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Chapter 11

Chapter 11. S N 1, S N 2, E1, E2 Reactions of Alkyl Halides. S ubstitution & E limination Reactions. . Ethanol. . Ethanol. . Substitution & Elimination Reactions. Substitution. “competing reactions”. - Elimination. nucleophile & base. substrate. solvent. nucleophile.

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Chapter 11

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  1. Chapter 11 SN1, SN2, E1, E2 Reactions of Alkyl Halides Chapter 11 - Substitution & Elimination Reactions

  2. Substitution & Elimination Reactions Chapter 11 - Substitution & Elimination Reactions

  3. Ethanol  Ethanol  Substitution & Elimination Reactions Substitution “competing reactions” -Elimination nucleophile & base Chapter 11 - Substitution & Elimination Reactions

  4. substrate solvent nucleophile leaving group - + Substitution - nucleophilicity - + … reaction rate is affected by all four. Chapter 11 - Substitution & Elimination Reactions

  5. solvent substrate nucleophile leaving group Elimination - basicity   ... reaction rate is affected by all four. Chapter 11 - Substitution & Elimination Reactions

  6. Substitution & Elimination (nucleophilicity & basicity) - +   Chapter 11 - Substitution & Elimination Reactions

  7. Mechanisms • Substitution • Elimination Chapter 11 - Substitution & Elimination Reactions

  8. Types of Substitution • Substitution, Nucleophilic, Bimolecular - SN2 • Substitution, Nucleophilic, Unimolecular - SN1 • Bimolecular or Unimolecular refers to the number of specie(s) present at the transition state, or ... • describes the timing of bond breaking between carbon (on the substrate) and the leaving group and bond forming between carbon (on the substrate) and the nucleophile. Chapter 11 - Substitution & Elimination Reactions

  9. Substitution Reactions … involve configurational inversion at the stereocenter. Chapter 11 - Substitution & Elimination Reactions

  10. 2-bromobutane CH3 HO H CH2CH3 Drawing Inversion Show the SN2 reaction of OH- with (R)-2-bromobutane. * CH3 Br H R S OH- CH3CH2 Chapter 11 - Substitution & Elimination Reactions

  11. a † b † a SN1 “-” inversion racemic mixtures carbocation intermediate b “+” “+” SN2 inversion “concerted” no intermediate Review chapter 9 slides 53 - 57. Chapter 11 - Substitution & Elimination Reactions

  12. SN1: SN2 : SN1 & SN2 … suggests that only atoms in S are involved in the transition state. … says that the reaction rate is affected only by S. … suggests that atoms in N & S are involved in the transition state. … says that the reaction rate is affected by both N & S. Chapter 11 - Substitution & Elimination Reactions

  13. Rate=k[ ] a † b † a SN1 “-” b “+” “+” SN2 † Rate=k[ ][ ] Chapter 11 - Substitution & Elimination Reactions

  14. SN1 & SN2 SN1 SN2 ‡ † carbocation intermediate “concerted” † Chapter 11 - Substitution & Elimination Reactions

  15. Factors effecting Rates of SN2 & SN1 Reactions -CH3CH2Br + Nu:  CH3CH2Nu + Br- • Structure of Substrate - steric effects. • Structure of Nucleophile. • Structure of Leaving Group. • Solvent. Chapter 11 - Substitution & Elimination Reactions

  16. Substrate - SN2 … concerted ... … back side attack ... Chapter 11 - Substitution & Elimination Reactions

  17. Substrate - SN2 1o … concerted ... … back side attack ... Chapter 11 - Substitution & Elimination Reactions

  18. Substrate - SN2 2o … concerted ... … back side attack ... Chapter 11 - Substitution & Elimination Reactions

  19. Substrate - SN2 3o … steric hindrance ... Chapter 11 - Substitution & Elimination Reactions

  20. Substrate - SN2 & SN1 Relative reactivity SN2 steric factors - reaction center neighbor. 2 x 106 4 x 105 500 <1 <1 1 12 1.2 x 106 SN1 electronic factors - carbocation stability. 1. Primary and methyl halides have less steric hindrance, thus only SN2. 2. Tertiary halides (also, allylic or benzylic) react via carbocation, thus SN1 exclusively. 3. 2o alkyl halides can react as SN1 or SN2, depending on nucleophile and solvent. Chapter 11 - Substitution & Elimination Reactions

  21. Attacking Nucleophile good (Underlined nucleophiles are also strong bases) moderate poor 1. SN2 involves substrate and nucleophile in the rate determining step (rds). Thus good nucleophile lowers the G‡ and therefore increases the reaction rate. 2. SN1 does not involve the nucleophile in the rate determining step. Thus nucleophile has no effect on the reaction rate. Chapter 11 - Substitution & Elimination Reactions

  22. Polar protic Polar aprotic F- F- Nucleophilicity Nucleophilicity Cl- Cl- Br- Br- I- I- Chapter 11 - Substitution & Elimination Reactions

  23. Species with higher electronegativity have tightly held nonbonding electrons and therefore less reactive towards forming new bonds. Nucleophilicity Nucleophilicity Increase in size and polarizability. Chapter 11 - Substitution & Elimination Reactions

  24. pKa 38 15.5 15.74 4.76 3.45 -7 -8 -9 Leaving group strength of conjugate acid stability of anion Good Poor reactivity as a leaving group 1. Good leaving group increases rates of SN1 & SN2. 2. The 1st three are such poor leaving group, no substitutions are observed. Chapter 11 - Substitution & Elimination Reactions

  25. Solvents Protic solvents: “…those that contain -OH or -NH groups …worst solvents for SN2 reactions.” Aprotic solvents: “…have strong dipoles but don’t have -OH or -NH groups. Best for SN2 reactions.” Chapter 11 - Substitution & Elimination Reactions

  26. Protic Solvent Common Solvents polarity Dielectric Constant 6 acetic acid 34 methanol 80 1. Contain–OH group. 2. R is either CH3–, CH3CH2 –, or in general, CnH2n+1 . 3. Hydrogen bond with Nu, decreases its reactivity, hinders SN2 . 4. Electrostatic interaction stabilizes carbocation, facilitates SN1. Chapter 11 - Substitution & Elimination Reactions

  27. Aprotic Solvent Common Solvents Diethyl ether Acetone DMSO DMF HMPA Dichloromethane polarity Dielectric Constant 30 4 48 38 21 9 1. Does not contain–OH group. 2. DMSO, DMF, HMPA, & acetone are polar aprotic, remaining two are weakly polar aprotic. 3. Solvate but not H-bonding with Nu, thus good for SN2. Chapter 11 - Substitution & Elimination Reactions

  28. Aprotic Solvent Protic Solvent Water DMSO DMF Methanol HMPA Acetone Acetic acid Dichloromethane Diethyl ether SN1 SN2 Dielectric Constant 80 60 40 20 0 Chapter 11 - Substitution & Elimination Reactions

  29. 2. If the concentration of ethanol is halved, how would it affect the rate of the reaction, 1. 3o alkyl halide, protic polar solvent, thus expect SN1. 3. Halve [CH3CH2OH] will have no effect on the rate . Chapter 11 - Substitution & Elimination Reactions

  30. 2. If the concentration of ethanol is halved, how would it affect the rate of the reaction, 1. 3o alkyl halide, aprotic polar solvent, most likely mechanism is SN1. 3. Halve [CH3CH2OH] will reduce the rate. 4. See next slide for more explanation... Chapter 11 - Substitution & Elimination Reactions

  31. The carbocation is reduced due to lower dielectric constant, thus slow down the reaction. The part of the reaction will not affect the rate of the reaction since it is after the slow step. Chapter 11 - Substitution & Elimination Reactions

  32. Comment on the nucleophilic substitution reaction, 1. Substrate: 2-chlorobutane forms a 2o carbocation. 2. Nucleophile: Methanol is a weak nucleophile. 3. Leaving group: Cl is a moderately leaving group. 4. Solvent: Methanol is a polar protic solvent, favors carbocation formation. Prediction: SN1 mechanism. Verification: If predicted mechanism is correct, one expects racemic mixture. Chapter 11 - Substitution & Elimination Reactions

  33. Comment on the nucleophilic substitution reaction, 1. Substrate: 1-Bromo-2-methlypropane forms primary alkyl halide. 2. Nucleophile: I- is a good nucleophile. 3. Leaving group: Br- is a good leaving group. 4. Solvent: DMSO is a polar aprotic solvent. Prediction: SN2 mechanism. Chapter 11 - Substitution & Elimination Reactions

  34. Comment on the nucleophilic substitution reaction, “S” 1. Substrate: (S)-2-Bromobutane is a secondary alkyl halide. 2. Nucleophile: Methylsulfide ion, CH3S-, is a good nucleophile. 3. Leaving group: Br- is a good leaving group. 4. Solvent: Acetone is a polar aprotic solvent. Prediction: SN2 mechanism. Verification: expect R product. Chapter 11 - Substitution & Elimination Reactions

  35. Prediction: SN1 mechanism and products are, Write the product(s) and predict the mechanism for 1. Substrate: A secondary alkyl halide, can be SN1 or SN2. 2. Nucleophile: Methanol is a poor nucleophile. 3. Leaving group: Cl is a moderate leaving group. 4. Solvent: Methanol is a polar protic solvent. This eliminates SN2. Chapter 11 - Substitution & Elimination Reactions

  36. Limiting Mechanisms • Substitution • Elimination Chapter 11 - Substitution & Elimination Reactions

  37. Synthesis of Alkene From halides - dehydrohalogenation (minus HX): Elimination From alcohol - dehydration (minus H2O): Chapter 7 slide 5 Chapter 11 - Substitution & Elimination Reactions

  38. Types of Elimination • Elimination, Bimolecular - E2 • Elimination, Unimolecular - E1 • Bimolecular or Unimolecular refers to the number of specie(s) involved at the transition state. • Bimolecular or Unimolecular describes the timing of bond breaking between carbon (on the substrate) and the leaving group and the formation of a double bond between the  carbon and  carbon. Chapter 11 - Substitution & Elimination Reactions

  39. Zaitsev’s rule Major Major Alkene having the greater number of substituents on the double bond generally is the major product. Chapter 11 - Substitution & Elimination Reactions

  40. E1 Mechanism Reaction of 2-Bromo-2-methlypropane and methanol. Step 1: same as SN1. E1 & SN1 always occur in conjunction with each other. Step 2: Chapter 11 - Substitution & Elimination Reactions

  41. E2 Mechanism Reaction of 1-Bromopropane and sodium methoxide in methanol. 1. Concerted. 2. H – C – H – Br are anti periplanar. Chapter 11 - Substitution & Elimination Reactions

  42. Comment on the reaction mechanism of the reaction, major major 1. 2-Methylpropene is an E1 product. 2. Ethyl-t-butyl ether is a SN1 product. 3. Heat favors elimination(higher G‡); no heat favors substitution (lower G‡). 4. E1and SN1 are always in competition of each other. Chapter 11 - Substitution & Elimination Reactions

  43. Major Predict whether the reaction will proceed predominately by E1 or E2 mechanism. Write the major organic product. 1. NaOH is a strong base. 2. 3o alkyl halide - carbocation formation. 3. H2O is a polar solvent. 4. Heat suggests elimination. Prediction: E1 Chapter 11 - Substitution & Elimination Reactions

  44. Major Predict whether the reaction will proceed predominately by E1 or E2 mechanism. Write the major organic product. 1. 3o alkyl halide - carbocation formation. 2. CH3CO2H is a weak polar solvent. Prediction: E1 Chapter 11 - Substitution & Elimination Reactions

  45. or Why Elimination ? non-Zaitsev Zaitsev co-planar elimination Chapter 11 - Substitution & Elimination Reactions

  46. Limiting Mechanisms • Substitution • Elimination Chapter 11 - Substitution & Elimination Reactions

  47. Flow Chart for Substitution and Elimination yes no yes no yes no yes no yes no yes no yes no For E1 and/or E2, watch for anti periplanar. Chapter 11 - Substitution & Elimination Reactions

  48. and/or Predict the mechanism and product(s) of 1. CH3OH is a poor attacking nucleophile. 2. CH3OH is a protic solvent, favors substitution. 3. 2o alkyl halide - carbocation formation. 4. I- is a good leaving group. Prediction: SN1 and/or E1. Possible products: Chapter 11 - Substitution & Elimination Reactions

  49. Predict the mechanism and product(s) of 1. O- is a good attacking nucleophile. 2. O- is a strong base. 3. 1o alkyl halide - SN2. 4. I- is a good leaving group. Prediction: SN2. Possible products: Chapter 11 - Substitution & Elimination Reactions

  50. Nucleophile Substrate Nucleophile Substrate Chapter 11 - Substitution & Elimination Reactions

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