Organic RXN Mechanism

Advanced Organic Chemistry Reaction Mechanisms Elsevier, 2002 Author: Reinhard Bruckner ISBN: 978-0-12-138110-3 Foreword, Page xv Preface to the English Edition, Pages xvii-xviii Preface to the German Edition, Pages xix-xxi Acknowledgments, Page xxiii 1 -Radical Substitution Reactions at the Saturated C Atom, Pages 1-42 2 -Nucleophilic Substitution Reactions at the Saturated C Atom, Pages 43-83 3 -Additions to the Olefinic C=C Double Bond, Pages 85-128 4 -β-Eliminations, Pages 129-167 5 -Substitution Reactions on Aromatic Compounds, Pages 169-219 6 -Nucleophilic Substitution Reactions on the Carboxyl Carbon (Except through Enolates), Pages 221-270 7 -Additions of Heteroatom Nucleophiles to Heterocumulenes. Additions of Heteroatom Nucleophiles to Carbonyl Compounds and Follow-up Reactions, Pages 271-304 8 -Addition of Hydride Donors and Organometallic Compounds to Carbonyl Compounds, Pages 305-3469 -Reaction of Ylides with Saturated or α,β-Unsaturated Carbonyl Compounds, Pages 347-372 10 -Chemistry of the Alkaline Earth Metal Enolates, Pages 373-434 11 -Rearrangements, Pages 435-476 12 -Thermal Cycloadditions, Pages 477-518 13 -Transition Metal-Mediated Alkenylations, Arylations, and Alkynylations, Pages 519-544 14 -Oxidations and Reductions, Pages 545-612 Subject Index, Pages 613-636 Foreword We are at the start of a revolution in molecular science that will more profoundly change our lives, our culture, indeed, our world than did the Industrial Revolution a century ago. From the human genome project, the largest natural product characterizattio effort ever, to the search for the molecular signatures of life on other planets, this molecular revolution is creating an ever-expanding view of ourselves and our univerrse At the core of this revolution is chemistry, the quintessential molecular science within which is organic chemistry, a discipline that will surely be the source of many of the major advances in chemistry, biology, medicine, materials science, and environmennta science in the 21st century. In his text on organic chemistry, the translation of which has been impressively led by Professors Harmata and Glaser, Professor Bruckner has masterfully addressed the core concepts of the discipline, providing a rich tapestry of information and insight. The student of contemporary organic chemistry will be well-served by the depth and quality of this treatment. The underlying philosophy of this text is that much of chemisstr can be understood in terms of structure, which in turn influences reactivity, ultimattel defining the higher order activities of synthesis.Whether one seeks to understtan nature or to create the new materials and medicines of the future, a key starting point is thus understanding structure and mechanism. Professor Bruckner addresses the interrelationship of structure and mechanism with the rich insight of one schooled at the interface of physical organic chemistry and syntheesis His treatment is impressively rigorous, integrated, and broad. He achieves breadth through the careful selection of representative and fundamental reactive intermediates and reactions. Rigor and integration derive from his disciplined adherence to structure, orbital theory, and mechanism. The result is a powerfully coherent treatment that enabble the student to address the rich subject matter at hand and importantly by analogy the far-ranging aspects of the field that lie beyond the scope of the book. Extending from his treatment of radicals, nucleophiles, carbenium ions, and organometallic agents to concerrte reactions and redox chemistry, Bruckner provides an analysis that effectively merges theory and mechanism with examples and applications. His selection of examplle is superb and is further enhanced by the contemporary references to the literature. The text provides clarity that is essential for facilitating the educational process. This is a wonderfully rich treatment of organic chemistry that will be a great value to students at any level. Education should enable and empower. This text does both, providing the student with the insights and tools needed to address the tremendous challenges and opportunities in the field. Congratulations to Professors Bruckner, Harmaata and Glaser for providing such a rich and clear path for those embarking on an understanding of the richly rewarding field of organic chemistry. Paul A.Wender Stanford University Preface to the English Edition Writing a textbook at any level is always a challenge. In organic chemistry, exciting new discoveries are being made at an ever-increasing pace. However, students of the subject still arrive in the classroom knowing only what they have been taught, often less. The challenge is to present appropriate review material, present venerable, classsi chemistry while dealing with the latest results, and, most importantly, provoke thought and discussion. At the time this book was written, there was a need for an advannce text that incorporated these aspects of our science. The German version of the text was designed for second-and third-year chemistry majors: 60–70% of the contents of this book address students before the “DiplomchemmikerVorexamen,” while the remaining 30–40% address them thereafter.The Germma book is typically used one year after a standard introductory textbook such as that by Vollhardt and Schore, Streitweiser and Heathcock, or McMurry. Accordingly, in the United States this text can be used in a class for advanced undergraduates or beginning graduate students. Curricula of other English-speaking countries should alllo the use of this text with optimum benefit at a similar point of progress. A good understanding of the fundamentals of organic and physical chemistry will suffice as a foundation for using this textbook to advantage. The approach taken in this book conveys the message that the underlying theory of organic chemistry pervades the entire science. It is not necessary at this level to restrric the learning of reactions and mechanisms to any particular order. MO theory and formalisms such as electron pushing with arrows are powerful tools that can be applied not only to the classic chemistry that led to their development but also to the most recently developed reactions and methods, even those that use transition metals. Theory, mechanism, synthesis, structure, and stereochemistry are discussed throughoou the book in a qualitative to semiquantitative fashion. Fundamental principles such as the Hammond postulate that can be applied in the most varied contexts are reinforrce throughout the book. Equations such as the Erying equation or the rate laws of all kinds of reactions are introduced with the view that they have context and meaniin and are not merely formulas into which numbers are plugged. The present text, to the best of our knowledge, does not duplicate the approach of any other treatment at a comparable level.We are convinced that this book, which has alreead filled a niche in the educational systems of German-and the French-speaking countries (a French translation appeared in 1999), will do the same in the textbook markke of English-speaking countries now that an English edition has become available. Preface to the English Edition xviii We hope that you enjoy many fruitful hours of insight in the course of studying this book, and we welcome your constructive comments on its content and approach. Michael Harmata Norman Rabjohn Distinguished Professor of Organic Chemistry Department of Chemistry University of Missouri Columbia, Missouri 65211 (for feedback: HarmataM@missouri.edu) Reinhard Bruckner Professor of Organic Chemistry Institut für Organische Chemie und Biochemie der Albert-Ludwigs-Universität Albertstrasse 21 79104 Freiburg, Germany (for feedback: reinhard.brueckner@organik.chemie.uni-freiburg.de) April 16, 2001 Preface to the German Edition To really understand organic chemistry requires three passes. First, one must familiariiz oneself with the physical and chemical properties of organic chemical compounds. Then one needs to understand their reactivities and their options for reactions. Finally, one must develop the ability to design syntheses. A typical schedule of courses for chemistry students clearly incorporates these three components. Introductory courses focus on compounds, a course on reaction mechanisms follows, and a course on advannce organic chemistry provides more specialized knowledge and an introduction to retrosynthesis. Experience shows that the second pass, the presentation of the material organized according to reaction mechanisms, is of central significance to students of organic chemisttry This systematic presentation reassures students not only that they can master the subject but also that they might enjoy studying organic chemistry. I taught the reaction mechanisms course at the University of Göttingen in the wintte semester of 1994, and by the end of the semester the students had acquired a compettenc in organic chemistry that was gratifying to all concerned. Later, I taught the same course again—I still liked its outline—and I began to wonder whether I should write a textbook based on this course. A text of this kind was not then available, so I presented the idea to Björn Gondesen, the editor of Spektrum. Björn Gondesen enthusiassticall welcomed the book proposal and asked me to write the “little booklet” as soon as possible. I gave up my private life and wrote for just about two years. I am grateful to my wife that we are still married; thank you, Jutta! To this day, it remains unclear whether Björn Gondesen used the term “little bookleet in earnest or merely to indicate that he expected one book rather than a series of volumes. In any case, I am grateful to him for having endured patiently the mutations of the “little booklet” first to a “book” and then to a “mature textbook.” In fact, the editor demonstrated an indestructible enthusiasm, and he remained supportive when I presented him repeatedly with increases in the manuscript of yet another 50 pages. The reader has Björn Gondesen to thank for the two-color production of this book. All “curved arrows” that indicate electron shifts are shown in red so that the student can easily grasp the reaction. Definitions and important statements also are graphically highlighted. In comparison to the preceding generation, students of today study chemistry with a big handicap: an explosive growth of knowledge in all the sciences has been accompaniie in particular by the need for students of organic chemistry to learn a greater numbbe of reactions than was required previously. The omission of older knowledge is possiibl only if that knowledge has become less relevant and, for this reason, the following reactions were omitted: Darzens glycidic ester synthesis, Cope elimination, SNi reaction, iodoform reaction, Reimer–Tiemann reaction, Stobble condensation, Perkin synthesis, benzoin condensation, Favorskii rearrangement, benzil–benzilic acid rearrangement, Hofmann and Lossen degradation, Meerwein–Ponndorf reduction, and Cannizarro re-Preface to the German Edition xx action. A few other reactions were omitted because they did not fit into the current presentation (nitrile and alkyne chemistry, cyanohydrin formation, reductive amination, Mannich reaction, enol and enamine reactions). This book is a highly modern text. All the mechanisms described concern reactions that are used today. The mechanisms are not just l’art pour l’art. Rather, they present a conceptual tool to facilitate the learning of reactions that one needs to know in any case. Among the modern reactions included in the present text are the following: BartoonMcCombie reaction, Mitsunobu reaction, Mukaiyama redox condensations, asymmettri hydroboration, halolactonizations, Sharpless epoxidation, Julia–Lythgoe and Peterrso olefination, ortho-lithiation, in situ activation of carboxylic acids, preparations and reactions of Gilman, Normant, and Knochel cuprates, alkylation of chiral enolates (with the methods by Evans, Helmchen, and Enders), diastereoselective aldol additions (Heathcock method, Zimmerman–Traxler model), Claisen–Ireland rearrangements, transition metal–mediated C,C-coupling reactions, Swern and Dess-Martin oxidations, reductive lithiations, enantioselective carbonyl reductions (Noyori, Brown, and Corey–Itsuno methods), and asymmetrical olefin hydrogenations. The presentations of many reactions integrate discussions of stereochemical aspects. Syntheses of mixtures of stereoisomers of the target molecule no longer are viewed as valuable—indeed such mixtures are considered to be worthless—and the control of the stereoselectivity of organic chemical reactions is of paramount significance. Hence, suitabbl examples were chosen to present aspects of modern stereochemistry, and these incllud the following: control of stereoselectivity by the substrate, the reagent, or an ancillliar reagent; double stereodifferentiation; induced and simple diastereoselectivity; Cram, Cram chelate, and Felkin–Anh selectivity; asymmetric synthesis; kinetic resolutiion and mutual kinetic resolution. You might ask how then, for heaven’s sake, is one to remember all of this extensive material? Well, the present text contains only about 70% of the knowledge that I would expect from a really well-trained undergraduate student; the remaining 30% presents material for graduate students. To ensure the best orientation of the reader, the sectiion that are most relevant for optimal undergraduate studies are marked in the marggi with a B on a gray background, and sections relevant primarily to graduate students are marked with an A on a red background. I have worked most diligently to show the reactions in reaction diagrams that include every intermediate—and in which the flow of the valence electrons is highlighted in color—and, whenever necessary, to further discuus the reactions in the text. It has been my aim to describe all reactions so well, that in hindsight—because the course of every reaction will seem so plausible—the readers feel that they might even have predicted their outcome. I tried especially hard to realiiz this aim in the presentation of the chemistry of carbonyl compounds. These mechaniism are presented in four chapters (Chapters 7–11), while other authors usually cover all these reactions in one chapter. I hope this pedagogical approach will render organic chemistry more comprehensible to the reader. Finally, it is my pleasure to thank—in addition to my untiring editor—everybody who contributed to the preparation of this book. I thank my wife, Jutta, for typing “version 1.0” of most of the chapters, a task that was difficult because she is not a chemist and that at times became downright “hair raising” because of the inadequacy of my dicta-Indicates relevance for undergraduate students BIndicates relevance for graduate students A Preface to the German Edition xxi tion. I thank my co-workers Matthias Eckhardt (University of Göttingen, Dr. Eckhardt by now) and Kathrin Brüschke (chemistry student at the University of Leipzig) for their careful reviews of the much later “version .10” of the chapters. Their comments and corrections resulted in “version .11” of the manuscript, which was then edited professionnall by Dr. Barbara Elvers (Oslo). In particular, Dr. Elvers polished the language of sections that had remained unclear, and I am very grateful for her editing. Dr.Wolfgaan Zettelmeier (Laaber-Waldetzenberg) prepared the drawings for the resulting “versiio .12,” demonstrating great sensitivity to my aesthetic wishes. The typsesetting was accompllishe essentially error-free by Konrad Triltsch (Würzburg), and my final review of the galley pages led to the publication of “version .13” in book form. The production department was turned upside-down by all the “last minute” changes—thank you very much, Mrs. Notacker! Readers who note any errors, awkward formulations, or inconsisteencie are heartily encouraged to contact me. One of these days, there will be a “versiio .14.” It is my hope that your reading of this text will be enjoyable and useful, and that it might convince many of you to specialize in organic chemistry. Reinhard Brückner Göttingen, August 8, 1996 Acknowledgments My part in this endeavor is over. Now, it is entirely up to the staff at Harcourt/Acadeemi Press to take charge of the final countdown that will launch Advanced Organic Chemistry: Reaction Mechanisms onto the English-speaking market. After three years of intense trans-Atlantic cooperation, it is my sincere desire to thank those individuaal in the United States who made this enterprise possible. I am extremely obliged to Professor Michael Harmata from the University of Missouri at Columbia for the great determination he exhibited at all phases of the project. It was he who doggedly did the legwork at the 1997 ACS meeting in San Francisco, that is, cruised from one sciennc publisher’s stand to the next, dropped complimentary copies of the German editiio on various desks, and talked fervently to the responsibles. David Phanco from Academic Press was immediately intrigued and quickly set up an agreement with the German publisher. David Phanco was farsighted enough to include Mike Harmata on board as a “language polisher” (of the translation) before he passed on the torch to Jeremy Hayhurst in what then was to become Harcourt/Academic Press. The latter’s sympathetic understanding and constant support in the year to follow were absolutely essential to the final success of the project: Mike Harmata, at that time a Humboldt Fellow at the University of Göttingen, and I needed to develop a very Prussian sense of discipline when doing our best to match the first part of the translation to the qualiit of the original. I am very much indebted to Professor Rainer Glaser, who reinforced the Missouri team and, being bilingual, finished the second half of the translation skillfuull and with amazing speed. He also contributed very valuably to improving the gallle proofs, as did Joanna Dinsmore, Production Manager at Harcourt/Academic Press. It is she who deserves a great deal of gratitude for her diligence in countless hours of proofreading, and for her patience with an author who even at the page proof stage felt that it was never too late to make all sorts of small amendments for the future reader’s sake. It is my sincere hope, Ms. Dinsmore, that in the end you, too, feel that this immense effort was worth the trials and tribulations that accompanied it. Reinhard Bruckner Freiburg, April 25, 2001 1 BB Radical Substitution Reactions at the Saturated C Atom In a substitution reaction a part X of a molecule R¬X is replaced by a group Y (Figure 1.1). The subject of this chapter is substitution reactions in which a part X that is bound to an sp3-hybridized C atom is replaced by a group Y via radical intermediiates Radicals are valence-unsaturated and therefore usually short-lived atoms or molecules. They contain one or more unpaired (“lone”) electrons. From inorganic chemistry you are familiar with at least two radicals, which by the way are quite stable: NO and O2. NO contains one lone electron; it is therefore a monoradical or simply a “radical.” O2 contains two lone electrons and is therefore a biradical. RR XY O C SMe S N N C O S CH2 CH2 CO2RC CH sp3 sp3 X = H, Hal, Y = H, Hal, OOH, + Reagent, – By-products , , Fig. 1.1. Some substrates and products of radical substitution reactions. 1.1 Bonding and Preferred Geometries in C Radicals, Carbenium Ions and Carbanions At the so-called radical center an organic radical R. has an electron septet, which is an electron deficiency in comparison to the electron octet of valence-saturated compounds. Carbon atoms are the most frequently found radical centers and most often have three neighbors (see below). Carbon-centered radicals with their electron septet occupy an intermeediat position between the carbenium ions, which have one electron less (electron sextet at the valence-unsaturated C atom), and the carbanions, which have one electron more (electron octet at the valence-unsaturated C atom). Since there is an electron deficiienc present both in C radicals and in carbenium ions, the latter are more closely relaate to each other than C radicals are related to carbanions. Because of this, C radicals and carbenium ions are also stabilized or destabilized by the same substituents. Nitrogen-centered radicals or oxygen-centered radicals are less stable than C-centered radicals They are higher in energy because of the higher electronegativity of these elements relative to carbon. Nitrogen-or oxygencenttere radicals of the cited substitution pattern consequently have only a limited chance to exist. 1Rsp323C #. 1Rsp32O# 1Rsp322N # 1 Radical Substitution Reactions at the Saturated C Atom 2 Which geometries are preferred at the valence-unsaturated C atom of C radicals, and how do they differ from those of carbenium ions or carbanions? And what types of bonding are found at the valence-unsaturated C atoms of these three species? It is simplest to clarify the preferred geometries first (Section 1.1.1). As soon as these geometries are known, molecular orbital (MO) theory will be used to provide a descriiptio of the bonding (Section 1.1.2). We will discuss the preferred geometries and the MO descriptions of C radicals and the corresponding carbenium ions or carbanions in two parts. In the first part we will examine C radicals, carbenium ions, and carbanions with a trivalent central C atom. The second part treats the analogous species with a divalent central C atom. A third part (species with a monovalent central C atom) can be dispensed with because the only species of this type that is important in organic chemistry is the alkynyl anion, which, however, is of no interest here. 1.1.1 Preferred Geometries The preferred geometries of carbenium ions and carbanions are correctly predicted by the valence shell electron pair repulsion (VSEPR) theory. The VSEPR theory, which comes from inorganic chemistry, explains the stereostructure of covalent compounds of the nonmetals and the main group metals. It makes no difference whether these compounds are charged or not. The VSEPR theory analyzes the stereostructure of these compounds in the environnmen of the central atom. This stereostructure depends mainly on (a) the number n of atoms or atom groups (in inorganic chemical terminology, referred to as ligands) linked to the central atom and (b) the number m of nonbonding valence electron pairs localized at the central atom. If the central atom under consideration is a C atom, n m 4. In this case, the VSEPR theory holds in the following shorthand version, which makes it possible to determine the preferred geometries: the compound considdere has the stereostructure in which the repulsion between the n bonding partners and the m nonbonding valence electron pairs on the C atom is as small as possible. This is the case when the orbitals that accommodate the bonding and the nonbonding electron pairs are as far apart from each other as possible. For carbenium ions this means that the n substituents of the valence-unsaturated central atom should be at the greatest possible distance from each other: • In alkyl cations R3C, n 3 and m 0. The substituents of the trivalent central atom lie in the same plane as the central atom and form bond angles of 120with each other (trigonal planar arrangement). This arrangement was confirmed experimenttall by means of a crystal structural analysis of the tert-butyl cation. • In alkenyl cations “C¬R, n 2 and m 0. The substituents of the divalent central atom lie on a common axis with the central atom and form a bond angle of 180. Alkenyl cations have not been isolated yet because of their low stabillit (Section 1.2). However, calculations support the preference for the linear structure. B 1.1 Bonding and Preferred Geometries in C Radicals, Carbenium Ions and Carbanions 3 According to the VSEPR theory, in carbanions the n substituents at the carbanionic C atom and the nonbonding electron pair must move as far away from each other as possible: • In alkyl anions R3C, n 3 and m 1. The substituents lie in one plane, and the central atom lies outside it. The carbanion center has a trigonal pyramidal geometrry The bond angles are similar to the tetrahedral angle (10928). This stereostruuctur may be called pseudotetrahedral when the carbanionic electron pair is counted as a pseudosubstituent. • In alkenyl anions “C¬R, n 2 and m 1. The substituents and the divalent central atom prefer a bent structure. The bond angle in alkenyl anions is approximately 120.When the nonbonding valence electron pair is considered as a pseudosubstituent of the carbanion center, this preferred geometry may also be called pseudotrigonal planar. The most stable structures of alkyl and alkenyl anions predicted with the VSEPR theory are supported by reliable calculations.There are no known experimental structuura data. In fact, up to recently, one would have cited the many known geometries of the lithium derivatives of these carbanions as evidence for the structure. One would simply have “dropped” the C¬Li bond(s) from these geometries. However, it is now known that the considerable covalent character of most C¬Li bonds makes organolitthiu compounds unsuitable models for carbanions. Since the VSEPR theory describes the mutual repulsion of valence electron pairs, it can hardly be used to make statements about the preferred geometries of C radicals. It is intuitively expected that C radicals assume a middle position between their carbenniu ion and carbanion analogs. In agreement with this, alkyl radicals are either planna (methyl radical) or slightly pyramidal but able to swing rapidly through the planar form (inversion) to another near-planar structure (tert-butyl radical). In addition, some carbon-centered radicals are considerably pyramidalized (e.g., those whose carbon center is substituted with several heteroatoms). Alkenyl radicals are bent, but they can undergo cis/trans isomerization through the linear form very rapidly. Because they are constrained in a ring, aryl radicals are necessarily bent. 1.1.2 Bonding The type of bonding at the valence-unsaturated C atom of carbenium ions, carbanions, and C-centered radicals follows from the geometries described in Section 1.1.1. From the bond angles at the central C atom, it is possible to derive its hybridization. Bond angles of 10928correspond to sp3, bond angles of 120correspond to sp2, and bond angles of 180correspond to sp hybridization. From this hybridization it follows which atomic orbitals (AOs) of the valence-unsaturated C atom are used to form the moleccula orbitals (MOs).The latter can, on the one hand, be used as bonding MOs. Each one of them then contains a valence electron pair and represents the bond to a substittuen of the central atom. On the other hand, one AO of the central atom represeent a nonbonding MO, which is empty in the carbenium ion, contains an electron 1 Radical Substitution Reactions at the Saturated C Atom 4 in the radical, and contains the nonbonding electron pair in the carbanion. How the valence electrons are distributed over the respective MO set follows from the Aufbau principle: they are placed, one after the other, in the MOs, in the order of increasing energy. The Pauli principle is also observed: any MO can take up only two electrons and only on the condition that they have opposite spins. The bonding at the valence-unsaturated C atom of carbenium ions R3Cis therefoor described by the MO diagram in Figure 1.2 (left), and the bonding of the valenceunsatturate C atom of carbenium ions of type “C¬R is described by the MO diagrra in Figure 1.3 (left). The MO description of R3Ccarbanions is shown in Figure 1.2 (right), and the MO description of carbanions of type “C¬R is shown in Figure 1.3 (right). The MO description of the radicals or employs the MO picture for the analogous carbenium ions or carbanions, depending on which of these species the geometry of the radical is similar to. In each case only seven instead of six or eight valence electrons must be accommodated (Figures 1.2 and 1.3, left). ˇ“ CR # R # nsp3 ssp3/AO′ ssp2/AO′ n2pz C C E Fig. 1.2. Energy levels and occupancies (red) of the MOs at the trivalent C atom of planar carbenium ions R3C(left) and pyramidal carbanions R3C(right). C nsp2ssp2/AO′ ssp/AO′ p2 /2 p p y y′ p2 /2 p p y y′ n2pz C E Fig. 1.3. Energy levels and occupancies (red) of the MOs at the divalent C atom of linear carbenium ions “C¬R (left) and bent carbanions “C¬R (right). 1.2 Stability of Radicals 5 1.2 Stability of Radicals Stability in chemistry is not an absolute but a relative concept. It always refers to a stability difference with respect to a reference compound. Let us consider the standard heats of reaction H0 of the dissociation reaction that is, the dissociaatio enthalpy (DE) of the broken C¬H bond. It reflects, on the one hand, the strength of this C¬H bond and, on the other hand, the stability of the radical R. producced As you see immediately, the dissociation enthalpy of the R¬H bond depends in many ways on the structure of R. But it is not possible to tell clearly whether this is due to an effect on the bond energy of the broken R¬H bond and/or an effect on the stability of the radical that is formed. R # R¬HSR # H #, B HC C H sp C H sp2 H2C C H Hsp2 H3C C H H2sp3 131 111 110 98 DE kcal/mol To what must one ascribe, for example, the fact that the dissociation enthalpy of a bond depends essentially on n alone and increases in the order n 3, 2, and 1? To help answer this question it is worthwhile considering the following: the dissociattio enthalpies of bonds such as and also depend heavily on n and increase in the same order, n3, 2, and 1. The extent of the n–dependence of the dissocation energies depends on the element which is cleaved off.This is only possible if the n–dependence reflects, at least in part, an n–dependence of the respective –element bond. (Bond enthalpy tables in all textbooks ignore this and assign a bond enthalpy to each –element bond that is dependent on the element but not on the value of n!) Hence, the bond enthalpy of every –element bond increases in the order n 3, 2, and 1. This is so because all –element bonds become shorter in the same order. This in turn is due to the s character of the –elemmen bond, which increases in the same direction. An immediate consequence of the different ease with which –element bonds dissociate is that in radical substitution reactions, alkyl radicals are preferentially formed. Only in exceptional cases are vinyl or aryl radicals formed. Alkynyl radicals do not appear at all in radical substitution reactions. In the following we therefore limit ourselves to a discussion of substitution reactions that take place via radicals of the general structure R1R2R3 1.2.1 Reactive Radicals If radicals R1R2R3 are produced by breaking the C¬H bond in molecules of the type R1R2R3C¬H, one finds that the dissociation enthalpies of such C¬H bonds difffe with molecular structure. Experience shows that these differences can be explained completely by the effects of the substituents R1, R2, and R3 on the stability of the radiccal R1R2R3 formed. C # C # C # . Cspn Cspn Cspn Cspn Cspn Cspn Cspn¬Br Cspn¬Cl, Cspn¬O, Cspn¬C, Cspn¬H 1 Radical Substitution Reactions at the Saturated C Atom 6 Table 1.1 shows one substituent effect, which influences the stability of radicals. The dissociation enthalpies of reactions that lead to radicals are listed. The substituent R varies from C2H5 through H2C“CH¬(vinyl substituent, vin) to C6H5¬ (phenyl substituent, Ph). The dissociation enthalpy is greatest for R = H. This shows that a radical center is stabilized by 9 kcal/mol by the neighboring C“C doubbl bond of an alkenyl or aryl substituent. R¬CH2 # HHH DE kcal/mol VB formulation of the radical R • 98 89 89 Table 1.1. Stabilization of Radicals by Unsaturated Substituents n2pz E p*C=C p*C=C pC=C pC=C 2pz 2pz (1st interaction) (2nd interaction) 1/2 the delocalization energy localized MOs localized MO delocalized MOs Fig. 1.4. Stabilization by overlap of a singly occupied 2pz AO with adjacent parallel or MOs. p*C“CpC“CIn the valence-bond (VB) model this effect results from the fact that radicals of this type can be described by superpositioning several resonance forms (Table 1.1, right). In the MO model, the stabilization of radical centers of this type is due to the overlap of the p system of the unsaturated substituent with the 2pz AO at the radical center (Figure 1.4). This overlap is called conjugation. 1.2 Stability of Radicals 7 H2C H H3C (H3C)2HC H (H3C)3C H H3C H HH HHHHH HHHHH HHHHH HHHH HHHHHHHHHHHHHHHH HH DE kcal/mol VB formulation of the radical R • 6 no-bond resonance forms 9 no-bond resonance forms 104 98 95 92 i.e., 1 no-bond resonance form per HTable 1.2. Stabilization of Radicals by Alkyl Substituents Table 1.2 illustrates an additional substituent effect on radical stability. Here the dissociiatio enthalpies of reactions that lead to polyalkylated radicals (Alk)3nHn are listed (“Alk” stands for alkyl group). From these dissociation enthalpies it can be seen that alkyl substituents stabilize radicals. A primary radical is 6 kcal/mol more stable, a secondary radical is 9 kcal/mol more stable, and a tertiary radical is 12 kcal/mol more stable than the methyl radical. C # In the VB model, this effect is explained by the fact that radicals of this type, too, can be described by the superpositioning of several resonance forms. These are the somewhat exotic no-bond resonance forms (Table 1.2, right). From the point of view of the MO model, radical centers with alkyl substituents have the opportunity to interrac with these substituents.This interaction involves the C¬H bonds that are in the position a to the radical center and lie in the same plane as the 2pz AO at the radical center. Specifically, sC¬H MOs of these C¬H bonds are able to overlap with the radicca 2pz orbital (Figure 1.5).This overlap represents the rare case of lateral overlap betwwee a s bond and a p orbital. It is referred to as hyperconjugation to distinguish it from lateral overlap between p bonds and p orbitals, which is referred to as conjugatiionWhen the sC¬H bond and the 2pz AO enclose a dihedral angle x that is differeen from that required for optimum overlap (0), the stabilization of the radical centte by hyperconjugation decreases. In fact, it decreases by the square of the cosine of the dihedral angle x. 1 Radical Substitution Reactions at the Saturated C Atom 8 1.2.2 Unreactive Radicals Just as several alkyl substituents increasingly stabilize a radical center (Table 1.2), two phenyl substituents stabilize a radical center more than one does. The diphenylmethyl radical (“benzhydryl radical”) is therefore more stable than the benzyl radical. The triphenylmethyl radical (“trityl radical”) is even more stable because of the three phenyl substituents. They actually stabilize the trityl radical to such an extent that it forms by homolysis from the so-called Gomberg hydrocarbon even at room temperatuur (Figure 1.6). Although this reaction is reversible, the trityl radical is present in equilibrium quantities of about 2 mol%. BA Fig. 1.6. Reversible formation reaction of the triphenylmethyl radical. The equilibrium lies on the side of the Gomberg hydrocarbon. H 2 Ph3 C Gomberg hydrocarbon Starting from the structure of the trityl radical, radicals were designed that can be obtained even in pure form as “stable radicals” (Figure 1.7).There are two reasons why these radicals are so stable. For one thing, they are exceptionally well resonancestabiilized In addition, their dimerization to valence-saturated species has a considerabbl reduced driving force. In the case of the trityl radical, for example, dimerization sC–H s*C–H n2pz E s*C–H sC–H 2pz 2pz (negligible interaction) (more important interaction) full conjugation energy localized MOs localized MO delocalized MOs Hb H Fig. 1.5. Stabilization by overlap of a singly occupied 2pz AO with vicinal nonorthogonal sC—H MOs. 1.3 Relative Rates of Analogous Radical Reactions 9 leads to the Gomberg hydrocarbon in which an aromatic sextet is lost. The trityl radicca can not dimerize giving hexaphenylethane, because too severe van der Waals repulssion between the substituents would occur.There are also stable N-or O-centered radicals.The driving force for their dimerization is weak because relatively weak N¬N or O¬O bonds would be formed. By the way, the destabilization of the dimerization product of a radical is often more important for the existence of stable radicals than optimum resonance stabilization. This is shown by comparison of the trityl radical derivatives A and B (Figure 1.7). In radical A the inclusion of the radical center in the polycycle makes optimum resonance stabilization possible because the dihedral angle x between the 2pz AO at the central atom and the neighboring p orbitals of the three surrounding benzene rings is exactly 0. And yet radical A dimerizes! In contrast, the trityl radical derivative B is distorted like a propeller, to minimize the interaction between the methoxy substituents on the adjacent rings. The 2pz AO at the central atom of radical B and the p orbitals of the surrounding benzene rings therefore form a dihedral angle x of a little more than 45. The resonance stabilization of radical B is therefore only one half as great—cos2 450.50—as that of radical A. In spite of this, radical B does not dimerize at all. O O O C C C C C C M M M M M e e e e e O O O O O O O O M M Me e e O O O O O O C C Ar Ar A Bis Dimer46° Fig. 1.7. Comparison of the trityl radical derivatives A and B; A dimerizes, B does not. 1.3 Relative Rates of Analogous Radical Reactions In Section 1.2.1 we discussed the stabilities of reactive radicals. It is interesting that they make an evaluation of the relative rates of formation of these radicals possible. 1 Radical Substitution Reactions at the Saturated C Atom 10 This follows from the Bell–Evans–Polanyi principle (Section 1.3.1) or the Hammond postulate (Section 1.3.2). 1.3.1 The Bell–Evans–Polanyi Principle In thermolyses of aliphatic azo compounds, two alkyl radicals and one equivalent of N2 are produced according to the reaction at the bottom of Figure 1.8. A whole series of such reactions was carried out, and their heats of reaction, that is, their reaction enthallpie Hr, were determined. Heat was taken up in all thermolyses. They were thus endothermic reactions (Hr has a positive sign). Each substrate was thermolyzed at several different temperatures T and the associated rate constants kr were determined. The temperature dependence of the kr values for each individual reaction was analyyze by using the Eyring equation (Equation 1.1). (1.1) kB: Boltzmann constant (3.298 1024 cal/K) T: absolute temperature (K) h: Planck’s constant (1.583 1034 cal.s) G‡: Gibbs free energy (kcal/mol) H‡: enthalpy of activation (kcal/mol) S‡: entropy of activation (cal mol1 K1) R: gas constant (1.986 cal mol1 K1) Equation 1.1 becomes Equation 1.2 after (a) dividing by T, (b) taking the logarithm, and (c) differentiating with respect to T. (1.2) With Equation 1.2 it was possible to calculate the activation enthalpy H‡ for each individual reaction. The pairs of values Hr/H‡, which were now available for each thermolysis, were plotted on the diagram in Figure 1.8, with the enthalpy change H on the vertical axis and the reaction progress on the horizontal axis. The horizontal axis is referred to as the reaction coordinate (RC). Among “practicing organic chemists” it is not accurattel calibrated. It is implied that on the reaction coordinate one has moved by x% toward the reaction product(s) when all the structural changes that are necessary en route from the starting material(s) to the product(s) have been x% completed. For five out of the six reactions investigated, Figure 1.8 shows an increase in the activation enthalpy H‡ with increasing positive reaction enthalpy Hr. Only for the sixth reaction—drawn in red in Figure 1.8—is this not true. Accordingly, except for this one reaction H‡ and Hr are proportional for this series of radical-producing thermolyyses This proportionality is known as the Bell–Evans–Polanyi principle and is descrribe by Equation 1.3. ¢HRT 0lnakr T b 0T kr kB T h exp a ¢GRT b kB T h exp a ¢HRT b exp a ¢SR b 1.3 Relative Rates of Analogous Radical Reactions 11 (1.3) The thermolyses presented in this chapter are one example of a series of analogous reactions. The Bell–Evans–Polanyi relationship of Equation 1.3 also holds for many other series of analogous reactions. 1.3.2 The Hammond Postulate In many series of analogous reactions a second proportionality is found experimentally, namely, between the free energy change (Gr; a thermodynamic quantity) and the free energy of activation (G‡, a kinetic quantity). In series of analogous reactions, a third parameter besides H‡ and G‡, no doubt also depends on the Hr and Gr values, respectively, namely, the structure of the transition state. This relationship is generally assumed or postulated, and only in a few cases has it been verified by calculations (albeei usually only in the form of the so-called “transition structures”; they are likely to resemble the structures of the transition state, however). This relationship is therefore not stated as a law or a principle but as a postulate, the so-called Hammond postulate. ¢H‡ const. const.¿ # ¢Hr 52 49 47 43 37 35 33 29 27 24 10 4 Starting material Transition state (TS) Product 0 2 Me + N2 2 Et + N2 2 Pr + N i 2 2 -Bu +N tert 2 2 R + N2 2 + N2 2 + N2 N N R R ∆ Reaction coordinate ∆H Fig. 1.8. Enthalpy change along the reaction coordinate in a series of thermolyses of aliphatic azo compounds. All thermolyses in this series except the one highlighted in color follow the Bell–Evans–Polanyi principle. B 1 Radical Substitution Reactions at the Saturated C Atom 12 What does the statement that increasingly endergonic reactions take place via increassingl product-like transition states mean for the special case of two irreversible endergonic analogous reactions, which occur as competitive reactions? With help from the foregoing statement, the outcome of this competition can often be predicted. The energy of the competing transition states should be ordered in the same way as the energy of the potential reaction products. This means that the more stable reaction product is formed via the lower-energy transition state. It is therefore produced more rapidly or, in other words, in a higher yield than the less stable reaction product. The form of the Hammond postulate just presented is very important in the analysis of the selectivity of many of the reactions we will discuss in this book in connection with chemoselectivity (definition in Section 1.7.2; also see Section 3.2.2), stereoselectivity (definition in Section 3.2.2), diastereoselectivity (definition in Section 3.2.2), enantioselecttivit (definition in Section 3.2.2), and regioselectivity (definition in Section 1.7.2). Selectivity means that one of several reaction products is formed preferentially or exclusiively In the simplest case, for example, reaction product 1 is formed at the expense of reaction product 2. Selectivities of this type are usually the result of a kinetically controlled reaction process, or “kinetic control.” This means that they are usually not the consequence of an equilibrium being established under the reaction conditions between the alternative reaction products 1 and 2. In this latter case one would have a thermodynamically controlled reaction process, or “thermodynamic control.” The Hammond postulate can be stated in several different ways. For individual reactions the following form of the Hammond postulate applies. In an endergonic reaction the transition state (TS) is similar to the product(s) with respect to energy and structure. Endergonic reactions thus take place through so-called late transitiio states. (A reaction is endergonic when the free energy change Gr, is greater than zero.) Conversely, in an exergonic reaction the transition state is similar to the starting material(s) with respect to energy and structure. Exergonic reactions thus take place via so-called early transition states. (A reaction is called exergonic when the change in the free energy Gr is less than zero.) For series of analogous reactions this results in the following form of the Hammond postulate: in a series of increasingly endergonic analogous reactions the transition state is increasingly similar to the product(s), i.e., increasingly late. On the other hand, in a series of increasingly exergonic analogous reactions, the transition state is increasingly similar to the starting material(s), i.e., increasingly early. Selectivity Hammond Postulate and Kinetically Determined Selectivities The Hammond Postulate With reference to the occurrence of this type of kinetically determined selectivities of organic chemical reactions, the Hammond postulate now states that: • If the reactions leading to the alternative reaction products are one step, the most stable product is produced most rapidly, that is, more or less selectively.This type of selectivity is called product-development control. 1.4 Radical Substitution Reactions: Chain Reactions 13 (1 or more steps) Substrate (Rsp3 X) and/or reagent and/or radical initiator (Section 1.5) Initiating radical (from substrate) (i.e., Rsp2•) or initiating radical (from reagent) 1.4 Radical Substitution Reactions: Chain Reactions Radical substitution reactions can be written in the following form: All radical substitution reactions are chain reactions. Every chain reaction starts with an initiation reaction. In one or more steps, this reaction converts a valence-saturated compound into a radical, which is sometimes called an initiating radical (the reaction arrow with the circle means that the reaction takes place through several intermediattes which are not shown here): Rsp3 Rsp3 X reagent radical initiator (cat.) Y • If these reactions are two step, the product that is derived from the more stable intermediate is produced more rapidly, that is, more or less selectively. • If these reactions are more than two step, one must identify the least stable intermeediat in each of the alternative pathways. Of these high-energy intermediattes the least energy-rich is formed most rapidly and leads to a product that, therefore, is then formed more or less selectively. The selectivity in cases 2 and 3 is therefore also due to “product development control.” The initiating radical is the radical that initiates a sequence of two, three, or more socallle propagation steps: B Initiating radical (from substrate) + reagent Initiating radical (from substrate) + . . . Rsp3 – X + Reagent Rsp3 – Y + By-product(s) kprop, l kprop, n kprop, ω . . . . . . . . . . . . Propagation steps: 1 Radical Substitution Reactions at the Saturated C Atom 14B Initiating radical (from reagent) Rsp3 – X Initiating radical (from reagent) + . . . Rsp3 – X + Reagent Rsp3 – Y + By-product(s) kprop, l kprop, n kprop, ω . . . . . . . . . . . . Propagation steps: Initiating radical and/or other radical intermediates Reaction of 2 radicals with each other kterm, A or kterm, B or . . . kterm, M or kterm, N or . . . 1 valence-saturated molecule (possible structures: A, B, . . .) Pair of valence-saturated molecules (possible structure: M/M', N/N', . . . ) Depending on whether the initiating radical comes from the substrate or the reagent, the propagation steps must be formulated as above or as follows: As the reaction equations show, the last propagation step supplies the initiating radical consumed in the first propagation step. From this you also see that the mass conversion of a chain reaction is described by an equation that results from the propagaatio steps alone: they are added up, and species that occur on both sides of the reaction arrow are dropped. If the radical intermediates of the propagation steps did nothing other than always enter into the next propagation step of the chain again, even a single initiating radical could initiate a complete starting material(s) → product(s) conversion. However, radicca intermediates may also react with each other or with different radicals.This makes them disappear, and the chain reaction comes to a stop. Reactions of the latter type therefore represent chain-terminating reactions or terminaatio steps of the radical chain. A continuation of the starting material(s) → produccts) conversion becomes possible again only when a new initiating radical is made available via the starting reaction(s).Thus, for radical substitutions via chain reactions to take place completely, new initiating radicals must be produced continuously. The ratio of the rate constants of the propagation and the termination steps determiine how many times the sequence of the propagation steps is run through before a termination step ends the conversion of starting material(s) to product(s). The rate constants of the propagation steps (kprop in the second-and third-to-last boxes of the present section) are greater than those of the termination steps (kterm in the fourth box), frequently by several orders of magnitude. An initiating radical can therefore initiiat from 1000 to 100,000 passes through the propagation steps of the chain. 1.5 Radical Initiators 15 How does this order of the rate constants come about? As higheneerg species, radical intermediates react exergonically with most reaction partners. According to the Hammond postulate, they do this very rapidly. Radicals actually often react with the first reaction partner they encounter.Their average lifetime is therefore very short.The probability of a termination step in which two such short-lived radicals must meet is consequently low. There is a great diversity of starting reaction(s) and propagation steps for radical substitution reactions. Bond homolyses, fragmentations, atom abstraction reactions, and addition reactions to C“C double bonds are among the possibilities. All of these reactions can be observed with substituted alkylmercury(II) hydrides as starting materiials For this reason, we will examine these reactions as the first radical reactions in Section 1.6. 1.5 Radical Initiators Only for some of the radical reactions discussed in Sections 1.6–1.9 is the initiating radicca produced immediately from the starting material or the reagent. In all other radicca substitution reactions an auxiliary substance, the radical initiator, added in a substoichiiometri amount, is responsible for producing the initiating radical. Radical initiators are thermally labile compounds, which decompose into radicals upon moderate heating.These radicals initiate the actual radical chain through the formattio of the initiating radical. The most frequently used radical initiators are azobisisobutyrronitril (AIBN) and dibenzoyl peroxide (Figure 1.9). After AIBN has been heated for only 1 h at 80C, it is half-decomposed, and after dibenzoyl peroxide has been heated for only 1 h at 95C, it is half-decomposed as well. kprop W kterm N N CN NC N N + + + OO OO O O O O OCO Azobisisobutyronitrile (AIBN) as radical initiator: Dibenzoyl peroxide as radical initiator: NC CN 2 2 2 2 Fig. 1.9. Radical initiators and their mode of action (in the “arrow formalism” for showing reaction mechanisms used in organic chemistry, arrows with half-heads show where single electrons are shifted, whereas arrows with full heads show where electron pairs are shifted). 1 Radical Substitution Reactions at the Saturated C Atom 16 1.6 Radical Chemistry of Alkylmercury(II) Hydrides Alkyl derivatives of mercury in the oxidation state 2 are produced during the solvomercuraatio of olefins (the first partial reaction of the reaction sequence in Figure 1.11). Reactions that take place via radical intermediates are occasionally also begun by radical initiators, which are present unintentionally. Examples are the autooxidation of ethers (see later: Figure 1.28) or one of the ways in which ozone is decomposed in the upper stratosphere. This decomposition is initiated by, among other things, the fluorochlorohydrocarbons (FCHCs), which have risen up there and form chlorine radicals under the influence of the short-wave UV light from the sun (Figure 1.10). They function as initiating radicals for the decomposition of ozone, which takes place via a radical chain. However, this does not involve a radical substitution reaction. Side Note 1.1 Decomposition of Ozone in the Upper Stratosphere O O O C C l l Cl O O Cl Cl O O Cl O O Cl O O O O O Net reaction: Initiation reaction: Propagation steps: 2 O3 3 O2 hrelatively long wave hrelatively long wave hUV FCHC , C H Cl F m n o p C H Cl F + Cl m n o p –1 Cl Cl Cl + ++ + + Fig. 1.10. FCHC-initiated decomposition of stratospheric ozone. R R Hg O O C R′ O R′′ R H O R′′ Hg(O C R′ )2 O R OH ′′ NaBH4 , Fig. 1.11. Net reaction (a) for the hydration of olefins (RCH3, RH) or (b) for the addition of alcohol to olefins (RCF3, Ralkyl) via the reaction sequence (1) solvomercuration of the olefin (for mechanism, see Figure 3.37; regioselectivity: Figure 3.38); (2) reduction of the alkylmercury compound obtained (for mechanism, see Figure 1.12). B 1.6 Radical Chemistry of Alkylmercury(II) Hydrides 17 R Hg OH OAc R Hg OH H R Hg OH H R OH Hg H R OH R Hg OH H R Hg OH R Hg OH R Hg OH R OH + + + ++ + Hg R OH R OHR OH R Hg R OH OH R R OH OH R Hg OH H R H OH R H OH + Hg Ionic prereaction: Initiation step: Propagation steps: Termination steps, for example: Net equation: Propagation steps: Σ Fig. 1.12. NaBH4 reduction of (bhydroxxyalkylmercury(II) acetates to alcohols and radical fragmentation of (b-hydroxyalkyl)mercury (II) hydrides. Oxymercuration provides (b-hydroxyalkyl)mercury(II) carboxylates while alkoxymercuraatio gives (b-alkoxyalkyl)mercury(II) carboxylates. These compounds can be reduuce with NaBH4 to (b-hydroxyalkyl)-or (b-alkoxyalkyl)mercury(II) hydrides. A ligaan exchange takes place at the mercury: a carboxylate substituent is replaced by hydrogen.The b-oxygenated alkylmercury(II) hydrides obtained in this way are so unstaabl that they react further immediately. These reactions take place via radical intermeddiates The latter can be transformed into various kinds of products by adjusting .the reaction conditions appropriately. The most important radical reactions of alkylmercury(II) hydrides are fragmentation to an alcohol (Figure 1.12), addition to a C“C double bond (Figure 1.13), and oxidation to a glycol derivative (Figure 1.14). The mechanisms for these reactions will be discussed below. When (b-hydroxyalkyl)mercury(II) acetates are treated with NaBH4 and no additioona reagent, they first form (b-hydroxyalkyl)mercury(II) hydrides.These decompose via the chain reaction shown in Figure 1.12 to give a mercury-free alcohol. Overall, a substitution reaction R¬Hg(OAc) → R¬H takes place. The initiation step for the chain reaction participating in this transformation is a homolysis of the C¬Hg bond. This takes place rapidly at room temperature and produces the radical and a b-hydroxylated alkyl radical. As the initiating radical, it starts the first of the two # Hg¬H 1 Radical Substitution Reactions at the Saturated C Atom 18 propagation steps. This first step is an atom transfer reaction or, more specifically, a hydrogen atom transfer reaction. The second propagation step involves a radical fragmentaation This is the decomposition of a radical into a radical with a lower moleculla weight and at least one valence-saturated compound (in this case, elemental mercurry) The net reaction equation is obtained according to Section 1.4 by adding up the two propagation steps. R Hg OMe OMe R R O O OMe R O O OMe R O O H OMe R O O H OMe R OH OMe R Hg OMe OMe R R Hg OMe H O O Subsequent ionic reaction: NaBH4 + + + + Hg + O2 R OH OMe R HgO2CCF3 OMe Propagation steps: NaBH4 Fig. 1.14. NaBH4-induced air oxidation of a (b-alkoxyalkyl)mercury (II) trifluoroacetate (see Figure 3.39) to a glycol derivative. + Hg R Hg OH CO2Me R CO2Me OH OH R CO2Me R CO2Me OH R CO2Me OH R CO2Me OH H R HgOAc OH R Hg OH OH R R Hg OH H + ++ + Propagation steps: NaBH4 Fig. 1.13. NaBH4-mediated addition of (bhydroxxyalkylmercury(II) acetates to an acceptorsubsttitute olefin. 1.7 Radical Halogenation of Hydrocarbons 19 These propagation steps are repeated many times while the organic mercury compooun is consumed and alcohol and elemental mercury are released. This process is interrupted only by termination steps (Figure 1.12). Thus, for example, two mercuryfrre radicals can combine to form one dimer, or a mercury-free and a mercurycontaainin radical can combine to form a dialkylmercury compound. (b-Hydroxyalkyl) mercury(II) acetates and NaBH4 react to form C-centered radicaal through the reaction steps shown in Figure 1.12 also when methyl acrylate is preseen in the reaction mixture. Under these conditions, these radicals can add to the C“C double bond of the ester (Figure 1.13). The addition takes place via a reaction chain, which comprises three propagation steps.The reaction product is a methyl ester, which has a carbon chain that is three C atoms longer than the carbon chain of the organomercuur compound. The radicals produced during the decomposition of alkylmercury(II) hydrides can also be added to molecular oxygen (Figure 1.14). A hydroperoxide is first produced in a chain reaction, which again comprises three propagation steps. However, it is unstabbl in the presence of NaBH4 and is reduced to an alcohol. 1.7 Radical Halogenation of Hydrocarbons Many hydrocarbons can be halogenated with elemental chlorine or bromine while beiin heated and/or irradiated together. The result is simple or multiple halogenations. 1.7.1 Simple and Multiple Chlorinations Presumably you are already familiar with the mechanism for the thermal chlorination of methane.We will use Figure 1.15 to review briefly the net equation, the initiation step, and the propagation steps of the monochlorination of methane. Figure 1.16 shows the energy profile of the propagation steps of this reaction. Csp3 H + Cl2 (Br2) Csp3 Cl (Br) + HCl (HBr) hv or BB CCll CCll H CH3 Cl H CH3 Cl Cl + + CH3 + Cl CH3 + 2 Cl CH4 CH3Cl + HCl + Cl2 (large excess) 400 °C ∆ Initiation step: Propagation steps: Fig. 1.15. Mechanism for monochlorination of methane with Cl2. A 1 Radical Substitution Reactions at the Saturated C Atom 20 Reaction coordinate E Cl + CH+ Cl • 24 Cl + •CH + HCl 2 3 Cl • + CH Cl + HCl 3 –26 +1 Starting materials TS1 I1 TS2 Products Fig. 1.16. Energy profile of the propagation steps of the monochlorination of methane with Cl2 (enthalpies in kcal/mol). In the energy profile, each of the two propagation steps is represented as a transittio from one energy minimum over an energy maximum into a new energy minimuum Energy minima in an energy profile characterize either long-lived species [startiin material(s), product(s)] or short-lived intermediates. On the other hand, energy maxima in an energy profile (transition states) are snapshots of the geometry of a moleccula system, whose lifetime corresponds to the duration of a molecular vibration (ca. 1013 s). A chemical transformation that takes place via exactly one transition state is called an elementary reaction. This holds regardless of whether it leads to a short-lived intermeediat or to a product that can be isolated. According to the definition, an n-step reaction consists of a sequence of n elementary reactions. It takes place via n transitiio states and (n 1) intermediates. In the reaction of a 1:1 mixture of methane and chlorine one does not obtain the monochlorination product selectively, but a 46:23:21:9:1 mixture of unreacted methane, mono-, di-, tri-, and tetrachloromethane. Thus all conceivable multiple chlorinaatio products are also produced. Multiple chlorinations, like monochlorinations, occur as radical chain substitutions. They are based on completely analogous propagattio steps (Figure 1.17). According to Figure 1.18, analogous propagation steps possess the same heat of reacttion independent of the degree of chlorination.With the help of Hammond’s postullate one concludes from this that the associated free activation energies should also be independent of the degree of chlorination. This means that the monochlorination of methane and each of the subsequent multiple chlorinations should take place with one and the same rate constant. This is essentially the case. The relative chlorination rates for CH4-nCln in the temperature range in question are 1 (n 0), 3 (n 1), 2 1.7 Radical Halogenation of Hydrocarbons 21 A C C C H H H 3–n n Cl 3–n n Cl 3– +1 n n Cl CCll CCll H CH3–n n Cl Cl H Cl + + + Cl + 2 Cl CH4 + HCl + Cl2 (comparable molar amount) 400 °C ∆ Initiation step: Propagation steps: CH Cl CH Cl CHCl CCl32 2 3 4 Fig. 1.17. Mechanism for the polychlorination of methane. (n 2), and 0.7 (n 3). The resulting lack of selectivity, fortunately, is of no concern in the industrial reactions of CH4 with Cl2.The four chlorinated derivatives of methane are readily separated from each other by distillation; each one is needed in large amounts. Reaction coordinate E Cl + CH Cl + Cl • 2 4–n n Cl + •CH Cl + HCl 2 3–n n Cl • + CH Cl + HCl • 3– +1 n n Ea,1 Ea,2 Fig. 1.18. Energy profile of the propagation steps of the polychlorinations CH3Cl → CH2Cl2, CH2Cl2 → CHCl3, and CHCl3 → CCl4 of methane (n 1–3 in the diagram), and of the monochlorination CH4 → CH3Cl (n 0 in the diagram). Cl O O Cl2 Diphosgene CH3 ,hCl O O CCl3 If only methyl chloride is needed, it can be produced essentially free of multiple chlorination products only if a large excess of methane is reacted with chlorine. In this case, there is always more unreacted methane available for more monochlorination to occur than there is methyl chloride available for a second chlorination. Another preparatively valuable multiple chlorination is the photochemical perchlorinaatio of methyl chloroformate, which leads to diphosgene: 1 Radical Substitution Reactions at the Saturated C Atom 22B Regioselectivity CH3 Cl + HCl CH3 + Cl2 CH2Cl + HCl CHCl2 CCl3 slower: + Cl , – HCl 2 even slower: + Cl , – HCl 2 ∆ ∆ Fig. 1.19. Industrial synthesis of benzyl chloride.Chemoselectivity 1.7.2 Regioselectivity of Radical Chlorinations Clean monochlorinations can be achieved only with hydrocarbons that react via resonancestabiilize radicals. They also exhibit high regioselectivity. This follows from the structuur of these resonance-stabilized radicals. In the industrial synthesis of benzyl chloride (Figure 1.19), only the H atoms in the benzyl position are replaced by Cl because the reaction takes place via resonancestabiilize benzyl radicals (cf. Table 1.1, bottom line) as intermediates. At a reaction temperature of 100C, the first H atom in the benzyl position is substituted a little less than 10 times faster (→ benzyl chloride) than the second (→ benzal chloride) and this is again 10 times faster than the third (→ benzotrichloride). A given molecular transformation, for example, the reaction C¬H → C¬Cl, is called regioselective when it takes place preferentially or exclusively at one place on a substrate. Resonance-stabilized radicals are produced regioselectively as a consequuenc of product-development control in the radical-forming step. Fig. 1.20. Industrial synthesis of allyl chloride. In the reaction example of Figure 1.20, the industrial synthesis of allyl chloride, only an H atom in the allylic position is substituted. Its precursor is a resonance-stabilized (Table 1.1, center line) allylic radical. Cl Cl Cl + HCl + Cl2 500 °C 500 °C Incidentally, this reaction of chlorine with propene is also chemoselective: Reactions in which the reagent effects preferentially or exclusively one out of severra types of possible transformations are chemoselective. 1.7 Radical Halogenation of Hydrocarbons 23 Table 1.3. Regioselectivity of Radical Chlorination of Isopentane Cl Cl Cl Cl + + + + Cl2, ∆ multiple chlorinated compounds In order to produce the above compounds in the individual case... The relative yields of the above monochlorination products are... ...H atoms were available for the substitution. Yields on a per-H-atom basis were... ... for the monochlorination product. In other words: in the position concerned is ... kC–H C–Cl, rel ..., that is, generally for ... ... 22% ... 1 33% 30% 15% ... 22% ... 4.4 3.3 ≡ 1 ≡ 1 2 6 3 ... 16.5% 5% 5% ... Csec H ... Ctert H H Cprim In the present case the only transformation that results is C¬H → C¬Cl, that is, a substitution, and not a transformation C“C Cl2 → Cl¬C¬C¬Cl, which would be an addition. Let us summarize. Large differences in stability between potential radical intermediaate guarantee high regioselectivity of radical substitution reactions. Small differences in stability between potential radical intermediates no longer guarantee regioselective chlorinations. Interestingly, however, they do not yet rule out a considerable measure of regiocontrol in analogous brominations.This is illustrated in the following by a comparriso of the chlorination (below) and bromination (Section 1.7.3) of isopentane. The chlorination of isopentane gives multiply chlorinated compounds as well as all four conceivable monochlorination products (Table 1.3).These monochlorination producct are obtained with relative yields of 22% (substitution of Ctert¬H), 33% (substituttio of Csec¬H), 30 and 15% (in each case substitution of Cprim¬H). Consequently, one cannot talk about the occurrence of regioselectivity. Two factors are responsible for this. The first one is a statistical factor. Isopentane contains a single H atom, which is part of a Ctert¬H bond.There are two H atoms that are part of Csec¬H bonds, and 6 3 9 H atoms as part of Cprim¬H bonds. If each H atom were substituted at the same rate, the cited monochlorides would be produced in a ratio of 1:2:6:3. This would correspond to relative yields of 8, 17, 50, and 25%. The discrepancy from the experimental values is due to the fact that H atoms bound to different types of C atoms are replaced by chlorine at different rates. The substitu-1 Radical Substitution Reactions at the Saturated C Atom 24 tion of Ctert¬H takes place via a tertiary radical. The substitution of Csec¬H takes place via the somewhat less stable secondary radical, and the substitution of Cprim¬H takes place via even less stable primary radicals (for the stability of radicals, see Table 1.2). According to Hammond’s postulate, the rate of formation of these radicals should decrease in the direction indicated. Hydrogen atoms bound to Ctert should thus be substittute more rapidly than H atoms bound to Csec, and these should in turn be substituute by Cl more rapidly than H atoms bound to Cprim. As the analysis of the regioselecctivit of the monochlorination of isopentane carried out by means of Table 1.3 shows, the relative chlorination rates of Ctert¬H, Csec¬H, and Cprim¬H are 4.4:3.3: 1, in agreement with this expectation. 1.7.3 Regioselectivity of Radical Brominations Compared to Chlorinations In sharp contrast to chlorine, bromine and isopentane form monosubstitution producct with pronounced regioselectivity (Table 1.4).The predominant monobromination product is produced in 92.2% relative yield through the substitution of Ctert¬H. The second most abundant monobromination product (7.4% relative yield) comes from the substitution of Csec¬H.The two monobromination products in which a primary H atom is replaced by Br occur only in trace quantities. The analysis of these regioselectiivitie illustrated in Table 1.4 gives relative rates of 2000, 79, and 1 for the brominattio of Ctert¬H, Csec¬H, and Cprim¬H, respectively. The low regioselectivity of the radical chain chlorination in Table 1.3 and the high regioselectivity of the analogous radical chain bromination in Table 1.4 are typical: bromine is generally considerably more suitable than chlorine for the regioselective halogenation of saturated hydrocarbons. Still, even the 93:7 regioselectivity in the bromination of isopentane is only somewhat attractive from a synthetic perspective. In the following we will explain mechanistically why the regioselectivity for chlorinatiio is so much lower than for bromination. How the enthalpy H of the substrate/reagent pair changes when and H¬Cl are produced from it is plotted for four radical chlorinations in Figure 1.21 (left). These give differently alkylated C radicals, which are the methyl, a primary, a secondary, and a tertiary radical.The reaction enthalpies Hr for all four reactions are known and are plotted in the figure. Only the methyl radical is formed slightly endotherrmicall (Hr1 kcal/mol).The primary radical, which is 6 kcal/mol more stabbl (cf.Table 1.2), is already formed exothermically with Hr5 kcal/mol. Secondary and tertiary radicals, which are 3 and 6 kcal/mol more stable than primary radicals are formed even more exothermically. Hammond’s postulate can be applied to this series of the selectivity-determining steps of the radical chlorination shown in Figure 1.21. They all take place via early transition states, that is, via transition states that are similar to the starting materials. The more stable the resulting radical, the more similar to the starting materials is the transition state. The stability differences between these radicals are therefore manifesste only to a very small extent as stability differences between the transition states that lead to them. All transition states are therefore very similar in energy, and thus R # R¬H/Cl # B 1.7 Radical Halogenation of Hydrocarbons 25 Table 1.4. Regioselectivity of Radical Bromination of Isopentane Br Br Br Br + + + + Br2, ∆ ... 92.2% ... 1 7.38% 0.28% 0.14% ... 92.2% ... 2000 79 ≡ 1 ≡ 1 2 6 3 ... 3.69% 0.047% 0.047% ... Csec H ... Ctert H H Cprim In order to produce the above compounds in the individual case... ...H atoms were available for the substitution. Yields on a per-H-atom basis were... ... for the monobromination product above. In other words: in the position concerned is ... kC–H C–Br, rel ..., that is, generally for ... multiple brominated compounds The relative yields of the above monobromination products are... C H+ Br •∆H ∆H +1 –5 +5 –8 +8 –11 Chlorination reaction coordinate Bromination reaction coordinate +13 +17 ≡ 0 ≡ 0 H C• + HHal 3 R • + HHal prim R • + HHal sec R • + HHal tert four small Ea values, obviously differing little from each other four larger Ea values, obviously differing more from each other C H+ Cl • Fig. 1.21. Thermochemical analysis of that propagation step of radical chlorination (left) and bromination (right) of alkanes that determines the regioselectivity of the overall reaction. The Hr values were determined experimentally; the H‡ values are estimated. 1 Radical Substitution Reactions at the Saturated C Atom 26 are passed through with very similar reaction rates. This means that the regioselectiviit of the radical chlorination under consideration is low. In radical brominations the energy profiles of the selectivity-determining step are completely different from what they are in analogous chlorinations. This is shown on the right side of Figure 1.21 and is rationalized as follows.The abstraction of a C-bound H atom by Cl atoms leads to the formation of an H-Cl bond with a bond enthalpy of 103 kcal/mol. In contrast, the abstraction of a C-bound H atom by a Br atom leads to the formation of a C-Br bond. Its bond enthalpy is 88 kcal/mol, which is 15 kcal/mol below the bond enthalpy of an H-Cl bond. Accordingly, even the most stable radical considered in Figure 1.21, the tertiary radical, is formed endothermically (Hr 5 kcal/mol). From the secondary through the primary to the methyl radical increasinngl less stable radicals are produced in the analogous brominations of this figure. They are therefore formed increasingly endothermically and consequently probably also increasingly endergonically. According to Hammond’s postulate, the selectivitydeterrminin step of radical brominations thus proceeds via late, that is, product-like, transition states. Consequently, the substituent effects on the free energy changes of the selectivity-determing step appear almost undiminished as substituent effects on the free energies of the respective transition states. These transition states are therefore passed through with very different rate constants.The regioselectivity of radical brominattion is consequently considerably higher than the regioselectivity of analogous chlorinattions At the end of Section 1.7.4 we will talk about an additional aspect of Figure 1.21. To understand this aspect, however, we must first determine the rate law according to which radical halogenations take place. 1.7.4 Rate Law for Radical Halogenations; Reactivity/Selectivity Principle A simplified reaction scheme for the kinetic analysis of radical chain halogenations can be formulated as follows: Hal2 Hal• + RH R• + Hal2 k1 k2 k1 k2 k3 k4 2 Hal• with Kdis = Hal H + R• R Hal + Hal• Let us assume that only the reaction steps listed in this scheme participate in the radical chain halogenations of hydrocarbons. Let us thus disregard the fact that chain termination can also occur owing to the radical-consuming reactions → R¬Hal and 2 → R¬R and possibly also by disproportionation of alkyl radicals R. to give the alkane, which has one H atom more, and the olefin, which has one H R # Hal # R # A 1.7 Radical Halogenation of Hydrocarbons 27 atom less. According to this scheme, the thermolysis of halogen molecules gives halogge atoms with the rate constant k1. On the one hand, these recombine with the rate constant k2 to form the halogen molecule again. On the other hand, the halogen atoms participate as the initiating radical in the first propagation step, which takes place with the rate constant k3. The second and last propagation step follows with the rate consttan k4. Explicit termination steps do not have to be considered in this approximate kinetic analysis. A termination step has already been implicitly considered as the reversal of the starting reaction (rate constant k2). As soon as all halogen atoms have been converrte back into halogen molecules, the chain reaction comes to a stop. The rate law for the halogenation reaction shown above is derived step by step in Equations 1.4–1.8.We will learn to set up derivations of this type in Section 2.4.1.There we will use a much simpler example.We will not discuss Bodenstein’s steady-state approxiimatio used in Equations 1.6 and 1.7 in more detail until later (Section 2.5.1). What will be explained there and in the derivation of additional rate laws in this book is sufficient to enable you to follow the derivation of Equations 1.4–1.8 in detail in a second pass through this book. At this stage, it is sufficient to know the result of this derivation, which is given as Equation 1.9: (1.9) It says: the substitution product R¬X is produced at a rate that is determined by two constants and two concentration terms. For given initial concentrations of the sub-Gross reaction rate k3 3RH42Kdis 3Hal42 1 Radical Substitution Reactions at the Saturated C Atom 28 strate R¬H and the halogen and for a given reaction temperature, the rate of formatiio of the substitution product is directly proportional to the rate constant k3, k3 beiin the rate constant of the propagation step in which the radical R. is produced from the hydrocarbon R¬H. Let us recall the energy profiles from Figure 1.21. They represent precisely the step of chlorination (left side) and bromination (right side), which determines the regioseleectivit and takes place with the rate constant k3. According to Section 1.7.3, this step is faster for chlorination than for bromination. If we look at the reaction scheme we set up at the beginning of this section, then this means that k3 (chlorination) k3 (bromination) Also, according to Equation 1.9, the overall reaction “radical chlorination” takes place on a given substrate considerably faster than the overall reaction “radical brominatioon. If we consider this and the observation from Section 1.7.3, which states that radicca chlorinations on a given substrate proceed with considerably lower regioselectiviit than radical brominations, we have a good example of the so-called reactivity/selectivity principle: 1.7.5 Chemoselectivity of Radical Brominations Let us go back to radical brominations (cf. Section. 1.7.3). The bromination of alkyl aromatics takes place completely regioselectively: only the benzylic position is brominattedThe intermediates are the most stable radicals that are available from alkyl aromattics namely, benzylic radicals. Refluxing ortho-xylene reacts with 2 equiv. of bromine to give one monosubstitution per benzylic position. The same transformation occurs when the reactants are irradiated at room temperature in a 1:2 ratio (Figure 1.22, right). The rule of thumb “SSS” applies to the reaction conditions that afford these benzylic substitutions chemoselectively. SSS stands for “searing heat sunlight S side chain substitution.” A highly reactive reagent generally reacts with lower selectivity than a less reactiiv reagent. BReactivity/Selectivity Principle Br Br Br Br + 2 Br2 cat. AlCl3 0 °C ∆ or hn Fig. 1.22. Competing chemoselectivities during the reaction of bromine with ortho-xylene by a polar mechanism (left) and a radical mechanism (right). B 1.7 Radical Halogenation of Hydrocarbons 29 Starting from the same reagents, one can also effect a double substitution on the aromaati ring (Figure 1.22, left). However, the mechanism is completely different (Figure 5.11 and following figures). This substitution takes place under reaction conditions in which no radical intermediates are formed. (Further discussion of this process will be presented in Section 5.2.1.) Under these reaction conditions, the rule of thumb “CCC” applies. CCC stands for “catalyst cold S core substitution.” Hydrogen atoms in the benzylic position can be replaced by elemental bromine as shown. This is not true for hydrogen atoms in the allylic position. With elemental bromine they react less rapidly than the adjacent olefinic C“C double bond does. As a consequence, bromine adds to olefins chemoselectively and does not affect allylic hydrogen (Figure 1.23, left). A chemoselective allylic bromination of olefins succeeds only according to the Wohl–Ziegler process (Figure 1.23, right), that is, with N-bromosuccinimide (NBS). Br2 Br Br B N OO Br, r AIBN (cat.) AIBN (cat.) Problem Solution Fig. 1.23. Bromine addition and bromine substitution on cyclohexene. Figure 1.24 gives a mechanistic analysis of this reaction. NBS is used in a stoichiomettri amount, and the radical initiator AIBN (cf. Figure 1.9) is used in a catalytic amount.The starting of the chain comprises several reactions, which in the end deliver Br. as the initiating radical. Figure 1.24 shows one of several possible starting reactiio sequences. Next follow three propagation steps. The second propagation step— something new in comparison to the reactions discussed before—is an ionic reaction between NBS and HBr. This produces succinimide along with the elemental bromine, which is required for the third propagation step. In the first propagation step of the Wohl–Ziegler bromination, the bromine atom abstracts a hydrogen atom from the allylic position of the olefin and thereby initiates a substitution. This is not the only reaction mode conceivable under these conditions. As an alternative, the bromine atom could attack the C“C double bond and thereby start a radical addition to it (Figure 1.25). Such an addition is indeed observed when cyclohexene is reacted with a Br2/AIBN mixture. The difference is that in the Wohl–Ziegler process there is always a much lower Br2 concentration than in the reaction of cyclohexene with bromine itself.Figure 1.25 shows qualitatively how the Br2 concentration controls whether the combined effect of on cyclohexene is an addition or a substitution.The decisive factor is that the addition takes place via a reversible step and the substitution does not. During the addition, a bromocyclohexyl radical forms from cyclohexene and in an equilibrium reaction. This radical is intercepted by forming dibromocyclohexane only when a high concentraatio of Br2 is present. However, if the concentration of Br2 is low, there is no such Br # Br # /Br2 NOO Br NC H H Br Br B B B B r r r r H Br Br H NC NN N N N OO O O O OO O O O BB B H H r r r B B B r r r NOO NC N N CN NC N N + + + + + + + + + + + NC NOO Br NC Initiation step: Propagation steps: fast, ionic Net equation Propagation steps: Σ 2 ∆ Fig. 1.24. Mechanism for the allylic bromination of cyclohexene according to the Wohl–Ziegler process. Br Br Br Br B B B r r r + + + k~Br k~H + Br2 + Br2 kadd kdis + HBr Fig. 1.25. Reaction scheme for the action of Br/Br2 on cyclohexene and the kinetic analysis of the resulting competition between allylic substitution (right) and addition (left) (in k~X, ~X means homolytic cleavage of a bond to atom X). 1.7 Radical Halogenation of Hydrocarbons 31 reaction. The bromocyclohexyl radical is then produced only in an unproductive equilibbriu reaction. In this case the irreversible substitution therefore determines the course of the reaction. Figure 1.26 gives a quantitative analysis of the outcome of this competition. Equatiio 1.14 provides the following decisive statement: The ratio of the rate of formation of the substitution product to the rate of formation of the addition product—which equals the ratio of the yield of the substitution product to the yield of the addition product—is inversely proportional to the concentration of Br2. k k add Br · ~ Br Br d dt = k~H Br Br Br Br2 d dt = k~Br Br Br = kadd kdis Br Br B B r r2 d dt = k k add · Br ~ kdis B B r r2 Br Br d d dt dt = k ·k ~H dis · 1 because k~H describes the rate-determining step of the allylic substitution because k~Br describes the rate-determining step of the addition reaction because the equilibrium condition is met Equation (1.12) in Equation (1.11) ⇒ Divide Equation (1.10) by Equation (1.13) ⇒ (1.10) (1.11) (1.12) (1.13) (1.14) Fig. 1.26. Derivation of the kinetic expression for the chemoselectivity of allylic substitution versus bromine addition in the system cyclohexene. The rate constants are defined in Figure 1.25. Br/Br2 /1 Radical Substitution Reactions at the Saturated C Atom 32 1.8 Autoxidations Reactions of compounds with oxygen with the development of flames are called combusttions In addition, flameless reactions of organic compounds with oxygen are known. They are referred to as autoxidations. Of the autoxidations, only those that take place via sufficiently stable radical intermediates can deliver pure compounds and at the same time appealing yields. Preparatively valuable autoxidations are therefore limited to substitution reactions of hydrogen atoms that are bound to tertiary, allylic, or benzyyli carbon atoms. An example can be found in Figure 1.27. Unintentional autoxidatiion can unfortunately occur at the O¬Cprim¬H of ethers such as diethyl ether or tetrahydrofuran (THF) (Figure 1.28). An Industrially Important Autoxidation The most important autoxidation used industrially is the synthesis of cumene hydroperooxid from cumene and air (i.e., “diluted” oxygen) (Figure 1.27). It is initiated by catalytic amounts of dibenzoyl peroxide as the radical initiator (cf. Figure 1.9). The cumyl radical is produced as the initiating radical from a sequence of three starting reactiions It is a tertiary radical, which is additionally stabilized by resonance. The cumyl radical is consumed in the first propagation step of this autoxidation and is regeneratte in the second propagation step. These steps alternate until there is a chain terminattion The autoxidation product, cumene hydroperoxide, is not isolated in pure form because all hydroperoxides are explosive. Instead the crude product is usually subjected to the cumene hydroperoxide rearrangement (see Section 11.4.1), which produces phenno and acetone.Worldwide, 90% of each of these industrially important chemicals is synthesized by this process. Unintentional Autoxidation of Ethers Two ethers that are frequently used as solvents are relatively easy to autoxidize—unfortunnately because this reaction is not carried out intentionally. Diethyl ether and THF form hydroperoxides through a substitution reaction in the a position to the oxygen atom (Figure 1.28). These hydroperoxides, incorrectly but popularly also referred to as “ether peroxides,” are fairly stable in dilute solution. However, they are highly explosiiv in more concentrated solutions or in pure form. Diethyl ether or THF must therefoor be used only when free of peroxide. What makes the a position of these ethers autoxidizable? a-Oxygenated radicals are stabilized by the free electron pairs on the heteroatom.When the sp3 orbitals that accommmodat the latter form a sufficiently small dihedral angle—0would be best—with the plane in which the half-occupied 2pz orbital at the radical center is located, the occuppie orbitals can overlap with the half-occupied orbital (Figure 1.29). This results in a small but definite energy gain. It is similar to the energy gain the half-occupied 2pz orbital of a radical center experiences as a result of overlap with a suitably oriented sC¬H MO (see Figure 1.5). Side Note 1.2 Autoxidations in Practice B 1.8 Autoxidations 33 O O H C C O O O O O O C C O OO O C C O O O O H H H O O O O O O H O , 2 ∆ (cat.) Initiation step: Propagation steps: 2 + CO2 + + + + + Fig. 1.27. Industrial synthesis of cumene hydroperoxide. OO OO O O OO O O O OO O O O HH OO O O O HH H O O O H Air, Air, Light Light Light Ether peroxide THF peroxide “Unknown” 2 Rad Rad Rad ++ + + + Initiation step: Propagation steps: Fig. 1.28. Autoxidation of diethyl ether and THF: net equations (top) and mechanism (bottom). 1 Radical Substitution Reactions at the Saturated C Atom 34 Fig. 1.29. MO diagram of a-oxygenated alkyl radicals. n2pz E 2pz Stabilization energy nO nO =^ O C tert-Butyl methyl ether is used routinely, especially in industry, as a substitute for dietthy ether. There are two reasons why it is not easy to autoxidize. In the tert-butyl group there is no H atom a to the heteroatom. In the methyl group such H atoms in the a position would be available but would have to be substituted via a radical, which, being unalkylated, is not very stable. 1.9 Defunctionalizations via Radical Substitution Reactions 1.9.1 Simple Defunctionalizations A series of functionalized hydrocarbons can be defunctionalized with the help of radicca substitution reactions. The functional group is then replaced by a hydrogen atom. The groups that can be removed in this way include iodide, bromide, and some sulfurcontaainin alcohol derivatives. Compounds with a homolysis-sensitive element– hydrogen bond serve as hydrogen atom donors. The standard reagent is Bu3Sn-H. A substitute that does not contain tin and is considerably less toxic is (Me3Si)3Si¬H. Defunctionalizations of this type are usually carried out for the synthesis of a hydrocarrbo or to produce a hydrocarbon-like substructure. Figure 1.30 illustrates the possibilities of this method using a deiodination and a debromination as examples. These reactions represent general synthetic methods for obtaining cyclic esters or ethers.We will see later how easy it is to prepare halides like those shown in Figure 3.36 from olefin precursors. 1.9 Defunctionalizations via Radical Substitution Reactions 35 Both in radical defunctionalizations effected with Bu3SnH and in those carried out with (Me3Si)3SiH, the radical formation is initiated by the radical initiator AIBN (Figuur 1.31). The initiation sequence begins with the decomposition of AIBN, which is triggered by heating or by irradiation with light, into the cyanated isopropyl radical. In the second step of the initiation sequence, the cyanated isopropyl radical produces the respective initiating radical; that is, it converts Bu3SnH into Bu3Sn. and (Me3Si)3SiH into (Me3Si)3Si.. The initiating radical gets the actual reaction chain going, which in each case comprises two propagation steps. Both Bu3SnH and (Me3Si)3SiH are able to defunctionalize alkyl iodides or bromides but not alcohols. On the other hand, in the so-called Barton–McCombie reaction they can defunctionalize certain alcohol derivatives, namely, ones that contain a C“S doubbl bond (e.g., thiocarboxylic esters or thiocarbonic esters). Figure 1.32 shows how the OH group of cholesterol can be removed by means of a Barton–McCombie reactiion The C“S-containing alcohol derivative used there is a xanthate (for the mechaniis of the formation reaction of xanthates, see Figure 7.4). Fig. 1.30. Dehalogenations through radical substitution reactions. I O O O O O Br O O O Bu SnH, 3 AIBN (cat.) AIBN (cat.) (Me Si) SiH, 3 3 Si(SiMe ) 3 3 Si(SiMe ) 3 3 N N CN NC N N + N NN NN C CC CC Initiation step: ∆ HHH HH SnBu3 SnBu3 ML3 ML3 ML3 ML3 ML3 ML3 ≡ ≡ Hal H Hal Propagation steps: R R H R R ++ + + ++ + + 2 or Fig. 1.31. Mechanism of the radical dehalogenations of Figure 1.30. 1 Radical Substitution Reactions at the Saturated C Atom 36 The starting sequence of this defunctionalization is identical to the one that was used in Figure 1.31 in connection with the dehalogenations. It thus leads via the initially formed Me2(NC) radicals to radicals. These radicals enter into the actual reaction chain, which consists of three propagation steps (Figure 1.33). The radical is a thiophile; that is, it likes to combine with sulfur. Thus the point of attack of the first propagation step is the double-bonded sulfur atom of the xanthate.The secoon propagation step is a radical fragmentation. Bu3Sn # Bu3Sn # C # H H H HO H H H H H MeS O S NaH; CS ; MeI 2 Bu SnH, 3 AIBN (cat.) Fig. 1.32. Defunctionalization of an alcohol by means of the radical substitution reaction of Barton and McCombie. MeS O S R B B u u 3 3 S S n n S S M M e e S S O O R R Bu3Sn S MeS O Bu Sn 3 Bu Sn 3 Bu Sn 3 R H H + + + R + R Fig. 1.33. Propagation steps of the Barton–McCombie reaction in Figure 1.32. Other C“S-containing esters derived from alcohols can also be defunctionalized accorrdin to Barton and McCombie. Imidazolylthiocarbonic esters, which in contrast to xanthates can be synthesized under neutral conditions, are one example. This is importaan for the defunctionalization of base-sensitive alcohols. Figure 1.34 shows a reaction of this type. If the corresponding xanthate was prepared through consecutive reactions with NaH, CS2, and MeI (for mechanism, see Figure 7.4), this compound would lose its cis configuration. This would occur because of the presence of the keto group. It would undergo a reversible deprotonation giving the enolate (cf. Figure 1.34).The latter would be reprotonated in part—actually even preferentially—such as to form the trans isomer. The starting sequence of the Barton–McCombie reaction in Figure 1.34 is again identiica to the one in Figure 1.31. However, because now Bu3SnD is the reducing agent instead of Bu3SnH, D is incorporated into the product instead of H. 1.9 Defunctionalizations via Radical Substitution Reactions 37 1.9.2 Defunctionalization via 5-Hexenyl Radicals: Competing Cyclopentane Formation The defunctionalizations discussed in Section 1.9.1 considered in a different way, are also reactions for producing radicals. Certain radicals ordinarily cannot be reduced to the corresponding hydrocarbon: the 5-hexenyl radical and its derivatives. These radicaal often cyclize (irreversibly) before they abstract a hydrogen atom from the reduciin agent. By this cyclization, the cyclopentylmethyl radical or a derivative of it is produuce selectively. An isomeric cyclohexyl radical or the corresponding derivative is practically never obtained. Often only the cyclized radical abstracts a hydrogen atom from the reducing agent. Figure 1.35 gives an example of a reaction of this type in the form of a cyclopentane annulation. The precursor to the cyclizable radical is again (cf. Figure 1.34) a thiocarbonic acid imidazolide, as shown in Figure 1.35. The reducing agent is (Me3Si)3SiH, but one also could have used Bu3SnH. AIBN functions as the radical initiator. After the usual ini-O HO O O H O O S SMe O HO O O H O O S SMe N N N N SN N H N N S O O O D NaH, CS , MeI 2 Na Na Na ( ) cis ( ) cis ( ) cis ( ) cis ( ) trans ( ) trans – Bu Sn , 3 D AIBN (cat.), hn Problem Solution Fig. 1.34. Deoxygenation/deuteration of alcohols via a radical substitution reaction. A Fig. 1.35. Cyclization of a 5-hexenyl radical intermediate from a Barton–McCombie defunctionalization as a method for cyclopentane annulation. 1 Radical Substitution Reactions at the Saturated C Atom 38 N N O S H H H H + cat. AIBN (Me Si) SiH 3 3 add drop by drop (Ring strain 10 kcal/mol) (Ring strain 16 kcal/mol) cis trans 5 (Me3Si)3Si N N O S N N O S (Me3Si)3Si N N O S (Me3Si)3Si N N O S (Me3Si)3Si H H H H H H H Si(SiMe3 )3 + + + + Si(SiMe ) 3 3 tiation sequence (Figure 1.31, formula lines 1 and 3) the initiating radical (Me3Si)3Si. is available, and a sequence of four propagation steps is run through (Figure 1.36). In the second propagation step the 5-hexenyl radical is produced, and in the third step it is cyclized. The cyclization leads stereoselectively to a cis-instead of a transannuulate bicyclic system. The reason for this is that the preferentially formed cis radical has less ring strain than its trans isomer. Yet, the cis-selectivity is due to kineeti rather than thermodynamic control. Therefore, it is a consequence of productdevellopmen control. It is interesting that one can also use the same reagents to defunctionalize the same thiocarbonic acid derivative without cyclization (Figure 1.37). To do this, one simply changes the sequence in which the reagents are added according to Figure 1.37. There is no cyclization when the substrate/AIBN mixture is added dropwise to an excess of the reducing agent. A relatively concentrated solution of the reducing agent is then al-Fig. 1.36. Propagation steps in the radical substitution/cyclization of Figure 1.35. 1.9 Defunctionalizations via Radical Substitution Reactions 39 ways available as a reaction partner for the substrate and the radicals derived from it. According to Figure 1.35, on the other hand, cyclization predominates when the reduccin agent/AIBN mixture is added to the substrate dropwise over several hours. In this way the substrate and the derived radicals are exposed to only an extremely diluut solution of the reducing agent during the entire reaction. According to Figure 1.38 the question whether cyclization takes place or not is deciide as soon as the C¬O bond of the substrate is cleaved and radical A is present. Radical A either cyclizes (at a rate that is equal to the product of the rate constant kcycl and the concentration of A) or it reacts with the silane. In the latter case, the rate is the product of the rate constant k~H → prim, the concentration of the radical A, and the concentration of the silane. Let us assume that the concentration of the silane does not change during the reduction. This assumption is not correct, but sufficiently accuraat for the present purpose. Then the ratio of the rates of the two alternative reactiion of the hexenyl radical A is equal to the yield ratio of the cyclized and the noncycllize reaction products. (1.15) According to Equation 1.15, the yield ratio of the two reduction products depends on a single variable, namely, the concentration of the reducing agent. This is in the denominator of Equation 1.15, which means two things: (1) when the radical intermeddiat A encounters a small amount of reducing agent, the diquinane is produced preferentially (see Figure 1.35) and (2) when the same radical encounters a large amount of reducing agent, the cyclopentane is preferentially formed (see Figure 1.37). % Cyclization to the diquinane %Reduction to cyclopentene kcycl kHSprim 1 31Me3Si23SiH4quasistationary N N O S H + cat. AIBN (Me to Si) SiH 3 3 add drop by drop Fig. 1.37. Cyclization-free defunctionalization of the thiocarbonic acid derivative from Figure 1.35. H H H H H (Me Si) SiH 3 3 (Me Si) SiH 3 3 kcycl k~H prim A Fig. 1.38. Reaction scheme for the kinetic analysis of the complementary chemoselectivity of the cyclizing defunctionalization (top reaction) of Figure 1.35 and the noncyclizing defunctionalization (bottom reaction) of Figure 1.37. 1 Radical Substitution Reactions at the Saturated C Atom 40 References B. Giese, “C-Radicals: General Introduction,” in Methoden Org. Chem. (Houben-Weyl) 4th ed. 1952-, C-Radicals (M. Regitz,B. Giese, Eds.),Vol. E19a, 1, Georg Thieme Verlag, Stuttgart, 1989. W. B. Motherwell and D. Crich, “Free-Radical Chain Reactions in Organic Chemistry,” Acadeemi Press, San Diego, CA, 1991. J. E. Leffler, “An Introduction to Free Radicals,”Wiley, New York, 1993. M. J. Perkins, “Radical Chemistry,” Ellis Horwood, London, 1994. J. Fossey, D. Lefort, J. Sorba, “Free Radicals in Organic Chemistry,” Wiley, Chichester, U.K., 1995. Z. B. Alfassi, (Ed.), “General Aspects of the Chemistry of Radicals,”Wiley, Chichester,U.K., 1999. Z. B. Alfassi, “The Chemistry of N-Centered Radicals,”Wiley, New York, 1998. Z. B. Alfassi, (Ed.), “S-Centered Radicals,”Wiley, Chichester, U.K., 1999. 1.2 D. D. M. Wayner and D. Griller, “Free Radical Thermochemistry,” in Adv. Free Radical Chem. (D. D. Tanner, Ed.), Vol. 1, Jai Press, Inc., Greenwich, CT, 1990. J. A. Martinho Simoes, A. Greenberg, J. F. Liebman (Eds.), “Energetics of Organic Free Radicals,” In: Struct. Energ. React. Chem. Ser. 1996, 4, Blackie, Glascow, U.K., 1996. D. Gutman, “The controversial heat of formation of the tert-C4H9 radical and the tertiary carboonhydrogen bond energy,” Acc. Chem. Res. 1990, 23, 375–380. J. C.Walton, “Bridgehead radicals,” Chem. Soc. Rev. 1992, 21 ,105–112. 1.3 E. Grunwald, “Reaction coordinates and structure/energy relationships,” Progr. Phys. Org. Chem. 1990, 17, 55–105. A. L. J. Beckwith, “The pursuit of selectivity in radical reactions,” Chem. Soc. Rev. 1993, 22, 143–161. 1.5 J. O. Metzger, “Generation of Radicals,” in Methoden Org. Chem. (Houben-Weyl) 4th ed. 1952-, C-Radicals (M. Regitz, B. Giese, Eds.), Vol. E19a, 60, Georg Thieme Verlag, Stuttgart, 1989. H. Sidebottom and J. Franklin, “The atmospheric fate and impact of hydrochlorofluorocarbons and chlorinated solvents,” Pure Appl. Chem. 1996, 68, 1757–1769. 1.6 G. A. Russell, “Free radical chain reactions involving alkyl-and alkenylmercurials,” Acc. Chem. Res. 1989, 22, 1–8. G. A. Russell, “Free Radical Reactions Involving Saturated and Unsaturated Alkylmercurials,” in Advances in Free Radical Chemistry (D. D. Tanner, Ed.), 1990, 1, Jai Press, Greenwich, CT. 1.7 J. O. Metzger, “Reactions of Radicals with Formation of C,Halogen-Bond,” in Methoden Org. Chem. (Houben-Weyl) 4th ed. 1952-, C-Radicals (M. Regitz, B. Giese, Eds.), Vol. E19a, 268, Georg Thieme Verlag, Stuttgart, 1989. References 41 K. U. Ingold, J. Lusztyk, K. D. Raner, “The unusual and the unexpected in an old reaction. The photochlorination of alkanes with molecular chlorine in solution,” Acc. Chem. Res. 1990, 23, 219–225. 1.8 J. O. Metzger, “Reactions of Radicals with Formation of C,O-Bond,” in Methoden Org. Chem. (Houben-Weyl) 4th ed. 1952-, C-Radicals (M. Regitz, B. Giese, Eds.), Vol. E19a, 383, Georg Thieme Verlag, Stuttgart, 1989. W.W. Pritzkow and V.Y. Suprun, “Reactivity of hydrocarbons and their individual C-H bonds in respect to oxidation processes including peroxy radicals,” Russ. Chem. Rev. 1996, 65, 497–503. Z. Alfassi, “Peroxy Radicals,”Wiley, New York, 1997. 1.9 J. O. Metzger, “Reactions of Radicals with Formation of C,H-Bond,” in Methoden Org. Chem. (Houben-Weyl) 4th ed. 1952-, C-Radicals (M. Regitz, B. Giese, Eds.), Vol. E19a, 147, Georg Thieme Verlag, Stuttgart, 1989. S.W. McCombie, “Reduction of Saturated Alcohols and Amines to Alkanes,” in Comprehensive Organic Synthesis (B. M. Trost, I. Fleming, Eds.), Vol. 8, 811, Pergamon Press, Oxford, 1991. B. Giese,A. Ghosez,T.Göbel, H. Zipse,“Formation of C-H Bonds by Radical Reactions,” in Methodde Org. Chem. (Houben-Weyl) 4th ed. 1952-, Stereoselective Synthesis (G. Helmchen, R.W. Hoffmann, J. Mulzer, and E. Schaumann, Eds.),Vol. E21d, 3913, Georg Thieme Verlag, Stuttgart, 1995. C. Chatgilialoglu, “Organosilanes as radical-based reducing agents in synthesis,” Acc. Chem. Res. 1992, 25, 180–194. V. Ponec, “Selective de-oxygenation of organic compounds,” Rec. Trav. Chim. Pays-Bas 1996, 115, 451–455. S. Z. Zard, “On the trail of xanthates: Some new chemistry from an old functional group,” Angew. Chem. 1997, 109, 724–737; Angew. Chem. Int. Ed. Engl. 1997, 36, 672–685. C. Chatgilialoglu and M. Newcomb, “Hydrogen donor abilities of the group 14 hydrides,” Adv. Organomet. Chem. 1999, 44, 67–112. P. A. Baguley and J. C. Walton, “Flight from the tyranny of tin: The quest for practical radical sources free from metal encumbrances,” Angew. Chem. 1998, 110, 3272–3283; Angew. Chem. Int. Ed. Engl. 1998, 37, 3072–3082. Further Reading A. Ghosez, B. Giese, H. Zipse,W. Mehl, “Reactions of Radicals with Formation of a C,C-Bond,” in Methoden Org. Chem. (Houben-Weyl) 4th ed. 1952-, C-Radicals (M. Regitz, B. Giese, Eds.), Vol. E19a, 533, Georg Thieme Verlag, Stuttgart, 1989. M. Braun, “Radical Reactions for Carbon-Carbon Bond Formation,” in Organic Synthesis Highligght (J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reißig, Eds.), VCH, Weinheim, New York, etc., 1991, 126–130. B. Giese, B. Kopping, T. Gobel, J. Dickhaut, G. Thoma, K. J. Kulicke, F. Trach, “Radical cyclization reactions,” Org. React. 1996, 48, 301–866. D. P. Curran, “The design and application of free radical chain reactions in organic synthesis,” Synthesis 1988, 489. T. V. RajanBabu, “Stereochemistry of intramolecular free-radical cyclization reactions,” Acc. Chem. Res. 1991, 24, 139–45. D. P. Curran, N. A. Porter, B. Giese (Eds.), “Stereochemistry of Radical Reactions: Concepts, Guidelines, and Synthetic Applications,” VCH,Weinheim, Germany, 1995. 1 Radical Substitution Reactions at the Saturated C Atom 42 C. P. Jasperse, D. P. Curran, T. L. Fevig, “Radical reactions in natural product synthesis,” Chem. Rev. 1991, 91, 1237–1286. G. Mehta and A. Srikrishna, “Synthesis of polyquinane natural products: An update,” Chem. Rev. 1997, 97, 671–720. V. K. Singh and B. Thomas, “Recent developments in general methodologies for the synthesis of linear triquinanes,” Tetrahedron 1998, 54, 3647–3692. S. Handa and G. Pattenden, “Free radical-mediated macrocyclizations and transannular cyclizatiion in synthesis,” Contemp. Org. Synth. 1997, 4, 196–215. G. Descotes, “Radical Functionalization of the Anomeric Center of Carbohydrates and Synthetic Applications,” in Carbohydrates (H. Ogura, A. Hasegawa, T. Suami, Eds.), 89, Kodansha Ltd, Tokyo, Japan, 1992. C.Walling and E. S. Huyser, “Free radical addition to olefins to form carbon-carbon bonds,” Org. React. 1963, 13, 92–149. B. Giese, T. Göbel, B. Kopping, H. Zipse, “Formation of C¬C bonds by addition of free radicals to olefinic double bonds,” in Stereoselective Synthesis (Houben-Weyl) 4th ed., (G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann, Eds.), 1996, Vol. E21 (Workbench Edition), 4, 2003–2287, Georg Thieme Verlag, Stuttgart. L. Yet, “Free radicals in the synthesis of medium-sized rings,” Tetrahedron 1999, 55, 9349–9403. B. K. Banik, “Tributyltin hydride induced intramolecular aryl radical cyclizations: Synthesis of biologiicall interesting organic compounds,” Curr. Org. Chem. 1999, 3, 469–496. F. W. Stacey and J. F. Harris, Jr., “Formation of carbon-heteroatom bonds by free radical chain additions to carbon-carbon multiple bonds,” Org. React. 1963, 13, 150–376. O. Touster, “The nitrosation of aliphatic carbon atoms,” Org. React. 1953, 7, 327–377. C. V.Wilson, “The reaction of halogens with silver salts of carboxylic acids,” Org. React. 1957, 9, 332–387. R. A. Sheldon and J. K Kochi, “Oxidative decarboxylation of acids by lead tetraacetate,” Org. Reacct 1972, 19, 279–421. 2 Nucleophilic Substitution Reactions at the Saturated C Atom 2.1 Nucleophiles and Electrophiles; Leaving Groups Stated with some exaggeration, organic chemistry is comparatively simple to learn becaaus most organic chemical reactions follow a single pattern. This pattern is A nucleophile is a species that attacks the reaction partner by making a pair of electrron available to it; it is thus an electron pair donor. An electrophile is a species that reacts by accepting a pair of electrons from the reaction partner so that it can be shared between them. An electrophile is thus an electron pair acceptor. For most organic chemical reactions, the pattern just specified can thus be written more briefly as follows: In this chapter we deal with nucleophilic substitution reactions at the saturated, that is, the sp3-hybridized C atom (abbreviated “SN reactions”). In these reactions, alkyl groups are transferred to the nucleophiles. Organic electrophiles of this type are referrre to as alkylating agents. They have the structure The group X is displaced by the nucleophile according to the equation 1R3n Hn2 Csp3¬X. N N u u E (+ by-products) E + As electron pair donors, nucleophiles must either contain an electron pair that is easily available because it is nonbonding or they must contain a bonding electron pair that can be donated from the bond involved and thus be made available to the reaction partner. From this it follows that nucleophiles are usually anions or neutrra species but not cations. In this book nucleophile is abbreviated as “Nu,” regarddles of charge. According to the definition, electrophiles are electron pair acceptors. They therefoor contain either a deficiency in the valence electron shell of one of the atoms they consist of or they are indeed valence-saturated but contain an atom from which a bonding electron pair can be removed as part of a leaving group. Concomitantly this atom accepts the electron pair of the nucleophile. Electrophiles are therefore, as a rule, cations or neutral compounds but not anions. In this book electrophile is abbreviated as “E,” regardless of charge. nucleophile + electrophile valence electron pair shift(s) product(s) Electrophiles and Nucleophiles B 2 Nucleophilic Substitution Reactions at the Saturated C Atom 44 as X. Consequently, both the bound group X and the departing entity Xare called leaving groups. Some uncharged and a few positively charged three-membered heterocycles also react as alkylating agents. Instead of simple alkyl groups, they transfer alkyl groups with a heteroatom in the b position. The most important heterocyycli alkylating agents of this type are the epoxides.When there are no Brønsted or Lewis acids present, epoxides act as b-hydroxy alkylating agents with respect to nucleophiles: According to this equation, the product is indeed produced by an SN reaction becaaus the nucleophile displaces an oxyanion as a leaving group from the attacked C atom. Nonetheless this oxyanion is still a part of the reaction product. In this respect this reaction can also be considered to be an addition reaction. An intermolecular addittio reaction is one that involves the combination of two molecules to form one new molecule. An intramolecular addition reaction is one that involves the combination of two moieties within a molecule to form one new molecule. 2.2 Good and Poor Nucleophiles Which nucleophiles can be alkylated rapidly and are thus called “good nucleophiles”? Or, in other words, which nucleophiles have “high nucleophilicity”? And which nucleophhile can be alkylated only slowly and are thus called “poor nucleophiles”? Or, in other words, which nucleophiles have “low nucleophilicity”? Or let us ask from the point of view of the alkylating agent:Which alkylating agents react rapidly in SN reacttion and thus are “good alkylating agents” (good electrophiles)? Which alkylating agents react slowly in SN reactions and thus are “poor alkylating agents” (poor electrophhiles) As emerges from these definitions, good and poor nucleophiles, high and low nucleophilicity, good and poor alkylating agents, good and poor electrophiles, and high and low electrophilicity are kinetically determined concepts. Answers to all these questions are obtained via pairs of SN reactions, which are carriie out as competition experiments. In a competition experiment two reagents react simultaneously with one substrate (or two substrates react simultaneously with one reagent). Two reaction products can then be produced. The main product is the compooun that results from the more reactive (synonymous with “faster reacting”) reactiio partner. Nu O Rx Nu O Rx Nu OH Rx + k aqueous workup Nu C X X Nu C sp3 sp3 + + k B 2.2 Good and Poor Nucleophiles 45 Accordingly, it is possible to distinguish between good and poor nucleophiles when SN reactions are carried out as competition experiments.There the nucleophiles are made available as mixtures to a standard alkylating agent. The nucleophile that reacts to form the main product is then the “better” nucleophile. As has been observed in the investigation of a large number of competition experiments of this type, gradations of the nucleophilicity exist that are essentially independent of the substrate. What are the causes behind the recurring gradation of this nucleophilicity series? Nucleophilicity obviously measures the ability of the nucleophile to make an electron pair available to the electrophile (i.e., the alkylating agent or the epoxide).With this as the basic idea, the experimentally observable nucleophilicity gradations can be interpprete as follows. • Within a group of nucleophiles that attack at the electrophile with the same atom, the nucleophilicity decreases with decreasing basicity of the nucleophile (Figure 2.1). Decreasing basicity is equivalent to decreasing affinity of an electron pair for a proton, which to a certain extent, is a model electrophile for the electrophiles of SN reactions. • This parallel between nucleophilicity and basicity can be reversed by steric effeccts Less basic but sterically unhindered nucleophiles therefore have a higher nucleophilicity than strongly basic but sterically hindered nucleophiles (Figure 2.2). This is most noticeable in reactions with sterically demanding alkylating agents or sterically demanding epoxides. Nucleophilicity Gradations OOOO R O ORO O R S O OO R S O OO R S O OO RO > HO > > >> ROH, H O >>> 2 Fig. 2.1. Nucleophilicity of O nucleophiles with different basicities. 2 Nucleophilic Substitution Reactions at the Saturated C Atom 46 2.3 Leaving Groups and the Quality of Leaving Groups In Figure 2.3 substructures have been listed in the order of their suitability as leaving groups in SN reactions. Substrates with good leaving groups are listed on top and substrrate with increasingly poor leaving groups follow. At the bottom of Figure 2.3 are RS > RO I > Br > Cl >> F RSH > ROHHO O H O > H2N NH2 H NH2 > B • Nucleophilicity decreases with increasing electronegativity of the attacking atom. This is true both in comparisons of atomic centers that belong to the same periio of the periodic table of the elements • and in comparisons of atomic centers from the same group of the periodic table: • The nucleophilicity of a given nucleophilic center is increased by attached heteroaatom that possess free electron pairs (-effect): The reason for this is the unavoidable overlap of the orbitals that accommodate the free electron pairs at the nucleophilic center and its neighboring atom. R N >> RO >> F 2 Et N >> Et O 3 2 RS >> Cl NEt NEt N N >> >> >> >> >> NLi NLi R O prim R OH prim R O sec R OH sec R O tert R OH tertNa Na Na Fig. 2.2. Nucleophilicity of N and O nucleophiles that are sterically hindered to different degrees. Rsec or tert OCR′ O Rtert OCR′ O R OH R OR′ R O PPh3 R OH R OR′ R OR′ LA R F R SR′(H),R SR′, O R SR′, OO R SR′2 R NR′2(H2), R NO2 ,R NR3 (H3) R P(OR′)2, O R PPh2 , O R PPh3 R CN HH Rtert OCR′ OH R OSCF3 O R OTf R OTs R OMs R OSOO Me R OSMe OO R I, R Br R Cl O Subst (Record holder; for R = allyl or benzyl ionic mechanism)Alkyl tosylate Alkyl mesylate Alkyl triflate ≡≡≡ O Good leaving groups: RHal and epoxides can be further activated with Lewis acids a leaving group in solvolyses in situ activation of the leaving group necessary very poor leaving group or not a leaving group Fig. 2.3. Leaving-group ability of various functional groups; LA Lewis acid. 2 Nucleophilic Substitution Reactions at the Saturated C Atom 48 substrates whose functional group is an extremely poor leaving group. In part the effeec of nucleophiles on substrates of the latter type does result in a reaction, but it is not an SN reaction. This is, for example, the case when the nucleophile abstracts an acidic proton in the a position to the functional group instead of replacing the functioona group. For example, SN reactions with ammonium salts, nitro compounds, sulfoxiides sulfones, sulfonium salts, phosphonic acid esters, phosphine oxides, and phosphooniu salts usually fail as a result of such a deprotonation. Another reaction competing with the substitution of a functional group by a nucleophile is an attack on the functional group by the nucleophile. For example, SN reactions of nitriles, phosphooni acid esters, and phosphonium salts often fail because of this problem. Alcohols, ethers, and carboxylic acid esters occupy an intermediate position. These compounds as such—except for the special cases shown in Figure 2.3—do not enter into any SN reactions with nucleophiles.The reason for this is that poor leaving groups would have to be released (OH, OR, O2CR; see below for details). However, these compounds can enter into SN reactions with nucleophiles when they are activated as oxonium ions, for example via a reversible protonation, via bonding of a Lewis acid (LA in Figure 2.3), or via a phosphorylation.Thus, upon attack by the nucleophile, bettte leaving groups (e.g., HOH, HOR, HO2CR, O“PPh3) can be released. Only special carboxylic acid esters and special ethers, namely epoxides, enter into SN reactions as such, that is, without derivatization to an oxonium ion (Figure 2.3, center). In carboxylic acid esters of secondary and tertiary alcohols, the carboxylate group O2CR can become a leaving group, namely in solvolyses (see below). With epoxides as the substrate, an alkoxide ion is also an acceptable leaving group. Its release, which is actuaall disadvantageous (see below) because of the high basicity, is in this case coupled with the compensating release of part of the 26 kcal/mol epoxide ring strain. Productdevellopmen control therefore makes this reaction path feasible. (Part of the epoxide strain is of course also released in the transition state of an SN reaction of an epoxide, which has been protonated or activated by a Lewis acid. Consequently, even in the presence of acids, epoxides react more rapidly than other ethers with nucleophiles.) What makes a leaving group good or bad in substrates that react with nucleophiles as alkylating agents? The Hammond postulate implies that a good leaving group is a stabilized species, not a high-energy species. Therefore good leaving groups are usualll weak bases, not strong bases. This can be rationalized as follows: A 1:1 mixture of a strong base with protons would be high in energy relative to the corresponding conjuggat acid. From this we can conclude that a mixture of a strongly basic leaving group with the product of an SN reaction is also relatively high in energy.Very basic leaving groups are produced relatively slowly according to Hammond. In other words, strong Brønsted bases are poor leaving groups; weak Brønsted bases are good leaving groups. The suitability of halide ions as leaving groups is predicted correctly based on this reasoning alone, where IBrClF. The trifluoromethanesulfonate anion (triflate anion) F3C¬SO3is for the same reason a far better leaving group than the p-toluenesulfonate anion (tosylate anion) Me¬C6H4¬SO3or the methanesulfonate anion (mesylate anion) H3C¬SO3. For this reason, HOH and ROH can leave protonnate alcohols or ethers as leaving groups, but neither the OHgroup (from alcohools nor the ORgroup (from ethers, except for epoxides, see above) can leave. 2.4 SN2 Reactions: Kinetic and Stereochemical Analysis—Substituent Effects on Reactivity 49 The lower the bond enthalpy of the bond between the C atom and the leaving group, the better the leaving group.This again follows from the Hammond postulate. For this reason as well, the suitability of the halide ions as leaving groups is predicted as IBrClF. Phosphoric acid derivatives (different from biochemistry!) and sulfuric acid derivatiive are not useful alkylating agents in organic chemistry. Exceptions are dimethyl sulfate and diethyl sulfate, which can be obtained commercially, as well as five-membeere cyclic sulfates.These compounds contain two transferable alkyl groups. But becaaus of the mechanism, the second alkyl group is transferred more slowly than the first one, if it is transferred at all. For these reasons, sulfates are not popular alkylatiin agents in organic synthesis. Furthermore, they do not even transfer the first alkyl moiety more rapidly than the alkyl sulfonates and alkyl halides ranked at the top in Figure 2.3. 2.4 SN2 Reactions: Kinetic and Stereochemical Analysis—Substituent Effects on Reactivity 2.4.1 Energy Profile and Rate Law for SN2 Reactions: Reaction Order An SN2 reaction refers to an SN reaction in which the nucleophile and the alkylating agent are converted into the substitution product in one step, that is, via one transition state (Figure 2.4). Do you remember the definition of an elementary reaction (Section 1.7.1)? The SN2 reaction is an elementary reaction. Recognizing this is a prerequisite for deriving the Nu X Nu R X R+ + k Fig. 2.4. Energy profile and rate law for SN2 reactions. B Reaction coordinate E Ea Nu Nu Nu Nu R + R X + X R R X where = exp( /) A RT k E– a dt d k = (2.1) (2.2) 2 Nucleophilic Substitution Reactions at the Saturated C Atom 50 Rate laws establish a relationship between • the change in the concentration of a product, an intermediate, or a starting material as a function of time, on the one hand • and the concentrations of the starting material(s) and possibly the catalyst • as well as the rate constants of the elementary reactions that are involved in the overall reactiion on the other hand. By “gross reaction rate” one understands either a product formation rate d[producct]dt or a starting material consumption rate d[starting material]/dt. The following applies unless the stoichiometry requires an additional multiplier: (2.3) With the help of the rate laws that describe the elementary reactions involved, it is possible to derive Equation 2.4: rate constantsER} (2.4) where the subscript ER refers to the elementary reactions participating in the overall reaction. If the right-hand side of Equation 2.4 does not contain any sums or differencces the sum of the powers of the concentration(s) of the starting material(s) in this expression is called the order m of the reaction. It is also said that the reaction is of the mth order. A reaction of order m 1 is a first-order reaction, or unimolecular.A reaction of order m 2 (or 3) is a second-(or third-) order reaction or a bimoleculla (or trimolecular) reaction. A reaction of order m, where m is not an integer, is a reaction of a mixed order. The rate laws for elementary reactions are especially easy to set up. The recipe for this is The rate of product formation or starting material consumption is equal to the produuc of the rate constant k for this elementary reaction and the concentration of all starting materials involved, including any catalyst. It turns out that all elementary reacttion are either first-or second-order reactions. d3starting material1s2 of the elementary reaction4 dt d3product of an elementary reaction4 dt d3final product4 dt f 53starting material1s2 and optionally catalyst4, d3final product4 dt d3starting material1s24 dt Side Note 2.1 Rate Laws rate law for the SN2 reaction because the rate law for any elementary reaction can be written down immediately. 2.4 SN2 Reactions: Kinetic and Stereochemical Analysis—Substituent Effects on Reactivity 51 Because the reactions we consider in this section are single-step and therefore elemenntar reactions, the rate law specified in Section 2.3 as Equation 2.1 is obtained for the rate of formation of the substitution product Nu¬R. It says that these reactions are bimolecular substitutions. They are consequently referred to as SN2 reactions. The bimolecularity makes it possible to distinguish between this type of substitution and SN1 reactions, which we will examine in Section 2.5: for a given concentration of the substrate, an increased concentration of the nucleophile increases the rate of formatiio of the SN2 product according to Equation 2.1 but not the rate of formation of the SN1 product(cf. Equation 2.9 in Section 2.5.1). The rate constant of each elementary reaction is related to its activation energy Ea by the Arrhenius equation. This of course also holds for the rate constant of SN2 reacttion (see Equation 2.2 in Figure 2.4). 2.4.2 Stereochemistry of SN2 Substitutions In sophomore organic chemistry you most likely heard that SN2 reactions take place stereoselectively. Let us consider Figure 2.5 as an example: the attack by potassium acettat on the trans-tosylate A gives exclusively the cyclohexyl acetate cis-B. No trans-isomme is formed. In the starting material, the leaving group is equatorial and the C¬H bond at the attacked C atom is axial. In the substitution product cis-B the acetate is axial and the adjacent H atom is equatorial. Thus a 100% inversion of the configuratiio has taken place in this SN2 reaction. This is also true for all other SN2 reactions investigated stereochemically. Fig. 2.5. Proof of the inversion of configuration at the attacked C atom in an SN2 reaction. B H OTs tert-B tert-B tert-B u O O O H u O O H O u –K OTs trans-A cis-B trans-B K but no The reason for the inversion of configuration is that SN2 reactions take place with a backside attack by the nucleophile on the bond between the C atom and the leaviin group. In the transition state of the SN2 reaction, the attacked C atom has five bonds. The three substituents at the attacked C atom not participating in the SN reactiio and this C atom itself are for a short time located in one plane: Nu X a b c X c ab Nu Nu c a b X + + δ δ 2 Nucleophilic Substitution Reactions at the Saturated C Atom 52 The SN2 mechanism is casually also referred to as an “umbrella mechanism.”The nucleoophil enters in the direction of the umbrella handle and displaces the leaving group, which was originally lying above the tip of the umbrella. The geometry of the transitiio state corresponds to the geometry of the umbrella, which is just flipping over. The geometry of the substitution product corresponds to the geometry of the flipped-over umbrella.The former nucleophile is located at the handle of the flipped-over umbrella. 2.4.3 A Refined Transition State Model for the SN2 Reaction; Crossover Experiment and Endocyclic Restriction Test Figure 2.6 shows several methylations, which in each case take place as one-step SN reactions. The nucleophile is in each case a sulfonyl anion; a methyl(arenesulfonate) reacts as electrophile. The experiments from Figure 2.6 were carried out to clarify whether these methylations take place inter-or intramolecularly. In experiment 1 the perprotio-sulfonyl anion [H6]-A reacts to form the methylated perprotio-sulfone [H6]-B. It is not known whether this is the result of an intra-or an intermolecular SN reaction. In experiment 2 of Figure 2.6, the sulfonyl anion [D6]-A, which is perdeuterated in both methyl groups, reacts to form the hexadeuterated methylsulfone [D6]-B. Even this result does not clarify whether the methylation is intrraor intermolecular. An explanation is not provided until the third experiment in Figure 2.6, a so-called crossover experiment. The purpose of every crossover experiment is to determine whether reactions take place intra-or intermolecularly. In a crossover experiment two substrates differing from each other by a double substituent variation are reacted as a mixture. This substrate mixture is subjected to precisely the same reaction conditions in the crossover experimmen that the two individual substrates had been exposed to in separate experiments. This double substituent variation allows one to determine from the structures of the reaction products their origin, i.e., from which parts of which starting materials they were formed (see below for details). The product mixture is then analyzed. There are two possible outcomes. It can contaai nothing other than the two products that were already obtained in the individual experiments. In this case, each substrate would have reacted only with itself.With the substrate mixture of the crossover experiment, this is possible only for an intramoleculla reaction. The product mixture of a crossover experiment could alternatively consist of four compounds.Two of them could not have arisen from the individual experiments. They could have been produced only by “crossover reactions” between the two componeent of the mixture. A crossover reaction of this type can only be intermolecular. In the third crossover experiment of Figure 2.6, a 1:1 mixture of the sulfonyl anions [H6]-A and [D6]-A was methylated. The result did not correspond to the sum of the individual reactions. Besides a 1:1 mixture of the methylsulfone [H6]-B obtained in experiimen 1 and the methylsulfone [D6]-B obtained in experiment 2, a 1:1 mixture of the two crossover products [H3D3]-B and [D3H3]-B was isolated, in the same yield. The fact that both [H3D3]-B and [D3H3]-B occurred proves that the methylation was intermolecular.The crossover product [H3D3]-B can only have been produced because a CD3 group was transferred from the sulfonyl anion [D6]-A to the deuterium-free sulfonyl anion [H6]-A. The crossover product [D3H3]-B can only have been produced B 2.4 SN2 Reactions: Kinetic and Stereochemical Analysis—Substituent Effects on Reactivity 53 because a CH3 group was transferred from the sulfonyl anion [H6]-A to the deuteriumcontaainin sulfonyl anion [D6]-A. The intramolecular methylation of the substrate of Figure 2.6, which was not obserrved would have had to take place through a six-membered cyclic transition state. In other cases cyclic six-membered transition states of intramolecular reactions are so favored that intermolecular reactions usually do not occur. It simply takes too long for CCHD33 OO SSSS OO OO CCHH33 OO OO CCDH33 OO SSSS OO OO CCDD33 OO OO CH3 O SS O O CH3 O O CD3 O SS O O CD3 O O Experiment 1 Experiment (Crossover experiment)3 Experiment 2 ++ + 25% [H ]-6 B 25% [H D ]-3 3 B 25% [D ]-6 B 25% [D H ]-3 3 B [H ]-+ [D ]-6 6 A A (50 : 50 mixture) [H ]-6 A [D ]-6 A Fig. 2.6. Determination of the mechanism of one-step SN reactions on methyl (arenesulfonates): intra-or intermolecularity. 2 Nucleophilic Substitution Reactions at the Saturated C Atom 54 the two reaction partners to find each other.Why then is a cyclic transition state not able to compete in the SN reactions in Figure 2.6? The conformational degrees of freedom of cyclic transition states are considerably limited or “restricted” relative to the conformational degrees of freedom of noncyclic transition states (cf. the fewer conformational degrees of freedom of cyclohexane vs n-hexane). Mechanistic investigations of this type are therefore also referred to as endocyycli restriction tests. They prove or refute in a very simple way certain transition state geometries because of this conformational restriction. The endocyclic restriction imposes limitations of the conceivable geometries on cyclic transition states. These geometries do not comprise all the possibilities that could be realized for intermoleculla reactions proceeding through acyclic transition states. In the SN reactions of Figure 2.6, the endocyclic restriction would therefore impose a geometry in an intramolecular substitution that is energetically disfavored relative to the geometry that can be obtained in an intermolecular substitution. As shown on the right in Figure 2.7, in an intramolecular substitution the reason for this is that the nucleophile, the attacked C atom, and the leaving group cannot lie on a common axis. However, such a geometry can be realized in an intermolecular reaction (see Figure 2.7, left). From this, one concludes that in an SN2 reaction the approach path of the nucleophile must be collinear with the bond between the attached C atom and the leaving group. This approach path is preferred in order to achieve a transition state with optimum bonding interactions. Let us assume that in the transition state, the distance between the nucleophile and the attacked C atom and between the leaving group and this C atom are exactly the same. The geometry of the transition state would then corresppon precisely to the geometry of an umbrella that is just flipping over. The attacked C atom would be—as shown in Figure 2.7 (left)—sp2-hybridized and at the center of a trigonal bipyramid. The nucleophile and the leaving group would be bound to this C atom via bonds. Both would come about by overlap with one lobe of the 2pz AO. For this reason, a linear arrangement of the nucleophile, the attacked C atom, and the leaving group is preferred in the transition state of SN reactions. Figure 2.7 (right) shows that in a bent transition state of the SN reaction neither the nucleophile nor the leaving group can form similarly stable bonds by overlap with the 2pz AO of the attacked C atom. Because the orbital lobes under consideration are not parallel, both the Nu. . .Csp2 and the Csp2. . . leaving group bonds would be bent. Bent bonds are weaker than linear bonds because of the smaller orbital overlap. This is known from the special case of bent C¬C bonds (Figure 2.8) as encountered, for example, in the very strained C¬C bonds of cyclopropane. Bent bonds are also used in the “banana bond” model to describe the C“C double bond in olefins. (In this model, the double bond is represented by two bent single bonds between sp3-hybridized C atoms; cf. introduction to Chapter 3.) Both types of bent C¬C bonds are less stabbl than linear C¬C bonds, such as in ethane. 2.4.4 Substituent Effects on SN2 Reactivity How substituents in the alkylating agent influence the rate constants of SN2 reactions can be explained by means of the transition state model developed in Section 2.4.3.This model makes it possible to understand both the steric and the electronic substituent effects. B 2.4 SN2 Reactions: Kinetic and Stereochemical Analysis—Substituent Effects on Reactivity 55 Fig. 2.8. Bond enthalpy (BE) of linear (left) and bent (middle and right; cf. explanatory text) C¬C bonds. H H H H H H H H H H H H HH HH H H H HH H H H 82.6 kcal/mol 2 72.9 kcal/mol × 65.3 kcal/mol BE HH HH Fig. 2.7. Illustration of the intermolecular course of the SN reactions of Figure 2.6; energy profiles and associated transition state geometries. Intramolecular Substitution Linear transition state possible Bent transition state enforced Ar′SO2H Ar C HH H O Ar′′SO2 CO S Ar′SO2 O O HHH H Ar′SO2 Ar H H H H Ar′′SO2 Csp2 O S O OO H Csp2 H H H Ar′SO2 Intermolecular Substitution S -Product N S -Product N or intermolecular Reaction coordinate Reaction coordinate intramolecular E Ea (linear) Ea (bent) When an SN2 alkylating agent is attacked by a nucleophile, the steric interactions become larger in the vicinity of the attacked C atom (Figure 2.9). On the one hand, the inert substituents come closer to the leaving group X. The bond angle between these substituents and the leaving group decreases from approximately the tetrahedral angle 10928to approximately 90. On the other hand, the attacking nucleophile approaache the inert substituents until the bond angle that separates it from them is also approximately 90.The resulting increased steric interactions destabilize the transition state. Consequently, the activation energy Ea increases and the rate constant decreaases It should be noted that this destabilization is not compensated for by the simultaaneou increase in the bond angle between the inert substituents from approximattel the tetrahedral angle to approximately 120. This has two consequences: kSN2 2 Nucleophilic Substitution Reactions at the Saturated C Atom 56 Besides these rate-reducing steric substituent effects, in SN2 reactions there is a rateincreeasin electronic substituent effect. It is due to facilitation of the rehybridization • The SN2 reactivity of an alkylating agent decreases with an increasing number of the alkyl substituents at the attacked C atom. In other words, branching at the C atom of the alkylating agent reduces its SN2 reactivity. This reduces the reactivvit so much that tertiary C atoms can no longer be attacked according to an SN2 mechanism at all: Nu + Me Et X X X X iPr tert-Bu kSN2, rel = 30 1 0.025 tiny Fig. 2.9. Steric effects on SN2 reactivity: substituent compression in the transition state. X c b a S -Product N Nu X ba c + Nu δδ three 109°28´ interactions six 90° interactions Reaction coordinate E Tendencies and Rules Generally stated, for SN2 reactivity we have k(Me¬X) k(Rprim¬X) k(Rsec¬X); k(Rtert¬X) ≈ 0 (unit: 1 mol1 s1). • The SN2 reactivity of an alkylating agent decreases with an increase in size of the alkyl substituents at the attacked C atom. In other words, branching in the alkylattin agent reduces its SN2 reactivity. This reduces the reactivity so much that a C atom with a tertiary C atom in the position can no longer be attacked at all according to an SN2 mechanism: Generally stated, for SN2 reactivity we have k(MeCH2¬X) k(RprimCH2¬ X) k(RsecCH2¬X); k(RtertCH2¬X) ≈ 0 (unit: 1 mol1 s1). Nu + MeCH2 EtCH2 X X X X iPrCH2 tert-BuCH2 1 0.4 0.03 tiny kSN2, rel = 2.5 SN1 Reactions: Kinetic and Stereochemical Analysis; Substituent Effects on Reactivity 57 Nu + Nu δ δ X X c d b a b c a d conjugative stabilization by overlap with the parallel antibonding MO of the π system ⇒ Fig. 2.10. Electronic effects on SN2 reactivity: conjugative stabilization of the transition state by suitably aligned unsaturated substituents. Nu + MeCH2 vinylCH2 X X X PhCH2 kSN2, rel = 1 40 120 B of the attacked C atom from sp3 to sp2 (Figure 2.10). This effect is exerted by unsaturaate substituents bound to the attacked C atom. These include substituents, such as alkenyl, aryl, or the C“O double bond of ketones or esters.When it is not prevented by the occurrence of strain, the p-electron system of these substituents can line up in the transition state parallel to the 2pz AO at the attacked C atom.This orbital thereby becomes part of a delocalized p-electron system. Consequently, there is a reduction in energy and a corresponding increase in the SN2 reaction rate. Allyl and benzyl halides are therefore just as good alkylating agents as methyl iodide: Because of the substituent effect just described, allyl and benzyl halides generally react with nucleophiles according to an SN2 mechanism. This occurs even though the SN1 reactivity of allyl and benzyl halides is higher than that of nonconjugated alkylatiin agents (see Section 2.5.4). a-Halogenated ketones and a-halogenated acetic acid esters also react with nucleophiile according to the SN2 mechanism. However, for them the alternative of an SN1 mechanism is completely out of the question. This is because it would have to take place via a carbenium ion, which would be extremely destabilized by the strongly electrronwithdrawing acyl or alkoxyacyl substituent. 2.5 SN1 Reactions: Kinetic and Stereochemical Analysis; Substituent Effects on Reactivity 2.5.1 Energy Profile and Rate Law of SN1 Reactions; Steady State Approximation Substitution reactions according to the SN1 mechanism take place in two steps (Figuur 2.11). In the first and slower step, heterolysis of the bond between the C atom and the leaving group takes place. A carbenium ion is produced as a high-energy, and con-2 Nucleophilic Substitution Reactions at the Saturated C Atom 58 sequently short-lived, intermediate. In a considerably faster second step, it combines with the nucleophile to form the substitution product Nu¬R. In a substitution according to the SN1 mechanism, the nucleophile does not actively attack the alkylating agent. The reaction mechanism consists of the alkylating agent dissociating by itself into a carbenium ion and the leaving group. Only then does the nucleophile change from a “spectator” into an active participant. Specifically, it interceept the carbenium ion to form the substitution product. What does the rate law for the substitution mechanism of Figure 2.11 look like? The rate of formation of the substitution product Nu¬R in the second step can immediattel be written as Equation 2.5 because this step represents an elementary reaction. Here, as in Figure 2.11, khet and kattack designate the rate constants for the heterolysis and the nucleophilic attack, respectively. However, Equation 2.5 cannot be correlated with experimentally determined data. The reason for this is that the concentration of the carbenium ion intermediate appeear in it. This concentration is extremely small during the entire reaction and consequuentl cannot be measured. However, one cannot set it equal to zero, either. In that case, Equation 2.5 would mean that the rate of product formation is also equal to zero and thus that the reaction does not take place at all. Accordingly, we must have a bettte approximation, one that is based on the following consideration: d [Nu R] dt = kattack [R ] [Nu ] kattack [R ] [Nu ] d [R dt = 0 within the limits of the Bodenstein approximation ] = khet [R X] (2.6) (2.5) (2.7) Fig. 2.11. Mechanism and energy profile of SN1 reactions: Ea,het designates the activation energy of the heterolysis, khet and kattack designate the rate constants for the heterolysis and the nucleophilic attack on the carbenium ion, respectively. Reaction coordinate E Nu Nu Nu X Ea, het + R + R + X R + X khet kattack 2.5 SN1 Reactions: Kinetic and Stereochemical Analysis; Substituent Effects on Reactivity 59 Equipped with the Bodenstein principle, let us now continue the derivation of the rate law for SN reactions that take place according to Figure 2.11. The completely inadeqquat approximation [carbenium ion] 0 must be replaced by Equation 2.6. Let us now set the left-hand side of Equation 2.6, the change of the carbenium ion concentrratio with time, equal to the difference between the rate of formation of the carbenniu ion and its consumption. Because the formation and consumption of the carbenniu ion are elementary reactions, Equation 2.7 can immediately be set up. If we now set the right-hand sides of Equations 2.6 and 2.7 equal and solve for the concentraatio of the carbenium ion, we get Equation 2.8.With this equation, it is possible to rewrite the previously unusable Equation 2.5 as Equation 2.9. The only concentration term that appears in this equation is the concentration of the alkylating agent. In contrras to the carbenium ion concentration, it can be readily measured. The rate law of Equation 2.9 identifies the SN reactions of Figure 2.11 as unimolecuula reactions. They are therefore referred to as SN1 reactions. The rate of product formation thus depends only on the concentration of the alkylating agent and not on the concentration of the nucleophile. This is the key experimental criterion for distinguisshin the SN1 from the SN2 mechanism. From Equation 2.9 we can also derive the following: the SN1 product is produced with the rate constant khet of the first reaction step. Thus the rate of product formatiio does not depend on the rate constant kattack of the second reaction step. In a multisste reaction, a particular step may be solely responsible for the rate of product formattion This is referred to as the rate-determining step. In the SN1 reaction, this step is the heterolysis of the alkylating agent. The energy profile of Figure 2.11 shows that here—as everywhere else—the rate-determining step of a multistep sequence is the step in which the highest activation barrier must be overcome. Equation 2.9 can also be interpreted as follows. Regardless of which nucleophile en-[Nu ] ⇒ [R ] d [Nu R] dt == [R X] kattack khet • [R X] khet • Equation 2.8 in Equation 2.5 ⇒ (2.8) (2.9) The concentration of an intermediate in a multistep reaction is always very low when it reacts faster than it is produced. If this concentration is set equal to zero in the derivation of the rate law, unreasonable results may be obtained. In such a cas