11. Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

1. 11. Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

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) • Nucleophiles that are Brønsted bases produce elimination d+ Acts as Nucleophile d+ Acts as Base

3. Why this Chapter? • Nucleophilic substitution, base induced elimination are among most widely occurring and versatile reaction types in organic chemistry • Reactions will be examined closely to see: • How they occur • What their characteristics are • How they can be used

4. 11.1 The Discovery of Nucleophilic Substitution Reactions:Walden Inversion • In 1896, 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

5. Reactions of the Walden Inversion • The reactions alter the array at the chirality center • The reactions involve substitution at that center • Therefore, nucleophilic substitution can invert the configuration at a chirality center • The presence of carboxyl groups in malic acid led to some dispute as to the nature of the reactions in Walden’s cycle

6. AnotherExample: • (+)-1-phenyl-2-propanol • (-)-1-phenyl-2-propanol • Used Tosylate as an excellent leaving group

7. Kinetics of Nucleophilic Substitution • Rate (V) = change in concentration with time • Depends on concentration(s), temperature, inherent nature of reaction (barrier on energy surface) • Arate lawdescribes relationship between the concentration of reactants and conversion to products • The rate law is a result of the mechanism • A rate constant (k) is the proportionality factor between concentration and rate • Kinetics = The study of rates of reactions • Rates ↓ as concentrations ↓ but k stays same • Rate units: [concentration]/time such as L/(mol x s) • The orderof a reaction is sum of the exponents of the concentrations in the rate law

8. 11.2 The SN2 Reaction • Reaction is with inversion at reacting center • Follows second order reaction kinetics • Ingold nomenclature to describe characteristic step: • S=substitution; N (subscript) = nucleophilic; 2 = both nucleophile and substrate in characteristic step (bimolecular) Rate is dependant on both Nucleophile & Substrate Rate = k [CH3-Br] [HO-]

9. SN2 Process The reaction involves a transition state in which both reactants are together

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

11. 11.3 Characteristics of the SN2Rxn 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‡).

12. The Substrate: Steric Effects on SN2 Reactions • SN2 Sensitive to steric effects 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.

13. The Substrate: Steric Effects : Order of Reactivity in SN2 • SN2 Sensitive to steric effects • No reaction at C=C (vinyl or Aryl halides)

14. The Nucleophile:in SN2 • Neutral or negatively charged Lewis base • Reaction increases coordination at nucleophile • Neutral nucleophile acquires positive charge • Anionic nucleophile becomes neutral d+ d+

15. The Nucleophile: Relative Reactivity in SN2 • 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 Nucleophiles

16. The Nucleophile: Examples

17. The Leaving Group: in SN2 • Stable anions that are weak bases are usually excellent leaving groups and can delocalize charge • very basic or very small grps are poor leaving groups • . Alkyl fluorides, alcohols, ethers, and amines do not typically undergo SN2 reactions.

18. The Leaving Group: in SN2 • -OH needs to be turned into a good leaving group. • So can convert to a • Cl • Br • Tos • Which are excellent leaving groups. (p-toluenesufonylchloride p-TosCl)

19. The Leaving Group: in SN2 • O of the epoxide can be turned into a good leaving group so epoxide can be opened with a weak nucleophile. • Addition of an acid (H+) will make epoxide C’s more electrophilic. • Cl- attacks less hindered site. • (If choice of epoxide C’s is 1o or 2o then major product is from attack at less hindered 1o • If choice of epoxide C’s is 1ovs 3o then major product is from attack at more + 3o) d+ d+

20. The Solvent: in SN2 • Solvents that can donate hydrogen bonds (protic) (-OH or –NH) slow SN2 reactions by associating with reactants • Energy is required to break interactions between reactant and solvent Caged nucleophiles can’t attack so well

21. The Solvent: in SN2 Poor for SN2 Good for SN2 Protic solvents (with -OH or –NH) slow SN2 reactions by complexing with reactants Polar aprotic solvents (no NH, OH, SH) form weaker interactions with substrate and permit fast SN2 reactions

22. 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 addition of the nucleophile

23. SN1 Reaction The reaction involves a planar carbocation intermediate

24. SN1 Energy Diagram • Called an SN1 reaction since rate is dependant only on substrate • SN1 occurs in two distinct steps while SN2 occurs with both events in same step • The slowest step (Rate-determining step) is formation of the carbocation intermediate Rate = k [RX]

25. Stereochemistry of SN1 Reaction • The planar intermediate leads to loss of chirality since a free carbocation is achiral Nucleophile can attack either face of planar carbocation Product is racemic or has some inversion

26. Stereochemistry of SN1 Reaction • Carbocation is biased to react on side opposite leaving group • Suggests reaction occurs with carbocation loosely associated with leaving group (in an ion pair) during nucleophilic addition

27. Stereochemistry of SN1 Reaction: Effects of Ion Pair Formation • If leaving group remains associated, then product has more inversion than retention • Product is only partially racemic with more inversion than retention • Associated carbocation and leaving group is an ion pair

28. Stereochemistry of SN1 Reaction: Example:

29. Learning Check: • The optically pure tosylate shown was heated in acetic acid to yield a product mixture. If complete inversion had occurred the optically pure acetate product would have [a]D=+53.6o However the product mix has [a]D =+5.3o. What percentage racemization and what percentage inversion has occurred?

30. Solution: • The optically pure tosylate shown was heated in acetic acid to yield a product mixture. If complete inversion had occurred the optically pure acetate product would have [a]D=+53.6o However the product mix has [a]D =+5.3o. What percentage racemization and what percentage inversion has occurred? +5.3 x 100 = 9.9 % inverted +53.6 So: 90.1 % racemic

31. 11.5 Characteristics of the SN1 Rxn Substrate: in SN1 • Ability to form stable carbocation intermediate best • Tertiary alkyl halide is most reactive by this mechanism • Remember Hammond postulate,”Any factor that stabilizes a high-energy intermediate stabilizes transition state leading to that intermediate”

32. Substrate: in SN1Allylic and Benzylic Halides Allylic and benzylic intermediates stabilized by delocalization of charge

33. Learning Check: • Rank the following substances in order of their expected SN1 reactivity:

34. Solution: • Rank the following substances in order of their expected SN1 reactivity: 1 4 2 3

35. Leaving Group: in SN1 • Critically dependent on leaving group • the larger halides ions are better leaving groups • H2O, formed when OH of an alcohol is protonated in acid • p-Toluensulfonate (TosO-) is excellent leaving group A leaving group won’t leave unless it’s stable on its own. (Weak conjugate bases of strong acids make great leaving groups).

36. Leaving Group: in SN1 H2O leaving group formed when OH of alcohol is protonated in acid rds Nucleophile attacks after rds

37. Nucleophiles: in SN1 • SN1 Reaction rate is not normally affected by nature or concentration of nucleophilesince nucleophilic addition occurs after formation of carbocation. Once the carbocation is formed the rest is quick and easy regardless of nature of nucleophile.

38. The Solvent: in SN1 • Solvents that stabilize the carbocation intermediate and also transition state and speeds rate • SN1 reactions go faster with polar protic solvents that cage the carbocation intermediate.

39. The Solvent: in SN1Polar Solvents Promote Ionization • Polar, protic and unreactive Lewis base solvents facilitate R+ formation

40. Learning Check: • Predict whether the following reactions is more likely to be SN1 or SN2.

41. Solution: • Predict whether the following reactions is more likely to be SN1 or SN2. 2o benzylic; forms stable carbocations or can be attacked from behind Good leaving group SN1 Good nucleophile Polar protic solvent 1o; easily attacked from behind; wouldn’t give stable carbocation Good leaving group SN2 Good nucleophile Polar aprotic solvent

42. Learning Check: • Predict whether the following reactions is more likely to be SN1 or SN2.

43. Solution: • Predict whether the following reactions is more likely to be SN1 or SN2. SN2 SN1 1o allylic; forms stable carbocations or can be attacked from behind 2o allylic; forms stable carbocations or can be attacked from behind Good leaving group Good leaving group after protonation with H+ Strong nucleophile Weak nucleophile Polar aprotic solvent Would not stabilize a carbocation intermediate Polar protic solvent Stabilizes carbocation intermediate

44. 11.6 Biological Substitution Rxns • SN1 and SN2 reactions are common in biochemistry • Unlike in the laboratory, substrate in biological substitutions is often organodiphosphate rather than an alkyl halide

45. Biological Substitution: Examples Biosynthesis of Geraniol in Roses SN1 SN1 E1

46. Biological Substitution: Examples Biosynthesis of Adrenaline SN2

47. 11.7 Elimination Reactions: of Alkyl Halides • Opposite of addition • Generates an alkene • Can compete with substitution and decrease yield, especially for SN1 processes

48. Elimination Reactions: E1 • Competes with SN1 • Favored over SN1 when have poor Nu- that can still be a base

49. Elimination Reactions: E1 Example • Competes with SN1 • Favored over SN1 when have poor Nu- that can still be a base SN1 E1

50. Elimination Rxns: Zaitsev’s Rule • In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates