Side Reactions in Organic Synthesis A Guide to Successful Synthesis Design

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Edition: 1st
Format: Paperback
Pub. Date: 2004-12-27
Publisher(s): Wiley-VCH
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Summary

Most syntheses in the chemical research laboratory fail and usually require several attempts before proceeding satisfactorily. Failed syntheses are not only discouraging and frustrating, but also cost a lot of time and money. Many failures may, however, be avoided by understanding the structure-reactivity relationship of organic compounds.This textbook highlights the competing processes and limitations of the most important reactions used in organic synthesis. By allowing chemists to quickly recognize potential problems this book will help to improve their efficiency and success-rate. A must for every graduate student but also for every chemist in industry and academia.Contents:1 Organic Synthesis: General Remarks 2 Stereoelectronic Effects and Reactivity 3 The Stability of Organic Compounds 4 Aliphatic Nucleophilic Substitutions: Problematic Electrophiles 5 The Alkylation of Carbanions 6 The Alkylation of Heteroatoms 7 The Acylation of Heteroatoms 8 Palladium-Catalyzed C-C Bond Formation 9 Cyclizations 10 Monofunctionalization of Symmetric Difunctional Substrates

Author Biography

<b>F. Zaragoza D&amp;ouml;rwald</b> studied chemistry at the Georg-August University of G&amp;ouml;ttengen and Universit&amp;eacute; Louis Pasteur, Strasbourg, where he obtained his Ph.D. in 1990 on the synthesis of natural products under the guidance of M. Franck-Neumann and M. Miesch. He spent each one postdoctoral year in the groups of A. Pfaltz (University of Basel) and A.P. Marchand (University of North Texas), and worked then on the synthesis of unnatural amino acids at the Technical University of Dresden. Since 1995 he has a position as medicinal chemist at Novo Nordisk A/S, M&amp;aring;l&amp;oslash;v, Denmark. His main interests are the development of parallel and solid-phase syntheses for lead identification and optimization.

Table of Contents

Preface ix
Glossary and Abbreviations xi
Organic Synthesis: General Remarks
1(16)
Introduction
1(1)
Synthesis Design
2(7)
Convergent vs Linear Syntheses
2(1)
Retrosynthetic Analysis
3(6)
Hard and Soft Acids and Bases
9(4)
The Curtin-Hammett Principle
13(4)
Stereoelectronic Effects and Reactivity
17(18)
Hyperconjugation with σ Bonds
17(2)
Hyperconjugation with Lone Electron Pairs
19(4)
Effects on Conformation
19(1)
The Anomeric Effect
20(1)
Effects on Spectra and Structure
21(2)
Hyperconjugation and Reactivity
23(7)
Basicity and Nucleophilicity
23(2)
Rates of Oxidation
25(1)
Rates of Deprotonation
26(1)
Other Reactions
27(3)
Conclusion
30(5)
The Stability of Organic Compounds
35(24)
Introduction
35(1)
Strained Bonds
35(6)
Incompatible Functional Groups
41(1)
Conjugation and Hyperconjugation of Incompatible Functional Groups
42(3)
Stability Toward Oxygen
45(7)
Hydrogen Abstraction
45(3)
Oxidation by Set
48(3)
Addition of Oxygen to C--C Double Bonds
51(1)
Detonations
52(7)
Aliphatic Nucleophilic Substitutions: Problematic Electrophiles
59(84)
Mechanisms of Nucleophilic Substitution
59(3)
Structure of the Leaving Group
62(10)
Good and Poor Leaving Groups
62(4)
Nucleophilic Substitution of Fluoride
66(4)
Nucleophilic Substitution of Sulfonates
70(2)
Structure of the Electrophile
72(71)
Steric Effects
72(3)
Conjugation
75(4)
Electrophiles with σ-Heteroatoms
79(5)
Electrophiles with β-Heteroatoms
84(2)
Electrophiles with α-Electron-withdrawing Groups
86(4)
Neighboring-group Participation
90(3)
Allylic and Propargylic Electrophiles
93(4)
Epoxides
97(46)
The Alkylation of Carbanions
143(86)
Introduction
143(1)
The Kinetics of Deprotonations
144(2)
Regioselectivity of Deprotonations and Alkylations
146(36)
Introduction
146(2)
Kinetic/Thermodynamic Enolate Formation
148(2)
Allylic and Propargylic Carbanions
150(5)
Succinic Acid Derivatives and Amide-derived Carbanions
155(2)
Bridgehead Carbanions
157(1)
Dianions
158(3)
α-Heteroatom Carbanions
161(10)
Vinylic Carbanions
171(2)
Acyl, Imidoyl, and Related Carbanions
173(2)
Aromatic Carbanions
175(5)
Aromatic vs Benzylic Deprotonation
180(2)
The Stability of Carbanions
182(47)
Introduction
182(1)
α-Elimination
183(1)
β-Elimination
184(6)
Cyclization
190(3)
Rearrangement
193(2)
Oxidation
195(1)
Other Factors which Influence the Stability of Carbanions
196(1)
Configurational Stability of Carbanions
197(32)
The Alkylation of Heteroatoms
229(32)
Alkylation of Fluoride
229(2)
Alkylation of Aliphatic Amines
231(3)
Alkylation of Anilines
234(5)
Alkylation of Alcohols
239(2)
Alkylation of Phenols
241(2)
Alkylation of Amides
243(5)
Alkylation of Carbamates and Ureas
248(2)
Alkylation of Amidines and Guanidines
250(1)
Alkylation of Carboxylates
251(10)
The Acylation of Heteroatoms
261(18)
Problematic Carboxylic Acids
261(6)
Sterically Demanding Carboxylic Acids
261(1)
Unprotected Amino and Hydroxy Carboxylic Acids
262(3)
Carboxylic Acids with Additional Electrophilic Groups
265(2)
Problematic Amines
267(4)
Sterically or Electronically Deactivated Amines
267(2)
Amino Acids
269(1)
Amines with Additional Nucleophilic Groups
270(1)
Problematic Alcohols
271(8)
Sterically Deactivated and Base-labile Alcohols
271(2)
Alcohols with Additional Nucleophilic Groups
273(6)
Palladium-catalyzed C-C Bond Formation
279(30)
Introduction
279(1)
Chemical Properties of Organopalladium Compounds
279(3)
Mechanisms of Pd-catalyzed C-C Bond Formation
282(5)
Cross-coupling
282(3)
The Heck Reaction
285(2)
Homocoupling and Reduction of the Organyl Halide
287(4)
Homocoupling and Oxidation of the Carbon Nucleophile
291(2)
Transfer of Aryl Groups from the Phosphine Ligand
293(1)
ipso- vs cine-Substitution at Vinylboron and Vinyltin Derivatives
294(1)
Allylic Arylation and Hydrogenation as Side Reactions of the Heck Reaction
295(1)
Protodemetalation of the Carbon Nucleophile
296(1)
Sterically Hindered Substrates
296(2)
Cyclometalation
298(2)
Chelate Formation
300(9)
Cyclizations
309(24)
Introduction
309(1)
Baldwins Cyclization Rules
309(6)
Structural Features of the Chain
315(4)
Ring Size
319(8)
Formation of Cyclopropanes
321(4)
Formation of Cyclobutanes
325(2)
Heterocycles
327(6)
Monofunctionalization of Symmetric Difunctional Substrates
333(22)
Introduction
333(1)
Monofunctionalization of Dicarboxylic Acids
334(2)
Monofunctionalization of Diols
336(6)
Monofunctionalization of Diamines
342(4)
Monoalkylation of C,H-Acidic Compounds
346(2)
Monoderivatization of Dihalides
348(7)
Index 355

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