Nucleophilic Substitutions of Alkyl Halides

1. Chapter 7-2. Reactions of Alkyl Halides: Nucleophilic Substitutions Based on McMurry’s Organic Chemistry, 6th edition

2. Polarity and Reactivity • Halogens are more electronegative than C. • Carbon-halogen bond is polar, so carbon has partial positive charge. • Carbon can be attacked by a nucleophile. • Halogen can leave with the electron pair.

3. 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)

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

5. Substitution vs. Elimination

6. 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.

7. SN2 Mechanism • One step: bond forming and bond breaking at same time. “concerted” process • Bimolecular nucleophilic substitution. • Rate = k [HO-] [CH3Br], first order in each reactant second order overall • Inversion of configuration.

8. 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

9. => SN1 Mechanism(1) Formation of carbocation (slow)

11. SN1 Mechanism (2) • Nucleophilic attack • Loss of H+ (if needed)

12. SN1 Energy Diagram • Forming the carbocation is endothermic • Carbocation intermediate is in an energy well.

13. SN1 Mechanism • Unimolecular nucleophilic substitution. • Two step reaction with carbocation intermediate. • Rate = k [RX] first order in the alkyl halidezero order in the nucleophile. • Racemization occurs.

14. Factors affecting the rates of SN Reactions • Concentration • Nature of the alkyl group • Nature of the nucleophile • Nature of the leaving group • Nature of the solvent

15. Structure of Substrate • Relative rates for SN2: CH3X > 1° > 2° >> 3° • Tertiary halides do not react via the SN2 mechanism, due to steric hindrance.

16. SN2: Reactivity of Substrate • Carbon must be partially positive. • Must have a good leaving group • Carbon must not be sterically hindered.

17. 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

18. For example:

19. Relative Reactivity of Nucleophiles • Depends on reaction and conditions • More basic nucleophiles react faster • Better nucleophiles are lower in a column of the periodic table • Anions are usually more reactive than neutrals

20. Nucleophilic Strength • Stronger nucleophiles react faster in SN2. • Strong bases are strong nucleophiles, but not all strong nucleophiles are basic.

21. Bulky Nucleophiles Sterically hindered for attack on carbon, so weaker nucleophiles.

22. Trends in Nuc. Strength • Decreases left to right on Periodic Table. More electronegative atoms less likely to form new bond: OH- > F-NH3 > H2O • Increases down Periodic Table, as size and polarizability increase: I- > Br- > Cl- • Of a conjugate acid-base pair, the base is stronger: OH- > H2O, NH2- > NH3

25. Polarizability Effect

26. 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

27. Leaving Group Ability • Electron-withdrawing • Stable once it has left (not a strong base) • Polarizable to stabilize the transition state.

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

30. Solvent Effects (1) Polar protic solvents (O-H or N-H) reduce the strength of the nucleophile. Hydrogen bonds must be broken before nucleophile can attack the carbon.

31. Solvent Effects (2) • Polar aprotic solvents (no O-H or N-H) do not form hydrogen bonds with nucleophile • Examples:

32. Rates of SN1 Reactions • 3° > 2° > 1° >> CH3X • Order follows stability of carbocations (opposite to SN2) • More stable ion requires less energy to form • Better leaving group, faster reaction (like SN2) • Polar protic solvent best: It solvates ions strongly with hydrogen bonding.

33. 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

34. Stereochemistry of SN2 Walden inversion SN2: Substitution Nucleophilic 2nd order

35. SN2 Energy Diagram • One-step reaction. • Transition state is highest in energy.

36. 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

38. Stereochemistry of SN1 Racemization: inversion and retention =>

39. Two Stereochemical Modes of Substitution • Substitution with inversion: • Substitution with retention:

40. The Walden Inversion (1896)

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

43. 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

45. 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

46. Hughes’ Proof of Inversion

47. Rearrangements • Carbocations can rearrange to form a more stable carbocation. • Hydride shift: H- on adjacent carbon bonds with C+. • Methyl shift: CH3- moves from adjacent carbon if no H’s are available.

48. Hydride Shift

49. Methyl Shift

50. Primary or methyl Strong nucleophile Polar aprotic solvent Rate = k[halide][Nuc] Inversion at chiral carbon No rearrangements Tertiary Weak nucleophile (may also be solvent) Polar protic solvent, silver salts Rate = k[halide] Racemization of optically active compound Rearranged products SN2 or SN1?