Preparative Organic Chemistry - Weygand and Hilgetag

PREPARATIVE ORGANIC CHEMISTRY

CONTRIBUTING AUTHORS

CH. BISCHOFF (BERLIN)P.-G. DIETRICH (BERLIN)I. EICHHORN (BERLIN)E. GRUNDEMANN (BERLIN)E. HOFT (BERLIN)G. LEHMANN (BERLIN)D. MURAWSKI (BERLIN)E. SCHMITZ (BERLIN)H. SEEBOTH (BERLIN)J. DAHLMANN (BERLIN)

H. DORN (BERLIN)H. GROSS (BERLIN)G. HILGETAG (BERLIN)O. KOVACS (SZEGED)D. MARTIN (BERLIN)R. OHME (BERLIN)H. SCHICK (BERLIN)M. SCHULZ (BERLIN)H. TEICHMANN (BERLIN)A. ZUBEK (BERLIN)

WEYGAND/HILGETAG

PREPARATIVEORGANIC CHEMISTRY

EDITED BY

G. HILGETAGAND

A. MARTINIInstitut fur Organische Chemie

der Deutschen Akademie der Wissenschaften zu Berlin

A Wiley-Inter science Publication

JOHN WILEY & SONSNew York London Sydney Toronto

Copyright 1972, by John Wiley & Sons, Inc.

All rights reserved. Published simultaneously in Canada.

No part of this book may be reproduced by any means, nor transmitted, nor translatedinto a machine language without the written permission of the publisher.

LIBRARY OF CONGRESS CA TALOGING IN PUBLICATION DA TA:Weygand, Conrad, 1890-1945.Weygand/Hilgetag, Preparative organic chemistry.

"A Wiley-Interscience publication."Translation of the 4th ed. of Organisch-chemische Experimentierkunst, edited by G.Hilge-

tag and A. Martini, which is an enlarged and updated version of part 2 of the original ed.Includes bibliographical references.1. Chemistry, Organic-Synthesis. I. Hilgetag, Gtinter, ed. II. Martini, A., ed. III. Title.

[DNLM: 1. Chemistry, Organic. QD 251 W5470 1972]QD262.W4613 547'.2 72-6800ISBN 0-471-93749-5

Printed in the German Democratic Republic

109 8 7 6 5 4 3 2 1

Foreword to the 4 th Edition

The first edition of " Organisch-chemische Experimentierkunst" by ProfessorConrad Weygand was published some 30 years ago. He divided the bookinto three parts, corresponding to the natural course of an organic-chemi-cal experiment, namely, construction of an apparatus, performance of thechemical reaction, and finally analysis and physical characterization of theproduct.

For arrangement of the actual chemical part, dealing with reactions, Weygandchose a particularly clear and satisfying division, which was then new, basedon the formation of the various carbon bonds. The first section of this partcontained the reactions on the pre-formed carbon skeleton, the second cont-ained the formation of CC bonds, the third the cleavage of CC bonds, andthe last the rearrangements of carbon compounds. This "Weygand key"has since been taken over as organizational principle in the Theilheimer series.Division according to reaction type has also been adopted recently in text-books, for example, in "Cahiers de Synthese Organique Methodes etTableaux d'Application".

After the tragic death of Professor Weygand in April 1945 preparation of thesecond edition was continued by his pupil and collaborator, Dr. Theo Sieben-mark.

The third edition, which appeared in 1964, was made possible by a numberof specialist chemists, mostly colleagues at the Institut fur Organische Chemieder Deutschen Akademie der Wissenschaften zu Berlin, who declared them-selves ready to revise the book completely. The subdivision into "Materialsand Operations " , " Reactions ", and " Chemical and Physical Characterization "was retained in that edition.

The present fourth edition consists only of the previous second part, " Re-actions". Except for the chapters "Preparative Work with Small Quantities"and "Solvents and Gases" (a new section) which are retained as Appendices,the previous first part, "Materials and Operations" has been omitted since inthe meanwhile monographs have appeared that treat this subject in greaterdetail. The previous third part, "Chemical and Physical Characterization",has also not been retained; it was too brief to provide a satisfactory guide andwe agree with various critics of the third edition that it is better to consultdetailed specialist books for chemical and physical analysis.

Vi Foreword to the 4 th Edition

The fourth edition has been expanded by a chapter on the "Formation ofCarbon-Phosphorus Bonds" and by another on the "Formation of Carbon-Deuterium Bonds". The chapter on "Alteration of Nitrogen Groups in Carbon-Nitrogen Compounds" has been substantially expanded, but the remainingparts of the book have merely been completed by inclusion of preparativeprocesses discovered in recent years.

As the contributors handled their chapters more or less contemporaneously,the literature throughout this edition has been taken into account up to 1967.

I am most grateful to the contributors for their rapid and conscientiousrevision or re-working of their chapters.

Berlin, 1968 G. Hilgetag

Summary of Contents

Introduction: Organization of the Material 1

Part A. Reactions on the Intact Carbon Skeleton1. Formation of carbon-hydrogen bonds

By Ch. Bischoff, P.-G. Dietrich, E. Hoft and D. Murawski (Berlin) 52. Formation of carbon-deuterium bonds

By D. Murawski (Berlin) 853. Formation of carbon-halogen bonds

By H. Dorn (Berlin) 1024. Formation of carbon-oxygen bonds

By M. Schulz and H. Seebach (Berlin) 2735. Cleavage of carbon-oxygen bonds

By H. Seebach and M. Schulz (Berlin) 3916. Formation of carbon-nitrogen bonds

By G. Lehmann and H. Teichmann (Berlin) 4047. Alteration of nitrogen groups in carbon-nitrogen compounds

By R. Ohme and A. Zubek (Berlin) 5498. Formation of carbon-sulfur bonds

By D. Martin (Berlin) 6009. Formation of carbon-phosphorus bonds

By H. Teichmann (Berlin) 69310. Formation of metal-carbon bonds

By J. Dahlmann (Berlin) 74811. Formation of carbon-carbon multiple bonds

By I. Eichhorn (Berlin) 813

Part B. Formation of New Carbon-Carbon BondsBy H. Gross, Ch. Bischoff, E. Hoft, and E. Grundemann (Berlin) 845

Part C. Cleavage of Carbon-Carbon BondsBy G. Hilgetag (Berlin) 1003

Part D. Rearrangement of Carbon CompoundsBy E. Schmitz (Berlin) 1053

Appendix I. Purification and drying of organic solventsBy H. Schick (Berlin) 1095

Appendix II. Preparation and purification of gasesBy H. Schick (Berlin) 1103

Appendix III. Preparative organic work with small quantitiesBy 5 . Kovacs (Szeged) 1107

vii

Contents

Introduction; Organization of the Material 1

PART A. Reactions on the Intact Carbon Skeleton 3

Chapter L Formation of carbon-hydrogen bonds 51.1. Formation of the carbon-hydrogen bond by addition 5

I. Addition of hydrogen to C=C bonds and aromatic systems 51. Chemical reducing agents 5

a. Reduction by non-noble metals 6i, Reduction by sodium and alcohols 6

ii, Reduction with sodium amalgam 7iii, Reduction with aluminum amalgam 8iv, Reduction by solutions of alkali or alkaline-earth metals in liquid am-

monia 8v, Reduction by lithium in organic amines 10

vi, Reduction by zinc, tin, or aluminum 11b. Electrolytic reduction 12c. Reduction by lithium aluminum hydride or similar compounds 13d. Reduction by diimine 15e. Other reducing agents 17

2. Catalytic hydrogenation 18a. Catalysts 18

i, Noble-metal catalysts (Adams catalysts) 19ii, Skeletal alloy catalysts (Raney metals) 22

iii, Metal catalysts 24iv, Copper oxide-chromium oxide catalysts (Adkins catalysts) 26v, Sulfide catalysts 27

b. Apparatus and procedure for hydrogenation 28i, Hydrogenation on a shaking machine 28ii, High-pressure hydrogenation 30

iii, Hydrogenation in a catalyst tube 31c. Examples of catalytic hydrogenation 32

i, Choice of catalyst 32ii, Hydrogenation of olefinic double bonds 32iii, Selective hydrogenation 33iv, Hydrogenation of aromatic compounds 36v, Hydrogenation of heterocycles 38

vi, Catalytic hydrogenation by bonded hydrogen 40ix

X Contents

II. Addition of hydrogen to C==C bonds 401. Chemical methods 412. Catalytic hydrogenation 43

III. Addition of hydrogen to C = O bonds 451. Reduction by non-noble metals 452. Meerwein-Ponndorf-Verley reduction 473. Reduction by lithium aluminum hydride 514. Reduction by complex boron hydrides 555. Catalytic reduction 596. Reduction by diimine 62

1.2. Formation of the carbon-hydrogen bonds by exchange 62I. Replacement of halogen by hydrogen 62

1. Replacement of halogen on single C-C bonds 63a. Direct replacement 63b. Replacement of halogen via intermediates 65

2. Replacement of halogen bound to olefinic or aromatic systems 653. Replacement of halogen in other surroundings (in acid chlorides) 66

II. Replacement of oxygen by hydrogen 681. Replacement of the hydroxyl group 682. Replacement of carbonyl-oxygen 71

a. Direct replacement 71b. Replacement of carbonyl oxygen via intermediates 74

i, Wolff-Kishner methods 74ii, Replacement of carbonyl oxygen via mercaptals 76

3. Replacement of oxygen in carboxyl or alkoxycarbonyl groups 764. Reduction of amides and lactams 79

III. Replacement of nitrogen by hydrogen 80IV. Replacement of sulfur by hydrogen 83

Chapter 2. Formation of carbon-deuterium bonds 85Introduction 85

2.1. Formation of the carbon-deuterium bond by addition 87I. Addition of D2O or DX to carbon-carbon multiple bonds 87

II. Addition of deuterium to carbon-carbon multiple bonds 88III. Addition of deuterium to carbonyl double bonds 90

2.2. Formation of the carbon-deuterium bond by exchange 91I. Replacement of metal by deuterium 91

II. Replacement of halogen by deuterium 92III. Replacement of oxygen by deuterium 93

2.3. Isotope exchange methods 94I. General 94

II. Exchange of labile bonded hydrogen 95III. Exchange reactions in alkaline media 96

1. Exchange in aqueous solution 962. Exchange in liquid [D3] ammonia 98

IV. Exchange reactions in acid media 99

Chapter 3. Formation of carbon-halogen bonds 1023.1. Formation of carbon-halogen bonds by addition 102

I. Addition of halogen or thiocyanogen to CC multiple bonds 1021. Properties and purification of halogens and thiocyanogen 1022. Addition of halogen to C = C bonds: general 105

Contents xi

3. Addition of halogen to simple unsaturated hydrocarbons 1064. Addition of halogen to polyenes 1095. Addition of halogen to steroids 1106. Addition of halogen to unsaturated alcohols or ethers I l l7. Addition of thiocyanogen to unsaturated compounds 1138. Addition of halogen to unsaturated carboxylic acids 1149. Addition of halogen to C = C bonds 115

10. Addition of halogen to aromatic hydrocarbons 117II. Addition of hydrogen halide to CC multiple bonds 119

1. Preparation and properties of hydrogen halides 1192. Addition of hydrogen halide to C = C bonds: general 1223. Addition of hydrogen halide to simple unsaturated hydrocarbons 1244. Addition of hydrogen halide to unsaturated alcohols, ethers, carbonyl com-

pounds, and nitriles 1285. Addition of hydrogen halide to C = C bonds 130

III. Addition of halogen to CC multiple bonds with simultaneous formation ofa CC, CO, or CN bond 1331. Addition of halogen to CC multiple bonds with simultaneous formation of

a CC bond 133a. Addition of a-halo ethers to C = C bonds 133b. Meerwein reaction (interaction of diazonium halides and CC multiple

bonds) 133c. Addition of acid chlorides to C = C bonds 134d. Addition of alkyl halides, etc., to C = C bonds 135

2. Addition of halogen to C = C bonds with simultaneous formation of a CObond 135a. Addition of hypohalite to C = C bonds (halohydrins) 136b. Formation of chlorohydrins by chromyl chloride 138c. Formation of halohydrins by halo amides 138d. Alkoxyhalogenation 140

3. Addition of halogen to CC multiple bonds with simultaneous formationof a CN bond 141

3.2. Formation of carbon-halogen bonds by exchange 143I. Replacement of hydrogen by halogen or thiocyanate 143

1. Replacement of hydrogen by halogen in aliphatic hydrocarbons 143a. Replacement of hydrogen by halogen in alkanes 143b., Replacement of hydrogen by halogen in olefins 145

2. Replacement of hydrogen by halogen in aromatic compounds: general 1503. Replacement of hydrogen by halogen in the nuclei of aromatic hydrocarbons 1534. Replacement of hydrogen by halogen in the side chain of aromatic hydro-

carbons 1575. Replacement of hydrogen by halogen in acetylenes 1596. Replacement of hydrogen by halogen in phenols, hydroxyphenylalkanoic

acids, aryl ethers, and aromatic amines 1617. Replacement of hydrogen by halogen in ethers 1698. Replacement of hydrogen by halogen in carboxylic acids 172

a. Replacement of hydrogen by halogen in aliphatic monocarboxylic acids 172b. Replacement of hydrogen by halogen in aliphatic dicarboxylic acids and

nitriles 177c. Replacement of hydrogen by halogen in aromatic carboxylic acids and

hydroxy and amino carboxylic acids 1809. Replacement of hydrogen by halogen in aromatic nitro compounds 184

10. Replacement of hydrogen by halogen in aldehydes and ketones 18511. Replacement of hydrogen by halogen in heterocycles 19712. Direct replacement of hydrogen by SCN in aromatic compounds 202

x ii Contents

II. Replacement of halogen by another halogen or by thiocyanate 2041. Replacement of halogen by fluorine 2042. Replacement of halogen by iodine, bromine, or chlorine 2093. Replacement of halogen by thiocyanate 213

III. Replacement of OH, OR, or = 0 by halogen 2141. Replacement of alcoholic OH by halogen 214

a. Replacement of alcoholic OH by fluorine 214b. Replacement of alcoholic OH by chlorine, bromine, or iodine by means

of hydrogen halides or acid halides 214i, Replacement of alcoholic OH by halogen by means of hydrogen halides 214ii, Replacement of alcoholic OH by halogen by means of acid halides.. 222

c. Replacement of alcoholic OH by halogen by means of triphenyl phosphiteand organic halides or halogen 227

d. Replacement of alcoholic OH by halogen by way of/7-toluenesulfonates 2292. Replacement of OH by halogen in hemiacetals: Henry synthesis of a-halo

ethers 2323. Replacement of acyloxy groups by halogen (halo sugars) 2344. Replacement of CO bonds by C-halogen bonds on fission of ethers or

acetals 2375. Replacement of OH by halogen in phenols or heterocycles 2406. Replacement of OH by halogen in the carboxyl group: carbonyl halides . . 242

a. Replacement of OH in the COOH group by fluorine 242b. Replacement of OH in the COOH group by chlorine, bromine, or iodine,

by means of inorganic acid halides 243c. Replacement of OH in the COOH group by chlorine or bromine by means

of organic acid halides 2477. Conversion of ^>C=O into ^>CC12 or ^>CBr2 251

IV. Replacement of CN bonds by C-halogen bonds 2531. Replacement of CN bonds by C-halogen bonds in aliphatic compounds 253

a. Replacement of CN bonds by C-halogen bonds in aliphatic amines bymeans of PC15 or PBr5 253

b. Replacement of CN bonds by CBr bonds in aliphatic amines bymeans of cyanogen bromide 254

c. Replacement of NH2 in aliphatic compounds by halogen by means of anitrosyl halide 256

d. Halo ketones from diazo ketones 256c. Carboxylic acid chlorides from iV-acylimidazoles 258

2. Replacement of C-N bonds by C-halogen bonds in aromatic compoundsand heterocycles 258a. Replacement of NH2 in aromatic compounds and heterocycles by Cl or

Br (Sandmeyer reaction) 259b. Replacement of NH2 in aromatic compounds by iodine 262c. Replacement of NH2 in aromatic compounds and heterocycles by Br

by means of diazonium perbromides 263d. Replacement of NH2 in aromatic compounds by Cl or Br (Schwechten

reaction) 264e. Replacement of NH2 in aromatic or heterocyclic compounds by fluorine(Schiemann reaction) 265f. Replacement of NO2 in heterocycles by halogen 268g. Replacement of NH2 in aromatic compounds by SCN 269

V. Replacement of CS bonds by C-halogen bonds 269VI. Replacement of CC bonds by C-halogen bonds 272

Chapter 4. Formation of carbon-oxygen bonds 2734.1. Formation of the carbon-oxygen bond by addition 273

I. Addition of oxygen to ethylenic bonds 2731. Molecular oxygen 273

Contents xiii

2. Ozone 2753. Epoxides from ethylenic derivatives 276

II. Addition of water to ethylenic bonds 280III. Addition of water to acetylenic bonds 283IV. Addition of hydroxyl groups to ethylenic bonds 286

1. Hydroxylation by organic peroxy acids 2862. Hydroxylation by potassium permanganate 2883. Hydroxylation by osmium tetroxide 2894. Hydroxylation by iodine-silver benzoate (Prevost reagent) 2905. Woodward c/s-hydroxylation 2916. Hydroxylation by hydrogen peroxide and inorganic catalysts 291

V. Addition of carboxylic acids and alcohols to olefins and acetylenes 292VI. Oxonium salts 299

42. Formation of the carbon-oxygen bond by replacement with formation of hydroxylor carbonyl groups 301

I. Replacement of hydrogen by oxygen 3011. Replacement of hydrogen by the hydroxyl group 3022. Formation of peroxides by autoxidation 306

a. Dangers in work with peroxides 306b. Formation of hydroperoxides 306c. Formation of dialkyl peroxides 310

3. Replacement of hydrogen by carbonyl-oxygen 311a. Preparation of aldehydes and ketones 311b. Preparation of quinones 316

4. Replacement of hydrogen by carboxyl-oxygen 3175. Dehydrogenation of alcohols to carbonyl compounds 321

a. Aldehydes 321b. Ketones 327c. Oxidation of polyhydric alcohols 331

6. Oxidation of alcohols and aldehydes to carboxylic acids 3317. Cannizzaro and Tishchenko reactions 334

II. Replacement of halogen by oxygen 3361. Replacement of halogen by the hydroxyl group 3372. Replacement of halogen by carbonyl-oxygen 3383. Replacement of halogen by carboxyl-oxygen 341

III. Replacement of nitrogen by oxygen 3421. Replacement of the amino group by the hydroxyl group 3422. Replacement of nitrogen by carbonyl-oxygen 3463. Replacement of nitrogen by carboxyl-oxygen 351

IV. Replacement of the sulfo group by the hydroxyl group 353

43 . Formation of the carbon-oxygen bond by replacement with formation of additionalcarbon-oxygen bonds 355

I. Ethers 3551. Ether formation by replacement of oxygen by oxygen 355

a. Removal of water from two molecules of alcohol 355b. Alkylation by dialkyl sulfates 358c. Alkylation by /7-toluenesulfonic esters 359

2. Ether formation by replacement of halogen by oxygen: alkylation by halo-gen compounds 361

3. Ether formation by replacement of nitrogen by oxygen: alkylation by diazo-methane 368

xiv Contents

II. Esters 3681. Replacement of oxygen by oxygen 368

a. Carboxylic esters from carboxylic acids and alcohols 368i, Esterification in absence of special catalysts 369

ii, Esterification with addition of catalysts 370b. Carboxylic esters by alkylation with dimethyl sulfate 373c. Carboxylic esters by acylation with acid anhydrides 374d. Carboxylic esters by transesterification 375e. Orthocarboxylic esters by transesterification 376

2. Replacement of halogen by oxygen 377a. Carboxylic esters by alkylation of salts of carboxylic acids by alkyl halides 377b. Carboxylic esters by acylation of alcohols or phenols by acid chlorides 378c. Orthocarboxylic esters from halogen compounds 379

3. Replacement of nitrogen by oxygen 379a. Carboxylic esters by alkylation with diazomethane 379b. Orthocarboxylic esters from formamide or carbimidic ester hydrochlorides 380

III. Acetals 3811. Replacement of oxygen by oxygen 381

a. Acetals from carbonyl compounds and alcohols 381b. Acetals by transacetalization 385

2. Replacement of halogen by oxygen 385IV. Carboxylic anhydrides 387

1. Carboxylic anhydrides by direct removal of water 3882. Carboxylic anhydrides by double reaction 388

Chapter 5. Cleavage of carbon-oxygen bonds 391I. Cleavage of ether bonds 391

II. Hydrolysis of carboxylic esters 396III. Hydrolysis of acetals, mercaptals, ketals, and orthoesters 400

Chapter 6. Formation of carbon-nitrogen bonds 4046.1. Formation of the carbon-nitrogen bond by addition 404

I. Addition of nitrogen compounds to C-C multiple bonds 4041. Addition of ammonia and its substitution products 4042. Addition of other nitrogen compounds 405

a. Addition of diazoalkanes and azides 405b. Addition of nitriles 406c. Addition of nitrogen oxides and oxychlorides 406

II. Addition of nitrogen compounds to C-N multiple bonds 4071. Addition of hydrogen cyanide derivatives 4072. Addition of cyanates and thiocyanates 410

III. Addition of nitrogen compounds to C = O bonds 411IV. Addition of nitrogen compounds to C = S bonds 412

6.2. Formation of the carbon-nitrogen bond by exchange 413I. Replacement of hydrogen by nitrogen 413

1. Nitration 413a. General; nitrating agents 413b. Nitration of aliphatic compounds 417c. Nitration of aromatic and heterocyclic compounds 419

2. Nitrosation 427a. General 427b. Nitrosation of aliphatic compounds 428

i, Preparation of oximes 428ii, Preparation of true nitroso compounds 430

Contents xv

c. Nitrosation of aromatic compounds 432i, Nitrosation of phenols and tertiary amines 432

ii, Nitrosation of secondary amines 433iii, Nitrosation of primary amines 434

3. Azo coupling 434a. General 434b. Coupling with compounds containing active methylene groups 436c. Azo coupling with aromatic components 439d. Oxidative azo coupling 442

4. Other reactions 443a. Introduction of amino groups 443b. Introduction of ammonium groups 446c. Introduction of diazo groups 446d. Direct introduction of diazonium .groups 447e. Ehrlich-Sachs reaction 447

II. Replacement of halogen by nitrogen 4481. Reaction of halogen compounds with ammonia derivatives 448

a. Alkylation 448b. Arylation 461c. Acylation 464d. Other reactions 472

i, Isocyanates from phosgene and amino compounds 472ii, Isocyanides and formamides from chloroform and amines 474

2. Reaction of halogen compounds with other nitrogen compounds 475a. With nitrites 475b. With azides 477c. With cyanides 479d. With cyanates 479

III. Replacement of oxygen by nitrogen 4801. Reactions of acid derivatives with nitrogen compounds 480

a. Reactions of free acids with nitrogen compounds 480b. Reactions of acid anhydrides with nitrogen compounds 484c. Reactions of esters with nitrogen compounds 488

i, Acylation of nitrogen compounds: by carboxylic esters,(488); by orthoesters (494); by imidic esters (496) 488

ii, Alkylation of nitrogen compounds: by sulfuric esters (497); by phos-phoric esters (499); by arenesulfonic esters (500) 497

d. Reactions of amides with nitrogen compounds 502e. Reactions of isocyanates with nitrogen compounds 503

2. Reactions of carbonyl compounds with nitrogen compounds 504a. Preparation of simple derivatives of carbonyl compounds 504

i, Preparation of imines, Schiff bases , 504ii, Preparation of hydrazones, semicarbazones, etc 508

iii, Preparation of oximes 513b. Preparation of amines with functional groups in the a-position 516

i, Preparation iV,iV-acetals, etc 516ii, Preparation of a-amino nitriles, hydantoins, etc 519

c. Preparation of amines by reductive alkylation 520i, Catalytically excited hydrogen as reducing agent 521

ii, Leuckart-Wallach reaction 5243. Reaction of alcohols and phenols with nitrogen compounds 527

a. Replacement of alcoholic hydroxyl groups by amino groups 527b. Reaction of phenols with ammonia, amines, and hydrazines 529

4. Reaction of ethers and oxonium salts with nitrogen compounds 532IV. Replacement of other elements by nitrogen 537

xvi Contents

1. Replacement of nitrogen by nitrogen 537a. Transamination (amine exchange reactions) 537b. Transamidation and related reactions 540c. Replacement of diazonium and diazo nitrogen 543

2. Replacement of carbon by nitrogen 5443. Replacement of sulfur by nitrogen 546

a. Replacement of sulfo groups by nitrogen 546b. Replacement of other sulfur groups by nitrogen 547

4. Replacement of metals by nitrogen 548

Chapter 7. Alteration of nitrogen groups in carbon-nitrogen compounds 549I. Formation of the N-H bond 549

1. Formation of the N-H bond by addition 549a. Preparation of hydrazo compounds from azo compounds 549b. Preparation of hydrazines from diazonium salts 550c. Preparation of amines from nitriles 551d. Preparation of secondary amines from Schiff bases 554e. Preparation of substituted hydrazines from hydrazones or azines 555

2. Preparation of the N-H bond by exchange 557a. Preparation of amines by reduction of nitro compounds 557b. Reduction of nitro compounds and oximes to hydroxylamines 563c. Preparation of amines by reduction of oximes and hydroxylamines 564d. Reduction of nitroso compounds to amines 566e. Reduction of nitrosamines to asymmetrically disubstituted hydrazines... 567f. Reduction of azo compounds to amines 568g. Reduction of azines, hydrazones, hydrazines, and hydrazides 570h. Reduction of azides 571i. Preparation of amines by cleavage of iV-nitrosamines 571

II. Reduction of TV-oxides 572III. Formation of the N-O bond 573

1. Formation of the N-O bond by addition 573a. Preparation of iV-oxides 573b. Azoxy compounds from azo compounds 575c. Oxidation of the nitroso and the oxime group to the nitro group 575

2. Formation of the N-O bond by exchange 576IV. Formation of the N-N bond by exchange 577

1. Preparation of nitrosamines and nitrosamides 5772. Preparation of nitramines and nitramides 5783. Diazotization of aromatic amines 5814. Preparation of azides 5835. Syntheses of hydrazines 5856. Diazoamino compounds (triazenes) 5877. Azo compounds 5888. Tetraalkyl-2-tetrazenes 5939. Azoxy compounds 594

10. Preparation of aliphatic diazo compounds 594V. Formation of the nitrogen-halogen bond 597

Chapter 8. Formation of carbon-sulfur bonds 6008.1. Formation of the carbon-sulfur bond by addition 600

I. Addition of sulfur compounds to C-C multiple bonds 6001. Addition of hydrogen sulfide and its derivatives 6002. Addition of other sulfur compounds 605

II. Addition of sulfur compounds to C-N multiple bonds 607III. Addition of sulfur compounds to C = O bonds 609

Contents xvii

8.2. Formation of the carbon-sulfur bond by exchange 611I. Replacement of hydrogen by sulfur groups 611

1. Introduction of the sulfonic acid group 611a. Aliphatic sulfonation 611b. Aromatic sulfonation by sulfuric acid or oleum 612

i, General 612ii, Sulfonation and the influence of substituents in the benzene series .. 616

iii, Sulfonation and the influence of substituents in the naphthalene,anthracene, and phenanthrene series 620

c. Sulfonation by sulfuric acid and oleum in the presence of catalysts 622d. Sulfonation with sulfur trioxide and its addition compounds 623e. Aromatic sulfonation by halosulfuric acids and other sulfonating agents 624

2. Introduction of the sulfonyl chloride group 6263. Direct introduction of the sulfone and sulfoxide group 6294. Direct introduction of the sulfinic acid group 6315. Introductionofthioxo,thio,andmercapto groups: preparation ofsulforylides 632

II. Replacement of halogen by sulfur groups 6341. Reaction of alkyl and aryl halides with salts and derivatives of hydrogen

sulfide 634a. Preparation of thiols and disulfides 634b. Preparation of sulfides and sulfonium salts 636c. Preparation of thioketones, mercaptals, and mercaptols 640

2. Reaction of acyl halides with hydrogen sulfide and its derivatives 6423. Reaction of alkyl halides with sulfites and sulfinic acids 6424. Preparation of thiocyanic and isothiocyanic esters 645

III. Replacement of oxygen by sulfur groups 6451. Reaction of alcohols with sulfur compounds 645

a. Reaction with hydrogen sulfide and its derivatives 645b. Reaction with sodium hydrogen sulfite 646

2. Reaction of alkene oxides (oxiranes) with sulfur compounds 6473. Reaction of carbonyl compounds with sulfur compounds 6484. Reaction of carboxylic acid derivatives with sulfur compounds 6525. Reaction of alkyl and dialkyl sulfates with sulfur compounds 653

IV. Replacement of nitrogen by sulfur 6531. Replacement of the amino group by sulfur groups 6532. Replacement of the imino group by sulfur groups 6573. Replacement of tertiary-bonded nitrogen and of the ammonium group by

sulfur groups 5574. Replacement of the nitro group by sulfur groups 659

V. Replacement of other elements by sulfur groups 6591. Reactions of Grignard reagents 6592. Reactions of other organometallic compounds 661

8.3. Preparation of organic sulfur compounds by alteration of sulfur groups 662I. Reduction of sulfur groups 662

II. Oxidation of sulfur groups 6651. Oxidation of thiols 6652. Oxidation of disulfides 6673. Oxidation of sulfides 6674. Oxidative halogenation of sulfur compounds; sulfonyl chlorides 669

III. Cleavage of sulfur bonds 6711. Cleavage of the C-S bond 6712. Cleavage of the S-H bond 6753. Cleavage of the S-S bond 6764. Cleavage of the S-Cl bond 678

a. Cleavage of sulfonyl chlorides 678b. Cleavage of sulfinyl and sulfenyl chlorides 681

xviii Contents

5. Cleavage of the S-O bond 6826. Cleavage of the S-N bond 683

IV. Preparation of thiocarbonic acid derivatives 6841. Thiocarbonic acids 6852. Chlorothioformic esters 6853. Thiocarbonic esters 686

a. Thiocarbonic half esters 686b. Thiocarbonic diesters 687

4. Thiocarbamic acid derivatives 688a. Salts 688b. Thiocarbamoyl chlorides 688c. Thiocarbamic esters (thiourethanes) 689

5. Bi(alkyl xanthates) and thiuram disulfides 6906. Isothiocyanic esters (mustard oils) 6907. Isothiourea salts 692

Chapter 9. Formation of carbon-phosphorus bonds 6939.1. Formation of the carbon-phosphorus bond by addition 693

I. Addition of phosphorus compounds to C-C multiple bonds 6931. Addition of compounds containing P-H bonds 693

a. Of phosphine and primary and secondary phosphines 693b. Of dialkyl phosphites 695

2. Addition of compounds containing P-halogen bonds 696a. Of phosphorus trihalides and halophosphines 696b. Of phosphorus pentachloride 699

3. Addition of tertiary phosphines and phosphites 699II. Addition of phosphorus compounds to C = O bonds 701

1. Addition of compounds containing P-H bonds 701a. Of phosphine and primary or secondary phosphines 701b. Of dialkyl phosphites 703

2. Addition of compounds containing P-Cl bonds 7053. Addition of tertiary phosphines and phosphites 705

III. Addition of phosphorus compounds to C = N bonds 706IV. Addition of phosphorus compounds to C = S bonds 708

9.2. Formation of the carbon-phosphorus bond by exchange 709I. Replacement of hydrogen by phosphorus 709

1. Replacement of hydrogen by phosphorus by means of phosphorus halides 709a. Direct reaction 709b. Reactions of Friedel-Crafts type 710c. Oxidative phosphonylation 713

2. Replacement of hydrogen by phosphorus by means of other phosphoruscompounds 714a. By means of P-H compounds 714b. By means of phosphorus(v) oxide or sulfide 715

II. Replacement of halogen by phosphorus 7161. Replacement of halogen by phosphorus by means of elemental phosphorus 7162. Replacement of halogen by phosphorus by means of phosphorus halides . 7183. Replacement of halogen by phosphorus by means of phosphines 720

a. By means of phosphine, primary or secondary phosphines, or their salts 720b. By means of tertiary phosphines 722

4. Replacement of halogen by phosphorus by means of phosphites 725a. By means of phosphorus triesters 725b. By means of phosphorus diesters 728

Contents xix

III. Replacement of oxygen by phosphorus 7301. Replacement of oxygen by phosphorus by means of elemental phosphorus 7302. Replacement of oxygen by phosphorus by means of phosphorus halides... 7303. Replacement of oxygen by phosphorus by means of phosphines 7314. Replacement of oxygen by phosphorus by means of phosphites and related

compounds 732a. By means of phosphites and other compounds containing P-H bonds 732b. By means of tertiary phosphites 734

IV. Replacement of other non-metals by phosphorus 7361. Replacement of nitrogen by phosphorus 736

a. By means of phosphorus halides 736b. By means of phosphines 737c. By means of phosphites 738

2. Replacement of phosphorus by phosphorus 7383. Replacement of sulfur by phosphorus 739

V. Replacement of metals by phosphorus 7391. Replacement of metals by phosphorus by means of elemental phosphorus 7392. Replacement of metals by phosphorus by means of phosphines and phos-

phonium salts 7393. Replacement of metals by phosphorus by means of phosphorus halides 740

a. By means of halides of trivalent phosphorus 740b. By means of phosphoryl halides 742c. By means of thiophoryl halides 743d. By means of phosphorus(v) chloride 745

4. Replacement of metals by phosphorus by means of esters 745a. By means of phosphorous esters 745b. By means of phosphoric and phosphonic esters 747

Chapter 10. Formation of metal-carbon bonds (organometallic compounds) 748Introduction 748Review of methods for preparation of organometallic compounds 751

I. Organic derivatives of elements of the First Group 7541. Organolithium compounds 7552. Organo-sodium and -potassium compounds 759

II. Organic derivatives of elements of the Second Group 7621. Organomagnesium compounds 7622. Organozinc compounds 7693. Organocadmium compounds 7714. Organomercury compounds 772

III. Organic derivatives of elements of the Third Group 7771. Organoboron compounds 7782. Organoaluminum compounds 780

IV. Organic derivatives of elements of the Fourth Group 7851. Organosilicon compounds 7852. Organotin compounds 7963. Organolead compounds 803

V. Organic derivatives of elements of the Fifth Group 8051. Organoarsenic compounds 8062. Organoantimony compounds 809

xx Contents

Chapter 11. Formation of carbon-carbon multiple bonds 81311.1. Ethylenic compounds 813

I. Isolated ethylenic bonds 8131. Removal of water from alcohols 8132. Removal of hydrogen halide 8193. Removal of halogen 8224. Cleavage of nitrogeneous compounds 824

II. Conjugated ethylenic bonds 8271. Dienes 8272. Polyenes 8283. Aromatic and heterocyclic double bonds 829

III. Cumulated double bonds 8321. Allenes 8322. Ketenes 836

11.2. Acetylenic bonds 8371. Dehydrohalogenation of dihalides or haloalkenes 8372. Dehalogenation 8403. Cleavage of nitrogenous compounds 840

PART B. Formation of new carbon-carbon bonds 8451.1. Formation of new carbon-carbon bonds by addition 845

I. Addition to C = C bonds 8461. Addition to ethylenic bonds 8462. Polymerization of ethylene derivatives 8483. Diene syntheses 8524. 1,3-Dipolar cyclo addition 8575. Syntheses of cyclobutane derivatives 8586. Addition of CH-acidic compounds (Michael addition) 8617. Addition of formaldehyde (Prins reaction) 8648. Addition of organic halogen compounds 8649. Addition of diazomethane or hydrogen cyanide 866

II. Addition to the C = O bond 8681. Addition of CH-acidic compounds (aldol condensation; Darzens reaction) 8682. Acyloin condensation 8723. Formation of pinacols 8734. Carbonylation (Kolbe-Schmitt reaction,-etc.) 8745. Cyanohydrin synthesis 8756. Addition of diazomethane to carbonyl groups 8777. Addition of Grignard reagents and other organometallic compounds 878

a. Treatment of Grignard reagents with ketones 879b. Treatment of Grignard reagents with esters 881c. Treatment of Grignard reagents with aldehydes 883d. Treatment of Grignard reagents with oxirane (ethylene oxide) or carbon

dioxide 8838. Syntheses by means of organo-lithium or -zinc compounds 884

III. Addition to C-N multiple bonds 8871. Addition of Grignard reagents 8872. Addition of CH-acidic compounds 8893. Addition of nitriles (Thorpe reaction) 8914. Addition of hydrogen cyanide or diazomethane 8925. Reactions of isocyanides 893

Contents xxi

1.2. Formation of new carbon-carbon single bonds by exchange 894I. C-C linkage by removal of hydrogen 894

1. Pyrochemical reactions 8942. Removal of hydrogen catalysed by aluminum chloride 8963. Oxidative removal of hydrogen ^ 8994. Photochemical dehydrodimerization and cyclodehydrogenation 902

II. C-C linkage by replacement of halogen by carbon 9031. Reaction with basic condensing agents 903

a. C-C linkage between two halides 903i, Syntheses of Wurtz type 903

ii, Ketone syntheses by means of organometallic compounds 910b. C-C linkage between halides and compounds containing active protons 912

i, Alkylation of active-methylene compounds 912ii, Acylation of active-methylene compounds 920

iii, Synthesis of alkyl, aryl, and acyl cyanides 922iv, Acylation and alkylation of unsaturated compounds 924

(ot) Reactions of phosphine alkylenes 924({$) Reactions of enamines 927(y) Reactions of acetylenes 929

2. Reactions with acidic condensing agents 932a. Friedel-Crafts synthesis 932

i, General 932ii, Alkylation of aromatic compounds 936iii, Acylation of aromatic compounds 938

(oc) Acylation by carbonyl chlorides 938(P) Acylation by carboxylic anhydrides or acids 939(y) Houben-Hoesch synthesis 941id) Preparation of cyclic ketones 941

iv, Synthesis of aromatic aldehydes 942v, Synthesis of aromatic carboxylic acids 945

vi, Acylation of alkanes, cycloalkenes, and alkanes 946b. Formation of diazo ketones by acylation of diazo-alkanes and -esters . . . 948

III. C-C linkage by replacement of hydroxyl by carbon 9491. Alkylation by alcohols 9492. Alkylation by aldehydes 9523. Chloromethylation 9524. Hydroxymethylation 9545. Aminomethylation (Mannich reaction) 9556. Sulfomethylation 958

IV. CC linkage by replacement of OR by carbon 9591. Ester condensation 9592. Simple reactions involving loss of ROH 964

V. CC linkage by replacement of O-acyl by carbon 9651. Acylation by carboxylic anhydrides 9652. Alkylation by esters, lactones, alkyl sulfates, or alkyl sulfonates 966

VI. CC linkage by replacement of nitrogen by carbon 9671. Removal of elemental nitrogen 967

a. Reactions of diazo esters 967b. Reactions of diazo ketones 967c. Reactions of diazonium salts 968

2. Removal of amines 970a. Alkylation by Mannich bases 970b. Acylation by carboxamide derivatives 973c. Formylation by formamide derivatives (Vilsmeier reaction) 974d. Various reactions involving CN cleavage 977

VII. CC linkage by replacement of sulfur by carbon , 987

xxii Contents

1.3. Formation of new carbon-carbon double bonds by exchange 979I. Removal of hydrogen with formation of a new ethylenic bond 979

II. Removal of halogen with formation of a new ethylenic bond 9791. Removal of halogen by means of metals 9792. Removal of halogen by means of alkalis 980

III. Formation of a new C = C bond by removal of halogen and oxygen 981IV. Formation of a new C = C bond by removal of water 981

1. Synthesis of oc,/?- and &y-unsaturated carboxylic acids 981a. Perkin synthesis 981b. Knoevenagel reaction 983c. Claisen synthesis of cinnamic esters 986d. Stobbe condensation 986

2. Synthesis of #,/?-unsaturated aldehydes and ketones 9863. Other condensations 989

a. Condensation with nuclear methyl groups 989b. Methine condensations 990c. Erlenmeyer amino acid synthesis 990d. Preparation of enamines 991

4. Preparation of unsaturated nitro compounds 9925. Preparation of aromatic systems 993

V. Removal of nitrogen with formation of a C = C bond 994VI. Removal of sulfur with formation of a C = C bond 995

VII. Removal of phosphorus with formation of a C = C bond (Wittig reaction) . . . 996PART C. Cleavage of carbon-carbon bonds 10031.1. Thermal decomposition 1003

I. Removal of carbon dioxide 10031. Carboxylic acids that are not easily decarboxylated 10042. Decarboxylation of carboxylic acids with increased electron affinity at the

a-carbon atom 1006a. Halogenated fatty acids and their salts 1006b. a-Nitro carboxylic acids 1007c. (x-Amino carboxylic acids 1007d. Dakin-West and related reactions 1008e. N- and O-Heterocyclic carboxylic acids 1009

3. Decarboxylation of carboxylic acids with a cationoid centre at the ^-carbonatom 1009a. Pyridineacetic acids 1009b. Malonic acids and anhydrides; decarboxylating acylation of arylacetic

acids 1009c. -Oxo acids 1012d. Aromatic hydroxy and amino carboxylic acids 1014e. jS,y-Unsaturated acids 1015f.

Contents xxiii

3. Ketene from acetone 10314. Cleavage of cyclohexene derivatives 10325. Conversion of lumisterol into tachysterol 1032

1.2. Oxidative cleavage of carbon-carbon bonds 1033I. Oxidative cleavage of CC bonds in alkenes and cycloalkanes 1033

1. Manufacture of fatty acids for soaps by the Fischer-Tropsch-Gatsch process 10332. Oxidation of cyclohexane to adipic acid by nitric acid 1033

II. Oxidative degradation of side chains on aromatic and heterocyclic rings 10341. Oxidative degradation of long aliphatic chains in aromatic or heterocyclic

systems 10342. Degradation of phenol homologs to phenolic carboxylic acids by an oxidative

alkali melt 1035III. Oxidative degradation of olefins 1035

1. Oxidative cleavage of unsaturated carbonyl compounds by alkali melts 10362. Oxidative cleavage of olefins to aldehydes by the usual oxidants 10373. Oxidative cleavage of olefins to ketones and carboxylic acids by the usual

oxidants 10374. Oxidative cleavage of olefins by ozone 10385. Wieland degradation of side chains 1039

IV. Oxidative cleavage of carbon-carbon bonds where a functional group is at theposition of cleavage 10401. Oxidative cleavage of secondary alcohols and ketones 10402. Oxidative cleavage of methyl ketones 10413. Cleavage by lead tetraacetate 1043

V. Oxidative degradation of aromatic and heterocyclic ring systems 10451. Oxidative cleavage of fused aromatic ring systems 10452. Oxidative cleavage of fused heterocyclic ring systems 10453. Fumaric acid from furfuraldehyde 1046

1.3. Hydrolytic cleavage 10461. Fencholic acid from fenchone 10462. Acid fission of /?-diketones and /?-oxy esters 1047

PART D. Rearrangements of carbon compounds 10531.1. Rearrangements with retention of the carbon skeleton 1054

I. Migration of a multiple bond 10541. Migration of a double bond 10542. Allylic rearrangement 10563. Migration of a triple bond 1058

II. Rearrangement with change of an oxygen group 10581. Conversion of epoxides into carbonyl compounds 10582. Willgerodt reaction 10593. Keto-enol tautomerism 10604. Isomerization of ketols (acyloins) 10615. Cannizzaro rearrangement 10626. Acyl-lactone rearrangement 10637. Other rearrangements 1063

III. Rearrangement of nitrogen compounds 10641. Amadori rearrangement 10642. Chapman rearrangement 10643. Rearrangement of amine oxides 10654. Neber rearrangement 1065

xxiv Contents

IV. Rearrangement of halogen compounds 10661. Isomerization 10662. Rearrangement during reaction of halogen compounds 1067

1.2. Rearrangement with extension of the carbon skeleton 1068I. Migration from oxygen to carbon 1068

1. Fries rearrangement 10682. Claisen rearrangement 10703. Baker-Venkataraman rearrangement 10714. Benzyl ether rearrangement 1071

II. Migration from nitrogen to carbon 10721. Benzidine rearrangement 10722. Emil Fischer indole synthesis 10733. Stevens rearrangement 10734. Sommelet rearrangement 1074

III. Migration from sulfur to carbon 1074IV. Benzyl-o-tolyl rearrangement 1075

1.3. Rearrangement with degradation of the carbon skeleton 1076I. Migration from carbon to oxygen 1076

1. Criegee rearrangement 10762. Hypochlorite rearrangement 1077

II. Migration from carbon to nitrogen 10771. Hofmann amide degradation 10772. Curtius degradation 10783. Beckmann rearrangement 10804. Schmidt reaction 1081

1.4. Rearrangement with reorganization of the carbon skeleton 1082I. Wagner-Meerwein rearrangement and related reactions 1082

1. Wagner-Meerwein rearrangement 10822. Pinacolin and retropinacolin rearrangements 10843. Dienone-phenol rearrangement 10854. Isomerization of hydrocarbons 1086

II. Cope rearrangement; valence isomerization 10871. Cope rearrangement 10872. Valence isomerization 10883. Benzilic acid rearrangement 10884. Favorski rearrangement 10895. Rearrangement on oxidation of dialkylacetylenes 1089

III. Rearrangement on decomposition of diazo compounds 10901. Wolff-Schroter rearrangement 10902. Rearrangement on treatment of carbonyl compounds with diazomethane . . 10923. Rearrangement of alkylcarbenes 10924. Rearrangement on treatment of amines with nitrous acid 1093

Appendix I. Purification and drying of organic solvents 1095Aliphatic hydrocarbons 1095Aromatic hydrocarbons 1095Chlorinated hydrocarbons 1096Alcohols 1096Ethers 1098Ketones 1100Carboxylic acids 1100

Contents xxv

Carboxylic anhydrides 1101Carboxylic esters 1101Carboxamides 1101Nitriles 1102Sulfur compounds 1102Nitrogen bases 1102Nitro compounds 1102

Appendix II. Preparation and purification of gases 1103Hydrogen 1103Oxygen 1104Nitrogen 1104Ammonia 1105Nitric oxide (NO) 1105Dinitrogen tetroxide (N2O4) 1105Carbon monoxide 1105Carbon dioxide 1106Phosgene 1106Hydrogen cyanide 1106Sulfur dioxide 1106Chlorine 1107Hydrogen halides 1107Ethylene 1107Acetylene 1107

Appendix III. Preparative organic work with small quantities 1107General 1107Weighing and measuring 1109Powdering, shaking, and stirring 1110Cooling and heating , 1111Recrystallization 1111

a. Preparation of the solution 1111b. Filtration and clarification 1114c. Isolation of the crystallizate 1117d. Drying of crystals 1120

Distillation 1120Distillation in steam 1124Sublimation 1125Extraction 1126Reaction under pressure 1128Subject Index 1129

Introduction: Organization of the Material

The very large number of preparatively useful reactions of organic chemistrycan be classified systematically and clearly by using the common characteristicof all organic compounds, namely, the carbon skeleton. The following casescan then be differentiated:1. The carbon skeleton is preformed in the starting material.

Examples: benozoic acid from toluene; acetaldehyde from ethanol.

2. The carbon skeleton is built up from two or more molecules with formationof a carbon-carbon bond.Examples: acetophenone from benzene and acetic anhydride (2 molecules); Michler's

ketone from dimethylaniline and phosgene (5 molecules); caoutchouc fromisoprene (many molecules).

3. The carbon skeleton is a residue obtained by partial degradation of astructure containing more carbon atoms.Examples: Enanthol from castor oil; phthalic acid from naphthalene.

4. The carbon skeleton is obtained from a pre-existing one by rearrangement.Example: pinacolin from pinacone.

We call these four types of reaction:1. Alteration to the molecule without change of the carbon skeleton.2. Construction of a carbon skeleton.3. Degradation of a carbon skeleton.4. Rearrangement of a carbon skeleton.

Ring closures do not require a position of their own. They usually resultfrom reactions analogous to those between two reactants and are thereforetreated together with them. Ring closures can also be assigned to four funda-mental types:1. Formation of phthalic anhydride from phthalic acid does not change any

part of the carbon skeleton, any more than does formation of pyrroles from1,4-diketones and ammonia.

2 Introduction: Organization of the Material

2. Formation of mesitylene from acetone corresponds to that of mesityl oxidefrom acetone.

3. Formation of cyclopentanone from calcium adipate corresponds exactly tothat of acetone from calcium acetate.

4. Formation of isobornyl chloride from camphene hydrochloride correspondsto that of pinacolin from pinacone.A very satisfactory picture emerges if one considers the typical chemical

processes that are brought together by this classification. Into group 1 (alter-ation) fall all those reactions such as hydrogenation, chlorination, nitration,oxidation, reduction, etc., that previous custom has always systematizedtogether. The second group (construction) comprises all those that lead toexpansion of the carbon skeleton by CC linkage, including addition tomultiple bonds, condensations (e.g., Wurtz-Fittig reactions, Friedel-Craftssyntheses, Mannich reactions), and polymerization. Separation of group 3(degradation) from group 4 (rearrangement) is new, but is clearly organic insense.

It is true that, for instance, one does not find under the keyword 'aldehyde'the preparation of benzaldehyde (a) from toluene by way of benzyl chloride orbenzaldehyde dichloride, (b) from benzene and hydrogen cyanide-hydrogenchloride (Gattermann-Koch) or from bromobenzene by way of phenyl-magnesium bromide and formic ester (Grignard), and (c) from stilbene andozone or from l,2-diphenyl-l,2-ethanediol and lead tetraacetate; but such acollection of syntheses is to be found in the systematic textbooks and referenceworks of organic chemistry, and the compass of the large reactions remainsnevertheless substantially intact in our treatment.

Subdivision of the very large first group (alteration) arises naturally from thefact one has to consider only the bonding of carbon to hydrogen, oxygen,nitrogen, sulfur, phosphorus, and metals; but formation of a carbon-carbonmultiple bond is also included in this group. The resulting sections of group 1are then further subdivided between two types of reaction that can be classifiedas addition and exchange. This subdivision into addition and exchange re-cations is also effected in group 2.

PART A

Reactions on theIntact Carbon Skeleton

CHAPTER 1

Formation of Carbon-Hydrogen Bonds

Compiled byCh. Bischoff, P.-G. Dietrich, E. Hoft, and D. Murawski*

1.1. Formation of the carbon-hydrogen by addition

Industrial hydrogenation of multiple CC bonds is nowadays effected to apreponderating extent by catalytic methods. Because of the many variationspossible they have also become a regular part of preparative and analyticalwork in the laboratory. Nevertheless, particularly in chemical research, otherreducing agents have established their place, and the more so because theysupplement catalytic procedures in the most satisfactory manner and evenexceed them in selectivity.

For instance, hydrogenation of an acetylenic bond on a suitable catalyst givesalmost exclusively c/s-ethylenic compounds, whereas the correspondingfra.y-compounds can be obtained by reduction with complex metallic hydridesor with sodium in liquid ammonia.1 Similar results are found for addition ofhydrogen to unsaturated compounds containing fused ring systems.2 Re-duction of C=O groups is carried out in the laboratory almost exclusively bychemical reducing agents.

I. Addition of hydrogen to C=C bonds and aromatic systems

1. Chemical reducing agentsThe most important processes for addition of hydrogen to the ethylenic

bond and to aromatic and heterocyclic systems comprise reduction by non-noble metals in suitable solvents. All other reducing agents, such as tin(n)chloride, hydrogen iodide, and even complex metal hydrides, are much lessimportant for reduction of multiple CC bonds.

Although the reducing action of the first-named systems was earlier ascribed to so-called"nascent hydrogen," it is now known, particularly through the work of Willstatter,3 Huckel,4

* We are grateful to Dr. R. Philippson for extensive preliminary work on this Section.1 L. Crombie, Quart. Rev. (London), 6,128 (1952); K. N. Campbell and L. T. Eby, / . Amer.

Chem. Soc, 63, (a) 216, (b) 2683 (1941).2 W. S. Johnson et al., J. Amer. Chem. Soc, (a) 78, 6302 (1956); (b) 82, 3409 (1960); (c)

R. H. Jaeger, Tetrahedron, 2, 326 (1958).3 R. Willstatter, F. Seitz, and E. Bumm, Ber. Deut. Chem. Ges., 61, 871 (1928).

4 W. Huckel and H. Bretschneider, Ann. Chem., 540, 157 (1939).

6 Formation of carbon-hydrogen bonds

and Birch5 and their collaborators, that easy electron-transfer from the metal to the electro-philic system is the prerequisite for this reduction and that discharge of a proton by theresulting carbanion follows as a secondary reaction. Variously high reduction potentials areachieved according to the choice of metal, solvent, and pH, thus affording the possibilityof reducing compounds of variously strong electron affinity.

However, Hiickel6 returned to the "nascent hydrogen" hypothesis in order to explainthe reduction of isolated aromatic nuclei by the system alkali-metal-liquid ammonia-alco-hol.5'7 Since this system contains no metal surface to catalyse the recombination of H atoms(2H -> H2), it may be the resulting concentration of free hydrogen atoms that triggers theprimary process.

a. Reduction by non-noble metals

i, Reduction by sodium and alcoholsAlthough isolated double bonds and monocyclic aromatic compounds are

usually not attacked by sodium and alcohols, it is fairly easy to reduce activateddouble bonds such as those in styrene or cinnamic acid. Thus, in compoundsof the type ArCH=CH[CH2]nCH=CHR it is possible to hydrogenateonly the double bond that is conjugated to the nucleus.8 Conjugated dienesare occasionally converted into olefins by addition of two H atoms; condensedaromatic systems are also partially hydrogenated, as described by Bamberger.For instance, anthracene and its derivatives afford the 9,10-dihydro com-pounds,9'10 and phenanthrene and acenaphthene give tetrahydro derivatives;9naphthalene gives dihydronaphthalene in ethanol but tetrahydronaphthalenein pentyl alcohol. Hydrogenation of nitrogen-containing heterocycles is fairlysuccessful,11 and naphthols and naphthylamines are reduced to the tretra-hydro stage still more easily. It is interesting that attack is on the substitutedring of/?-naphthylamine,12 but mainly on the unsubstituted ring of a-naphthyl-amine. Cyclic ketones can be prepared from naphthyl ethers in good yield13if the reaction is carried only to the dihydro stage and the resulting enol ethersare then hydrolysed.

The technique of such reductions with sodium and alcohols is the same asthat for Bouveault-Blanc reduction of esters (see page 76). Ethanol is usuallyused, although higher alcohols are preferable because of their higher boilingpoints. Large quantities of vapor are usually evolved and can badly overloadcondensers of the normal type, so it is advantageous to use condensers withlarge bulbs which can accomodate large amounts of condensate without toogreatly decreasing the cross-section of the tube. Use of metal condensers is

5 A. J. Birch, Quart. Rev. (London), 4, 69 (1950).

6 W. Hiickel, B. Graf, and D. Miinkner, Ann. Chem., 614, 47 (1958).

7 (a) C. B. Wooster, U.S. Pat. 2.182.242; Chem. Abstr., 34, 1993 (1940); (b) J. P. Wibaut

and F. A. Haak, Rec. Trav. Chim., 67, 85 (1948).8 B. Loev and C. R. Dawson, / . Amer. Chem. Soc, 78, 1180 (1956).

9 E. Bamberger and W. Lodter, Ber. Deut. Chem. Ges., 20, 3077 (1887).

10 G. H. Daub and W. C. Doyle, / . Amer. Chem. Soc, 74, 4449 (1952).

11 D. Papa, E. Schwenk, and E. Klingsberg, J. Amer. Chem. Soc, 73, 253 (1951);

O. Neunhoeffer and H. Ulrich, Chem. Ber., 88, 1123 (1955).12

E. B. H. Waser and H. Mollering, Org. Syn., 9, 84 (1929).13

J. W. Cornforth and R.Robinson, / . Chem. Soc, 1949, 1855; M. D. Softer, R. A.Stewart, J. C. Cavagnol, H. E. Gellerson, and E, A. Bowler, / . Amer. Chem. Soc, 72, 3704(1950).

Addition of hydrogen to C = C bonds and aromatic systems 7

often recommended. For safety the reaction vessel should be placed on asand-bath and not on a water-bath or Babo funnel.

Ladenburg's preparation of piperidine from pyridine14 will be described as an example:Pyridine (20 g) in anhydrous ethanol (150 g) is placed in a round-bottomed flask under areflux condenser and warmed on the water-bath. Then sodium pieces (75 g) are added nottoo slowly. As soon as the reaction slackens or sodium ethoxide separates, more ethanol isadded and the reaction is brought to conclusion as fast as possible. When all the sodiumhas been consumed, the mixture is allowed to cool, treated with an equal volume of water,and distilled in steam. The distillate is neutralized with hydrochloric acid and evaporated todryness. Piperidine hydrochloride is obtained as residue in almost quantitative yield and canbe recrystallized from ethanol.

ii9 Reduction with sodium amalgamThe reducing action of sodium amalgam is similar to that of sodium and

alcohol. Double bonds are resistant when isolated but reactive when conjugated.According to Kuhn and Hoflfer,15 polyenes always add the hydrogen at theends of the conjugated system.

The necessary conditions of reduction seem in general to be somewhat milder.Thus the reagent is inferior to the combination of sodium and alcohol forhydrogenation of cyclic systems, but now selective reduction of unsaturatedcarboxylic acids containing a furan16 or a thiophen ring17 is possible. An-thracene and its derivatives,18 acridine,19 and also resorcinol are convertedinto dihydro derivatives; according to the conditions, terephthalic acid givesdi- or tetra-hydroterephthalic acid or /?-toluic acid.20 Sodium amalgam hasbeen repeatedly recommended for selective hydrogenation of a C=C bond ina,/?-unsaturated nitriles,21 ketones,22 lactams,23 and carboxylic acids.24

The amalgam can be prepared according to a prescription in OrganicSyntheses.25 It is used in water, in anhydrous ethanol,23 in alkali hydroxidesolutions,24 or even in glacial acetic acid.22 It is sometimes advisable to bufferthe resulting sodium hydroxide by adding CO2. The process is barely practic-able for reduction of large quantities of unsaturated compounds. If one con-siders the necessity to regenerate the mercury and the inconvenience of workwith large amounts of mercury, it is evident that catalytic methods will oftenbe preferable.

For the preparation of 3-phenylpropionic acid (hydrocinnamic acid), as described byHenle,26 cinnamic acid (15 g) is dissolved in 5% sodium hydroxide solution (75 ml) withwarming, the solution is cooled, and freshly prepared 2.5 % sodium amalgam is added slowly

14 A. Ladenburg, Ann. Chem., 247, 51 (1888).

15 R. Kuhn and M. Hoffer, Ber. Deut. Chem. Ges., 65, 170 (1932).

16 A. S. Carter, / . Amer. Chem. Soc, 50, 2303 (1928).

17 L. J. Owen and F. F. Nord, / . Org. Chem., 15, 988 (1950).

18 E. L. May and E. Mosettig, / . Amer. Chem. Soc, 70, 688, 1077 (1948).

19 R. R. Burtner and J. W. Cusic, / . Amer. Chem. Soc, 65, 1583 (1943).

20 R. Willstatter, F. Seitz, and E. Bumm, Ber. Deut. Chem. Ges., 61, 871 (1928).

2 1 S. Widequist, Ark. Kemi, 26 A, No. 16, 10 (1948).

22 J. F. J. Dippy and R. H. Lewis, Rec. Trav. Chim., 56, 1000 (1937); A. A. Challis and

G. R. Clemo, / . Chem. Soc, 1947, 1692.2 3

G. R. Clemo and L. K. Mishra, / . Chem. Soc, 1953, 192.24

W. E. Bachmann and R. E. Holmen, / . Amer. Chem. Soc, 73, 3660 (1951).25

W. R. Brasen and C. R. Hauser, Org. Syn., 34, 56 0*954).26

L. Gattermann and H. Wieland, "Die Praxis des organischen Chemikers," Walter deGruyter and Co., Berlin, 1947.


in small pieces with efficient stirring. After consumption of about 300-350 g of alloy, asample of the solution is treated with hydrochloric acid and then again with sodium hydroxidesolution. If this no longer decolorizes permanganate, the whole liquid is decanted from themercury, which is then washed with a little water. The solution and washings are neutralizedwith hydrochloric acid, filtered again if necessary, treated with concentrated hydrochloricacid (15 ml), and extracted with ether. The extract is dried with sodium sulfate and the etheris distilled off. The residual oil solidifies when rubbed. The yield amounts to about 12 g,corresponding to 79%. Recrystallization from not too little warm water gives the pure acid,which melts at 48.7.

Hi, Reduction with aluminum amalgamA number of sensitive substances can be advantageously reduced by alu-

minum amalgam since the reaction medium can in this case easily be keptexactly neutral. It is often possible to reduce only one of the conjugated doublebonds of fulvenes and indene and fluorene derivatives of analogous structure.27The process is particularly suitable for hydrogenation of unsaturated esters28 '29that might be hydrolysed in alkaline solution.

Aluminum amalgam, prepared by Wislicenus' method,28 and moist etherare usually used, being allowed to react with the unsaturated compound for1-2 days with occasional addition of a little water.

Benzylindene. 1-Benzylideneindene (5 g) is dissolved in ether and treated, until decolorized,with freshly prepared aluminum amalgam (15 g) with occasional addition of a little water.This requires 6-24 h. The mixture is filtered, the residue is well washed with ether, the solutionis dried and freed from ether by distillation, and the residue is fractionated. The resultingbenzylindene distils between 183 and 185 at 13 mm.

Benzylidenefluorene, furfurylidenefluorene, and other derivatives can be similarly reduced.27

iv, Reduction by solutions of alkali or alkaline-earth metals in liquid ammoniaSolutions of alkali metals in liquid ammonia constitute strongly nucleophilic

reagents, but nevertheless their efficiency for reduction of unsaturated hydro-carbons barely surpasses that of the systems described above.

Apart from exceptional cases,30 isolated double bonds and monocyclicaromatic systems are not attacked. Conjugated double bonds,4 '31 however,aryl-substituted ethylenes,32 and polycyclic aromatic compounds4*33 can bepartially hydrogenated with considerable success. Dimerization or furtherchain-formation of the starting material often occurs as a side reaction.

An excess of sodium is usually used, at 70 or 33 (carbon dioxide bathor boiling point of ammonia). Ether, tetrahydrofuran, and benzene and its

2 7 J. Thiele et al, Ann. Client., 347, 249, 275, 290 (1906).

2 8 H. Wislicenus, / . Prakt. Chem., 54, 18 (1896).

2 9 N. A. Milas and D . Fles, / . Amer. Chem. Soc, 78, 5903 (1956).

3 0 N. A. Nelson and J. C. Wollensak, / . Amer. Chem. Soc, 80, 6626 (1958).

3 1 R. Ya. Levina, V. R. Skvarchenko, V. N . Kosstin, E. G. Treshchova, and A. S. Okune-

vich, Sbornik State* Obshch. Khim., Akad. Nauk SSSR, 1, 355 (1953); Chem. Abstr., 49, 829(1955).

3 2 K. Ziegler, H. Colonius, and O. ScMfer, Ann. Chem., 473, 36 (1929); C. B. Wooster and

J. F. Ryan, / . Amer. Chem. Soc, 56,1133 (1934); H. Gilman and J. C. Bailie, / . Amer. Chem.Soc, 65, 267 (1943); W. F . Erman and T. F . Flautt, / . Org. Chem., 27, 1526 (1962).

3 3 P. Lebeau and M. Picon, C. R. Hebd. Seances Acad. ScL, 158, 1514 (1914); 173, 84

(1921); C. B. Wooster and F. B. Smith, / . Amer. Chem. Soc, 53, 179 (1931).


homologs have been recommended as solvents. Subsequent addition of am-monium salts or alcohols removes the excess of metal and simultaneouslyprotonizes the carbanions that are formed as primary product. Free carboxylicacids react only with difficulty under the above conditions and are advantage-ously neutralized beforehand with sodium amide. The following directions havebeen given for preparation of 9,10-dihydro-9-phenanthroic add:34

9-Phenanthroic acid (5.69 g), sodium amide (1 g), and liquid ammonia (90 ml) are placedin a reaction vessel fitted with a reflux condenser that can be cooled to 70 by alcohol-Dry Ice and with a magnetic stirrer. The mixture is stirred until the sodium amide is whollydissolved (ca. 4 h) and thereafter freshly cut, small pieces of sodium (1.2 g) are added during1 h. The dark red mixture is stirred for a further 1.5 h and then slowly decolorized by ethanol(10 ml). The ammonia is then allowed to evaporate, the residue dissolved in water andacidified with hydrochloric acid, and the thick brown oil is extracted in ether (two 25-mlportions). The united extracts are washed with water, dried over anhydrous sodium sulfate,and treated with Norite. Evaporation of the ether yields the dihydro acid of m.p. 122-124.

Solutions of the more active metals lithium and potassium have been valuablefor hydrogenation of C=C bonds of #,/?-unsaturated ketones2a'35*36 and arylethers.37

A striking improvement in technique was found in the addition of alcohols.This procedure, discovered by Wooster7a and developed chiefly by Birch,38reduces isolated aromatic rings. Benzene and its homologs are reduced to1,4-dihydro derivatives,39 which can be rearranged by NaNH2 in liquidammonia40 to the corresponding conjugated dienes and then further transform-ed into cyclohexene derivatives. Condensed aromatic systems are, of course,also attacked: for instance, 1,4,5,8-tetrahydronaphthalene is obtained fromnaphthalene6'39 3,8-dihydropyrene from pyrene,41 and hexahydrophenan-threne in 94% yield from tetrahydrophenanthrene;42 1-naphthol is convertedinto 5,8-dihydro-l-naphthol in 97% yield.43 The method has found particularlywide application for partial hydrogenation of aryl ethers44 which, without the

O(ref. 46)

34 H. de Koning et aL, Rec Trav. Chim., 83, 364 (1964).

3 5 G . L . Chetty et aL, Tetrahedron, 22, 2311 (1966); R. H. Jager, Tetrahedron, 2, 326(1958).

36 F. H. Howell and D. A. H. Taylor, / . Chem. Soc, 1958, 1248; D. H. R. Barton et aL,

J. Chem. Soc, 1954,903; R. E. Schaub and M. J. Weiss, Chem. & Ind. (London), 1961, 2003;R. Vilotti and A. Bowers, Gazz. Chim. Ital, 93, 1695 (1963); P. Westerhof, Rec. Trav. Chim.,83, 1069 (1964).

37 A. Sandoval et aL, J. Amer. Chem. Soc, 11, 148 (1955); J. A. Barltrop and N. A. J.

Rogers, / . Chem. Soc, 1958, 2566.38

A. J. Birch et aL, J. Chem. Soc, 1944, 430; 1946, 593; 1951, 1945.39

W. Hiickel et aL, Chem. Ber., 88, 388, 346 (1955); C. A. Grob and P. W. Schiess, Helv.Chim. Acta, 43, 1546 (1960).

4 0 A. J. Birch, / . Chem. Soc, 1950, 1551.

4 1 O. Neunhoeffer, H. Woggon, and S. Dahne, Ann. Chem., 612, 98 (1958).

4 2 S. Mejer, Bull. Acad. Polon. ScL, Sir. Sci. Chim., 10, 463 (1962).

4 3 C. D. Gutsche and H. H. Peter, Org. Syn., 37, 80 (1957).

4 4 R. Grewe, E. Nolte, and R.-H. Rotzoll, Chem. Ber., 89, 600 (1956).


addition of alcohol, are usually merely dealkylated; hydrolysis of the 2,5-dihydrogenated enol ethers formed as primary products gives unsaturatedcyclic ketones.38'45 Similar products can be prepared from correspondinganiline derivatives.47 Aromatic carboxylic acids can also be reduced in thering, hydrogenation being almost wholly at the 1,4-positions;48 a convenientsynthesis of 1,4-dihydrobenzoic acid is described in Organic Syntheses.49

The procedure has been variously adapted to advantage. Wooster7a andBirch38' 40 generally add an alcoholic solution of the substance to a solutionof sodium in liquid ammonia. Wibaut and Haak7b add sodium to a solutionor suspension of the substance in liquid ammonia and alcohol. Wilds andNelson50 recommend solutions of lithium and add the alcohol last to thereaction medium. Lithium has recently been recommended also by otherauthors51 as a powerful reagent. On the other hand, magnesium in ammoniaand alcohols is said to be a reducing agent of specific activity.52

For the preparation of l,2-dimethyl-l,4-cyclohexadiene from 0-xylene Huckel andWorffel39 recommend the Birch method:

Apparatus: Reductions in liquid ammonia are carried out in a cylindrical vessel of 11capacity and 8 cm diameter. This vessel is fitted with two ground necks at the top to take adropping funnel and a stirrer, two glass tubes with taps for introduction and removal ofammonia, and a position for insertion of a cold-reading thermometer. Ammonia, pre-driedby soda lime and potassium hydroxide, is introduced with cooling by methanol and solidcarbon dioxide and evacuation of the vessel and, whilst in the liquid state, freed from thelast traces of moisture by small pieces of sodium.

A mixture of 0-xylene (54 g) and anhydrous methanol (51 g) is dropped slowly into asolution of sodium (30 g) in liquid ammonia (400 ml) at 70 to 65, and the whole isstirred until the blue color is discharged. The ammonia is then evaporated, the residue istreated with water, and the hydrocarbon mixture is separated. The dihydro-o-xylene can bepurified by way of the di- or the tetra-bromide; however, it is advantageous to submit themixed product once more to reduction; the desired hydrocarbon is then obtained in 91 %yield.

A reducing agent similar to the above solutions of metals was found in solidhexaamminecalcium, Ca(NH3)6. This can be used at room temperature inethereal suspension, i.e., it avoids the use of liquid ammonia. The unsubstitutedring of 1-methylnaphthalene is hydrogenated specifically by this reagent.53

Reviews by Watt54 and Birch54 should be consulted for more detailed accounts of reduc-tion by metals in liquid ammonia.

v, Reduction by lithium in organic aminesWhen compared with the corresponding solutions in ammonia, solutions

of lithium in amines appear as stronger but less selective reducing agents.4 5

S. M. Mukherji and N. K. Bhattacharyya, / . Amer. Chem. Soc, 75, 4698 (1953); J. S.Mills, H. J. Ringold, and C. Djerassi, / . Amer. Chem. Soc, 80, 6118 (1958).

4 6 B. Weinstein and A. Fenselau, / . Org. Chem., 30, 3209 (1965).

4 7 G. Stork and W. N. White, / . Amer. Chem. Soc, 78, 4604 (1956).

4 8 M. E. Kuehne and B. F. Lambert, / . Amer. Chem. Soc, 81, 4278 (1959).

4 9 M. E. Kuehne and B. F. Lambert, Org. Syn., 43, 22 (1963).

50 A. L. Wilds and N. A. Nelson, / . Amer. Chem. Soc, 75, 5360 (1953).

51 B. A. Lewis and R. A. Raphael, / . Chem. Soc, 1962, 4263; R. E. Juday et al., J. Med.

Chem., 7, 519 (1964).52

P. Markoff and Ch. Iwanoff, Tetrahedron Lett., 1962, 1139.53

H. Boer and P. M. Duinker, Rec. Trav. Chim., 11, 346 (1958).54

G. W. Watt, Chem. Rev., 46, 316 (1950); A. J. Birch, Quart. Rev. {London), 4, 69 (1950).55

R. A. Benkeser et al, J. Amer. Chem. Soc, 11, 3230, 6042 (1955).


Amines are better solvents than ammonia for most organic substances, andtheir higher boiling points permit higher working temperatures. Thus, onreduction of aromatic compounds, not only is the initial step (1,4-addition)facilitated, but so also are isomerization of the primary product to the conju-gated diene and then further reduction to the singly unsaturated dihydro-aromatic derivative. In fact, isolation of the dihydro derivative is rarely describ-ed when this process is used; on the other hand, 1-ethylcyclohexene is obtainedin good yield from ethylbenzene;55 also, conjugated dienes are convertedsatisfactorily into sterically homogeneous olefins.56

Sometimes even isolated double bonds are attacked,57*58 wherefore cyclo-hexane derivatives usually appear as by-products on hydrogenation of aromaticcompounds by this method.

The reaction can be effected at low temperature or at the boiling point ofthe amine. Methylamine or a lower homolog, ethylenediamine,58 or an alkyl-aniline56 is usually used. They often act simultaneously as proton donors, butin other cases ammonium salts must be added after termination of the reaction.In reductions of abietic acid derivatives it was shown that reaction of lithiumin ethylamine is milder than in presence of terf-pentyl alcohol.59 A review ofthese reactions is given by Birch and Smith.60

The reduction of phenethyl alcohol to l-(2-hydroxyethyl)-cyclohexene55 will be describedas an example: Lithium wire (14 g) and anhydrous ethylamine (500 ml) are placed in a500-ml three-necked flask fitted with a stirrer, a dropping funnel, and a reflux condenserwith dry-ice cooling. Phenethyl alcohol (48.8 g) is added with stirring in 8-10 h. The initialblue color disappears fairly quickly and other color changes occur. All operations areconducted under an atmosphere of nitrogen. At the end of the reaction time, the ecxess oflithium is removed with a tongs, and the mixture is decomposed by cautious addition ofammonium chloride to decoloration. The ethylamine is then distilled off and the residue istreated dropwise with water whilst cooling. The organic phase is removed in ether and driedover magnesium sulfate. Distillation of the ethereal solution affords the l-(2-hydroxyethyl)-cyclohexene (b.p. 74-75/2 mm) in 67% yield.

vi, Reduction with zinc, tin, or aluminumIt is rare today that reduction of ethylenic compounds by zinc and acids has

advantages over catalytic hydrogenation; however, it is still used for selectivereduction of steroids,61*62 unsaturated diketones,62"64 and ethylenic derivativescontaining sensitive functional groups.65 The normal method is to use zinc

56 K. Ziegler et al, Ann. Chem., 528, 101 (1937); 567, 1 (1950).

57 G. Ohloff, H. Farnow, and G. Schade, Chem. Ber., 89, 1549 (1956); E. J. Corey and

E. W. Cantrall, / . Amer. Chem. Soc, 81, 1745 (1959).58

L. ReggeJ, R. A. Friedel, and I. Wender, / . Org. Chem., 22, 891 (1957).59

A. W. Burgstahler and L. R. Warden, / . Amer. Chem. Soc, 86, 96 (1964); A. Taharaand O. Hoshino, Tetrahedron Lett., 1966, 3825.

6 0 A. J. Birch and H. Smith, Quart. Rev. {London), 12, 17 (1958).

6 1 L. F. Fieser, S. Rajagopalan, E. Wilson, and M. Tishler, / . Amer. Chem. Soc, 73, 4133

(1951).6 2

E. M. Chamberlin, W. V. Ruyle, A. E. Erickson, J. M. Chemerda, L. M. Aliminosa,R. L. Erickson, G. E. Sita, and M. Tishler, / . Amer. Chem. Soc, 75, 3477 (1953).

6 3 P. Karrer and C.H.Eugster, Helv. Chim. Acta, 32, 1934 (1949); R. Ramassent and

A. Rassat, Bull. Soc. Chim. France, 1963, 2214.6 4

H. B. Henbest, M. Smith, and A. Thomas, / . Chem. Soc, 1958, 3293.65

F. Bergel and J. A. Stock, / . Chem. Soc, 1957, 4563; E. A. Fehnel and M. Carnack,/ . Amer. Chem. Soc, 70, 1813 (1948).


dust in glacial acetic acid or, as described by Kuhn and Winterstein,66 inpyridine and glacial acetic acid; the advantage of the latter combination, whichhas been used for mild reduction of polyenes67 and cyanine dyes, is connectedwith the presence of small amounts of water or alcohol. Reductions have alsobeen carried out with zinc and mineral acid in aqueous medium, in which caseuse of coppered zinc dust is recommended. Tin and hydrochloric acid haverecently been applied for reduction of isoquinolinium salts.68

As example may be chosen the reduction of pyrrole, which can be interrupted relativelysuccessfully at the dihydro stage. Andrews and McElvain69 give the following variation ofthe original prescription by Knorr and Rabe:69

20% Hydrochloric acid (500 ml) in a not too small flask is cooled (ice-salt) to 0; zinc dust(200 g) is added with vigorous stirring and then pyrrole (50 g) slowly from a dropping funnel.If the temperature at the beginning of the reaction is above about 10 the reaction becomesso fast as to be uncontrollable. After all the pyrrole has been added, during about 1 h, themixture is treated with concentrated hydrochloric acid (300 ml), stirred for a further 2 hwhilst the temperature is kept between 15 and 25, removed from the cooling bath, stirredat room temperature for a further 4.5 h, and filtered from unchanged zinc which is thenwashed with a little water. Alkali is added to the filtrate until the zinc hydroxide is redissolvedand the whole is distilled in steam until the distillate is no longer alkaline to litmus. Next,the distillate is acidified with hydrochloric acid and evaporated to dryness on a steam-bath,and the sticky residue is treated with 40% sodium hydroxide solution and extracted twicewith ether. These extracts are dried with sodium sulfate and distilled, affording pyrroline(28.5 g) which boils between 89 and 92 and gives a crystalline hydrochloride, m.p. 162-163.The yield thus amounts to 56 %, by-products being mainly in the higher-boiling fractions.

Kekule70 recommended zinc and alkali hydroxide solutions for preparationof the so-called "nascent hydrogen". Somewhat similarly, Raney nickel alloysin aqueous alkali have been used repeatedly for reductions. The aluminium thatgoes into solution in these reactions reduces naphthalene and its substitutionproducts,71 cyclooctatetraene,72 and in particular 3-arylacrylic acids73 in goodyield.

b. Electrolytic reduction

Electrolytic methods have been applied for reduction of CC multiplebonds more widely than is generally appreciated. Addition of hydrogen is oftenaccompanied by simultaneous reduction of other functional groups, as when


tetrahydro-8-quinolinol is obtained in 95% yield from 8-quinolinol76 but asearly as 1896 Ahrens77 used electrolytic reduction to convert pyridine intopiperidine.

In spite of the good yields obtained, the electrolytic process has never becometruly popular in laboratory practice; it is probably not merely the apparatusbut also experience in the electrochemical field that are lacking. A review bySwann78 may be consulted for further references to the literature.

c. Reduction by lithium aluminum hydride or similar compounds

The applicability of lithium aluminum hydride to reduction of C=C bondsis strongly dependent on their position in the molecule, on the reaction tempe-rature, and on the solvent.

When the usual method of operation is used, namely, in boiling ether,addition of hydrogen is limited to special circumstances. Isolated as well asconjugated olefinic bonds, and aromatic systems, are normally resistant; ful-venes are exceptional, being converted relatively well into alkylcyclopentadienes.Nitrogen heterocycles are attacked more easily at the C=N than at the C=Cbond, wherefore, for instance, pyridine and quinoline afford their 1,2-dihydroderivatives.79

Even ethylenic bonds in #,/?-position to polar groups are not always reduced.As a general rule, applicability of the reaction is confined to the groups

ArC=CC=O (cinnamic acid derivatives,80'81 chalcones82) andArC=CN


in good yield.81 Low temperatures and avoidance of an excess of hydride favorexclusive reduction of the functional groups; on the other hand, in some casesit was possible to attack only the ethylenic bond, e.g., in the conversion ofl-phenyl-2-nitro-l-propene into l-phenyl-2-nitropropane88 and the preparationof diphenylacetaldehyde from diphenylketene.89

Appreciably more severe conditions and thus generally shorter reactiontimes can be achieved by working in higher-boiling solvents, mainly homologousethers, tetrahydrofuran, or dioxan. For instance, in di-w-butyl ether smallamounts of piperidine are obtained from pyridine,90 and allyl alcohol is atleast partly converted into 1-propanol.81 Ether-benzene mixtures have beenrecommended for preparation of dihydro derivatives of acridine and similarheterocyclic compounds,79 and quinoUne has been reduced by diethylhydrido-aluminum in benzene to di- and tetra-hydroquinoline.91 A very powerful,but not generally applicable, reducing agent is a solution of lithium aluminumhydride in diethylene glycol monoethyl ether; it is thermally stable up to 200and has the advantage that it moderates the violence of the hydrolysis that isnecessary in all cases; even acenaphthylene is reduced to acenaphthene quanti-tatively by this method.92

At elevated temperature, if necessary under pressure, and in absence of asolvent, aluminum-hydrogen compounds add to ethylenes, monosubstitutedethylenes (RCH=CH2), and asymmetrically disubstituted ethylenes(R2C=CH2).93.Under more severe conditions this reaction can be appliedalso to cycloolefins, except for cyclohexene. A1H reacts at 70, but LiAlH4 is bet-ter used at 110-120. Symmetrically disubstituted ethylenes (RCH=CHR)react only under conditions where A1H3 and LiAlH4 are no longer stable, butin isolated cases the reaction can be carried through with dialkylhydridoalu-minums, which are thermally more stable. Hydrolysis of the organoaluminumcompounds that are first formed affords the saturated hydrocarbons. Themuch lower capacity for addition makes selective reductions possible, as, forinstance, the ready conversion of 4-vinylcyclohexene into 4-ethylcyclohexene.

A selective reduction that can be readily carried out is involved in the preparation ofisopropylcyclopentadiene:94 Dimethylfulvene (53 g) in anhydrous ether (200 ml) is droppedslowly into a solution of LiAlH4 (18 g) in ether (200 ml). The mixture becomes warm, theyellow color of the fulvene disappears, and a colorless precipitate is formed. At the end ofthe reaction (about 2 h) the addition compound is decomposed by methanol (100 ml) withcooling, and sufficient 2N hydrochloric acid is added to give a clear solution. The ethereallayer is separated, washed with dilute sodium carbonate solution, and dried over sodiumsulfate. Then the ether is removed and the residue is fractionated in a vacuum. Isopropyl-cyclopentadiene (38.4 g, 71 %) is obtained as a colorless liquid of b.p. 32-34/23 mm.

Substances that are very sparingly soluble in ether are best reduced by theso-called Soxhlet extraction technique. The following directions are recordedfor the preparation of tryptamine:95

8 8 R. T. Gilsdorf and F . F . Nord, / . Amer. Chem. Soc, 74, 1837 (1952).

8 9 V. M. Micovic, M. M. Rogic, and M. Lj. Mihailovic", Tetrahedron, 1, 340 (1957).

9 0 P. de Mayo and W. Rigby, Nature, 166, 1075 (1950).

9 1 W. P. Neumann, Ann. Chem., 618, 90 (1958).

9 2 I. Goodman, / . Chem. Soc, 1951, 2209.

9 3 K. Ziegler, H.-G. Gellert, H. Martin, K. Nagel, and J. Schneider, Ann. Chem., 589, 91

(1954).9 4

K. Hafner, Ann. Chem., 606, 79 (1957).9 5

E. H. P. Young, / . Chem. Soc, 1958, 3493.

Addition of hydrogen to CC bonds and aromatic systems 15

3-(2-Nitrovinyl)indole (15 g) is extracted during 8 h from a Soxhlet thimble into a flaskcontaining LiAlH4 (15 g) in anhydrous ether (300 ml). The mixture is then treated with water(80 ml), slowly and with cooling, and filtered. The ether solution is separated, dried oversodium sulfate, and saturated with hydrogen chloride. Tryptamine hydrochloride (12.7 g)is thus obtained, melting at 249-250 (decomp.) after recrystallization from methanol-ethylacetate.

Other complex metal hydrides can only rarely be applied to reduction ofC = C bonds. Sodium borohydride, which can be used in aqueous-alcoholicsolution, seems not normally to attack ethylenic bonds. A few cases only ofpartial reduction of cyclic iminum salts96 and of selective reduction of unusuallyactivated ethylenic bonds97 have been reported. However, some polynitroaromatic compounds, e.g., 1,3,5-trinitrobenzene, can be converted in highyield with saturation of the aromatic system into nitrocyclohexanes or nitro-cyclohexenes.98 Sodium hydridotrimethoxyborate has proved valuable as amild reducing agent for preparation of a series of nitroparaffins from nitro-alkenes."

Monographs100 should be consulted for comprehensive studies of these reductions.

d. Reduction by diimine

An increasingly important place in recent literature is being taken by paperson the reduction of olefinic double bonds by hydrazine in conjunction withoxidizing agents such as oxygen, peroxides (particularly in the presence ofcatalytic amounts of Cu2+), mercuric oxide, hexacyanoferrate, iodine,e t c 101,102 jkjg p r o c e s s saturates not only conjugated but also isolated doublebonds. Diimine is formed as the actual hydrogenating agent; it is a short-livedspecies which can be obtained for this purpose also from other sources.101 '102The following methods of obtaining it are important, as well as the oxidationof hydrazine: thermal decomposition of arenesulfonohydrazides103*104 and9,10-anthracenediimine;105 spontaneous decarboxylation of azodicarboxylicacids on acidification of their salts;1 0 3 '1 0 4 '1 0 6 and alkaline fission of chlor-

9 6 W. Awe, H. Wichmann, and R. Buerhop, Chem. Ber., 90, 1997 (1957); R. E. Lyle,

R. E. Adel, and G. G. Lyle, / . Org. Chem., 24, 342 (1954); N . Kinoshita, M. Hamana, andT. Kawasaki, Chem. & Pharm. Bull. {Tokyo), 10, 753 (1962).

97 J. Fajkos, Collect. Czech. Chem. Commun., 23, 2155 (1958); M. Miyano and M.Matsui,

Chem. Ber., 91, 2044 (1958); J. Knabe, P. Herbort, and N. Ruppentahl, Arch. Pharm., 299,534 (1966).

9 8 T. Severin and R. Schmitz, Chem. Ber., 95, 1417 (1962).

9 9 H. Shechter, D. E. Ley, and E. B. Robertson, Jr., / . Amer. Chem. Soc, 78, 4984 (1956).

100 N. G. Gaylord, "Reduction with Complex Metal Hydrides," Interscience Publishers,

Inc., New York, 1956; (b) A. Hajos, "Komplexe Hydride und ihre Anwendung in derorganischen Chemie," VEB Verlag der Wissenschaften, Berlin, 1966.

101 Review: S. Hmrig, H. R. Miiller, and W. Thier, Angew. Chem., 77, 368 (1965).

102 (a) A. Fiirst, R. C. Berlo, and S. Hooton, Chem. Rev., 65, 51 (1965); (b) B. F. Aylward

and M. Sawistowska, Chem. & Ind. (London), 1962, 484.103

E. E. van Tamelen, / . Amer. Chem. Soc, 83, 3725, 3729 (1961).1 0 4

S. Hunig, H. R. Miiller, and W. Thier, Angew. Chem. Int. Ed. Engl, 2, 214 (1963);Tetrahedron Lett., 1961, 353.

105 E. J. Corey and W. L. Mock, / . Amer. Chem. Soc, 84, 685 (1962).

106 E. J. Corey et al, Tetrahedron Lett., 1961, 347; / . Amer. Chem. Soc, 83, 2957 (1961)


amine107 or chloroacetohydrazide hydrochloride.108 Particular importanceattaches to this hydrogenation because, in contrast to other chemical reducingagents, diimine effects stereospecific ds-addition of the hydrogen; this isevident, inter alia, in the partial reduction of carbon-carbon triple bonds(giving m-olefins) and in the formation of homogeneous #2^0-2,3-dideuterio-succinic acid from maleic acid and deuterated diimine.106 Unlike catalytichydrogenation, which also leads to predominatingly ds-addition products,diimine causes neither shift of the double bond nor stereoisomerization.109From results to date, the following rules have been set up for these hydro-genations:161

1. Unsymmetrical double bonds, as in NO2 , N=C, ^>S=O, also CEEEN, are hardlyattacked at all, nor are bonds that are susceptible to other reducing agents. For instance,diallyl sulfide can be converted into dipropyl sulfide without fission of the SS linkage.110Carbonyl groups are, however, reducible (see page 62).

2. trans-Otefins are reduced faster than cw-olefins. For example, under standard conditionsfumaric acid reacts ten times as fast as maleic acid.101 In some special cases these differencesare so great as to control completely the course of the reaction, as-frans-frans-cyclododeca-triene affords a mixture of 95 % of cw-dodecene and 5 % of dodecane without a detectabletrace of fraws-dodecene.111

3. The rate of reaction decreases with increase in the number of substituents on the doublybonded atoms. However, not all substituents have the same influence. Terminal doublebonds react faster than those in the interior of a chain;112 and with further increase in thenumber of substituents on the double bond there may be no reduction at all. Relative ratesof reaction measured by Hiinig et a/.106 are: maleic acid 10, methylmaleic acid 0.7, dimethyl-maleic acid 0, and ethylenetetracarboxylic acid (dicarboxymaleic acid 0.3). Nevertheless,under other conditions dimethylmaleic acid also can be reduced.109

4. /?flra-Substituents in the benzene ring of cinnamic acid have practically no influence onthe rate of reduction.

For hydrogenation with hydrazine Asinger and his collaborators112 passeda stream of oxygen (60 ml/min) into a mixture of hydrazine monohydrate(145 mmoles), anhydrous ethanol (60 ml), and glacial acetic acid (63 mmoles)and after 30 seconds added the unsaturated hydrocarbon (34 mmoles); thecourse of reduction was then followed by gas chromatography.

For reduction by potassium azodicarboxylate Hamersma and Snyder113 give the followingprescription:

A solution of glacial acetic acid (1.3 g) in dioxan (5 ml) is dropped in 30 min into a mixtureof potassium azodicarboxylate (5 g), dioxan (50 ml), and methyl cinnamate (2 g) with stir-ring under nitrogen. After 9 hours a further equal amount of acid is added, and after a totalof 19 hours the mixture is worked up. Gas chromatography showed the product to contain93 % of 3-phenylpropionic acid.

Reduction by sodium hydrazide is a varian

Preparative Organic Chemistry - Weygand and Hilgetag

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