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EXERCISES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Chapter 1 Good-Leaving Groups on sp3 Carbons: Substitution and Elimination, Reactions of Simple Alkenes .................... 13 Chapter 2 Additions to Aldehydes and Ketones .............................................. 19 Chapter 3 Derivatives of Carboxylic Acids.................................................... 29 Chapter 4 Conjugated Additions to Electron-Deficient Alkenes ............................ 41 Chapter 5 Reactions via Enols and Enolates .................................................. 49 Chapter 6 Reactions via Carbanions Stabilized by Functional Groups Other than Carbonyls ......................................... 59 SOLUTIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 Chapter 1 Good-Leaving Groups on sp3 Carbons: Substitution and Elimination, Reactions of Simple Alkenes ................... 63 Chapter 3 Derivatives of Carboxylic Acids.................................................... 83 Chapter 4 Conjugated Additions to Electron-Deficient Alkenes ............................ 99 Chapter 5 Reactions via Enols and Enolates ................................................ 107 Chapter 6 Reactions via Carbanions Stabilized by Functional Groups Other than Carbonyls ......................................
Two Hundred Exercises in Mechanistic Organic Chemistry © GalChimia, S.L., 2004 Two Hundred Exercises in Mechanistic Organic Chemistry Gabriel Tojo Suárez Profesor Titular de Química Orgánica University of Santiago de Compostela qogatojo@uscmail.usc.es 4 5 Preface Learning the mechanistic basis of Organic Chemistry is like mastering chess. In this game, one needs to know how to move the pieces before embarking in a match. Similarly, a student in Organic Chemistry begins by learning a list of simple reactions. This allows at a later stage to explain the complex mechanisms that intervene in many organic reactions and consist in a chain of simple reactions operating in a sequential way. This book is aimed at students who have completed a learning cycle of Organic Chemistry and need to settle their mechanistic knowledge. One of these students should be able to solve each problem in about half an hour. A bachelor of Organic Chemistry should be able to do it in about ten minutes, while a professional Organic Chemist should consume less than two minutes. There is no way to scientifically prove that a certain mechanism is correct. A mechanism can only be proved wrong. Mechanisms admitted as correct are those that explain the experimental data and have been able to resist all attempts at proving their falsehood. On the other hand, only a few simple reactions have been studied in detail from the mechanistic point of view. The reactions depicted in this book are complex, and none have been studied in detail. Consequently, the proposed solutions represent the opinion of author. Proposing a reasonable mechanism is more relevant than hitting the right one. Many exercises admit more than one sensible mechanism and the proposed solutions represent reasonable, but not unique, answers. No enterprise would meet an end if the goal is the perfection. It is better to make soon a good job than never a perfect one. Many people wait for the perfect moment to have children in order to give them the best possible education. Often the resulting delay causes them to be biologically unable to be parents. Bearing in mind that having children is so satisfactory that it is worth even in a very imperfect way, I have written this book. I hope to be able to be proud of this intellectual offspring in spite of its deficiencies. Santiago, May 20th 2002 Gabriel Tojo 6 7 Contents ABBREVIATIONS 9 EXERCISES 11 Chapter 1 Good-Leaving Groups on sp 3 Carbons: Substitution and Elimination, Reactions of Simple Alkenes 13 Chapter 2 Additions to Aldehydes and Ketones 19 Chapter 3 Derivatives of Carboxylic Acids 29 Chapter 4 Conjugated Additions to Electron-Deficient Alkenes 41 Chapter 5 Reactions via Enols and Enolates 49 Chapter 6 Reactions via Carbanions Stabilized by Functional Groups Other than Carbonyls 59 SOLUTIONS 61 Chapter 1 Good-Leaving Groups on sp 3 Carbons: Substitution and Elimination, Reactions of Simple Alkenes 63 Chapter 3 Derivatives of Carboxylic Acids 83 Chapter 4 Conjugated Additions to Electron-Deficient Alkenes 99 Chapter 5 Reactions via Enols and Enolates 107 Chapter 6 Reactions via Carbanions Stabilized by Functional Groups Other than Carbonyls 121 8 9 Abbreviations 15-crown-5 1,4,7,10,13- pentaoxacyclopentadecane Ac acetyl, CH 3 C(=O)– B: base Bn benzyl, PhCH 2 – Boc tert-butoxycarbonyl, t-BuOC(=O)– Bu n-butyl t-Bu tert-butyl, Me 3 C– cat. catalytic Cbz benzyloxycarbonyl, BnOC(=O)– conc. concentrated CSA camphorsulfonic acid DABCO 4-diazabicyclo[2.2.2]octane DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DMAP p-(dimethylamino)pyridine DMSO dimethyl sulfoxide, MeS(=O)Me Et ethyl, CH 3 CH 2 – HMPA hexamethylphosphoramide, (Me 2 N) 3 P=O KHMDS KN(SiMe 3 ) 2 LDA lithium diisopropylamide, iPr 2 NLi LHMDS LiN(SiMe 3 ) 2 MCPBA m-choroperoxybenzoic acid Me methyl, CH 3 – MOM methoxymethyl, MeOCH 2 – Ms mesyl, MeSO 2 – NBS N-bromosuccinimide Pd/C palladium on activated carbon Ph phenyl Piv pivaloyl, Me 3 CC(=O)– PMB p-methoxybenzyl, p-MeOC 6 H 4 CH 2 – PMP p-methoxyphenyl, p-MeOC 6 H 4 – iPr isopropyl, Me 2 CH– PPTS pyridinium p-toluenesulfonate ref. reflux rt room temperature SEM 2-(trimethylsilyl)ethoxymethyl, TMSCH 2 CH 2 OCH 2 – TBAF tetrabutylammonium fluoride TBDPS tert-butyldiphenylsilyl, t-BuPh 2 Si– TBS tert-butyldimethylsilyl, t-BuMe 2 Si– TES triethylsilyl, Et 3 Si– Tf trifluoromethanesulfonyl (triflyl) TFA trifluoroacetic acid THF tetrahydrofuran THP tetrahydropyran-2-yl TIPS triisopropylsilyl TMS trimethylsilyl, Me 3 Si– Tol p-tolyl, p-MeC 6 H 4 – Tr triphenylmethyl (trityl), Ph 3 C– Troc 2,2,2-trichloroethoxicarbonyl Ts p-toluenesulfonyl, p-MeC 6 H 4 SO 2 – 10 . Two Hundred Exercises in Mechanistic Organic Chemistry © GalChimia, S.L., 2004 Two Hundred Exercises. Compostela qogatojo@uscmail.usc.es 4 5 Preface Learning the mechanistic basis of Organic Chemistry is like mastering chess. In this game, one needs to know how to move the pieces before embarking in a