11. Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

1. 11. Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations Based on McMurry’s Organic Chemistry, 6th edition

2. Alkyl Halides React with Nucleophiles and Bases • Alkyl halides are polarized at the carbon-halide bond, making the carbon electrophilic • Nucleophiles will replace the halide in C-X bonds of many alkyl halides (reaction as Lewis base)

3. Alkyl Halides React with Nucleophiles and Bases • Nucleophiles that are Brønsted bases produce elimination

4. Substitution vs. Elimination

5. The Nature of Substitution • Substitution requires that a "leaving group", which is also a Lewis base, departs from the reacting molecule. • A nucleophile is a reactant that can be expected to participate as a Lewis base in a substitution reaction.

6. Substitution Mechanisms • SN1 • Two steps with carbocation intermediate • Occurs in 3°, allyl, benzyl • SN2 • Concerted mechanism - without intermediate • Occurs in primary, secondary

7. The SN2 Reaction • Reaction occurs with inversion of configuration at electrophilic C • Follows second order reaction kinetics • Ingold nomenclature to describe rate-determining step: • S=substitution • N (subscript) = nucleophilic • 2 = both nucleophile and electrophile in rate-determining step (bimolecular)

8. SN2 Process • The transition state for the rate-determining (and only) step contains both reactants (substrate alkyl halide and nucleophile).

9. SN2 Transition State • The transition state of an SN2 reaction has a planar arrangement of the carbon atom and the remaining three groups • Hybridization is sp2

12. Sensitive to steric effects Methyl halides are most reactive Primary are next most reactive Unhindered secondary halides react under some conditions Tertiary are unreactive by this path No reaction at C=C (vinyl or aryl halides) 11.5 Characteristics of the SN2 Reaction

13. Order of Reactivity in SN2 • The more alkyl groups connected to the reacting carbon, the slower the reaction

14. Vinyl and Aryl Halides:

15. Order of Reactivity in SN2

16. The Nucleophile • Neutral or negatively charged Lewis base • Reaction increases coordination (adds a new bond) at the nucleophile • Neutral nucleophile acquires positive charge • Anionic nucleophile becomes neutral • See Table 11-1 for an illustrative list

17. For example:

19. Relative Reactivity of Nucleophiles • Depends on reaction and conditions • More basic nucleophiles react faster (for similar structures. See Table 11-2) • Better nucleophiles are lower in a column of the periodic table • Anions are usually more reactive than neutrals

21. The Leaving Group • A good leaving group reduces the energy of activation of a reaction • Stable anions that are weak bases (conjugate bases of strong acids) are usually excellent leaving groups • Stronger bases (conjugate bases of weaker acids) are usually poorer leaving groups

22. The Leaving Group

23. Poor Leaving Groups • If a group is very basic or very small, it does not undergo nucleophilic substitution.

24. The Solvent • Protic solvents (which can donate hydrogen bonds; -OH or –NH) slow SN2 reactions by associating with reactants (anions). • Energy is required to break interactions between reactant and solvent • Polar aprotic solvents (no NH, OH, SH) form weaker interactions with substrate and permit faster reaction

25. Some Polar Aprotic Solvents

26. Summary of SN2 Characteristics: • Substrate:CH3->1o>2o>>3o(Steric effect) • Nucleophile: Strong, basic nucleophiles favor the reaction • Leaving Groups: Good leaving groups (weak bases) favor the reaction • Solvent: Aprotic solvents favor the reaction; protic reactions slow it down by solvating the nucleophile • Stereochemistry: 100% inversion

27. Prob. 11.36 Arrange in order of SN2 reactivity

28. 11.6 The SN1 Reaction • Tertiary alkyl halides react rapidly in protic solvents by a mechanism that involves departure of the leaving group prior to the addition of the nucleophile. • Reaction occurs in two distinct steps, while SN2 occurs in one step (concerted). • Rate-determining step is formation of carbocation:

29. SN1 Reactivity:

30. SN1 Energy Diagram k1 k-1 k2

31. Rate-Limiting Step • The overall rate of a reaction is controlled by the rate of the slowest step • The rate depends on the concentration of the species and the rate constant of the step • The step with the largest energy of activation is the rate-limiting or rate-determining step. • See Figure 11.9 – the same step is rate-determining in both directions)

32. SN1 Energy Diagram k1 k-1 k2

34. Stereochemistry of SN1 Reaction • The planar carbocation intermediate leads to loss of chirality • Product is racemic or has some inversion

36. Stereochemistry of SN1 Reaction • Carbocation is usually biased to react on side opposite leaving group because it is unsymmetrically solvated • The second step may occur with the carbocation loosely associated with leaving group. • The result is racemization with some inversion:

37. Effects of Ion Pair Formation

38. Prob. 11.9: What is the % inversion & racemization?

39. 11.9 Characteristics of the SN1 Reaction • Tertiary alkyl halide is most reactive by this mechanism • Controlled by stability of carbocation

40. Relative Reactivity of Halides:

41. Delocalized Carbocations • Delocalization of cationic charge enhances stability • Primary allyl is more stable than primary alkyl • Primary benzyl is more stable than allyl

43. Allylic and Benzylic Halides • Allylic and benzylic intermediates stabilized by delocalization of charge (See Figure 11-13) • Primary allylic and benzylic are also more reactive in the SN2 mechanism

45. Relative SN1 rates (formolysis):RCl + HCOO-1

46. Formation of the allylic cation:

47. Effect of Leaving Group on SN1 • Critically dependent on leaving group • Reactivity: the larger halides ions are better leaving groups • In acid, OH of an alcohol is protonated and leaving group is H2O, which is still less reactive than halide • p-Toluensulfonate (TosO-) is an excellent leaving group

48. Nucleophiles in SN1 • Since nucleophilic addition occurs after formation of carbocation, reaction rate is not normally affected by nature or concentration of nucleophile • The nucleophile must be preferably neutral (not basic; example: CH3OH rather than CH3O-) to prevent competition with elimination reactions.

50. Solvent Is Critical in SN1 • The solvent stabilizes the carbocation, and also stabilizes the associated transition state. This controls the rate of the reaction. Solvation of a carbocation by water