(BQ) Part 1 book Advanced organic chemistry (Part A: Structure and mechanisms) has contents: Chemical bonding and molecular structure; stereochemistry, conformation, and stereoselectivity; structural effects on stability and reactivity; nucleophilic substitution; polar addition and elimination reactions.
Advanced Organic Chemistry FIFTH EDITION Part A: Structure and Mechanisms Advanced Organic Chemistry PART A: Structure and Mechanisms PART B: Reactions and Synthesis Advanced Organic FIFTH EDITION Chemistry Part A: Structure and Mechanisms FRANCIS A CAREY and RICHARD J SUNDBERG University of Virginia Charlottesville, Virginia Francis A Carey Department of Chemistry University of Virginia Charlottesville, VA 22904 Richard J Sundberg Department of Chemistry University of Virginia Charlottesville, VA 22904 Library of Congress Control Number: 2006939782 ISBN-13: 978-0-387-44897-8 (hard cover) ISBN-13: 978-0-387-68346-1 (soft cover) e-ISBN-13: 978-0-387-44899-3 Printed on acid-free paper ©2007 Springer Science+Business Media, LLC All rights reserved This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now know or hereafter developed is forbidden The use in this publication of trade names, trademarks, service marks and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights springer.com Preface This Fifth Edition marks the beginning of the fourth decade that Advanced Organic Chemistry has been available As with the previous editions, the goal of this text is to allow students to build on the foundation of introductory organic chemistry and attain a level of knowledge and understanding that will permit them to comprehend much of the material that appears in the contemporary chemical literature There have been major developments in organic chemistry in recent years, and these have had a major influence in shaping this new edition to make it more useful to students, instructors, and other readers The expanding application of computational chemistry is reflected by amplified discussion of this area, especially density function theory (DFT) calculations in Chapter Examples of computational studies are included in subsequent chapters that deal with specific structures, reactions and properties Chapter discusses the principles of both configuration and conformation, which were previously treated in two separate chapters The current emphasis on enantioselectivity, including development of many enantioselective catalysts, prompted the expansion of the section on stereoselective reactions to include examples of enantioselective reactions Chapter 3, which covers the application of thermodynamics and kinetics to organic chemistry, has been reorganized to place emphasis on structural effects on stability and reactivity This chapter lays the groundwork for later chapters by considering stability effects on carbocations, carbanions, radicals, and carbonyl compounds Chapters to review the basic substitution, addition, and elimination mechanisms, as well as the fundamental chemistry of carbonyl compounds, including enols and enolates A section on of the control of regiochemistry and stereo- chemistry of aldol reactions has been added to introduce the basic concepts of this important area A more complete treatment, with emphasis on synthetic applications, is given in Chapter of Part B Chapter deals with aromaticity and Chapter with aromatic substitution, emphasizing electrophilic aromatic substitution Chapter 10 deals with concerted pericyclic reactions, with the aromaticity of transition structures as a major theme This part of the text should help students solidify their appreciation of aromatic stabilization as a fundamental concept in the chemistry of conjugated systems Chapter 10 also considers v vi Preface the important area of stereoselectivity of concerted pericyclic reactions Instructors may want to consider dealing with these three chapters directly after Chapter 3, and we believe that is feasible Chapters 11 and 12 deal, respectively, with free radicals and with photochemistry and, accordingly, with the chemistry of molecules with unpaired electrons The latter chapter has been substantially updated to reflect the new level of understanding that has come from ultrafast spectroscopy and computational studies As in the previous editions, a significant amount of specific information is provided in tables and schemes These data and examples serve to illustrate the issues that have been addressed in the text Instructors who want to achieve a broad coverage, but without the level of detail found in the tables and schemes, may choose to advise students to focus on the main text In most cases, the essential points are clear from the information and examples given in the text itself We have made an effort to reduce the duplication between Parts A and B In general, the discussion of basic mechanisms in Part B has been reduced by crossreferencing the corresponding discussion in Part A We have expanded the discussion of specific reactions in Part A, especially in the area of enantioselectivity and enantioselective catalysts We have made more extensive use of abbreviations than in the earlier editions In particular, EWG and ERG are used throughout both Parts A and B to designate electron-withdrawing and electron-releasing substituents, respectively The intent is that the use of these terms will help students generalize the effect of certain substituents such as C=O, C≡N, NO2 , and RSO2 as electron withdrawing and R (alkyl) and RO (alkoxy) as electron releasing Correct use of this shorthand depends on a solid understanding of the interplay between polar and resonance effects in overall substituent effects This matter is discussed in detail in Chapter and many common functional groups are classified Several areas have been treated as “Topics” Some of the Topics discuss areas that are still in a formative stage, such as the efforts to develop DFT parameters as quantitative reactivity indices Others, such as the role of carbocations in gasoline production, have practical implications We have also abstracted information from several published computational studies to present three-dimensional images of reactants, intermediates, transition structures, and products This material, including exercises, is available at the publishers web site, and students who want to see how the output of computations can be applied may want to study it The visual images may help toward an appreciation of some of the subtle effects observed in enantioselective and other stereoselective reactions As in previous editions, each chapter has a number of problems drawn from the literature A new feature is solutions to these problems, which are also provided at the publisher’s website at springer.com/carey-sundberg Our goal is to present a broad and fairly detailed view of the core area of organic reactivity We have approached this goal by extensive use of both the primary and review literature and the sources are referenced Our hope is that the reader who works through these chapters, problems, topics, and computational studies either in an organized course or by self-study will be able to critically evaluate and use the current literature in organic chemistry in the range of fields in which is applied, including the pharmaceutical industry, agricultural chemicals, consumer products, petroleum chemistry, and biotechnology The companion volume, Part B, deals extensively with organic synthesis and provides many more examples of specific reactions Acknowledgment and Personal Statement The revision and updating of Advanced Organic Chemistry that appears as the Fifth Edition spanned the period September 2002 through December 2006 Each chapter was reworked and updated and some reorganization was done, as described in the Prefaces to Parts A and B This period began at the point of conversion of library resources to electronic form Our university library terminated paper subscriptions to the journals of the American Chemical Society and other journals that are available electronically as of the end of 2002 Shortly thereafter, an excavation mishap at an adjacent construction project led to structural damage and closure of our departmental library It remained closed through June 2007, but thanks to the efforts of Carol Hunter, Beth Blanton-Kent, Christine Wiedman, Robert Burnett, and Wynne Stuart, I was able to maintain access to a few key print journals including the Journal of the American Chemical Society, Journal of Organic Chemistry, Organic Letters, Tetrahedron, and Tetrahedron Letters These circumstances largely completed an evolution in the source for specific examples and data In the earlier editions, these were primarily the result of direct print encounter or search of printed Chemical Abstracts indices The current edition relies mainly on electronic keyword and structure searches Neither the former nor the latter method is entirely systematic or comprehensive, so there is a considerable element of circumstance in the inclusion of specific material There is no intent that specific examples reflect either priority of discovery or relative importance Rather, they are interesting examples that illustrate the point in question Several reviewers provided many helpful corrections and suggestions, collated by Kenneth Howell and the editorial staff of Springer Several colleagues provided valuable contributions Carl Trindle offered suggestions and material from his course on computational chemistry Jim Marshall reviewed and provided helpful comments on several sections Michal Sabat, director of the Molecular Structure Laboratory, provided a number of the graphic images My co-author, Francis A Carey, retired in 2000 to devote his full attention to his text, Organic Chemistry, but continued to provide valuable comments and insights during the preparation of this edition Various users of prior editions have provided error lists, and, hopefully, these corrections have vii viii Acknowledgment and Personal Statement been made Shirley Fuller and Cindy Knight provided assistance with many aspects of the preparation of the manuscript This Fifth Edition is supplemented by the Digital Resource that is available at springer.com/carey-sundberg The Digital Resource summarizes the results of several computational studies and presents three-dimensional images, comments, and exercises based on the results These were developed with financial support from the Teaching Technology Initiative of the University of Virginia Technical support was provided by Michal Sabat, William Rourk, Jeffrey Hollier, and David Newman Several students made major contributions to this effort Sara Fitzgerald Higgins and Victoria Landry created the prototypes of many of the sites Scott Geyer developed the dynamic representations using IRC computations Tanmaya Patel created several sites and developed the measurement tool I also gratefully acknowledge the cooperation of the original authors of these studies in making their output available Problem Responses have been provided and I want to acknowledge the assistance of R Bruce Martin, David Metcalf, and Daniel McCauley in helping work out some of the specific kinetic problems and in providing the attendant graphs It is my hope that the text, problems, and other material will assist new students to develop a knowledge and appreciation of structure, mechanism, reactions, and synthesis in organic chemistry It is gratifying to know that some 200,000 students have used earlier editions, hopefully to their benefit Richard J Sundberg Charlottesville, Virginia March 2007 Introduction This volume is intended for students who have completed the equivalent of a two-semester introductory course in organic chemistry and wish to expand their understanding of structure and reaction mechanisms in organic chemistry The text assumes basic knowledge of physical and inorganic chemistry at the advanced undergraduate level Chapter begins by reviewing the familiar Lewis approach to structure and bonding Lewis’s concept of electron pair bonds, as extended by adding the ideas of hybridization and resonance, plus fundamental atomic properties such as electronegativity and polarizability provide a solid foundation for qualitative descriptions of trends in reactivity In polar reactions, for example, the molecular properties of acidity, basicity, nucleophilicity, and electrophilicity can all be related to information embodied in Lewis structures The chapter continues with the more quantitative descriptions of molecular structure and properties that are obtained by quantum mechanical calculations Hückel, semiempirical, and ab initio molecular orbital (MO) calculations, as well as density functional theory (DFT) are described and illustrated with examples This material is presented at a level sufficient for students to recognize the various methods and their ranges of application Computational methods can often provide insight into reaction mechanisms by describing the structural features of intermediates and transition structures Another powerful aspect of computational methods is their ability to represent electron density Various methods of describing electron density, including graphical representations, are outlined in this chapter and applied throughout the remainder of the text Chapter explores the two structural levels of stereochemistry— configuration and conformation Molecular conformation is important in its own right, but can also influence reactivity The structural relationships between stereoisomers and the origin and consequences of molecular chirality are discussed After reviewing the classical approach to resolving racemic mixtures, modern methods for chromatographic separation and kinetic resolution are described The chapter also explores how stereochemistry affects reactivity with examples of diastereoselective and enantioselective reactions, especially those involving addition to carbonyl groups Much of today’s work in organic chemistry focuses on enantioselective reagents and catalysts The enantioselectivity of these reagents usually involves rather small and sometimes subtle differences in intermolecular interactions Several of the best-understood enantioselective ix x Introduction reactions, including hydrogenation, epoxidation of allylic alcohols, and dihydroxylation of alkenes are discussed Chapter provides examples of structure-stability relationships derived from both experimental thermodynamics and computation Most of the chapter is about the effects of substituents on reaction rates and equilibria, how they are measured, and what they tell us about reaction mechanisms The electronic character of the common functional groups is explored, as well as substituent effects on the stability of carbocations, carbanions, radicals, and carbonyl addition intermediates Other topics in this chapter include the Hammett equation and related linear free-energy relationships, catalysis, and solvent effects Understanding how thermodynamic and kinetic factors combine to influence reactivity and developing a sense of structural effects on the energy of reactants, intermediates and transition structures render the outcome of organic reactions more predictable Chapters to relate the patterns of addition, elimination, and substitution reactions to the general principles developed in Chapters to A relatively small number of reaction types account for a wide range of both simple and complex reactions The fundamental properties of carbocations, carbanions, and carbonyl compounds determine the outcome of these reactions Considerable information about reactivity trends and stereoselectivity is presented, some of it in tables and schemes Although this material may seem overwhelming if viewed as individual pieces of information, taken in the context of the general principles it fills in details and provides a basis for recognizing the relative magnitude of various structural changes on reactivity The student should strive to develop a sufficiently broad perspective to generate an intuitive sense of the effect of particular changes in structure Chapter begins the discussion of specific reaction types with an examination of nucleophilic substitution Key structural, kinetic, and stereochemical features of substitution reactions are described and related to reaction mechanisms The limiting mechanisms SN and SN are presented, as are the “merged” and “borderline” variants The relationship between stereochemistry and mechanism is explored and specific examples are given Inversion is a virtually universal characteristic of the SN mechanism, whereas stereochemistry becomes much more dependent on the specific circumstances for borderline and SN mechanisms The properties of carbocations, their role in nucleophilic substitution, carbocation rearrangements, and the existence and relative stability of bridged (nonclassical) carbocations are considered The importance of carbocations in many substitution reactions requires knowledge of their structure and reactivity and the effect of substituents on stability A fundamental characteristic of carbocations is the tendency to rearrange to more stable structures We consider the mechanism of carbocation rearrangements, including the role of bridged ions The case of nonclassical carbocations, in which the bridged structure is the most stable form, is also discussed Chapter considers the relationship between mechanism and regio- and stereoselectivity The reactivity patterns of electrophiles such as protic acids, halogens, sulfur and selenium electrophiles, mercuric ion, and borane and its derivatives are explored and compared These reactions differ in the extent to which they proceed through discrete carbocations or bridged intermediates and this distinction can explain variations in regio- and stereochemistry This chapter also describes the E1, E2, and E1cb mechanisms for elimination and the idea that these represent specific cases within a continuum of mechanisms The concept of the variable mechanism can explain trends in reactivity and regiochemistry in elimination reactions Chapter focuses on the fundamental properties and reactivity of carbon nucleophiles, including The steric dependence is imposed by the bulky trimethylamine leaving group In the TS for anti elimination, steric repulsion is increased as R1 and R2 increase in size When the repulsion is sufficiently large, the TS for syn elimination is preferred 563 SECTION 5.10 Elimination Reactions R1 R2 R2 H N+(CH3)3 R1 D D H D R2 H H R1 R1 N+(CH3)3 H R2 D H –B –B anti TS syn TS Another aspect of the stereochemistry of elimination reactions is the ratio of E-and Z-products The proportion of Z-and E-isomers of disubstituted internal alkenes formed during elimination reactions depends on the identity of the leaving group Halides usually give mainly the E-alkenes.299 Bulkier groups, particularly arenesulfonates, give higher proportions of the Z-alkene Sometimes, more Z-isomer is formed than Eisomer The preference for E-alkene probably reflects the unfavorable steric repulsions present in the E2 transition state leading to Z-alkene High Z:E ratios are attributed to a second steric effect that becomes important only when the leaving group is large The conformations leading to E-and Z-alkene by anti elimination are depicted below OSO2Ar OSO2Ar H R R H E-alkene R H R H Z-alkene H H –B –B When the leaving group and base are both large, conformation is favored because it permits the leaving group to occupy a position removed from the -alkyl substituents, while also maintaining an anti relationship to the -hydrogen Anti elimination through a TS arising from conformation gives Z-alkene 5.10.4 Dehydration of Alcohols The dehydration of alcohols is an elimination reaction that takes place under acidic rather than basic conditions and involves an E1 mechanism.300 The function of the acidic reagent is to convert the hydroxyl group to a better leaving group by protonation H+ RCHCH2R' OH 299 300 RCHCH2R' –H2O RCHCH2R' –H+ RCH CHR' O+H2 H C Brown and R L Kliminsch, J Am Chem Soc., 87, 5517 (1965); I N Feit and W H Saunders, Jr., J Am Chem Soc., 92, 1630 (1970) D V Banthorpe, Elimination Reactions, Elsevier, New York, 1963, pp 145–156 564 CHAPTER Polar Addition and Elimination Reactions This elimination reaction is the reverse of acid-catalyzed hydration, which was discussed in Section 5.2 Since a carbocation or closely related species is the intermediate, the elimination step is expected to favor the more-substituted alkene The E1 mechanism also explains the trends in relative reactivity Tertiary alcohols are the most reactive, and reactivity decreases going to secondary and primary alcohols Also in accord with the E1 mechanism is the fact that rearranged products are found in cases where a carbocation intermediate would be expected to rearrange R R3CCHR' + H+ R3CCHR' O+H2 OH R3CCHR' + R2CCHR' + R R2C C R' For some alcohols, exchange of the hydroxyl group with solvent competes with dehydration.301 This exchange indicates that the carbocation can undergo SN capture in competition with elimination Under conditions where proton removal is rate determining, it would be expected that a significant isotope effect would be seen, which is, in fact, observed H* PhCHCHPh H2SO4 H2O OH PhCH CHPh kH/kD = 1.8 Ref 302 5.10.5 Eliminations Reactions Not Involving C−H Bonds The discussion of elimination processes thus far has focused on reactions that involve removal of a proton bound to a ß-carbon, but it is the electrons in the C−H bond that are essential to the elimination process Compounds bearing other substituents that can release electrons undergo -eliminations Many such reactions are known, and they are frequently stereospecific Vicinal dibromides can be debrominated by certain reducing agents, including iodide ion The stereochemical course in the case of 1,1,2-tribromocyclohexane was determined using a 82 Br-labeled sample prepared by anti addition of 82 Br to bromocyclohexene Exclusive anti elimination gave unlabeled bromocyclohexene, whereas 82 Br-labeled product resulted from syn elimination Debromination with sodium iodide was found to be cleanly an anti elimination.303 82Br NaI 82Br Br 301 302 303 Br anti elimination product C A Bunton and D R Llewellyn, J Chem Soc., 3402 (1957); J Manassen and F S Klein, J Chem Soc., 4203 (1960) D S Noyce, D R Hartter, and R M Pollack, J Am Chem Soc., 90, 3791 (1968) C L Stevens and J A Valicenti, J Am Chem Soc., 87, 838 (1965) The iodide-induced reduction is essentially the reverse of a halogenation Application of the principle of microscopic reversibility suggests that the reaction proceeds through a bridged intermediate.304 565 SECTION 5.10 Elimination Reactions I– I +Br *Br Br Br Br *Br The rate-determining expulsion of bromide ion through a bridged intermediate requires an anti orientation of the two bromides The nucleophilic attack of iodide at one bromide enhances its nucleophilicity and permits formation of the bridged ion The stereochemical preference in noncyclic systems is also anti, as indicated by the fact that meso-stilbene dibromide yields trans-stilbene, whereas d,l-stilbene dibromide gives mainly cis-stilbene under these conditions.94 Br Br I– Ph Ph Ph Ph I– Ph Ph Ph Ph Br Br Structures of type M−C−C−X in which M is a metal and X is a leaving group are very prone to elimination with formation of a double bond One example is acid-catalyzed deoxymercuration.305 The ß-oxyorganomercurials are more stable than similar reagents derived from more electropositive metals, but are much more reactive than simple alcohols For example, CH3 CH OH CH2 HgI is converted to propene under acid-catalyzed conditions at a rate that is 1011 times greater than dehydration of 2-propanol under the same conditions These reactions are believed to proceed through a bridged mercurinium ion by a mechanism that is the reverse of oxymercuration (see Section 5.6) I IHg Hg + O+CH3 + CH3OH H One of the pieces of evidence supporting this mechanism is the fact that the H ‡ for deoxymercuration of trans-2-methoxycyclohexylmercuric iodide is about kcal/mol less than for the cis isomer Only the trans isomer can undergo elimination by an anti process through a chair conformation HgI OCH3 HgI OCH3 HgI 304 305 fast OCH3 HgI slow OCH3 C S T Lee, I M Mathai, and S I Miller, J Am Chem Soc., 92, 4602 (1970) M M Kreevoy and F R Kowitt, J Am Chem Soc., 82, 739 (1960) 566 CHAPTER Polar Addition and Elimination Reactions Comparing the rates of acid-catalyzed ß-elimination of compounds of the type MCH2 CH2 OH yields the reactivity order for ß-substituents IHg ∼ Ph3 Pb ∼ Ph3 Sn > Ph3 Si > H The relative rates are within a factor of ten for the first three, but these are 106 greater than for Ph3 Si and 1011 greater than for a proton There are two factors involved in these very large rate accelerations One is bond energies The relevant values are Hg−C= 27 < Pb−C= 31 < Sn−C = 54 < Si−C = 60 < H−C = 96 kcal/mol.306 The metal substituents also have a very strong stabilizing effect for carbocation character at the ß-carbon This stabilization can be pictured either as a orbital-orbital interaction in which the carbon-metal bond donates electron density to the adjacent p orbital, or as formation of a bridged species M C C M or C C There are a number of synthetically valuable ß-elimination processes involving organosilicon307 and organotin308 compounds Treatment of ß-hydroxyalkylsilanes or ß-hydroxyalkylstannanes with acid results in stereospecific anti eliminations that are much more rapid than for compounds lacking the group IV substituent H CH3CH2CH2 OH H CH2CH2CH3 (CH3)3Si H H2SO4 CH3CH2CH2 H CH2CH2CH3 Ref 309 CH3 H Ph3Sn OH H CH3 H+ H CH3 H CH3 Ref 310 ß-Halosilanes also undergo facile elimination when treated with methoxide ion Br CH3(CH2)3CHCHSi(CH3)3 NaOCH3 CH3(CH2)3CH CHBr Br Ref 311 306 307 308 309 310 311 D D Davis and H M Jacocks, III, J Organomet Chem., 206, 33 (1981) A W P Jarvie, Organomet Chem Rev Sect A, 6, 153 (1970); W P Weber, Silicon Reagents for Organic Synthesis, Springer-Verlag, Berlin, 1983; E W Colvin, Silicon in Organic Synthesis, Butterworths, London, 1981 M Pereyre, J -P Quintard, and A Rahm, Tin in Organic Synthesis, Butterworths, London, 1987 P F Hudrlick and D Peterson, J Am Chem Soc., 97, 1464 (1975) D D Davis and C E Gray, J Org Chem., 35, 1303 (1970) A W P Jarvie, A Holt, and J Thompson, J Chem Soc B, 852 (1969); B Miller and G J McGarvey, J Org Chem., 43, 4424 (1978) Fluoride-induced ß-elimination of silanes having leaving groups in the ß-position are important processes in synthetic chemistry, as, for example, in the removal of ß-trimethylsilylethoxy groups 567 SECTION 5.10 Elimination Reactions + – RCO2CH2CH2Si(CH3)3 + R4N F RCO2– + CH2 CH2 + FSi(CH3)3 Ref 312 These reactions proceed by alkoxide or fluoride attack at silicon that results in C−Si bond cleavage and elimination of the leaving group from the ß-carbon These reactions are stereospecific anti eliminations Nu: (CH3)Si3 RCH (CH3)3SiNu CHR + RCH CHR + X– X ß-Elimination reactions of this type can also be effected by converting a ß-hydroxy group to a better leaving group For example, conversion of ß-hydroxyalkylsilanes to the corresponding methanesulfonates leads to rapid elimination.313 (CH3)3SiCH2CR2 CH3SO2Cl H2C CR2 OH -Trimethylsilylalkyl trifluoroacetates also undergo facile anti elimination.314 The ability to promote ß-elimination and the electron-donor capacity of the ß-metalloid substituents can be exploited in a very useful way in synthetic chemistry.315 Vinylstannanes and vinylsilanes react readily with electrophiles The resulting intermediates then undergo elimination of the stannyl or silyl substituent, so that the net effect is replacement of the stannyl or silyl group by the electrophile The silyl and stannyl substituents are crucial to these reactions in two ways In the electrophilic addition step, they act as electron-releasing groups that promote addition and control the regiochemistry A silyl or stannyl substituent strongly stabilizes carbocation character at the ß-carbon atom and thus directs the electrophile to the -carbon E RCH CHMR'3 + E+ RCHCMR3 + RCH CHE Computational investigations indicate that there is a ground state interaction between the alkene orbital and the carbon-silicon bond that raises the energy of the 312 313 314 315 P Sieber, Helv Chim Acta, 60, 2711 (1977) F A Carey and J R Toler, J Org Chem., 41, 1966 (1976) M F Connil, B Jousseaune, N Noiret, and A Saux, J Org Chem., 59, 1925 (1994) T H Chan and I Fleming, Synthesis, 761 (1979); I Fleming, Chem Soc Rev., 10, 83 (1981) 568 CHAPTER Polar Addition and Elimination Reactions HOMO and enhances reactivity.316 MP3/6-31G* calculations indicate a stabilization of 38 kcal/mol, which is about the same as the value calculated for an -methyl group.317 Furthermore, this stereoelectronic interaction favors attack of the electrophile anti to the silyl substituent The reaction is then completed by the elimination step in which the carbon-silicon or carbon-tin bond is broken Allyl silanes and allyl stannanes are also reactive toward electrophiles and usually undergo a concerted elimination of the silyl substituent (CH3)3SiCH2CH CH2 + I2 CH2 CHCH2I Ref 318 (CH3)3SiCH2CH CH(CH2)5CH3 + (CH3)3CCl C(CH3)3 TiCl4 CH2 CHCH(CH2)5CH3 Ref 319 (CH3)3SnCH2 CH2 CH CH2 CH2 + BrCH2CH C(CH3)2 CH2 CH (CH2)2CH C(CH3)2 Ref 320 (CH3)3SnCH2CH CH2 + (CH3O)2CHCH2CH2Ph (Et)2AlSO4 CH2 CHCH2CHCH2CH2Ph OCH3 Ref 321 The common mechanistic pattern in these reactions involves electron release toward the developing electron deficiency on the C(2) of the double bond Completion of the reaction involves loss of the electron-donating group and formation of the double bond Further examples of these synthetically useful reactions can be found in Section 9.3 in Part B E+ RCH CH CH2 RCH CHCH2E M 316 317 318 319 320 321 S D Kahn, C F Pau, A R Chamberlin, and W J Hehre, J Am Chem Soc., 109, 650 (1987) S E Wierschke, J Chandrasekhar, and W L Jorgensen, J Am Chem Soc., 107, 1496 (1985) D Grafstein, J Am Chem Soc., 77, 6650 (1955) I Fleming and I Paterson, Synthesis, 445 (1979) J P Godschalx and J K Stille, Tetrahedron Lett., 24, 1905 (1983) A Hosomi, H Iguchi, M Endo, and H Sakurai, Chem Lett., 977 (1979) General References 569 G V Boyd, in The Chemistry of Triple-Bonded Functional Groups, Supplement 2, S Patai, ed., John Wiley & Sons, New York, 1994, Chap A F Cockerill and R G Harrison, The Chemistry of Double-Bonded Functional Groups, Part 1, S Patai, ed., John Wiley & Sons, New York, 1977, Chap P B de la Mare and R Bolton, Electrophilic Additions to Unsaturated Systems, 2nd Edition, Elsevier, New York, 1982 J G Gandler, in The Chemistry of Double-Bonded Functional Groups, Supplement A, Vol 2, S Patai, ed., John Wiley & Sons, New York, 1989, Chap 12 G H Schmid, in The Chemistry of Double-Bonded Functional Groups, Supplement A, Vol 2, S Patai, ed., John Wiley & Sons, New York, 1989, Chap 11 P J Stang and F Diederich, eds., Modern Acetylene Chemistry, VCH Publishers, Weinheim, 1995 W H Saunders, Jr., and A F Cockerill, Mechanisms of Elimination Reactions, John Wiley & Sons, New York, 1973 Problems (References for these problems will be found on page 1160.) 5.1 Which compound of each pair will react faster with the specified reagent? Explain your answer a 1-hexene or E-3-hexene with bromine in acetic acid b cis- or trans-4-(t-butyl)cyclohexylmethyl bromide with KOC CH3 in t-butyl alcohol c 2-phenylpropene or 4-(1-methylethenyl)benzoic acid with sulfuric acid in water d CH2 CH3 or CH(CH3)2 CH(CH3)2 toward acid-catalyzed hydration e CH3CH(CH2)3CH3 SO2Ph or CH3CH(CH2)3CH3 OSO2Ph with KOC CH3 in t-butyl alcohol f 4-bromophenylacetylene or 4-methylphenylacetylene with Cl2 in acetic acid g O or OC2H5 toward acid-catalyzed hydration PROBLEMS 570 CHAPTER Polar Addition and Elimination Reactions 5.2 Predict the structure, including stereochemistry, of the product(s) expected for the following reactions If more than one product is shown, indicate which is major and which is minor a CH2OH Ph C CH2CH Br2 CH2 C12H15O2Br CH2OH b DCl C6H8DCl c O NaOEt erythro-ArCCHCHAr C15H9Cl3O EtOH Cl Cl d (CH3)2C H2O CH3 C10H18 heat (CH3)3+N e CH3 C CH3 C CH3 CH3 CH3 Cl2 CCl4 C11H17Cl CH3 f CH3 KOC(C2H5)3 Cl g CH3 CH=CH2 1) Hg(OAc)2 CH3OH C10H13ClHgO 2) NaCl h 571 PhC Cl2 CCH2CH3 C10H10Cl2 CH3CO2H + PROBLEMS C12H13ClO2 5.3 The reaction of the cis and trans isomers of N ,N ,N -trimethyl-(4-tbutylcyclohexyl)ammonium chloride with K +− O-t-Bu in t-butyl alcohol have been compared The cis isomer gives 90% 4-t-butylcyclohexene and 10% N ,N dimethyl-(4-t-butylcyclohexyl)amine, whereas the trans isomer gives only the latter product in quantitative yield Explain the different behavior of the two isomers 5.4 For E2 eliminations in 2-phenylethyl systems with several different leaving groups, both the primary kinetic isotope effect and Hammett have been determined Deduce information about the nature and location (early, late) of the TS in the variable E2 spectrum How does the identity of the leaving group affect the nature and location of the TS? X kH /kD Br OTs + S CH3 + N CH3 7.11 5.66 5.07 2.98 2.1 2.3 2.7 3.7 5.5 Predict the effect on the 1-butene, Z-2-butene, and E-2-butene product ratio when the E2 elimination (KOEt, EtOH) of erythro-3-deuterio-2-bromobutane is compared with 2-bromobutane Which alkene(s) will increase in relative amount and which will decrease in relative amount? Explain the basis of your answer 5.6 Arrange the following compounds in order of increasing rate of acidcatalyzed hydration: ethene, propene, 2-cyclopropylpropene, 2-methylpropene, 1-cyclopropyl-1-methoxyethene Explain the basis of your answer 5.7 Discuss the factors that are responsible for the regiochemistry and stereochemistry observed for the following reactions a D D D Ph (CH3)3C HCl D Ph Cl (CH3)3C D H D b D D Ph H H C(CH3)3 DBr Ph C(CH3)3 Ph + Ph C(CH3)3 Br Br E-isomer 81% 19% Z-isomer 40% 60% H C(CH3)3 H 572 c CHAPTER CF3CO2H O2CCF3 Polar Addition and Elimination Reactions CH2 CH3 d Br CH3 (CH3)3C Br2 (CH3)3C CH3 Br 5.8 Explain the mechanistic basis of the following observations and discuss how the observation provides information about the reaction mechanism a When 1-aryl-2-methyl-2-propyl chlorides (8-A) react with NaOCH3 , roughly 1:1 mixtures of internal (8-B) and terminal alkene (8-C) are formed By using the product ratios, the overall reaction rate can be dissected into the rates for formation of 8-B and 8-C The rates are found to be substituent dependent for 8-B ( = +1 4) but not for 8-C ( = −0 ± 1) All the reactions are second order, first order in reactant and first order in base ArCH2C(CH3)2 NaOCH3 ArCH C(CH3)2 + ArCH2C Cl CH2 CH3 8-A 8-B 8-C b When 1,3-pentadiene reacts with DCl, more E-4-chloro-5-deuterio-2-pentene (60–75%) is formed than E-4-chloro-1-deuterio-2-pentene (40–25%) c When indene (8-D) is brominated in CCl4 , it gives some 15% syn addition, but indenone (8-E) gives only anti addition under these conditions When the halogenation of indenone is carried out using Br−Cl, the product is trans-2bromo-3-chloroindenone 8-E 8-D O d The acid-catalyzed hydration of allene gives acetone, not allyl alcohol or propanal e In the addition of HCl to cyclohexene in acetic acid, the ratio of cyclohexyl acetate to cyclohexyl chloride drops significantly when tetramethylammonium chloride is added in increasing concentrations The rate of the reaction is also accelerated These effects are not observed with styrene f The value for elimination of HF using K+− O-t-Bu from a series of 1-aryl2-fluoroethanes increases from the mono- to di- and trifluoro derivatives, as indicated below ArCH2 CF3 ArCH2 CHF2 = +4 04 = +3 56 ArCH2 CH2 F = +3 24 5.9 Suggest mechanisms that account for the outcome of the following reactions: PROBLEMS a Si(CH3)3 1) Br2, CH2Cl2 2) NaOCH3, CH3OH Br b Si(CH3)3 NaO2CCH3 CH3CO2H OH c Br Br heat Br Br optically active racemic d Br2 Br Br 5.10 The rates of bromination of internal alkynes are roughly 100 times greater that the corresponding terminal alkynes For hydration, however, the rates are less than 10 times greater for the disubstituted compounds Account for this difference by comparison of the mechanisms for bromination and hydration 5.11 The bromination of 3-aroyloxycyclohexenes gives rise to a mixture of stereoisomeric and regioisomeric products The product composition for Ar = phenyl is shown Account for the formation of each of these products Br ArCO2 573 Br2 Br Br + ArCO2 ArCO2 Br Br + ArCO2 Br Br + ArCO2 Br 5.12 The Hammett correlation of the acid-catalyzed dehydration of 1,2-diaryl ethanols has been studied The correlation resulting from substitution on both the 1- and + 2-aryl rings is: log k = −3 78 Ar + 23 Ar − 18 Rationalize the form of this correlation equation What information does it give about the involvement of the Ar ring in the rate-determining step of the reaction? ArCHCH2Ar ′ OH H+ ArCH CHAr ′ 574 5.13 The addition of HCl to alkenes such as 2-methyl-1-butene and 2-methyl-2-butene in nitromethane follow a third-order rate expression: CHAPTER Polar Addition and Elimination Reactions Rate = k HCl alkene It has also been established that there is no incorporation of deuterium into the reactant at 50% completion when DCl is used Added tetraalkylammonium chloride retards the reaction, but the corresponding perchlorate salt does not Propose a reaction mechanism that is consistent with these observations + 5.14 In the bromination of substituted styrenes, a plot is noticeably curved If the extremes of the curve are taken to represent straight lines, the curve can be resolved into two Hammett relationships with = −2 for EWG substituents and = −4 for ERG substituents The corresponding -methylstyrenes give a similarly curved plot The stereoselectivity of the reaction of the methylstyrenes is also dependent on the substituents The reaction is stereospecifically anti for strong EWGs, but is only weakly stereoselective, e.g., 63% anti:37% syn, for methoxy Discuss a possible mechanistic basis for the curved Hammett plots and the relationship to the observed stereochemistry 5.15 The second-order rate constants and solvent kinetic isotope effects for acidcatalyzed hydration are given below for several 2-substituted 1,3-butadienes The products are a mixture of 1,2- and 1,4-addition What information these data provide about the mechanism of the reaction? R R c-C3 H5 CH3 Cl H C H5 O k2 M −1 s−1 kH + /kD+ 22 × 10−2 19 × 10−5 01 × 10−8 96 × 10−8 60 1.2 1.8 1.4 1.8 - 5.16 The reaction of both E- and Z-2-butene with acetic acid to give 2-butyl acetate is catalyzed by various strong acids With DBr, DCl, and CH3 SO3 H in CH3 CO2 D, the reaction proceeds with largely (84 ± 2%) anti addition If the reaction is stopped short of completion, there is no incorporation of deuterium into unreacted alkene, nor any interconversion of the E- and Z-isomers When the catalyst is changed to CF3 SO3 H, the recovered butene shows small amounts of 1-butene and interconversion of the 2-butene stereoisomers The stereoselectivity of the reaction drops to 60–70% anti addition How can you account for the changes that occur when CF3 SO3 H is used as the catalyst, as compared with the other acids? 5.17 A comparison of rate and product composition of the products from reaction of t-butyl chloride with NaOCH3 in methanol and methanol-DMSO mixtures has been reported Some of the data are shown below Interpret the changes in rates and product composition as the amount of DMSO in the solvent mixture is increased 100% MeOH 36.8% DMSO Product comp.(%) Ether Alkene NaOMe M Rate k × 104 s−1 00 20 25 30 40 50 70 75 80 90 00 2.15 2.40 2.30 2.26 2.36 2.56 73.8 26.2 62.9 32.1 58.6 41.4 2.58 51.7 48.3 2.64 2.74 52.2 Product comp.(%) Ether Alkene Product comp.(%) Rate Ether Alkene k × 104 s−1 0.81 1.52 50 50 24 53 1.90 2.65 10 89 4.11 11 98 4.59 6.16 6.81 41 38 95 96 Rate k × 104 s−1 47.8 575 64.2% DMSO 24 76 0 100 100 100 10 17 24 5.18 a The gas phase basicity of substituted -methyl styrenes follows the YukawaTsuno equation with r + = The corresponding r + for 1-phenylpropyne is 1.12 and for phenylacetylene it is 1.21 How are these values related to the relative stability of the carbocations formed by protonation? styrene – H3O+ complex TS1 TS2 1-phenylethyl cation + H2O complex protonated 1-phenylethyl alcohol C C1 C H9 C2 C8 styrene + H3O+ 46.4 TS2 17.6 1-phenylethyl cation + H2O 11.7 15.7 styrene – H3O+ complex TS1 0.9 –1.7 0.0 protonated cation - H2O 1-phenylethyl alcohol complex Fig 5.P18b Reaction profile for ionization and protonation routes to 1-phenylethylium cation Relative energies are in kcal/mol Reproduced from the Bulletin of the Chemical Society of Japan., 71, 2427 (1998) PROBLEMS 576 Table 5.P18b Selected Structural Parameters, Charge Densities, and Energies of Reactants and Transition States for Formation of a 1-Phenylethylium Ion CHAPTER Polar Addition and Elimination Reactions TS1 Bond length Protonated Alcohol C(1)−C(7) C(7)−C(8) C(7)−O C(8)−C(10) Charge on Ph Relative energy 474 500 641 093 225 −1 420 481 077 091 369 09 TS2 Styrene-H3 O+ Complex 457 367 1.478 1.353 1.472 1.343 608 196 17 2.118 0.111 15.7 −0 002 46.4 Phenylethylium Cation-H2 O Complex 395 469 639 098 468 00 Styrene b The acid-catalyzed hydration of styrene and the dissociation of protonated 1-phenylethanol provide alternative routes to the 1-phenylethylium cation The resonance component (r + of the Yukawa-Tsuno equations are 0.70 and 1.15, respectively The reactions have been modeled using MP2/6-31G∗ calculations and Figure 5.P18b gives the key results Table 5.P18b lists some of the structural features of the reactants, TSs, and products Interpret and discuss these results 5.19 Crown ethers have been found to catalyze the ring opening of epoxides by I2 and Br The catalysts also improve the regioselectivity, favoring addition of the halide at the less-substituted position A related structure (shown on the right) is an even better catalyst Indicate a mechanism by which these catalytic effects can occur O + dibenzo-18crown-6 Br2 Ph I2 Ph S O N N 92% OH dibenzo-18crown-6 O O Br PhOCH2 PhOCH2 + OH O I H H O O 5.20 The chart below shows the regio- and stereoselectivity observed for oxymercuration reduction of some 3- and 4-alkylcyclohexenes Provide an explanation for the product ratios in terms of the general mechanism for oxymercuration discussed in Section 5.6.1 100% 3% 53% 2% CH3 (CH3)3C (CH3)3C (CH3)3C 12% 95% 5% 50% 47% CH3 CH3 4% 79% 50% 5.21 Solvohalogenation can be used to achieve both regio- and stereochemical control for synthetic purposes in alkene addition reactions Some examples are shown below Discuss the factors that lead to the observed regio- or stereochemical outcome a Control of the stereochemistry of an epoxide: CH3 H 3C Br CH3 OH NBS H2O O H EtOH O CH3 O H O NaOH O H direct epoxidation O H b Formation of cis-diols: CH3 Ph2CHCO2 NBS CH3 HO Br CH3 OH 1) KOtBu Ph2CHCO2H CH3 CH3 2)K2CO3 CH3 CH3 CH3 CH3 c Chemoselective functionalization of polyalkenes: CH2OCH3 CH2OCH3 NBS Br t-BuOH, H2O OH 577 PROBLEMS .. .Advanced Organic Chemistry PART A: Structure and Mechanisms PART B: Reactions and Synthesis Advanced Organic FIFTH EDITION Chemistry Part A: Structure and Mechanisms FRANCIS A CAREY and RICHARD... Topic 12 .1 Computational Interpretation of Diene and Polyene Photochemistry General References Problems 10 81 10 81 10 91 1096 10 97 11 00 11 09 11 12 11 16 11 18 11 25 11 32... Dihydroxylation of Alkenes 2.6 Double Stereodifferentiation: Reinforcing and Competing Stereoselectivity 11 9 11 9 11 9 12 1 12 2 12 6 12 8 13 1 13 3 13 6 14 2 14 2 15 2 16 1 16 7 16 9 17 0 18 2 18 9 18 9 19 3