Goals

1. Chapter 9: Elimination Reactions of Alkyl Halides: Competition between Substitutions and Eliminations

2. Goals • After this chapter, you should be able to: • Predict products of E2 and E1 reactions • Determine stereochemistry of E2/E1 Products • Determine whether SN2, SN1, E1 or E2 will occur

3. What is an SN2 Reaction? • SN2 mechanism; S for substitution, N for nucleophilic and 2 because two molecules collide at the critical point in the reaction.

4. Review: An SN2 Reaction

5. Stereochemistry of Inversion • If the nucleophile and the leaving group are both high in the R/S priority order, this means that an R alkyl halide gives an S product, and vice-versa

6. Energy of Inversion

7. Energy of Inversion

8. With SN2, Size of Substituent Groups Matters Relative Reactivity Toward SN2 tertiary< secondary< primary < methyl

9. Kinetics of Nucleophilic Substitution • Rate = k[RBr][Nu-] • Second order kinetics

10. Effect of Bond Strength of the Leaving Group on SN2 Reactivity • Since the carbon-halogen bond strength increases up the periodic table the relative SN2 reactivity of the alkyl halide is: RF < RCl < RBr < RI TosO- is a better leaving group than I- OH-, NH2-, and RO- are worse than F-

11. Nucleophilicity: CH3CO2(-) < Cl(-) < Br(-) < N3(-) < CH3O(-) < CN(-) < I(-) < SCN(-) < CH3S(-)

12. Nucleophilicity • Parallels basicity • H2O < C2H3O2- < OH- • Increases down the periodic table • I- < Cl- < F- • Anions are more nucleophilic than neutral compounds • The solvent matters!

13. Solvent Effects Consider KBr as a nucleophile source • Protic solvents with –OH, -NH slow SN2 rxn • These solvents cluster around the nucleophile lowering the effective nucleophilicity • Polar aprotic solvents speed SN2 • These solvents cluster around the metal ion of the salt freeing the nucleophile to be nucleophilic.

14. Characteristics of SN2 Reactions • Single Step Mechanism • Inversion of configuration • SN2 reactions are generally reliable only when the alkyl halide is primary • Halogen is generally Cl or Br since • C-F bond is too strong • C-I bond is weak and compounds are unstable

15. An SN2 Reaction

16. SN1 Reactions • SN1 reactions proceed by a two step mechanism • First: Leaving group leaves giving a carbocation • Second: Nucleophile attacks carbocation

17. Review: An SN1 Reaction

18. SN1 Reactions

19. Leaving Groups OH- < NH2 -<RO- F - < Cl - < Br - < I < TosO- Susceptibility to leaving

20. Evidence for SN1 Kinetics • The reaction rate is only dependent upon the concentration of the substance with the leaving group • R-X  R+ + X- is a slow = rate determining • Racemic mixtures are usual • Carbocation formation • Rate = k[R-X] where X is leaving group

21. SN1 Reaction Rates • Depend on stability of the carbocation • More stable carbocation=faster reaction -CH3 < 1° < » 2° < 3° Relative Stability of Carbocation

22. The Nucleophile and SN1 • NO EFFECT!

23. Energy for SN1

24. Solvent Effects on SN1 • Polar solvents stabilize the intermediate carbocation.

25. Summary SN1 • Fastest with • Compounds that form stable carbocation • Good leaving group • Nucleophiles that are not basic to prevent competing elimination reactions • Polar solvents

26. An SN1 Reaction

27. Elimination Reactions • Zaitsev’s Rule: • Base induced elimination reactions generally give the more highly substituted double bond alkene product

28. An E2 Reactions

29. E2 Reactions • Single step attack of nucleophile on hydrogen on carbon adjacent to the carbon containing the leaving group.

30. E2 Kinetics • The rate of the reaction is dependent upon the concentration of the compound containing the leaving group and the nucleophile base. • Rate = k[RX][Base]

31. Geometry of E2 • All atoms involved are in same plane • The hydrogen and leaving group are anti

32. Cycloalkane E2: What do you expect?

33. E2 Reaction

34. An E2 Reactions

35. Zaitsev’s Rule Limitations • Don’t use for conjugated double bonds. • You can trick the reaction into favoring the least substituted alkene by using a Bulky base.

36. Zaitsev’s Rule Limitations • Don’t use for conjugated double bonds. • You can trick the reaction into favoring the least substituted alkene by using a Bulky base.

37. E1 Reactions • First step is identical to SN1 – Elimination of the leaving group giving a carbocation • First step is slow and rate determining • Second step is the attack of a hydrogen on a carbon adjacent to the carbocation • Racemic mixtures are usual

38. The E1 Reaction

39. E1 Kinetics • Rate = k[R-X] E

40. Nucleophile Anionic Nucleophiles(Weak Bases)(RS-, SCN-, I-, Br-, N3-, CN- etc.) Anionic Nucleophiles(Strong Bases: HO-, RO-) Neutral Nucleophiles(H2O, ROH, RSH, R3N) Alkyl Group PrimaryRCH2- Rapid SN2 substitution. The rate may be reduced by substitution of b-carbons, as in the case of neopentyl. Rapid SN2 substitution. E2 elimination may also occur.e.g. ClCH2CH2Cl   + KOH ___> CH2=CHCl SN2 substitution. (N @ S >>O) SecondaryR2CH- SN2 substitution plus E2 elimination (depends on basicity of the nucleophile). The rate of substitution may be reduced by branching at the b-carbons, and this will increase elimination. E2 elimination will dominate. SN2 substitution. (N @ S >>O)In high dielectric ionizing solvents, such as water, dimethyl sulfoxide & acetonitrile, SN1 and E1 products may be formed slowly. TertiaryR3C- E2 elimination will dominate with most nucleophiles (even if they are weak bases). No SN2 substitution due to steric hindrance.In high dielectric ionizing solvents, such as water, dimethyl sulfoxide & acetonitrile, SN1 and E1 products may be expected. E2 elimination will dominate. No SN2 substitution will occur. In high dielectric ionizing solvents SN1 and E1 products may be formed. E2 elimination with nitrogen nucleophiles (they are bases). No SN2 substitution. In high dielectric ionizing solvents SN1 and E1 products may be formed. AllylH2C=CHCH2- Rapid SN2 substitution for 1° and 2°-halides. For 3°-halides a very slow SN2 substitution or, if the nucleophile is moderately basic, E2 elimination.In high dielectric ionizing solvents, such as water, dimethyl sulfoxide & acetonitrile, SN1 and E1 products may be observed. Rapid SN2 substitution for 1° halides (note there are no b hydrogens. E2 elimination will compete with substitution in 2°-halides, and dominate in the case of 3°-halides.In high dielectric ionizing solvents SN1 and E1 products may be formed. Nitrogen and sulfur nucleophiles will give SN2 substitution in the case of1° and 2°-halides. 3°-halides will probably give E2 elimination with nitrogen nucleophiles (they are bases).In high dielectric ionizing solvents SN1 and E1 products may be formed. Water hydrolysis will be favorable for 2° & 3°-halides. BenzylC6H5CH2- Rapid SN2 substitution for 1° and 2°-halides. For 3°-halides a very slow SN2 substitution or, if the nucleophile is moderately basic, E2 elimination.In high dielectric ionizing solvents, such as water, dimethyl sulfoxide & acetonitrile, SN1 and E1 products may be observed. Rapid SN2 substitution for 1° halides (note there are no b hydrogens. E2 elimination will compete with substitution in 2°-halides, and dominate in the case of 3°-halides.In high dielectric ionizing solvents SN1 and E1 products may be formed. Nitrogen and sulfur nucleophiles will give SN2 substitution in the case of1° and 2°-halides. 3°-halides will probably give E2 elimination with nitrogen nucleophiles (they are bases).In high dielectric ionizing solvents SN1 and E1 products may be formed. Water hydrolysis will be favorable for 2° & 3°-halides.