1. Organic Chemistry Chapter 8

2. Substitution and Elimination If an sp 3 C is bonded to electronegative atom Substitution reactions and Elimination reactions are possible This chapter is all about substitution

3. S N 2 and S N 1 Reactions SN2 - Reaction – bonds break and form at the same time example SN1 - CX bond breaks, forming a C+ then reacts with a nucleophile SN1SN1 SN2SN2

4. Nucleophilic Substitution Reactions Either mechanism depends on the: structure of the alkyl halide reactivity of the nucleophile concentration of the nucleophile The solvent in which the Rx is carried out The leaving group

5. S N 2 Mechanism It’s a Substitution Reaction (S) It’s Nucleophilic (N) It’s rate is second order (2) –Called bimolecular (rate is dependent on 2 reactants) (Substitution Nucleophilic Bimolecular) Rate = k [RX] [Nu:] (Because rate is dependent of BOTH RX and Nu: it is 2 nd. order.)

6. S N 2 Mechanism S N 2 Mechanism involves a “backside attack”

7. S N 2 Mechanism The “backside attack” causes an Inversion of Configuration Careful now….. Doesn’t mean R becomes S – new atoms are involved

8. Steric Hindrance Groups that block the path from the nucleophile to the electrophilic atom produce steric hindrance This results in a rate differences or no reaction at all methyl halide ethyl halide isopropyl halide t-butyl halide

9. Steric Hindrance Activation Energy is higher due to steric hindrance…..

10. Substitution Reactions Depend on a Good Leaving Group R-Falkyl fluorides R-Clalkyl chlorides R-Bralkyl bromides R-Ialkyl iodides Alkyl Halides make good “leaving groups” –They are easily displaced by another atom –They allow the Conversion of alkyl halides to other functional groups

12. S N 2 Mechanism The Leaving Groups also affects rate RI reacts fastest, RF slowest –Iodide is the best “leaving group” –Fluoride is the worst “leaving group” (…reacting with the same alkyl halide under the same conditions)

13. Basicity The weaker the basicity of a group, the better the leaving ability. (Lewis base = e - pair donor) –Leaving ability depends on basicity because a weak base does not SHARE its e - as well as a strong base. –Weak bases are not strongly bonded to a carbon (weak bases are GOOD leaving groups)

14. Nucleophiles – Strong/Weak Good/Bad Stronger base Weaker base Better nucleophile poorer nucleophile OH - >H 2 O CH 3 O - >CH 3 OH - NH 2 >NH 3 CH 3 CH 2 NH - >CH 3 CH 2 NH 2 (conjugate acids)

15. Nucleophiles The strength of nucleophile depends on reaction conditions. In the GAS phase (not usually used), direct relationship between basicity and nucleophilicity

16. Solvent Effects In a solution phase reaction, the solvent plays a large role in how the reaction will occur Solvent effects can cause just the opposite of what might be the expected behavior of the nucleophile Solvents are categorized as either protic or aprotic

17. Protic Solvents Protic solvents has a H bonded to a N or O –It is a H bonder –Examples: H 2 O, CH 3 OH, NH 3, etc –Solvent is attracted to the Nucleophile and hinders its ability to attack the electrophile

18. Aprotic Solvents Use an aprotic solvent Solvates cations Does not H bond with anions (nucleophile free) Partial + charge is on inside of molecule Negative charge on surface of molecule (solvates cation) Examples include: –DMSO (dimethyl sulfoxide) –DMF (dimethyl formamide) –Acetone (CH 3 COCH 3 ) DMSO DMF

19. Nucleophiles In the organic solvent phase, INVERSE relationship between basicity and nucleophilicity with a protic solvent Question…

20. Nucleophiles Solvents can solvate the nucleophile –Usually this is NOT good because the nucleophile is “tied up” in the solvent and LESS REACTIVE. Ion-dipole interactions

21. Nucleophiles Solvents can solvate the nucleophile (Methanol is a polar protic solvent.)

22. S N 2 Reactions

24. S N 2 reactions might be reversible Leaving group would become the nucleophile Compare basicity (nucleophile strength) to see which is a better leaving group. The stronger base will displace the weaker base –If basicity is similar, the Rx will be reversible

25. S N 2 Reactions Compare basicity to see which is a better nucleophile.

27. S N 1 Reactions Reaction of t-butyl bromide with water should be slow –water is a poor nucleophile –t-butyl bromide is sterically hindered However –Reaction is a million times faster than with CH 3 Br (Maybe not an S N 2 reaction!)

28. S N 1 Reactions

29. S N 1 Mechanism Rate determining step does not involve nucleophile Step 2 Step 1

30. S N 1 Mechanism

31. S N 1 Reactivity Relative Reactivities in an S N 1 Reaction 1 o RX < 2 o RX < 3 o RX Increasing Reactivity

32. S N 1 Stereochemistry Because a planer carbocation is formed, nucleophilic attack is possible on both sides, so both isomers are possible

33. S N 1 Stereochemistry SN1 should yield racemic mixture but it doesn’t This is due to the steric hindrance of the leaving group

34. Stereochemistry As the leaving group goes (Marvin K) it blocks the path of any incoming nucleophiles

35. S N 1 vs S N 2 Inversion of configuration racemization with partial inversion

36. What Makes S N 1 Reactions work the best Good Leaving Group –The weaker the base, the less tightly it is held (I - and Br - are weak bases) Carbocation –How stable is the resulting carbocation? 3 o > 2 o > 1 o > methyl Increasing Stability

37. What Doesn’t Matter In an S N 1 Reactions The Nucleophile It has NO EFFECT on rate of Rx!!! Solvolysis Reactions (the nucleophile is also the solvent)

38. Carbocation Rearrangements Since a carbocation is the intermediate, you may see rearrangements in an S N 1 Rx No rearrangements in an SN2 Rx

39. Carbocation Rearrangement Methyl Shift

40. Benzylic, Allylic, Vinylic, and Aryl Halides Benzylic and allylic halides can readily undergo S N 2 unless they are 3 o –(steric hindrance)

41. Benzylic, Allylic, Vinylic, and Aryl Halides B enzylic and allylic halides can also undergo S N 1 (they form stable carbocations) Even though 1 o RX do not go S N 1, 1 o benzylic and 1 o allylic CAN react S N 1!

42. Vinylic,and Aryl Halides Vinylic halides and aryl halides –do not undergo S N 1 or SN 2 reactions!  e - repel incoming Nucleophile

43. S N 1 vs S N 2 Review

44. S N 1 vs S N 2 Methyl, 1 o RX … 2 o RX … 3 o RX … Vinylic, aryl RX … 1 o, 2 o benzylic, allylic RX … 3 o benzylic, allylic RX … S N 2 only S N 1 and S N 2 S N 1 only neither S N 1 nor S N 2 S N 1 and S N 2 S N 1 only

45. Role of the Solvent In an S N 1, a carbocation and halide ion are formed –Solvation provides the energy for X - being formed –In S N 1 the solvent “pulls apart” the alkyl halide –S N 1 cannot take place in a nonpolar solvent or in the gas phase –Increasing the polarity of the solvent will INCREASE the rate of Rx if none of the REACTANTS are charged. –If reactants are charged it will DECREASE the rate.

46. Role of the Solvent So…. In an S N 1 reaction, the reactant is RX. The intermediate is charged and is STABILIZED by a POLAR solvent A POLAR solvent increases the rate of reaction for an S N 1 reaction. (However, this is true only if the reactant is uncharged.)

47. *

48. Role of the Solvent In S N 2 In an S N 2 reaction, one of the reactants is the nucleophile (usually charged). The POLAR solvent will usually stabilize the nucleophile. A POLAR solvent decreases the rate of reaction for an S N 2 reaction. (However, this is true only if the nucleophile is charged.)

49. Polar Aprotic Solvents Polar Aprotic Solvents include: –DMFN,N-dimethylformamide –DMSOdimethylsulfoxide –HMPAhexamethylphosphoramide –THFTetrahydrofuran –And even… acetone

50. Polar Aprotic Solvents –do not H bond –solvate cations well –do NOT solvate anions (nucleophiles) well –good solvents for S N 2 reactions

51. Polar Aprotic Solvents DMSO DMF Acetone HMPA

52. Nucleophile Review

54. S N 1/S N 2 Problems -1 Predict the type of mechanism for this reaction, and the stereochemistry of each product

55. S N 1/S N 2 Problems -1 Predict the type of mechanism for this reaction, and the stereochemistry of each product

56. S N 1/S N 2 Problems -2 Predict the mechanism of this reaction

57. S N 1/S N 2 Problems -2 Predict the mechanism of this reaction

58. S N 1/S N 2 Problems -3 Predict the mechanism. If the starting material has the R configuration, predict the configuration of product

59. S N 1/S N 2 Problems -3 Predict the mechanism. If the starting material has the R configuration, predict the configuration of product

60. S N 1/S N 2 Problems -4 Predict the mechanism + acetic acid Br OCCH 3 O O CH 3 COH + HBr

61. S N 1/S N 2 Problems -4 Predict the mechanism + acetic acid Br OCCH 3 O O CH 3 COH + HBr

62. S N 1/S N 2 Problems -5 Predict the mechanism

63. S N 1/S N 2 Problems -5 Predict the mechanism

64. END