Advanced Organic Chemistry FIFTH EDITION Part B: Reactions and Synthesis Advanced Organic Chemistry PART A: Structure and Mechanisms PART B: Reactions and Synthesis Advanced Organic Chemistry FIFTH EDITION Part B: Reactions and Synthesis FRANCIS A. CAREY and RICHARD J. SUNDBERG University of Virginia Charlottesville, Virginia 123 FrancisA.Carey RichardJ.Sundberg DepartmentofChemistry DepartmentofChemistry UniversityofVirginia UniversityofVirginia Charlottesville,VA22904 Charlottesville,VA22904 LibraryofCongressControlNumber:2006939782 ISBN-13:978-0-387-68350-8(hardcover) e-ISBN-13:978-0-387-44899-2 ISBN-13:978-0-387-68354-6(softcover) Printedonacid-freepaper. ©2007SpringerScience+BusinessMedia,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 connectionwithanyformofinformationstorageandretrieval,electronicadaptation,computersoftware,or bysimilarordissimilarmethodologynowknoworhereafterdevelopedisforbidden. Theuseinthispublicationoftradenames,trademarks,servicemarksandsimilarterms,eveniftheyare notidentifiedassuch,isnottobetakenasanexpressionofopinionastowhetherornottheyaresubject toproprietaryrights. 9 8 7 6 5 4 3 2(corrected2ndprinting,2008) springer.com Preface Themethodsoforganicsynthesishavecontinuedtoadvancerapidlyandwehavemade anefforttoreflectthoseadvancesinthisFifthEdition.Amongthebroadareasthathave seen major developments are enantioselective reactions and transition metal catalysis. Computational chemistry is having an expanding impact on synthetic chemistry by evaluating the energy profiles of mechanisms and providing structural representation of unobservable intermediates and transition states. The organization of Part B is similar to that in the earlier editions, but a few changeshavebeenmade.Thesectiononintroductionandremovalofprotectinggroups has been moved forward to Chapter 3 to facilitate consideration of protecting groups throughout the remainder of the text. Enolate conjugate addition has been moved from Chapter 1 to Chapter 2, where it follows the discussion of the generalized aldol reaction. Several new sections have been added, including one on hydroalumination, carboalumination,andhydrozirconationinChapter4,anotherontheolefinmetathesis reactions in Chapter 8, and an expanded discussion of the carbonyl-ene reaction in Chapter 10. Chapters 1 and 2 focus on enolates and other carbon nucleophiles in synthesis. Chapter1discussesenolateformationandalkylation.Chapter2broadensthediscussion to other carbon nucleophiles in the context of the generalized aldol reaction, which includes the Wittig, Peterson, and Julia olefination reactions. The chapter considers the stereochemistry of the aldol reaction in some detail, including the use of chiral auxiliaries and enantioselective catalysts. Chapters 3 to 5 focus on some fundamental functional group modification reactions. Chapter 3 discusses common functional group interconversions, including nucleophilic substitution, ester and amide formation, and protecting group manipula- tions. Chapter 4 deals with electrophilic additions to double bonds, including the use of hydroboration to introduce functional groups. Chapter 5 considers reductions by hydrogenation, hydride donors, hydrogen atom donors, and metals and metal ions. Chapter 6 looks at concerted pericyclic reactions, including the Diels-Alder reaction, 1,3-dipolar cycloaddition, [3,3]- and [2,3]-sigmatropic rearrangements, and thermal elimination reactions. The carbon-carbon bond-forming reactions are empha- sized and the stereoselectivity of the reactions is discussed in detail. v vi Chapters 7 to 9 deal with organometallic reagents and catalysts. Chapter 7 considersGrignardandorganolithiumreagents.Thediscussionoforganozincreagents Preface emphasizes their potential for enantioselective addition to aldehydes. Chapter 8 discusses reactions involving transition metals, with emphasis on copper- and palladium-mediated reactions. Chapter 9 considers the use of boranes, silanes, and stannanes in carbon-carbon bond formation. These three chapters focus on reactions such as nucleophilic addition to carbonyl groups, the Heck reaction, palladium- catalyzed cross-coupling, olefin metathesis, and allyl- boration, silation, and stanny- lation. These organometallic reactions currently are among the more important for construction of complex carbon structures. Chapter 10 considers the role of reactive intermediates—carbocations, carbenes, andradicals—insynthesis.Thecarbocationreactionscoveredincludethecarbonyl-ene reaction,polyolefincyclization,andcarbocationrearrangements.Inthecarbenesection, addition (cyclopropanation) and insertion reactions are emphasized. Catalysts that provide both selectivity and enantioselectivity are discussed. The section on radicals considers both intermolecular and intramolecular (cyclization) addition reactions of radicals are dealt with. The use of atom transfer steps and tandem sequences in synthesis is also illustrated. Chapter 11 focuses on aromatic substitution, including electrophilic aromatic substitution, reactions of diazonium ions, and palladium-catalyzed nucleophilic aromatic substitution. Chapter 12 discusses oxidation reactions and is organized on the basis of functional group transformations. Oxidants are subdivided as transition metals, oxygen and peroxides, and other oxidants. Chapter13illustratesapplicationsofsyntheticmethodologybymultistepsynthesis and perhaps provides some sense of the evolution of synthetic capabilities. Several syntheses of two relatively simple molecules, juvabione and longifolene, illustrate some classic methods for ring formation and functional group transformations and, in the case of longifolene, also illustrate the potential for identification of relatively simple starting materials by retrosynthetic analysis. The syntheses of Prelog-Djerassi lactone highlight the methods for control of multiple stereocenters, and those of the TaxolprecursorBaccatinIIIshowhowsynthesisofthatdenselyfunctionalizedtricyclic structurehasbeenaccomplished.ThesynthesisofepothiloneAillustratesbothcontrol ofacyclicstereochemistryandmacrocyclizationmethods,includingolefinmetathesis. The syntheses of (cid:2)+(cid:3)-discodermolide have been added, illustrating several methods foracyclicstereoselectivityanddemonstratingthevirtuesofconvergency.Thechapter ends with a discussion of solid phase synthesis and its application to syntheses of polypeptides and oligonucleotides, as well as in combinatorial synthesis. ThereisincreasedemphasisthroughoutPartBontherepresentationoftransition structures to clarify stereoselectivity, including representation by computational models. The current practice of organic synthesis requires a thorough knowledge of molecular architecture and an understanding of how the components of a structure can be assembled. Structures of enantioselective reagents and catalysts are provided tohelpstudentsappreciatethethree-dimensionalaspectsoftheinteractionsthatoccur in reactions. A new feature of this edition is a brief section of commentary on the reactions in most of the schemes, which may point out a specific methodology or application. Instructors who want to emphasize the broad aspects of reactions, as opposed to specificexamples,maywishtoadvisestudentstoconcentrateonthemainflowofthe text,reservingtheschemesandcommentaryforfuturereference.Asmentionedinthe Acknowledgment and Personal Statement, the selection of material in the examples vii and schemes does not reflect priority, importance, or generality. It was beyond our capacitytosystematicallysurveythemanyexamplesthatexistformostreactiontypes, Preface and the examples included are those that came to our attention through literature searches and reviews. Several computational studies have been abstracted and manipulable three- dimensional images of reactants, transition structures, intermediates, and products provided. This material provides the opportunity for detailed consideration of these representations and illustrates how computational chemistry can be applied to the mechanisticandstructuralinterpretationofreactivity.Thismaterialisavailableinthe Digital Resource at springer.com/carey-sundberg. Asinpreviouseditions,theproblemsaredrawnfromtheliteratureandreferences are given. In this addition, brief answers to each problem have been provided and are available at the publishers website. 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 adjacentconstructionprojectledtostructuraldamageandclosureofourdepartmental library.ItremainedclosedthroughJune2007,butthankstotheeffortsofCarolHunter, BethBlanton-Kent,ChristineWiedman,RobertBurnett,andWynneStuart,Iwasable 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 TetrahedronLetters.Thesecircumstanceslargelycompletedanevolutioninthesource 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 editionreliesmainlyonelectronickeywordandstructuresearches.Neithertheformer northelattermethodisentirelysystematicorcomprehensive,sothereisaconsiderable 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 providevaluablecommentsandinsightsduringthepreparationofthisedition.Various usersofprioreditionshaveprovidederrorlists,and,hopefully,thesecorrectionshave ix x been made. Shirley Fuller and Cindy Knight provided assistance with many aspects of the preparation of the manuscript. Acknowledgment andPersonalStatement 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 computationalstudiesandpresentsthree-dimensionalimages,comments,andexercises based on the results. These were developed with financial support from the Teaching TechnologyInitiativeoftheUniversityofVirginia.Technicalsupportwasprovidedby Michal Sabat, William Rourk, Jeffrey Hollier, and David Newman. Several students made major contributions to this effort. Sara Higgins Fitzgerald 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 developedthemeasurementtool.Ialsogratefullyacknowledgethecooperationofthe 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, DavidMetcalf,andDanielMcCauleyinhelpingworkoutsomeofthespecifickinetic 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 June 2007