Substitution and Elimination Reactions PDF

Chapter 9 Substitution and Elimination Reactions Paula Yurkanis Bruice...

Chapter 9 Substitution and Elimination Reactions Paula Yurkanis Bruice University of California, Santa Barbara © 2017 Pearson Education, Inc.  The Families of Group II © 2017 Pearson Education, Inc.  The Compounds in Group II Are Electrophiles All of the compounds in Group II have an electron-withdrawing atom or group that is attached to an sp3 carbon. © 2017 Pearson Education, Inc.  Because Group II Compounds Are Electrophiles, They React with Nucleophiles substitution reaction—the electronegative group is replaced by another group. elimination reaction—the electronegative group is eliminated along with a hydrogen. © 2017 Pearson Education, Inc.  Alkyl Halides the first of the families in Group II Alkyl halides have relatively good leaving groups. © 2017 Pearson Education, Inc.  A Substitution Reaction more precisely called a nucleophilic substitution reaction because the atom replacing the halogen is a nucleophile © 2017 Pearson Education, Inc.  What is the Mechanism of the Reaction? The kinetics of a reaction—the factors that affect the rate of the reaction—help determine the mechanism. The Rate Law The rate law tells us what molecules are involved in the transition state of the rate-limiting step. an SN2 reaction substitution nucleophilic bimolecular © 2017 Pearson Education, Inc.  Relative Rates of an SN2 Reaction © 2017 Pearson Education, Inc.  Inverted Configuration If the halogen is bonded to an asymmetric center, the product will have the inverted configuration. © 2017 Pearson Education, Inc.  Summary of the Experimental Evidence for the Mechanism of an SN2 Reaction 1. Both the alkyl halide and the nucleophile are in the transition state of the rate-limiting step. 2. The relative rate: primary alkyl halide > secondary alkyl halide > tertiary alkyl halide 3. The configuration of the product is inverted compared to the configuration of the reacting chiral alkyl halide. © 2017 Pearson Education, Inc.  The Mechanism back-side attack © 2017 Pearson Education, Inc.  Why Back-Side Attack? © 2017 Pearson Education, Inc.  Why Bimolecular? © 2017 Pearson Education, Inc.  Why Do Methyl Halides React the Fastest and Tertiary the Slowest? steric hindrance © 2017 Pearson Education, Inc. Steric Hindrance Decreases the Rate © 2017 Pearson Education, Inc.  Both are Primary Alkyl Halides, but They React at Different Rates © 2017 Pearson Education, Inc.  Although it is Primary, it Reacts Very Slowly © 2017 Pearson Education, Inc.  Why the Configuration of the Product is Inverted © 2017 Pearson Education, Inc.  The Weakest Base is the Best Leaving Group © 2017 Pearson Education, Inc.  The Rate of an SN2 Reaction is Affected by the Leaving Group © 2017 Pearson Education, Inc.  Bases and Nucleophiles A base shares its lone pair with a proton. A nucleophile shares its lone pair with an atom other than a proton. © 2017 Pearson Education, Inc.  Base Strength and Nucleophile Strength A negatively charged atom is a stronger base and a better nucleophile than the same atom that is neutral. © 2017 Pearson Education, Inc.  Base Strength and Nucleophile Strength If atoms are in the same row, the strongest base is the best nucleophile. © 2017 Pearson Education, Inc.  Polarizability The larger the atom, the more polarizable it is (can move more freely toward a positive charge). © 2017 Pearson Education, Inc.  Polarizability versus Nucleophilicity Does the greater polarizability of the larger atoms make up for their decreased basicity that makes them poorer nucleophiles? No, if they are in an aprotic polar solvent. I− is still the poorest nucleophile. Yes, if they are in a protic polar solvent. I− is now the best nucleophile. © 2017 Pearson Education, Inc.  Solvents nonpolar solvents: hexane, benzene Negatively charged species cannot dissolve in nonpolar solvents. protic polar solvents: have a hydrogen attached to an O (water, alcohols) aprotic polar solvents: do not have a hydrogen attached to an O © 2017 Pearson Education, Inc.  Base Strength and Nucleophile Strength The strongest base is the best nucleophile unless they differ in size and they are in a protic polar solvent. © 2017 Pearson Education, Inc.  Why Do Protic Polar Solvents Make the Strongest Bases the Poorest Nucleophiles? F− is the best nucleophile in an aprotic polar solvent. I− is the best nucleophile in a protic polar solvent. Strong bases form strong ion–dipole interactions. The ion–dipole interactions must be broken before the nucleophile can react. © 2017 Pearson Education, Inc.  Aprotic Polar Solvents They can solvate a cation (+) better than they can solvate an anion (−). © 2017 Pearson Education, Inc.  Steric Hindrance Decreases Nucleophilicity tert-Butoxide ion is a stronger base than ethoxide ion, but it is a poorer nucleophile. Its large size makes it difficult for it to approach the back side of the carbon. © 2017 Pearson Education, Inc.  SN2 Reactions Can Be Used to Make a Variety of Compounds The reactions are irreversible because a weak base cannot displace a strong base. © 2017 Pearson Education, Inc.  Synthesizing an Amine K2CO3 makes the solution basic so that the amine will exist in its basic form. © 2017 Pearson Education, Inc.  A Substitution Reaction a tertiary alkyl halide and a poor nucleophile The reaction is surprisingly fast, so it must be taking place by a different mechanism. © 2017 Pearson Education, Inc.  The Rate Depends Only on the Concentration of the Alkyl Halide The Rate Law Only the alkyl halide is in the transition state of the rate-limiting step. an SN1 reaction substitution nucleophilic unimolecular © 2017 Pearson Education, Inc.  Solvolysis Reaction Most SN1 reactions are solvolysis reactions; the solvent is the nucleophile. © 2017 Pearson Education, Inc.  The Mechanism The leaving group departs before the nucleophile approaches. The slow step is carbocation formation. © 2017 Pearson Education, Inc.  The Reaction Coordinate Diagram © 2017 Pearson Education, Inc.  Substitution Reactions of Alkyl Halides Primary alkyl halides undergo only SN2 reactions. Secondary alkyl halides undergo only SN2 reactions. Tertiary alkyl halides undergo only SN1 reactions. © 2017 Pearson Education, Inc.  The Product is a Pair of Enantiomers If the halogen is bonded to an asymmetric center, the product will be a pair of enantiomers. © 2017 Pearson Education, Inc.  Why a Pair of Enantiomers? © 2017 Pearson Education, Inc.  Most SN1 Reactions Lead to Partial Racemization Generally more inverted product is formed, because the front side is partially blocked. © 2017 Pearson Education, Inc.  Summary of the Experimental Evidence for the Mechanism of an SN1 Reaction 1. The rate of the reaction depends only on the concentration of the alkyl halide. 2. Tertiary alkyl halides, but not primary or secondary alkyl halides, undergo SN1 reactions. 3. If the halogen is attached to an asymmetric center, the product will be a pair of enantiomers. © 2017 Pearson Education, Inc.  The Weakest Base is the Best Leaving Group © 2017 Pearson Education, Inc.  Comparing SN2 and SN1 Reactions © 2017 Pearson Education, Inc.  Rate Law for the Reaction of an Alkyl Halide with a Nucleophile primary alkyl halides and methyl halides only SN2 They cannot form carbocations. secondary alkyl halides only SN2 Carbocation formation is too slow to make up for the large concentration of the nucleophile in a solvolysis reaction. tertiary alkyl halides only SN1 They cannot undergo back-side attack. © 2017 Pearson Education, Inc.  Alkyl Halides Undergo Substitution and Elimination Reactions In an elimination reaction, a halogen is removed from one carbon and a hydrogen is removed from an adjacent carbon. A double bond is formed between the two carbons from which the atoms were removed. © 2017 Pearson Education, Inc.  An E2 Reaction The alkyl halide and the base are in the transition state of the rate-limiting step. © 2017 Pearson Education, Inc.  The Mechanism for an E2 Reaction © 2017 Pearson Education, Inc.  The Halogen Comes off the Alpha Carbon; the Hydrogen Comes off the Beta Carbon dehydrohalogenation © 2017 Pearson Education, Inc.  An E2 Reaction is Regioselective The major product is the most stable alkene. The most stable alkene is generally obtained by removing a hydrogen from the beta carbon that is bonded to the fewest hydrogens. © 2017 Pearson Education, Inc.  The More Stable Alkene Has the More Stable Transition State The major product is the more stable alkene. © 2017 Pearson Education, Inc.  Alkene-Like Transition State © 2017 Pearson Education, Inc.  More E2 Reactions © 2017 Pearson Education, Inc.  Limitations of Zaitsev’s Rule Zaitsev’s rule leads to the more substituted alkene. If there is conjugation, the more substituted alkene might not be the more stable alkene. © 2017 Pearson Education, Inc.  Limitations of Zaitsev’s Rule If the alkyl halide and the base are both bulky, the base will remove the more accessible hydrogen, which will lead to formation of the less stable product. © 2017 Pearson Education, Inc.  The Steric Properties of the Base Affect the Product Distribution © 2017 Pearson Education, Inc.  Alkyl Fluorides Form the Less Stable Alkene The major product of the E2 reaction of an alkyl fluoride is the less stable alkene. © 2017 Pearson Education, Inc.  The Transition State is Carbanion-Like Because the leaving group is poor, the transition state is carbanion-like. © 2017 Pearson Education, Inc.  Carbocation and Carbanion Stability © 2017 Pearson Education, Inc.  The Leaving Group Affects the Product Distribution © 2017 Pearson Education, Inc.  Relative Reactivities of Alkyl Halides in an E2 Reaction © 2017 Pearson Education, Inc.  An E1 Reaction Only the alkyl halide is in the transition state of the rate-limiting step. © 2017 Pearson Education, Inc.  The Mechanism for an E1 Reaction © 2017 Pearson Education, Inc.  How Does a Weak Base Remove a Proton from an sp3 Carbon? 1. The presence of the positive charge greatly reduces the pKa. 2. Hyperconjugation weakens the C—H bond by draining electron density. © 2017 Pearson Education, Inc.  An E1 Reaction is Regioselective like an E2 reaction The major product is the more stable alkene. The more stable alkene is obtained by removing a hydrogen from the beta carbon that is bonded to the fewest hydrogens. © 2017 Pearson Education, Inc.  The More Stable Alkene is the Major Product The transition state leading to the more stable alkene is more stable. © 2017 Pearson Education, Inc.  The Weakest Base is the Best Leaving Group © 2017 Pearson Education, Inc.  Competition between E2 and E1 Reactions Primary and secondary alkyl halides undergo E2 reactions. Tertiary alkyl halides undergo both E2 and E1 reactions. rate = k2[alkyl halide] [base] + k1[alkyl halide] For tertiary alkyl halides that can undergo both E2 and E1 reactions: An E2 reaction is favored by a high concentration of a strong base. An E1 reaction is favored by a low concentration of a weak base. © 2017 Pearson Education, Inc.  Anti Elimination is Preferred Anti requires the molecule to be in a staggered conformation. Back-side attack achieves the best overlap of interacting orbitals. Anti avoids repulsion of the electron-rich base with the electron-rich leaving group. © 2017 Pearson Education, Inc.  An E2 Reaction is Stereoselective The alkene with the bulkiest groups on opposite sides of the double is formed in greater yield, because it is the more stable alkene. © 2017 Pearson Education, Inc.  Anti Elimination © 2017 Pearson Education, Inc.  The More Stable Product is Easier to Form © 2017 Pearson Education, Inc.  The Major Product of an E2 Reaction (the largest groups are on opposite sides) © 2017 Pearson Education, Inc.  When Only One Hydrogen is Bonded to the β-Carbon, the Major Product of an E2 Reaction Depends on the Structure of the Alkyl Halide © 2017 Pearson Education, Inc.  When Only One Hydrogen is Bonded to the β-Carbon, the Major Product of an E1 Reaction is Still the More Stable Alkene © 2017 Pearson Education, Inc.  Summary of the Stereochemistry of Substitution and Elimination Reactions © 2017 Pearson Education, Inc.  E2 Elimination from Six-Membered Rings Both groups being eliminated must be in axial positions. © 2017 Pearson Education, Inc.  Both H and Cl Must Be Axial Therefore, only the less stable conformer undergoes an elimination reaction. © 2017 Pearson Education, Inc.  Rate Constant for the Elimination Reaction k′Keq The value of Keq depends on whether the reaction takes place through the more stable conformer or through the less stable conformer. Keq is large Keq is small © 2017 Pearson Education, Inc.  The Reaction is Fast Elimination occurs through the more stable conformer. © 2017 Pearson Education, Inc.  The Reaction is Slow Elimination occurs through the less stable conformer. © 2017 Pearson Education, Inc.  E1 Elimination from Six-Membered Rings The H and Cl do not have to be in axial positions because the reaction is not concerted. © 2017 Pearson Education, Inc.  SN2 and E2 Reactions of Alkyl Halides © 2017 Pearson Education, Inc.  Under SN2/E2 Conditions Primary Alkyl Halide = Primarily Substitution © 2017 Pearson Education, Inc.  Steric Hindrance Favors Elimination The nucleophile is hindered from getting to the back side of the carbon. © 2017 Pearson Education, Inc.  Under SN2/E2 Conditions Secondary Alkyl Halide = Substitution and Elimination Substitution is favored by a weak base. Elimination is favored by a strong base. © 2017 Pearson Education, Inc.  Bulky Bases Favor Elimination © 2017 Pearson Education, Inc.  Although They Are Neutral Bases, They Are Strong Bases © 2017 Pearson Education, Inc.  A High Temperature Favors Elimination Why? Because elimination has a greater ∆S‡. Elimination forms three products. Substitution forms two products. © 2017 Pearson Education, Inc.  Under SN2/E2 Conditions Tertiary Alkyl Halide = Only Elimination © 2017 Pearson Education, Inc.  Under SN1/E1 Conditions Tertiary Alkyl Halides Undergo Substitution and Elimination © 2017 Pearson Education, Inc.  The Product a Tertiary Alkyl Halide Forms Depends on Base Strength weak base: SN1 and E1 with substitution favored strong base: only elimination (E2) © 2017 Pearson Education, Inc.  Summary of the Products Obtained from Substitution and Elimination Reactions © 2017 Pearson Education, Inc.  Benzyl and Phenyl Groups © 2017 Pearson Education, Inc.  Benzylic and Allylic Halides Undergo SN2 Reactions Unless benzylic and allylic halides are tertiary, they readily undergo SN2 reactions. © 2017 Pearson Education, Inc.  Benzylic and Allylic Halides Undergo SN1 Reactions Benzylic and allylic halides also undergo SN1 reactions because they form relatively stable carbocations. © 2017 Pearson Education, Inc.  The SN1 Reaction of an Allylic Halide Can Form Two Products © 2017 Pearson Education, Inc.  Benzylic and Allylic Halides Undergo E2 Reactions The product is relatively stable because it has conjugated double bonds. © 2017 Pearson Education, Inc.  Benzylic and Allylic Halides Undergo E1 Reactions Benzylic and allylic halides also undergo E1 reactions because they form relatively stable carbocations. © 2017 Pearson Education, Inc.  Vinylic and Aryl Halides Cannot Undergo SN2 Reactions © 2017 Pearson Education, Inc.  Vinylic and Aryl Halides Cannot Undergo SN1 or E1 Reactions The carbocation is too unstable to be formed. © 2017 Pearson Education, Inc.  A Vinylic Halide Can Undergo an E2 Reaction A strong base (−NH2) is required. © 2017 Pearson Education, Inc.  Solvation Polar solvents stabilize charges. © 2017 Pearson Education, Inc.  If a Reactant is Charged, Increasing the Polarity of the Solvent Decreases the Rate © 2017 Pearson Education, Inc.  If the Reactants are Neutral, Increasing the Polarity of the Solvent Increases the Rate © 2017 Pearson Education, Inc.  How the Solvent Affects the Rate of the SN1 and E1 Reactions of an Alkyl Halide If the reactants are neutral, the charge on the reactants is less than the charge on the transition state. Increasing the polarity of the solvent stabilizes the transition state more than it stabilizes the reactant—so the reaction is faster. © 2017 Pearson Education, Inc.  The Rate of an SN1 Reaction of an Alkyl Halide Increases as the Polarity of the Solvent Increases © 2017 Pearson Education, Inc.  How the Solvent Affects the Rate of SN2 and E2 Reactions of Alkyl Halides If a reactant is charged, the charge on the reactants is more than the charge on the transition state. Increasing the polarity of the solvent stabilizes the reactants more than it stabilizes the transition state—so the reaction is slower. © 2017 Pearson Education, Inc.  What Solvent Should Be Used? an SN2 or E2 reaction of an alkyl halide with a charged nucleophile/base should be carried out in an aprotic polar solvent. an SN2 or E2 reaction of an alkyl halide with a neutral nucleophile/base should be carried out in a polar solvent. an SN1 or E1 reaction of an alkyl halide should be carried out in a polar solvent. © 2017 Pearson Education, Inc.  The Williamson Ether Synthesis making the alkoxide ion © 2017 Pearson Education, Inc.  Examples of the Williamson Ether Synthesis © 2017 Pearson Education, Inc.  The Williamson Ether Synthesis No ether is formed. The less hindered group should be provided by the alkyl halide. © 2017 Pearson Education, Inc.  Using Elimination Reactions to Synthesize Alkenes To synthesize an alkene, use the most hindered alkyl halide possible to maximize elimination and minimize substitution. © 2017 Pearson Education, Inc.  Strong Base E2 Weak Base E1 + SN1 The strength of the base affects the amount of the alkene formed. © 2017 Pearson Education, Inc.  Intermolecular versus Intramolecular SN2 Reactions © 2017 Pearson Education, Inc.  The Intramolecular Reaction is Favored When a Five- or Six-Membered Ring Can Be Formed © 2017 Pearson Education, Inc.  Designing a Synthesis © 2017 Pearson Education, Inc.  Designing a Synthesis © 2017 Pearson Education, Inc.  Designing a Synthesis © 2017 Pearson Education, Inc.  Designing a Synthesis © 2017 Pearson Education, Inc.