Chapter 6 Ionic Reactions Nucleophilic Substitution and Elimination Reactions of Alkyl Halides Created by Professor William Tam & Dr. Phillis Chang Copyright © 2014 by John Wiley & Sons, Inc. All rights reserved. About The Authors These PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang. Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem. Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew. © 2014 by John Wiley & Sons, Inc. All rights reserved. Table of Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. (hyperlinked) Alkyl Halides Nucleophilic Substitution Reactions Nucleophiles Leaving Groups Kinetics of a Nucleophilic Substitution Reaction: An SN2 Reaction A Mechanism for the SN2 Reaction Transition State Theory: Free-Energy Diagrams The Stereochemistry of SN2 Reactions The Reaction of tert-Butyl Chloride with Water: An SN1 Reaction A Mechanism for the SN1 Reaction Carbocations The Stereochemistry of SN1 Reactions Factors Affecting the Rates of SN1 and SN2 Reactions Organic Synthesis: Functional Group Transformations Using SN2 Reactions Elimination Reactions of Alkyl Halides The E2 Reaction The E1 Reaction How to Determine Whether Substitution or Elimination Is Favored Overall Summary © 2014 by John Wiley & Sons, Inc. All rights reserved. Table of Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. Alkyl Halides Nucleophilic Substitution Reactions Nucleophiles Leaving Groups Kinetics of a Nucleophilic Substitution Reaction: An SN2 Reaction A Mechanism for the SN2 Reaction Transition State Theory: Free-Energy Diagrams The Stereochemistry of SN2 Reactions The Reaction of tert-Butyl Chloride with Water: An SN1 Reaction A Mechanism for the SN1 Reaction Carbocations The Stereochemistry of SN1 Reactions Factors Affecting the Rates of SN1 and SN2 Reactions Organic Synthesis: Functional Group Transformations Using SN2 Reactions Elimination Reactions of Alkyl Halides The E2 Reaction The E1 Reaction How to Determine Whether Substitution or Elimination Is Favored Overall Summary © 2014 by John Wiley & Sons, Inc. All rights reserved. In this chapter we will consider: What groups can be replaced (i.e., substituted) or eliminated The various mechanisms by which such processes occur The conditions that can promote such reactions © 2014 by John Wiley & Sons, Inc. All rights reserved. 1. Alkyl Halides An alkyl halide has a halogen atom bonded to an sp3-hybridized (tetrahedral) carbon atom The carbon–chlorine and carbon– bromine bonds are polarized because the halogen is more electronegative than carbon © 2014 by John Wiley & Sons, Inc. All rights reserved. Iodine does not have a permanent dipole, but the bond is easily polarizable Iodine is a good leaving group due to its polarizability, i.e. its ability to stabilize a negative charge due to its large atomic size © 2014 by John Wiley & Sons, Inc. All rights reserved. C X X = Cl, Br, I Halogens are more electronegative than carbon © 2014 by John Wiley & Sons, Inc. All rights reserved. Different Types of Organic Halides Alkyl halides (haloalkanes) sp3 Attached to 1 carbon atom C Cl a 1o chloride Attached to 2 carbon atoms C C Attached to 3 carbon atoms C Br a 2o bromide © 2014 by John Wiley & Sons, Inc. All rights reserved. C C I a 3o iodide Vinyl halides (Alkenyl halides) sp2 X Aryl halides sp2 X benzene or aromatic ring Acetylenic halides (Alkynyl halides) sp X © 2014 by John Wiley & Sons, Inc. All rights reserved. sp C X 3 Alkyl halides sp2 X Prone to undergo Nucleophilic Substitutions (SN) and Elimination Reactions (E) (the focus of this Chapter) sp2 X sp X Different reactivity than alkyl halides, and do not undergo SN or E reactions © 2014 by John Wiley & Sons, Inc. All rights reserved. 2. Nucleophilic Substitution Reactions Nu + (nucleophile) The Nu⊖ donates an e⊖ pair to the substrate C X (substrate) The bond between C and LG breaks, giving both e⊖ from the bond to LG Nu C (product) The Nu⊖ uses its e⊖ pair to form a new covalent bond with the substrate C © 2014 by John Wiley & Sons, Inc. All rights reserved. + X (leaving group) The LG gains the pair of e⊖ originally bonded in the substrate Timing of The Bond Breaking & Bond Making Process Two types of mechanisms ● 1st type: SN2 (concerted mechanism) R HO Br C R R transition state (T.S.) © 2014 by John Wiley & Sons, Inc. All rights reserved. ● 2nd type: SN1 (stepwise mechanism) Step (1): R R (k 1 ) R C Br R C + Br slow R R r.d.s. k1 << Step (2) R R H (k 2 ) R C + H 2O R C O H fast R R fast © 2014 by John Wiley & Sons, Inc. All rights reserved. k2 and k3 3. Nucleophiles A reagent that seeks a positive center Nucleophile – “nucleus” “loving” “phile” – derived from the Greek word philia meaning “loving” © 2014 by John Wiley & Sons, Inc. All rights reserved. Has an unshared pair of e⊖ e.g.: HO , CH3O , H2N H2O, NH3 (negative charge) (neutral) This is the positive center that the Nu⊖ seeks C © 2014 by John Wiley & Sons, Inc. All rights reserved. X Examples: HO (Nu O H (Nu H H + C CH3 Cl ) (substrate) H H + C H CH3 Cl ) (substrate) H H + Cl C CH3 OH (product) (L.G.) H H C H + Cl CH3 O (L.G.) H H H (product) C + H3O CH3 OH © 2014 by John Wiley & Sons, Inc. All rights reserved. 4. Leaving Groups To be a good leaving group, the substituent must be able to leave as a relatively stable, weakly basic molecule or ion e.g.: I⊖, Br⊖, Cl⊖, TsO⊖, MsO⊖, H2O, NH3 OTs = O O S O OMs = O O S CH3 (Mesylate) O CH3 (Tosylate) © 2014 by John Wiley & Sons, Inc. All rights reserved. 5. Kinetics of a Nucleophilic Substitution Reaction: An SN2 Reaction The rate of the substitution reaction is linearly dependent on the concentration of HO⊖ and CH3Br Overall, a second-order reaction bimolecular © 2014 by John Wiley & Sons, Inc. All rights reserved. 5A. How Do We Measure the Rate of This Reaction? e.g.: HO (Nu ) H + H H C Cl H (substrate) HO C H H (product) + Cl (leaving group) The rate of reaction can be measured by ● The consumption of the reactants (HO⊖ or CH3Cl) or ● The appearance of the products (CH3OH or Cl⊖) over time © 2014 by John Wiley & Sons, Inc. All rights reserved. Concentration, M Graphically… [CH3Cl] ↓ [CH3OH] ↑ Time, t Rate = Δ[CH3Cl] Δt =− [CH3Cl]t=t − [CH3Cl]t=0 Time in seconds © 2014 by John Wiley & Sons, Inc. All rights reserved. Concentration, M Initial Rate [CH3Cl]t=0 [CH3Cl]t=t [CH3Cl] Time, t [CH3Cl]t=t − [CH3Cl]t=0 Initial Rate =− (from slope) Δt © 2014 by John Wiley & Sons, Inc. All rights reserved. Example: HO + Cl CH3 [OH⊖]t=0 60oC H2O [CH3Cl]t=0 HO CH3 + Cl Initial rate mole L-1, s-1 Result 1.0 M 0.0010 M 4.9 × 10-7 1.0 M 0.0020 M 9.8 × 10-7 Doubled 2.0 M 0.0010 M 9.8 × 10-7 Doubled 2.0 M 0.0020 M 19.6 × 10-7 Quadrupled © 2014 by John Wiley & Sons, Inc. All rights reserved. Conclusion: HO + Cl CH3 60oC H2O HO CH3 + Cl ● The rate of reaction is directly proportional to the concentration of either reactant. ● When the concentration of either reactant is doubled, the rate of reaction doubles. © 2014 by John Wiley & Sons, Inc. All rights reserved. The Kinetic Rate Expression HO + Cl CH3 60oC H2O HO CH3 + Cl Rate α [OH⊖][CH3Cl] Rate = k[OH⊖][CH3Cl] k= Initial Rate [OH⊖][CH3Cl] = 4.9 × 10-7 L mol-1 s-1 © 2014 by John Wiley & Sons, Inc. All rights reserved. 5B. What is the Order of This Reaction? This reaction is said to be second order overall We also say that the reaction is bimolecular We call this kind of reaction an SN2 reaction, meaning substitution, nucleophilic, bimolecular © 2014 by John Wiley & Sons, Inc. All rights reserved. 6. A Mechanism for the SN2 Reaction H HO H C HO Br H C H H negative HO⊖ brings an e⊖ pair to δ+C; δ–Br begins to move away with an e⊖ pair Br H transition state (T.S.) O–C bond partially formed; C–Br bond partially broken. Configuration of C begins to invert © 2014 by John Wiley & Sons, Inc. All rights reserved. O–C bond formed; Br⊖ departed. Configuration of C inverted 7. Transition State Theory: Free-Energy Diagrams A reaction that proceeds with a negative free-energy change (releases energy to its surroundings) is said to be exergonic A reaction that proceeds with a positive free-energy change (absorbs energy from its surroundings) is said to be endergonic © 2014 by John Wiley & Sons, Inc. All rights reserved. At 60oC (333 K) DGo = -100 kJ/mol ● This reaction is highly exergonic DHo = -75 kJ/mol ● This reaction is exothermic © 2014 by John Wiley & Sons, Inc. All rights reserved. ● Its equilibrium constant (Keq) is ln Keq = = DGo = –RT ln Keq –DGo RT –(–100 kJ/mol) (0.00831 kJ K-1 mol-1)(333 K) = 36.1 Keq = 5.0 x 1015 © 2014 by John Wiley & Sons, Inc. All rights reserved. A Free Energy Diagram for a Hypothetical SN2 Reaction That Takes Place with a Negative DGo © 2014 by John Wiley & Sons, Inc. All rights reserved. The reaction coordinate indicates the progress of the reaction, in terms of the conversion of reactants to products The top of the energy curve corresponds to the transition state for the reaction The free energy of activation (DG‡) for the reaction is the difference in energy between the reactants and the transition state The free energy change for the reaction (DGo) is the difference in energy between the reactants and the products © 2014 by John Wiley & Sons, Inc. All rights reserved. A Free Energy Diagram for a Hypothetical Reaction with a Positive Free-Energy Change © 2014 by John Wiley & Sons, Inc. All rights reserved. 7A. Temperature & Reaction Rate Distribution of energies at two different temperatures. The number of collisions with energies greater than the free energy of activation is indicated by the corresponding shaded area under each curve. A 10°C increase in temperature will cause the reaction rate to double for many reactions taking place near room temperature © 2014 by John Wiley & Sons, Inc. All rights reserved. The relationship between the rate constant (k) and DG‡ is exponential : k = k0 e DG‡/RT e = 2.718, the base of natural logarithms Distribution of energies at two different temperatures. The number of collisions with energies greater than the free energy of activation is indicated by the corresponding shaded area under each curve. k0 = absolute rate constant, which equals the rate at which all transition states proceed to products (At 25oC, k0 = 6.2 ╳ 1012 s1 ) © 2014 by John Wiley & Sons, Inc. All rights reserved. Distribution of energies at two different temperatures. The number of collisions with energies greater than the free energy of activation is indicated by the corresponding shaded area under each curve. A reaction with a lower free energy of activation (DG‡) will occur exponentially faster than a reaction with a higher DG‡, as dictated by k = k0 e © 2014 by John Wiley & Sons, Inc. All rights reserved. DG‡/RT Free Energy Diagram of SN2 Reactions Free Energy T.S. DG HO- + CH3Br DGo DG = free energy of activation DGo = free energy change CH3OH + Br- Reaction Coordinate Exothermic (DGo is negative) Thermodynamically favorable process © 2014 by John Wiley & Sons, Inc. All rights reserved. 8. The Stereochemistry of SN2 Reactions Inversion of configuration HO CH3 + C Br H CH2CH3 (R) (inversion) CH3 HO C H (S) CH2CH3 © 2014 by John Wiley & Sons, Inc. All rights reserved. + Br Example: CH3 Nu⊖ attacks from the TOP face. I + OCH3 (inversion of configuration) CH3 OCH3 +I © 2014 by John Wiley & Sons, Inc. All rights reserved. Example: Nu⊖ attacks from the BACK side. (inversion of configuration) © 2014 by John Wiley & Sons, Inc. All rights reserved. 9. The Reaction of tert -Butyl Chloride with Water: An SN1 Reaction © 2014 by John Wiley & Sons, Inc. All rights reserved. The rate of SN1 reactions depends only on concentration of the alkyl halide and is independent of concentration of the Nu⊖ Rate = k[tBuCl] In other words, it is a first-order reaction unimolecular nucleophilic substitution © 2014 by John Wiley & Sons, Inc. All rights reserved. 9A. Multistep Reactions & the RateDetermining Step In a multistep reaction, the rate of the overall reaction is the same as the rate of the SLOWEST step, known as the rate-determining step (r.d.s) For example: Reactant k1 k2 Intermediate (slow) (fast) 1 k3 Intermediate (fast) 2 k1 << k2 or k3 © 2014 by John Wiley & Sons, Inc. All rights reserved. Product Fig. 6.5 A B C The opening A is much smaller than openings B and C The overall rate at which sand reaches to the bottom of the hourglass is limited by the rate at which sand falls through opening A Opening A is analogous to the rate-determining step of a multistep reaction © 2014 by John Wiley & Sons, Inc. All rights reserved. 10. A Mechanism for the SN1 Reaction A multistep process slow r.d.s. © 2014 by John Wiley & Sons, Inc. All rights reserved. Free Energy Diagram of SN1 Reactions intermediate © 2014 by John Wiley & Sons, Inc. All rights reserved. Step (2) CH3 CH3 C + H2O CH3 (k 2 ) fast CH3 H CH3 C O CH3 H © 2014 by John Wiley & Sons, Inc. All rights reserved. Free Energy Diagram of SN1 Reactions intermediate © 2014 by John Wiley & Sons, Inc. All rights reserved. Step (2) CH3 CH3 C + H2O CH3 (k 2 ) fast CH3 H CH3 C O CH3 H fast © 2014 by John Wiley & Sons, Inc. All rights reserved. Free Energy Diagram of SN1 Reactions intermediate © 2014 by John Wiley & Sons, Inc. All rights reserved. Step (2) CH3 CH3 C + H2O CH3 (k2) fast CH3 H CH3 C O CH3 H k1 << k2 and k3 fast © 2014 by John Wiley & Sons, Inc. All rights reserved. 2 intermediates and 3 transition states (T.S.) The most important T.S. for SN1 reactions is T.S. (1) of the ratedetermining step (r.d.s.) CH3 CH3 C Br CH3 © 2014 by John Wiley & Sons, Inc. All rights reserved. 11. Carbocations 11A. The Structure of Carbocations Carbocations are trigonal planar The central carbon atom in a carbocation is electron deficient; it has only six e⊖ in its valence shell The p orbital of a carbocation contains no electrons, but it can accept an electron pair when the carbocation undergoes further reaction H3C H3C C CH3 © 2014 by John Wiley & Sons, Inc. All rights reserved. 11B. The Relative Stabilities of Carbocations General order of reactivity (towards SN1 reaction) ● 3o > 2o >> 1o > methyl The more stable the carbocation formed, the faster the SN1 reaction © 2014 by John Wiley & Sons, Inc. All rights reserved. Stability of cations most stable (positive inductive effect) R R C > R C > R > C H C R R H H H H H Resonance stabilization of allylic and benzylic cations CH2 CH2 © 2014 by John Wiley & Sons, Inc. All rights reserved. etc. 12. Stereochemistry of SN1 Reactions Ph CH3 CH3OH Br CH2CH3 (S ) Ph C CH3OH CH3 CH2CH3 50:50 chance CH3 C OCH3 CH2CH3 (R) and (S) racemic mixture (trigonal planar) CH3OH attack from left Ph CH3OH attack from right (1 : 1) © 2014 by John Wiley & Sons, Inc. All rights reserved. racemic mixture ( 1 : 1 ) Example: (R) Br H2O (SN1) (R) (carbocation) OH H2O attack from TOP face H2O + OH (one enantiomer) slow r.d.s. (S) H2O H O H H2O attack from BOTTOM face © 2014 by John Wiley & Sons, Inc. All rights reserved. H O H Example: I t Me OMe Me MeOH tBu Bu Me +tBu OMe MeOH slow r.d.s. Me t MeOH t Bu Bu O H MeOH Me Me CH3 t MeOH Bu trigonal planar © 2014 by John Wiley & Sons, Inc. All rights reserved. O Me H 13. Factors Affecting the Rates of SN1 and SN2 Reactions The structure of the substrate The concentration and reactivity of the nucleophile (for SN2 reactions only) The effect of the solvent The nature of the leaving group © 2014 by John Wiley & Sons, Inc. All rights reserved. 13A. The Effect of the Structure of the Substrate General order of reactivity (towards SN2 reaction) ● Methyl > 1o > 2o >> 3o > vinyl or aryl DO NOT undergo SN2 reactions © 2014 by John Wiley & Sons, Inc. All rights reserved. For example: R Br + HO R OH + Br Relative Rate (towards SN2) CH3 CH3CH2 Br CH3CH Br CH3 C CH2Br CH3 CH3 CH3 Br methyl 2 10 6 1 o 4 10 2 4 o 500 CH3 CH3 C Br CH3 o neopentyl 3 1 <1 Most reactive Least reactive © 2014 by John Wiley & Sons, Inc. All rights reserved. Compare H HO C H H H HO C CH3 H Br faster HO C H H Br H + Br slower HO CH3 © 2014 by John Wiley & Sons, Inc. All rights reserved. + Br CH3 CH3 C H HO C t Bu HO Br H CH3 C CH3 Br CH3 very slow HO extremely slow © 2014 by John Wiley & Sons, Inc. All rights reserved. CH3 + Br C CH3 CH3 Note NO SN2 reaction on sp2 or sp carbons sp2 sp2 sp © 2014 by John Wiley & Sons, Inc. All rights reserved. Reactivity of the Substrate in SN1 Reactions General order of reactivity (towards SN1 reaction) ● 3o > 2o >> 1o > methyl The more stable the carbocation formed, the faster the SN1 reaction © 2014 by John Wiley & Sons, Inc. All rights reserved. Stability of cations most stable (positive inductive effect) R R C R > R R C R > H H C H > H H C H Allylic halides and benzylic halides also undergo SN1 reactions at reasonable I rates Br an allylic bromide a benzylic iodide © 2014 by John Wiley & Sons, Inc. All rights reserved. Resonance stabilization for allylic and benzylic cations © 2014 by John Wiley & Sons, Inc. All rights reserved. 13B. The Effect of the Concentration & Strength of the Nucleophile For SN1 reaction Recall: Rate = k[RX] ● The Nu⊖ does NOT participate in the r.d.s. ● Rate of SN1 reactions are NOT affected by either the concentration or the identity of the Nu⊖ © 2014 by John Wiley & Sons, Inc. All rights reserved. For SN2 reaction Recall: Rate = k[Nu⊖][RX] ● The rate of SN2 reactions depends on both the concentration and the identity of the attacking Nu⊖ © 2014 by John Wiley & Sons, Inc. All rights reserved. Identity of the Nu⊖ ● The relative strength of a Nu⊖ (its nucleophilicity) is measured in terms of the relative rate of its SN2 reaction with a given substrate rapid Good Nu⊖ Poor Nu: Very slow © 2014 by John Wiley & Sons, Inc. All rights reserved. The relative strength of a Nu⊖ can be correlated with 3 structural features ● A negatively charged Nu⊖ is always a more reactive Nu⊖ than its conjugate acid e.g. HO⊖ is a better Nu⊖ than H2O and RO⊖ is better than ROH ● In a group of Nu⊖s in which the nucleophilic atom is the same, nucleophilicities parallel basicities e.g. for O compounds, RO⊖ > HO⊖ >> RCO2⊖ > ROH > H2O © 2014 by John Wiley & Sons, Inc. All rights reserved. ● When the nucleophilic atoms are different, then nucleophilicities may not parallel basicities e.g. in protic solvents HS⊖, NC⊖, and I⊖ are all weaker bases than HO⊖, yet they are stronger Nu⊖s than HO⊖ HS⊖ > NC⊖ > I⊖ > HO⊖ © 2014 by John Wiley & Sons, Inc. All rights reserved. 13C. Solvent Effects in SN2 & SN1 Reactions SN2 reactions are favored by polar aprotic solvents (e.g., acetone, DMF, DMSO) SN1 reactions are favored by polar protic solvents (e.g., EtOH, MeOH, H2O) © 2014 by John Wiley & Sons, Inc. All rights reserved. Classification of solvents Non-polar solvents (e.g. hexane, benzene) Solvents Polar solvents Polar protic solvents (e.g. H2O, MeOH) Polar aprotic solvents (e.g. DMSO, HMPA) © 2014 by John Wiley & Sons, Inc. All rights reserved. SN2 Reactions in Polar Aprotic Solvents ● The best solvents for SN2 reactions are Polar aprotic solvents, which have strong dipoles but do not have OH or NH groups Examples CH3 O S O H CH3 (DMSO) CH3 N CH3 (DMF) O P NMe Me2N NMe2 2 (HMPA) © 2014 by John Wiley & Sons, Inc. All rights reserved. CH3CN (Acetonitrile) Polar aprotic solvents tend to solvate metal cations rather than nucleophilic anions, and this results in “naked” anions of the Nu⊖ and makes the e⊖ pair of the Nu⊖ more available CH3O Na DMSO CH3O + DMSO Na "naked anion" © 2014 by John Wiley & Sons, Inc. All rights reserved. Tremendous acceleration in SN2 reactions with polar aprotic solvent CH3Br + NaI CH3I + NaBr Solvent Relative Rate MeOH 1 DMF 106 © 2014 by John Wiley & Sons, Inc. All rights reserved. SN2 Reactions in Polar Protic Solvents ● In polar protic solvents, the Nu⊖ anion is solvated by the surrounding protic solvent which makes the e⊖ pair of the Nu⊖ less available and thus less reactive in SN2 reactions OR H RO H Nu H OR H OR © 2014 by John Wiley & Sons, Inc. All rights reserved. Halide Nucleophilicity in Protic Solvents ● I⊖ > Br⊖ > Cl⊖ > F⊖ RO H RO H H RO OR H F - H OR H H OR (stro n g ly so lv a te d ) RO H I OR - H OR (w e a k ly so lv a te d ) Thus, I⊖ is a stronger Nu⊖ in protic solvents, as its e⊖ pair is more available to attack the substrate in the SN2 reaction. © 2014 by John Wiley & Sons, Inc. All rights reserved. Halide Nucleophilicity in Polar Aprotic Solvents (e.g. in DMSO) ● F⊖ > Cl⊖ > Br⊖ > I⊖ Polar aprotic solvents do not solvate anions but solvate the cations The “naked” anions act as the Nu⊖ Since F⊖ is smaller in size and the charge per surface area is larger than I⊖, the nucleophilicity of F⊖ in this environment is greater than I⊖ © 2014 by John Wiley & Sons, Inc. All rights reserved. Solvent plays an important role in SN1 reactions but the reasons are different from those in SN2 reactions Solvent effects in SN1 reactions are due largely to stabilization or destabilization of the transition state © 2014 by John Wiley & Sons, Inc. All rights reserved. Polar protic solvents stabilize the development of the polar transition state and thus accelerate this ratedetermining step (r.d.s.): © 2014 by John Wiley & Sons, Inc. All rights reserved. 13D. The Nature of the Leaving Group Leaving groups depart with the electron pair that was used to bond them to the substrate The best leaving groups are those that become either a relatively stable anion or a neutral molecule when they depart © 2014 by John Wiley & Sons, Inc. All rights reserved. The better a species can stabilize a negative charge, the better the LG in an SN2 reaction SN1 Reaction: C X C slow r.d.s. SN2 Reaction: Nu: slow C X r.d.s. Nu C X C + X X © 2014 by John Wiley & Sons, Inc. All rights reserved. Nu C +X Examples of the reactivity of some X⊖: CH3O + CH3–X CH3–OCH3 + X Relative Rate: ⊖ Best X ⊖ HO , Worst X H2N, <<F < Cl < Br < I < TsO RO ~0 1 200 10,000 30,000 60,000 Note: Normally R–F, R–OH, R–NH2, R–OR’ do not undergo SN2 reactions. © 2014 by John Wiley & Sons, Inc. All rights reserved. a poor leaving group R O H Nu ✔ a good H a strong basic anion R Nu leaving group © 2014 by John Wiley & Sons, Inc. All rights reserved. + H2O weak base Other weak bases that are good leaving groups: © 2014 by John Wiley & Sons, Inc. All rights reserved. 14. Organic Synthesis: Functional Group Transformation Using SN2 Reactions OH HO CN Br MeS MeO HS SMe © 2014 by John Wiley & Sons, Inc. All rights reserved. SH Me O I I Me C C Br N3 O Me NMe3 Br MeCOO Me3N N3 © 2014 by John Wiley & Sons, Inc. All rights reserved. Examples: NaOEt,?? DMSO Br I O NaSMe,?? DMSO © 2014 by John Wiley & Sons, Inc. All rights reserved. SMe Examples: ?? I CN (o ptically active , chiral) (o ptically active , chiral) ● Need SN2 reactions to control stereochemistry ● But SN2 reactions give the inversion of configurations, so how do you get the “retention” of configuration here?? ● Solution: “double inversion” “retention” © 2014 by John Wiley & Sons, Inc. All rights reserved. ?? I CN (o ptically active , chiral) (o ptically active , chiral) NaBr DMSO NaCN DMSO (SN2 with inversion) Br (SN2 with inversion) (Note: Br⊖ is a stronger Nu than I⊖ in polar aprotic solvent.) © 2014 by John Wiley & Sons, Inc. All rights reserved. 14A. The Nonreactivity of Vinylic and Phenyl Halides X C C X vinylic halide phenyl halide Vinylic and phenyl halides are generally unreactive in SN1 or SN2 reactions © 2014 by John Wiley & Sons, Inc. All rights reserved. Examples NaCN Br DMSO I NaSMe HMPA No Reaction No Reaction © 2014 by John Wiley & Sons, Inc. All rights reserved. 15. Elimination Reactions of Alkyl Halides Substitution Elimination © 2014 by John Wiley & Sons, Inc. All rights reserved. Substitution reaction (SN) and elimination reaction (E) are processes in competition with each other e.g. I t BuOK t BuOH t O Bu + SN2: 15% © 2014 by John Wiley & Sons, Inc. All rights reserved. E2: 85% 15A. Dehydrohalogenation β hydrogen β carbon Br β H LG H C carbon C X halide as LG t BuOK t o BuOH, 60 C + KBr β hydrogen ⊖OtBu © 2014 by John Wiley & Sons, Inc. All rights reserved. t + BuOH 15B. Bases Used in Dehydrohalogenation Conjugate base of alcohols is often used as the base in dehydrohalogenations Na R−O−H NaH R−O⊖ + Na⊕ + H2 R−O⊖ + Na⊕ + H2 © 2014 by John Wiley & Sons, Inc. All rights reserved. 16. The E2 Reaction Br EtO + + EtOH + Br H Rate = k[CH3CHBrCH3][EtO⊖] Rate determining step involves both the alkyl halide and the alkoxide anion A bimolecular reaction © 2014 by John Wiley & Sons, Inc. All rights reserved. Mechanism for an E2 Reaction Et O Et O CH3 α Cβ C H H Br H H H H EtO⊖ removes a b proton; C−H breaks; new p bond forms and Br begins to depart C CH3 C H H Br Partial bonds in the transition state: C−H and C−Br bonds break, new p C−C bond forms © 2014 by John Wiley & Sons, Inc. All rights reserved. H H C C + Et OH CH3 H + Br C=C is fully formed and the other products are EtOH and Br⊖ Free Energy Diagram of E2 Reaction Free Energy T.S. DG‡ E2 reaction has ONE transition state CH3CHBrCH3 - + EtO CH2=CHCH3 + EtOH + Br Reaction Coordinate Rate = k[CH3CHBrCH3][EtO⊖] Second-order overall bimolecular © 2014 by John Wiley & Sons, Inc. All rights reserved. - 17. The E1 Reaction E1: Unimolecular elimination CH3 CH3 CH3 H 2O CH3 C OH + CH2 C CH3 C Cl CH3 CH3 CH3 slow (major (SN1)) (minor (E1)) r.d.s H2O as CH3 nucleophile CH3 C CH3 H2O as base © 2014 by John Wiley & Sons, Inc. All rights reserved. Mechanism of an E1 Reaction carbon β hydrogen H H2O slow r.d.s. fast + H3O (E1 product) fast H2O O H HO 2 H OH + H3O (SN1 product) © 2014 by John Wiley & Sons, Inc. All rights reserved. Free Energy Diagram of E1 Reaction © 2014 by John Wiley & Sons, Inc. All rights reserved. Step (1): CH3 CH3 C Cl CH3 Aided by the polar solvent, a chlorine departs with the e⊖ pair that bonded it to the carbon H 2O (k 1 ) slow r.d. step CH3 CH3 C + Cl CH3 Produces relatively stable 3o carbocation and a Cl⊖. The ions are solvated (and stabilized) by surrounding H2O molecules © 2014 by John Wiley & Sons, Inc. All rights reserved. Free Energy Diagram of E1 Reaction © 2014 by John Wiley & Sons, Inc. All rights reserved. Step (2) H 3C H 3C H C C H + H 2O (k 2 ) H 3C fast H 3C H H2O molecule removes one of the b hydrogens which are acidic due to the adjacent positive charge. An e⊖ pair moves in to form a double bond between the b and carbon atoms CH2 + H O H H Produces alkene and hydronium ion © 2014 by John Wiley & Sons, Inc. All rights reserved. 18. How To Determine Whether Substitution or Elimination Is Favoured All nucleophiles are potential bases and all bases are potential nucleophiles Substitution reactions are always in competition with elimination reactions Different factors can affect which type of reaction is favoured © 2014 by John Wiley & Sons, Inc. All rights reserved. 18A. SN2 vs. E2 (a) (b) Nu (a) H C C X SN2 H C Nu (b) C E2 C C + X + Nu H + X © 2014 by John Wiley & Sons, Inc. All rights reserved. Primary Substrate With a strong base, e.g. EtO⊖ ● Favor SN2 Br N aO Et OEt SN2: 90% + E tO H E 2 : (1 0 % ) © 2014 by John Wiley & Sons, Inc. All rights reserved. Secondary Substrate With a strong base, e.g. EtO⊖ ● Favor E2 + N aO Et Br E2: 80% + E tO H OEt SN2: 20% © 2014 by John Wiley & Sons, Inc. All rights reserved. Tertiary Substrate With a strong base, e.g. EtO⊖ ● E2 is highly favored Br NaOEt EtOH + E2: 91% © 2014 by John Wiley & Sons, Inc. All rights reserved. OEt SN1: 9% Base/Nu⊖: Small vs. Bulky Unhindered “small” base/Nu⊖ NaOMe Br MeOH OMe SN2: 99% + E2: 1% Hindered “bulky” base/Nu⊖ t KO Bu Br t BuOH t + O Bu SN2: 15% E2: 85% © 2014 by John Wiley & Sons, Inc. All rights reserved. Basicity vs. Polarizability O O O CH3 CH3 C O (weak base) Br EtO (strong base) + SN2: 100% E2: 0% OEt + SN2: 20% © 2014 by John Wiley & Sons, Inc. All rights reserved. E2: 80% Tertiary Halides: SN1 vs. E1 & E2 Br EtO OEt + (strong base) E2: 100% SN1: 0% EtOH OEt + heat E1 + E2: 20% SN1: 80% © 2014 by John Wiley & Sons, Inc. All rights reserved. 19. Overall Summary SN1 SN2 CH 3 X RCH2X R' RCHX R' RCX R" ─ ─ Very fast Mostly Very little; Mostly SN2 with Solvolysis possible; weak bases; e.g. with H2O; e.g. with CH3COO⊖ MeOH Very favorable with weak bases; e.g. with H2O; MeOH ─ E1 E2 ─ ─ ─ Hindered bases give mostly alkenes; e.g. with tBuO⊖ Very little Strong bases promote E2; e.g. with RO⊖, HO⊖ Strong bases Always competes promote E2; with SN1 e.g. with RO⊖, HO⊖ © 2014 by John Wiley & Sons, Inc. All rights reserved. Review Problems CN SN2 with inversion t Bu (2 ) I O H O NaH Et 2 O H⊖ I O Intramolecular SN2 © 2014 by John Wiley & Sons, Inc. All rights reserved. (3 ) CH 3 HCl OH t Bu Cl⊖ attacks from top face CH 3 O t H H CH 3 t Bu SN1 with racemization Bu Cl⊖ attacks from bottom face sp2 hybridized carbocation © 2014 by John Wiley & Sons, Inc. All rights reserved. END OF CHAPTER 6 © 2014 by John Wiley & Sons, Inc. All rights reserved.