Catalyzed Living Radical Polymerization

5.9.3 Living Radical Mini-emulsion Polymerization

5.9.3.1 Mini-emulsion with Reverse Atom-Transfer Radical Polymerization

5.9.3.2 Mini-emulsion with AGET Atom-Transfer Radical Polymerization

5.9.3.3 Mini-emulsion with Nitroxide-Mediated Polymerization

5.9.4 Living Radical Emulsion Polymerization

5.9.4.1 Emulsion with Nitroxide-Mediated Polymerization

5.9.4.2 Emulsion with Reversible Addition–Fragmentation Chain-Transfer Polymerization

5.9.5 Homogeneous Aqueous Living Radical Polymerization

5.9.5.1 Homogeneous Aqueous Atom-Transfer Radical Polymerization

5.9.5.2 Homogeneous Aqueous Reversible Addition–Fragmentation Chain-TransferPolymerization

6 Special Techniques with Water


6.1 Organic Synthesis “On Water”

6.1.1 On-Water Reactions

6.1.1.1 Diels–Alder Reactions

6.1.1.2 Dipolar Cycloadditions

6.1.1.3 Cycloadditions of Azodicarboxylates

6.1.1.4 Claisen Rearrangement

6.1.1.5 Passerini and Ugi Reactions

6.1.1.6 Nucleophilic Opening of Three-Membered Rings


6.1.1.7 Nucleophilic Substitution Reactions

6.1.1.8 Transformations Catalyzed by Transition Metals

6.1.1.9 Metal-Free Carbon-Carbon Bond-Forming Processes

6.1.1.10 Bromination Reactions

6.1.1.11 Oxidations and Reductions

6.1.2 Theoretical Studies

6.1.3 Concluding Remarks


6.2 Sub- and Supercritical Water

6.2.1 Properties of Water

6.2.1.1 Macroscopic Properties

6.2.1.2 Microscopic Properties

6.2.1.3 Special Aspects of Heterogeneous Catalysis

6.2.2 Synthesis Reactions

6.2.2.1 Hydrolysis/Water Addition Reactions

6.2.2.2 Condensation/Water Elimination Reactions

6.2.2.3 Addition Reactions

6.2.2.3.1 Hydroformylation

6.2.2.3.2 Diels–Alder Reaction

6.2.2.3.3 Other Addition and Coupling Reactions

6.2.2.4 Rearrangements

6.2.2.5 Oxidations

6.2.2.6 Reductions

6.2.2.6.1 Using Formic Acid/Formates

6.2.2.6.2 Using Hydrogen and a Noble Metal Catalyst

6.2.2.6.3 Using Zinc

6.2.3 Summary

6.2.4 Outlook

6.2.5 Conclusion



6.3 �-Cyclodextrin Chemistry in Water

6.3.1 Cyclodextrins as Mass-Transfer Additives or Organocatalysts forOrganic Synthesis in Water

6.3.1.1 Glycoside Hydrolysis Using Modified Æ- and �-Cyclodextrin Dicyanohydrins in Water

6.3.1.2 Oxidation of Benzylic Alcohols

6.3.1.3 Deprotection of Aromatic Acetals under Neutral Conditions Using�-Cyclodextrin in Water

6.3.1.4 Cyclodextrin-Promoted Synthesis of 3,4,5-Trisubstituted Furan-2(5H)-ones

6.3.1.5 �-Cyclodextrin-Catalyzed Strecker Synthesis of Æ-Aminonitriles in Water

6.3.1.6 Synthesis of 3-Hydroxy-3-(1H-indol-3-yl)-1,3-dihydro-2H-indol-2-ones underNeutral Conditions in Water

6.3.1.7 Synthesis of Pyrrole-Substituted 1,3-Dihydro-2H-indol-2-ones

6.3.1.8 Friedel–Crafts Alkylation of Indoles

6.3.1.9 Supramolecular Synthesis of Selenazoles Using Selenourea in Water

6.3.1.10 Cyclodextrin-Promoted Nucleophilic Opening of Oxiranes

6.3.1.11 Cyclodextrin-Promoted Michael Reactions of Thiols to Conjugated Alkenes

6.3.1.12 Cyclodextrin-Promoted Mild Oxidation of Alcohols with1-Hydroxy-1,2-benziodoxol-3(1H)-one 1-Oxide

6.3.1.13 Synthesis of Thiiranes from Oxiranes in the Presence of �-Cyclodextrin in Water

6.3.2 Cyclodextrins as Organocatalyst Solubilizers

6.3.2.1 For Organocatalysts with an Adamantyl Subunit

6.3.2.2 For Organocatalysts with a 4-tert-Butylphenyl Subunit

6.3.3 Cyclodextrins as Mass-Transfer Additives in Aqueous Organometallic Catalysis

6.3.4 Cyclodextrins as Ligands for Metal-Catalyzed Reactions

6.3.5 Cyclodextrins as Stabilizers of Water-Soluble Noble Metal Nanoparticles

6.3.6 Cyclodextrins as Dispersing Agents of Catalytically Active Solids

6.3.6.1 Cyclodextrins as Dispersing Agents of Supported Metals

6.3.6.2 Cyclodextrins as Dispersing Agents of Metallic Powder


7 Industrial Application


7.1 Hydroformylation

7.1.2 Immobilized Oxo Catalysts

7.1.3 Biphasic Catalyst System

7.1.4 Ruhrchemie/Rh�ne-Poulenc Process

7.1.4.1 Reaction

7.1.4.2 Recycle and Recovery of the Aqueous Catalyst

7.1.4.2.1 Recycle

7.1.4.2.2 Recovery

7.1.4.3 Economics of the Process

7.1.4.4 Environmental Aspects

7.1.5 Conclusions


7.2 Industrial Applications Other than Hydroformylation

7.2.1 Classical Reactions

7.2.1.1 Hydrolysis

7.2.1.2 Hydration

7.2.1.3 Homogeneous Mixed-Solvent Systems

7.2.1.4 Heterogeneous Mixed-Solvent Systems

7.2.2 Metal-Catalyzed Reactions

7.2.2.1 Palladium-Catalyzed Coupling Reactions

7.2.2.2 Palladium-Catalyzed Telomerization of Butadiene

7.2.2.3 Lewis Acid Catalysis

7.2.3 Enzymatic Reactions

7.2.3.1 Synthesis of Tamiflu

7.2.3.2 Synthesis of Statins (Lipitor and Crestor)

7.2.3.3 Synthesis of LY300164

7.2.3.4 Synthesis of Pregabalin

7.2.3.5 Synthesis of 6-Aminopenicillanic Acid

7.2.3.6 Synthesis of Rhinovirus Protease Inhibitor Intermediates


7.2.3.7 Synthesis of a GABA Inhibitor

7.2.3.8 Synthesis of an HIV Protease Inhibitor

7.2.3.9 Synthesis of Pelitrexol

7.2.4 Other Reactions

7.2.5 Conclusions and Perspectives

8 Perspective: The New World of Organic Chemistry Using Water as SolventS. Kobayashi

8 Perspective: The New World of Organic Chemistry Using Water as Solvent

8.1 Palladium-Catalyzed Allylic Amination Using Aqueous Ammonia

8.2 Aldehyde Allylation with Allylboronates in Aqueous Media

8.3 Catalytic Use of Indium(0) for C-C Bond Transformations in Water

8.4 Conclusions and Outlook

Keyword Index

Author Index

Abbreviations


Abstracts


Water is a unique liquid that unites within it an unusually large number of anomalouschemical and physical properties. This review discusses a number of these propertieswith a special focus on how these impact on the reactivity of neutral and ionic organicmolecules in aqueous solution. Both homogeneous and heterogeneous aqueous reactionconditions are discussed.

O

HH O

HO

H

H

H

O

H

H

H

OHH

HO H

OH

HO

H

HOH

O HH

Keywords: water • hydrogen bonding • hydrophobic hydration • hydrophobic interac-tions • ionic hydration • thermodynamics • transition-state theory • solvent parameters •

catalysis • green chemistry

3.1 Asymmetric Oxidation Reactions: Sulfoxidation, Epoxidation, Dihydroxylation, andAminohydroxylationT. Katsuki

The following asymmetric oxidation reactions using transition-metal catalysts or organo-catalysts in water or in aqueous–organic solvent systems are discussed: sulfoxidation, ep-oxidation, dihydroxylation, and aminohydroxylation. Although various oxidants areavailable for these oxidation reactions, a particular focus is placed on those processes us-ing aqueous hydrogen peroxide, an atom-efficient and inexpensive reagent. Some exam-ples of how water affects oxidative catalysis with transition-metal complexes are also de-scribed.

SR2R1 S

R2R1transition-metal catalyst, aq H2O2

H2O or aqueous−organic solvent

O

Water in Organic Synthesis: Abstracts 29

O

transition-metal catalyst or organocatalyst

aq H2O2, O2, or aq t-BuOOH

H2O or aqueous−organic solvent

transition-metal catalyst

K3Fe(CN)6, aq H2O2

aqueous−organic solvent

transition-metal catalyst

aqueous−organic solvent

HO OH

HO HN

R2

R1 R3

R4 R2

R1

R4

R3

R2

R1

R4

R3

R5

R2

R1

R4

R3

XN

R5M+

Keywords: aminohydroxylation • aqueous–organic systems • asymmetric catalysis • di-hydroxylation • epoxidation • hydrogen peroxide • molecular oxygen • organocatalysis •

sulfoxidation • transition-metal catalysis • water


Alkenes, alkynes, arenes, and hetarenes in aqueous systems can be hydrogenated withwater-soluble transition-metal complexes as well as with colloidal (nanosize) metal cata-lysts. In the case of water-insoluble substrates, the reactions proceed in aqueous–organicbiphasic mixtures. Several water-soluble ligands (mostly tertiary phosphines) have beendeveloped for the synthesis of soluble metal complex catalysts for hydrogenation. Chiralphosphine complexes are efficient for asymmetric hydrogenation of prochiral alkenes.Selective hydrogenation of dienes to monoenes and alkynes to alkenes has also been de-veloped in aqueous systems; in the latter case, a substantial degree of stereoselectivity forthe Z- or E-alkenes can also be achieved. Hydrogenation of polymers in aqueous emul-sions leads to products with improved properties regarding strength and chemical stabil-ity. Stabilized metal colloids play a prominent role in the hydrogenation of arenes andhetarenes in aqueous systems; stable and catalytically highly active colloids can be ob-tained by using commercially available or easily prepared protective polymers or surfac-tants.


H2water-soluble complex catalysts

or

stabilized metal nanoparticles

N NH

H2O H2O

+

+

Keywords: alkenes • alkynes • arenes • asymmetric hydrogenation • biodiesel • biphasic •

chiral phosphine • colloids • dienes • hetarenes • hydrogenation • polymers • lignin degra-dation compounds • microemulsion • palladium • poly(butadiene) • rhodium • ruthenium •

soybean oil • styrene–butadiene rubber • sulfonated triphenylphosphine


The activity and selectivity of hydroformylation catalysts can be modified by the presenceof phosphorus-, nitrogen-, or sulfur-containing monodentate or polydentate ligands. Inaddition, functionalization of the ligands with an appropriate number of ionic or hydro-philic solubilizing groups can lead to a very high solubility in water. This chapter de-scribes the hydroformylation of alkenes in aqueous media, with discussion of the ligandsand catalysts used, the mechanism, and industrial application. Hydrocarboxylation in wa-ter is also discussed.

catalyst

aqueous solvent+

linear branched

X = H, OH

HX+ CO +R1R1 O

XH

O

XH

R1

Keywords: hydroformylation • phosphine ligands • mechanism • sulfonated phosphines •

TPPTS • rhodium catalysts • asymmetric hydroformylation • hydrocarboxylation


Conjugate addition reactions of H-, C-, N-, O-, and S-nucleophiles, generally called Michaeladditions, are frequently used in the synthesis of a wide range of �-functionalized com-


pounds from alkenes or alkynes bearing electron-withdrawing groups. The use of waterin organic synthesis has been expanding steadily as a result of academic curiosity as wellas environmental consciousness. Remarkable progress has been made in aqueous conju-gate addition reactions in recent years. In this review, the description of methods for con-jugate addition reactions in aqueous media is subdivided on the basis of the variousclasses of nucleophiles: H-, C-, N-, O-, and S-nucleophiles. In addition, these are furthersubdivided on the basis of the catalytic reaction conditions: catalyst-free, metal-complexcatalyst, and metal-free catalyst (organocatalyst).

EWG + EWGNu

EWG = CHO, COR1, CO2R1, CONR12, CN, NO2, PO(OR1)2, SO2R1;

Nu = H, CR23, NR2

2, OR2, SR2

Nu−H2O

Keywords: asymmetric synthesis • aza-Michael addition • catalyst-free • conjugate addi-tion • conjugate reduction • metal-complex catalysis • metal-free catalysis • Michael addi-tion • Mukaiyama–Michael addition • organocatalysis • oxa-Michael addition • thia-Michaeladdition • aqueous conditions


This chapter describes methods for cyclopropanation reactions in water, including tran-sition-metal-mediated reactions of diazo compounds, triphenylarsine-mediated cyclopro-panation, and radical reaction of halogenated compounds with zinc. It focuses on the lit-erature published in the period 2000–2010.

Ph + +

catalyst

H2O, 25 oC, 24 hCO2Et

N2

Ph CO2Et Ph CO2Et

N

N N

N

SO3NaNaO3S

SO3Na

SO3Na

Mcatalyst =

M = FeCl, Ru(CO)

Keywords: cyclopropanes • alkene cyclopropanation • asymmetric cyclopropanation •

asymmetric catalysis • chiral complexes • radical cyclization • arsonium ylides



Next to the known favorable properties of water itself, such as being cost efficient, non-toxic, and nonflammable, the use of water as a reaction medium for homogeneous alkenemetathesis has various advantages. For instance, it allows the modification of biomole-cules as well as the mild and convenient synthesis of polymers from cyclic alkenes viaemulsion ring-opening polymerization. The catalysts of choice for aqueous alkene me-tathesis are almost exclusively based on ruthenium, and certain strategies have been de-veloped in order to enhance their stability in aqueous media and provide robust catalyticsystems with long active lifetimes. These strategies include various catalyst modifica-tions, immobilization of the catalyst, or working in emulsions.

This chapter focuses on alkene metathesis reactions performed in water or in water–organic solvent mixtures. Both the homogeneous and heterogeneous variants of aqueousmetathesis reaction are presented. The stability of common metathesis catalysts in aque-ous media is discussed, stressing the exceptionally high stability of ruthenium alkylidenecomplexes in water. The application of aqueous alkene metathesis in protein modifica-tion is presented.

Ru

Cl

Cl

OPri

N N MesMes

N

Me

EtEt

I−Ru

Cl

Cl

OPri

N N MesMes

NMe3

Cl−

NH3

Cl−

5 mol% catalyst, H2OMe3NMe3N

Cl−Cl−

Keywords: alkenes • carbenes • carbon-carbon bonds • carbon-carbon coupling • crossmetathesis • emulsion polymerization • ligands • metal–carbene complexes • metathesis •

molybdenum catalysts • protein modification • ruthenium catalysts • ruthenium com-plexes • ring-closing metathesis • ring-opening polymerization • supported catalysis • water

4.1 Reduction of Carbonyl Groups and Imino GroupsX. Wu and J. Xiao

Carbonyl and imino groups appear in countless compounds, and their reduction is one ofthe most fundamental reactions in synthetic chemistry. This chapter deals with the re-duction of carbonyl and imino compounds in water, covering nonasymmetric hydrogena-tion and transfer hydrogenation of aldehydes, ketones, carbon dioxide, and imino bonds,and asymmetric hydrogenation and transfer hydrogenation of ketones and imino species.

R1 R2

X

R1 R2

XH[H]

catalyst, H2O

X = O, NR3; [H] = H2, HCO2H, HCO2H, iPrOH


Keywords: ketones • aldehydes • carbon dioxide • imines • iminium salts • alcohols •

amines • hydrogenation • transfer hydrogenation • asymmetric catalysis


Metal-mediated Barbier–Grignard-type addition of simple alkyl groups, allyl groups, andbenzyl groups to carbonyl compounds and imine derivatives in aqueous media, as well asthe mechanisms and synthetic applications of such reactions, are reviewed in this chap-ter.

R1X +Z

R2 R3

M, H2O

R1 = alkyl, allyl, benzyl; Z = O, NR4

R2 R3

R1 ZH

Keywords: aldehyde • allylation • alkylation • Barbier–Grignard-type reactions • benzyla-tion • imines • indium • nucleophilic addition • organic halides • tin • zinc


Metal-mediated and -catalyzed Barbier–Grignard-type addition of aromatic groups, vinylgroups, and alkynyl groups to carbonyl compounds and imine derivatives in aqueous me-dia, as well as the mechanisms and synthetic applications of such reactions, are reviewedin this chapter.

+Z

R2 R3

MLn (cat.), H2OR1MX

R1 = aryl, vinyl; Z = O, NR4

R2 R3

ZHR1

X = O, NR4

R1 +X

R2 R3

MLn (cat.), H2O

R1

XR2

R3

Keywords: aldehydes • alkynes • alkynylation • arylation • Barbier–Grignard-type reac-tions • copper • gold • imines • nucleophilic addition • rhodium • ruthenium • silver • tran-sition-metal catalysis


This chapter highlights development in aldol-type bond-forming reactions catalyzed bymetal complexes and organocatalysts in aqueous media with and without the additionof organic solvents.


O

R1

R2

R3

OH

O

R1R2

OSiR43

R1R2

R3CHO

small organic molecules

aqueous solvents

metal complexes

Keywords: aldol reaction • Mukaiyama reaction • Lewis acid • aldols • hydroxymethyla-tion • asymmetric synthesis • organocatalysis • water


Mannich reactions and Baylis–Hillman reactions are C-C bond-forming transformationsthat give access to highly functionalized compounds. Mannich products, i.e. �-amino car-bonyl compounds, are generated from imines and enolizable carbonyl derivatives, where-as Baylis–Hillman products, i.e. Æ-methylene-�-hydroxy carbonyl compounds, are ob-tained from aldehydes and Æ,�-unsaturated carbonyl derivatives. These reactions are cat-alyzed by metals, organocatalysts, or enzymes, and the development of water-tolerantcatalysts has allowed these reactions to be carried out under aqueous conditions. Insome cases the use of additives such as surfactants has allowed the complete omissionof organic solvents, with the reactions proceeding in the presence of only water. The useof water as a solvent for organic reactions in some cases promotes an acceleration of therate of the reaction and/or an increase in stereoselectivity. Furthermore, the harmless andenvironmentally benign character of water makes it an environmentally acceptable sol-vent. This review covers methods for promoting Mannich reactions and Baylis–Hillmanreactions under aqueous conditions (homogeneous solvent mixtures) or in the presenceof water (biphasic solvent systems), and the beneficial effect of water is illustrated and ex-plained.

R2 H

NR1

R2

NH

Mannich reaction:

+catalyst, H2O

O

R4

R3R4

R3

OR1

R1 H

O

R1 R2

OOHO

R2+

Baylis–Hillman reaction:

catalyst, H2O

Keywords: Mannich reaction • Baylis–Hillman reaction • imines • enolates • Lewis acidcatalysts • Lewis base catalysts • Brønsted acids • Brønsted bases • chiral amines • organo-metallic catalysts • organocatalysts • enamines • �-amino carbonyl derivatives • Æ-methyl-ene-�-hydroxy carbonyl derivatives • acrylic compounds • Æ,�-unsaturated carbonyl deriv-atives • water • surfactants



This chapter is devoted to the systematic discussion of relevant examples of cycloadditionand cyclization reactions that occur in water or aqueous media. In order to broaden thediscussion and enhance the relevance, comparisons between water-promoted reactionsand the same reactions carried out in organic solvents are presented whenever possible.The organization of the chapter reflects the main kinds of cycloadditions and cycliza-tions. For the sake of clarity, Diels–Alder, hetero-Diels–Alder, and Lewis acid catalyzedDiels–Alder reactions are presented first, followed by 1,3-dipolar cycloadditions. The lat-ter reactions are arranged according to the 1,3-dipole type, namely nitrile imines, nitrileoxides, diazo compounds, azides, azomethine ylides, and nitrones. A further section ofthe chapter is devoted to the presentation of water-promoted Barbier-type cyclizations,epoxide-opening cascade cyclizations, and radical cyclizations.

H2O, 90 oCO

O

O

CO2H

CO2H

OO

CO2HH2O

CO2H

Keywords: Diels–Alder cycloadditions • Lewis acids • 1,3-dipolar cycloadditions • nitrileimines • nitrile oxides • azides • azomethine ylides • nitrones • Barbier cyclizations • epoxidering opening • radical cyclizations


This reviews describes the beneficial effects of aqueous media on both the reactivity andselectivity of sigmatropic rearrangements, electrocyclic reactions, and ene reactions.

Cl

O "on water"

23 oC, 120 h

Cl

OH

100%

Keywords: sigmatropic rearrangements • Claisen rearrangement • Cope rearrangement •

electrocyclic reactions • ene reaction


Substitution of allylic alcohols, ethers, and esters with C-, N-, O-, and S-nucleophiles pro-ceeds in water in the presence of water-compatible palladium complexes to give the cor-responding substituted products. In addition to these reactions, metal-mediated (e.g. indi-um or zinc) allylic substitutions, calixarene catalysis, heterogeneous catalysis, as well asasymmetric catalysis are also described.

Indoles and electron-rich aromatics react with carbonyl compounds and electron-de-ficient alkenes in water to give the corresponding substituted products (e.g., 3-substituted


indoles). These reactions are also discussed in this chapter, together with selected exam-ples of recent progress in nucleophilic aromatic substitution in water.

R1 R2

X[Pd]/L, H2O

R1 R2

Pd

R1 R2

Nu

R2R1

Nu

+

+ Nu−

L = water-compatible ligand

NH

NH

X

R1 R2

NH

R1X

R2

XHR1

R1

Keywords: allylic substitution • �-allylpalladium • allylic ester • allylic alcohol • indium •

zinc • calixarene • amphiphilic polymer • heterogeneous catalysis • asymmetric catalysis •

asymmetric substitution • bis(indolyl)methane • 3-substituted indole • Michael addition •

haloarene • intramolecular cyclization • scandium(III) tris(dodecyl sulfate) • tungstophos-phate • copper—porphyrazine


This chapter describes the best available methods to perform palladium- and copper-cata-lyzed Heck and cross-coupling reactions in neat water. The chapter is divided into twogeneral sections according to the metal catalyst employed. Each section is further subdi-vided by the type of bond formed and the specific type of coupling which leads to thisbond formation. Both homo- and heterogeneous catalysis protocols are considered. Thechapter provides the reader with background information, evaluated methods, practicalapplications, and a detailed overview of the latest trends in palladium- and copper-cata-lyzed aqueous Heck-type and cross-coupling reactions, covering the literature up to 2011.

Pd Cu

H2O

Mizoroki–Heck

Suzuki–Miyaura

Sonogashira–Hagihara

Hiyama

Kosuki–Migita–Stille

UllmannNegishi

C—H activation

cyanation

Buchwald–Hartwig


Keywords: aqueous • palladium catalysts • copper catalysts • palladacycles • supportedcatalysis • Heck reaction • Suzuki coupling • Stille coupling • Sonogashira reaction • Hiyamacoupling • Negishi coupling • C-H activation • Buchwald–Hartwig amination • cyanation


Epoxides and aziridines are excellent synthetic intermediates, since they are readily con-verted into other functional groups such as diols, amino alcohols, and diamines. Whilethere are many reports of ring-opening reactions of these cyclic compounds with variousnucleophiles in organic solvents, including asymmetric versions, similar reactions in wa-ter seem to be difficult, since water may attack these substrates instead of attack of thedesired nucleophile. However, because the use of water is attractive not only for the de-velopment of green chemistry but also for exploring unique reactivity, significant effortstoward developing these reactions in water have been made. In this chapter, ring-openingreactions of epoxides and aziridines in water as the sole solvent are discussed.

X

R1 XH

NuR2

R1 Nu

XHR2

+

R1

R2

nucleophile, H2O

X = O, NR3; Nu = OH, OR4, NR4R5, N3, SR4

Keywords: amino alcohols • aziridines • diamines • enantioselectivity • epoxides • Lewisacid/surfactant combined catalysts • ring opening • sulfanyl alcohols

5.6 Asymmetric Æ-Functionalization of Carbonyl Compounds and Alkylation of EnolatesS. Shirakawa and K. Maruoka

The asymmetric Æ-functionalization of carbonyl compounds in aqueous media is intro-duced in this chapter. Representative examples of asymmetric alkylations, alkenylations,and heteroatom functionalizations of various carbonyl compounds under aqueous/organ-ic biphasic phase-transfer conditions are summarized along with detailed experimentalprocedures. The organocatalyzed asymmetric Æ-alkylation and Æ-oxidation reactions ofaldehydes in aqueous media are also described.

R1

O

R2

E++

chiral phase-transfer catalyst

aqueous/organic biphasic system

R1

O

R2

E∗

Keywords: alkylation • alkenylation • alkynylation • oxidation • amination • fluorination •

phase-transfer catalysis • organocatalysis • asymmetric synthesis • asymmetric catalysis


Catalytic oxidations of alcohols, benzylic and allylic oxidations, and oxidations of sul-fides, using the environmentally benign dioxygen and hydrogen peroxide as the stoichio-metric oxidant, in aqueous mono- or biphasic systems in the absence of organic solvents,are reviewed. Other oxidants, such as sodium hypochlorite, receive a cursory mention.There is a marked trend toward the use of relatively simple complexes of inexpensive


and more readily available first-row elements (Fe, Mn, and Cu) rather than noble-metalcomplexes. Methods using organocatalysts, notably stable N-oxyl radicals, are becomingincreasingly popular, largely owing to the fact that they are “heavy metal free”. At thesame time, noble-metal nanoparticles (particularly Au and Pd) are becoming increasinglypopular as quasi-homogeneous catalysts for alcohol oxidations. Enzymatic oxidations inconjunction with dioxygen (oxidases) or hydrogen peroxide (peroxidases) are also re-viewed. These various catalytic methodologies constitute green and sustainable alterna-tives to traditional oxidations employing atom-inefficient and toxic stoichiometric oxi-dants.

OH

R1

O

R1

air

watercatalyst

Keywords: green chemistry • catalytic oxidation • stable N-oxyl radicals • noble-metalnanoparticles • enzymatic oxidations • cross-linked enzyme aggregates (CLEAs) • Baeyer–Villiger monooxygenases • flavins • laccase • alcohol oxidation • enantioselective sulfoxi-dation • allylic oxidation • benzylic oxidation


Phosphinate salts play a central role in the radical reduction of organic halides and Bar-ton–McCombie deoxygenation in aqueous media. The phosphinate-mediated reactionsare advantageous due to the low cost, low toxicity, and easy removal of phosphorus-basedinorganic salts. Water as a reaction medium enhances the efficiency of radical addition toalkenes and imines, atom transfer radical cyclization, and allylation of organic halides.

R1XO

R1

SMe

SH

P

OO−

Hinitiator, H2O

R1H

HP

OO−

Hinitiator, H2O

Keywords: radical addition • radical cyclization • radical reaction • reduction • silanes •

germanes • phosphinic acids • deoxygenation • boranes • addition • allylation • atom trans-fer reaction



In this chapter, living (controlled) radical polymerizations using aqueous media are dis-cussed with some selected examples from four typical categories, i.e. mini-emulsion,emulsion, suspension (dispersed or heterogeneous), and homogeneous systems.

L

R1

R2

R1

R2stimulus

H2O

dormant active

R2

R1

propagation

ON

R4

R3

S

Z

S, , halogenL =

Keywords: living radical polymerization • suspension polymerization • mini-emulsion •

emulsion • metal-catalyzed living radical polymerization • atom-transfer radical polymer-ization • nitroxide-mediated polymerization • reversible addition–fragmentation chain-transfer polymerization


This chapter surveys reactions that benefit from being performed “on water”: when in-soluble reactant(s) are stirred in aqueous emulsions or suspensions without the additionof any organic cosolvents. A considerable rate acceleration is often observed in reactionscarried out under these conditions compared to those in organic solvents.

N

N

CO2Me

CO2Me

N

N

CO2Me

MeO2C

+

"on water"

10−15 min

Keywords: on water • Diels–Alder reaction • dipolar cycloaddition • Claisen rearrange-ment • Passerini reaction • Ugi reaction • ring-opening reaction • nucleophilic substitution •

catalysis • coupling reactions • multicomponent reactions • Wittig reaction • bromination •

oxidation • reduction


The reasons to investigate reactions in sub- and supercritical water (SSCW) lie in the ex-traordinary properties of this reaction medium. The high ionic product in the subcriticalrange and the high solubility of compounds in the supercritical range enable a variety ofreactions. The most investigated type of reaction is hydrolysis. Here, water is reactant, sol-vent, and catalyst or catalyst precursor, forming aqueous H+ or OH– ions. A very importantclass of reactions comprises aldol condensation and aldol splitting. In contrast to ambientconditions, these reactions, as well as the Cannizzaro reaction, do not need strong basesas catalysts. Additions and C-C bond-formation reactions are driven by the high pressure


applied in sub- and supercritical water. Here, organometallic reactions such as hydrofor-mylation, Glaser coupling, and especially the Heck reaction are studied. The Diels–Alderreaction can be performed in water at lower temperature, but in the supercritical rangethe solubility of the components is higher, which leads to high reaction rates and yields.Various rearrangements have also been studied, most of them in the subcritical range tobenefit from the high ionic product. The formation of e-caprolactam is of great technicalinterest, the pinacol rearrangement switches the favored product pathway with reactionconditions, and the Claisen rearrangement gives high yields in a special reactor with lowmixing and heating times. Oxidations and reductions are typically catalyzed by heteroge-neous (e.g., metal-on-support) catalysts. Here, the challenge is to find a catalyst that sur-vives the reaction conditions and also shows good selectivity. Successful studies with het-erogeneous metal catalysts are therefore limited. On the other hand, such reactions arewidely used for degradation of biomass. In contrast, oxidations of alkylarenes with man-ganese(II) bromide as catalyst give high yields of the corresponding carbon acids. Homo-geneous reductions with formic acid or its salts are often applied to avoid heterogeneouscatalysts in reductions.

H2O

300−450 oC, 20−35 MPa

HO OH

O

H2O

375−380 oC, 22.5−25 MPa

Keywords: subcritical water • supercritical water • ionic product • tunable solvent • hy-drolysis • condensation • hydroformylation • Diels–Alder reaction • coupling reactions • re-arrangements • oxidation • reduction


This chapter highlights the most relevant reactions using cyclodextrins as mass-transferadditives, organocatalysts, solubilizers of organocatalysts, ligands for organometalliccomplexes, stabilizers of noble-metal nanoparticles, or dispersing agents for catalyticallyactive solids. The emphasis is on reactions where the cyclodextrins are readily availableand for which the performance has been demonstrated in terms of activity and selectivi-ty. Throughout this chapter, the modification of cyclodextrins is correlated to the abilityto interact with organic guest or to adsorb on the surface of solids.

aqueous phase

product

PS

substrate


Keywords: cyclodextrin • mass-transfer additive • organocatalyst • ligand • stabilizer • dis-persing agent • organometallic complex • metallic nanoparticle • supported metal


The only large-scale and industrially used version of aqueous–biphasic homogeneous ca-talysis is Ruhrchemie/Rh�ne-Poulenc�s hydroformylation process for the manufacture ofbutanal from propene and syngas, which is the focus of this chapter.

reactor (CSTR) decanter

process water replenishment

Flow Sheet of the Ruhrchemie/Rhône−Poulenc Process

strip column

vent

vent

i/n-separation

propene

catalystrecycle

process watersyngas

crudeiPrCHO/PrCHO

iPrCHO

PrCHOliquid

PrCHOvapor

AB

C

D EF

Keywords: hydroformylation • homogeneous catalysis • water-soluble rhodium com-plexes • aqueous–biphasic process • industrial scale • propene • butanal • catalyst recovery •

catalyst recycling • economics


The choice of solvents is an important matter for green chemical processes in industry. Inthis chapter, industrial applications of organic reactions in water other than hydrofor-mylation are discussed. Classical reactions, metal-catalyzed reactions such as palladium-catalyzed coupling, and enzymatic reactions are highlighted.

N

O

Br N

O

CO2H

1.

Pd/C, Na2CO3, MeOH/H2O (1:1)

reflux, 5 h

2. filtration

3. concd HCl

(HO)2B CO2H

93−96%

multikilogram scale


Keywords: Aldol reaction • aqueous conditions • Baylis–Hillman reaction • enzyme catal-ysis • green chemistry • hydration • hydrolysis • kinetic resolution • Lewis acid catalysis •

palladium catalysis • phase-transfer catalysis • Suzuki coupling • transition-metal cataly-sis • water


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