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, 7th 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. 11.1 The Discovery of the Walden Inversion • In 1896, Paul Walden showed that (-)-malic acid could be converted to (+)-malic acid by a series of chemical steps with achiral reagents • This established that optical rotation was directly related to chirality and that it changes with chemical alteration • Reaction of (-)-malic acid with PCl5 gives (+)-chlorosuccinic acid • Further reaction with wet silver oxide gives (+)-malic acid • The reaction series starting with (+) malic acid gives (-) acid

7. The Walden Inversion (1896)

9. Significance of the Walden Inversion • The reactions involve substitution at the chiral center • Therefore, nucleophilic substitution can invert the configuration at a chirality center

10. 11.2 Stereochemistry of Nucleophilic Substitution • A more rigorous Walden cycle using 1-phenyl-2-propanol (Kenyon and Phillips, 1929) • Only the second and fifth steps are reactions at carbon • Inversion must occur in the substitution step

12. The inversion step (step 2):

13. Two Stereochemical Modes of Substitution • Substitution with inversion: • Substitution with retention: (Note: if both occur simultaneously, the result is racemization)

14. Hughes’ Proof of Inversion • React S-2-iodo-octane with radioactive iodide • Observe that racemization (loss of optical activity) of mixture is twice as fast as incorporation of label • Racemization in one reaction step would occur at same rate as incorporation

15. Hughes’ Proof of Inversion

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

17. 11.3 Kinetics of Nucleophilic Substitution • Rate is the change in concentration with time • Depends on concentration(s), temperature, inherent nature of reaction (energy of activation) • Arate law describes the relationship between the concentration of reactants and the overall rate of the reaction • A rate constant (k) is the proportionality factor between concentration and rate

18. Kinetics of Nucleophilic Substitution Rate = d[CH3Br]/dt = k[CH3Br][OH-1] This reaction is second order: two concentrations appear in the rate law SN2: Substitution Nucleophilic 2nd order

19. 11.2 The SN2 Reaction • Reaction occurs with inversion at reacting center • Follows second order reaction kinetics • Ingold nomenclature to describe rate-determining step: • S=substitution • N (subscript) = nucleophilic • 2 = both nucleophile and substrate in rate-determining step (bimolecular)

20. SN2 Process

21. 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

24. 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) 11.3 Characteristics of the SN2 Reaction

25. Reactant and Transition-state Energy Levels Affect Rate Higher reactant energy level (red curve) = faster reaction (smallerG‡). Higher transition-state energy level (red curve) = slower reaction (largerG‡).

27. Steric Effects on SN2 Reactions The carbon atom in (a) bromomethane is readily accessible resulting in a fast SN2 reaction. The carbon atoms in (b) bromoethane (primary), (c) 2-bromopropane (secondary), and (d) 2-bromo-2-methylpropane (tertiary) are successively more hindered, resulting in successively slower SN2 reactions.

28. Steric Effect in SN2

29. Steric Hindrance Raises Transition State Energy Very hindered • Steric effects destabilize transition states • Severe steric effects can also destabilize ground state

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

31. Vinyl and Aryl Halides:

32. Order of Reactivity in SN2

33. 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

34. For example:

36. 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

38. 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

39. The Leaving Group

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

41. Converting a poor LG to a good LG:

42. 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

43. Some Polar Aprotic Solvents

45. 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

46. Prob. 11.37 Arrange in order of SN2 reactivity

47. 11.4 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:

48. SN1 Reactivity:

49. SN1 Energy Diagram

50. 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)