Elimination Reactions of Alkyl Halides : Chapter 9

1. Elimination Reactions of Alkyl Halides :Chapter 9 Competition Between Substitution and Elimination Chapter 9

2. Contents of Chapter 9 • The E2 Reaction • The E1 Reaction • Competition Between E2 and E1 Reactions • Stereochemistry of Elimination Reactions • Elimination from Cyclic Compounds • Competition Between Substitution and Elimination • Substitution and Elimination Reactions in Synthesis Chapter 9

3. Elimination Reactions A compound with an electronegative atom bonded to an sp3 carbon, when approached by a nucleophile/base can undergo either a substitution reaction OR an elimination reaction In this chapter we start with elimination rxns then work subst/elim competition Chapter 9

4. The E2 Reaction Chapter 9

5. The E2 Reaction: Regioselectivity 2-bromobutane has two structurally different -carbons from which to abstract a hydrogen E2 rxns give more stable alkene if possible Chapter 9

6. The E2 Reaction: Regioselectivity Zaitsev’s rule: The more substituted alkene will be formed in elimination reactions Chapter 9

7. The E2 Reaction: Regioselectivity • Zaitsev’s rule does not apply when the base is bulky • E2 Rxn is kinetically-controlled Chapter 9

8. The E2 Reaction: Regioselectivity • Zaitsev’s rule does not apply when the leaving group is poor • E2-carbanion mechanism operative Chapter 9

9. major product The E2 Reaction: Regioselectivity Zaitsev’s rule may not apply when conjugated dienes might be formed Chapter 9

10. The E2 Reaction: Regioselectivity The major product of an E2 reaction is the more substituted alkene unless: • the base is large (i.e. bulky) • the leaving group is poor (i.e. F–) • the less substituted –carbon is allylic or benzylic (ie. more stable) Chapter 9

11. The E1 Reaction • “E1” stands for “Elimination unimolecular” • The E1 reaction is a two-step reaction • The first step is rate-determining Chapter 9

12. Increasing reactivity and C+ stability The E1 Reaction Relative reactivities of alkyl halides in an E1 reaction are similar to the relative stabilities of carbocations 3o benzylic > 3o allylic > 2o benzylic > 2o allylic > 3o > 1o benzylic > 1o allylic  2o > 1o > vinyl Chapter 9

13. The E1 Reaction • E1 reaction involves a carbocation • Therefore rearrangements must be considered Chapter 9

14. Competition Between E2 and E1 Reactions Summary of the Reactivity of Alkyl Halides in Elimination Reactions primary alkyl halide E2 only unless b-hinderred secondary alkyl halide E1 and E2 tertiary alkyl halide E1 and E2 Chapter 9

15. Competition Between E2 and E1 Reactions • E2 reaction is favored by the same factors that favor SN2 reactions over SN1 • primary alkyl halide electrophiles • a high concentration of a strong base (e.g. HO– or –NH2) in 1°, 2°, or 3° electrophiles • an aprotic polar solvent in 1°, 2°, or 3° electrophiles • An E1 reaction is favored by • a weak base (e.g. a neutral solvent) • a polar protic solvent (e.g. H2O or ROH) Chapter 9

16. Stereochemistry of Elimination Reactions • If the elimination reaction removes two substituents from the same side of the molecule it is syn elimination • If the elimination reaction removes two substituents from opposite sides of the molecule it is anti elimination Chapter 9

17. The E2 Reaction: Stereochemistry • The E2 Reaction is stereoselective, but not stereospecific if 2 b H’s are available on carbon bearing eliminated H • The H leading to more stable E isomer is selected to be extracted from b carbon regardless of streochem at a carbon Chapter 9

18. In an E2 reaction, the bonds to the eliminated substituents must be in the same plane In this course E2 eliminations will all go via anti-periplanar conformation Product analysis possible by drawing Newman projections if only 1 b H is available The E2 Reaction: Stereochemistry Chapter 9

19. (2S,3S)-2-bromo-3-phenylbutane (E)-2-phenyl-2-butene (2S,3R)-2-bromo-3-phenylbutane (Z)-2-phenyl-2-butene The E2 Reaction: Stereochemistry When only one hydrogen is on the  carbon predominantly anti elimination leads to high stereospecificity Chapter 9

20. The E2 Reaction: Stereochemistry • Retro-pro-Fischer analysis can be done to track stereochemistry of reaction • For anti elimination put  H on vertical and leaving group on horizontal pos’n • Erase LG and  H, draw double bond (2S,3R)-2-bromo-3-phenylbutane Z isomer Chapter 9

21. The E1 Reaction: Stereochemistry • With C+ both syn and anti elimination can occur, so E1 reaction forms both E and Z products regardless of whether b-carbon is bonded to one or two H’s • Product stability leads to stereoselectivity but not stereospecificity Chapter 9

22. E2 Reactions of Cyclic Compounds E2 reaction of cyclic compounds follows the same stereochemical rules as from open-chain compounds Chapter 9

23. E2 Reactions of Cyclic Compounds The E2 reaction of menthyl chloride violates Zaitsev’s rule Chapter 9

24. E1 Reactions of Cyclic Compounds When a cyclohexyl chloride undergoes an E1 reaction, there is no requirement that the two groups to be eliminated be diaxial Chapter 9

25. E1 Reactions of Cyclic Compounds Carbocation rearrangements must be considered for E1 reactions Chapter 9

26. Competition Between Substitution and Elimination • Conditions that favor E2 also favor SN2 • Conditions that favor E1 also favor SN1 • No need to worry about SN2/E1 or SN1/E2 combinations • First decide whether the reaction would favor SN2/E2 or SN1/E1 reactions • If the halide is primary, only SN2/E2 need be considered • If the halide is secondary or tertiary, SN2/E2 or SN1/E1 depends on reaction condition Chapter 9

27. Competition Between Substitution and Elimination • SN2/E2 reactions are favored by high conc of a good nuc/strong base and polar aprotic solvent. • SN1/E1 reactions are favored by poor nuc/weak base and polar protic solvents Chapter 9

28. Competition Between SN2 and E2 • Primary halides generally undergo substitution, although if the halide or the base is hindered, elimination is possible, favorable if heated • Secondary halides are more difficult to predict • The stronger and more hindered the base, the more elimination product is produced • The higher the temperature, the more elimination product is produced • Tertiary halides never undergo SN2 reaction - elimination is the only possibility Chapter 9

29. Competition Between SN1 and E1 • Because SN1 and E1 reactions both proceed through a carbocation, they have the same rate-determining step • Primary halides do not undergo either SN1 or E1 reactions • For secondary and tertiary halides, raising the temperature increases the elimination product Chapter 9

30. Williamson Ether Synthesis • If you want to synthesize butyl propyl ether you have a choice of starting materials • Other ethers should be made by choosing least-hindered electrophile if possible • Ethers usually best made by SN2 rxn Chapter 9

31. ethyl bromide tert-butoxide tert-butyl ethyl ethene ion ether Williamson Ether Synthesis • If you want to prepare tert-butyl ethyl ether the starting materials must be an ethyl halide and tert-butoxide ion • When ethoxide ion and tert-butyl bromide are used, only elimination product is produced Chapter 9

32. Substitution and Elimination Reactions in Synthesis SN1/E1 conditions are rarely useful synthetically Chapter 9

33. Designing a Synthesis How would you carry out the following? Chapter 9

34. Designing a Synthesis • Under E2 conditions a tertiary halide would yield only the elimination product Chapter 9

35. Designing a Synthesis • We know also that Br2 addition to an alkene yields only the anti product • Overall we might propose: Chapter 9

36. Designing a Synthesis Chapter 9

37. Designing a Synthesis Only method we know to prepare a ketone is to add water to an alkyne Chapter 9

38. Designing a Synthesis The alkyne can be prepared by two successive E2 reactions on a vicinal dihalide Chapter 9

39. Designing a Synthesis The vicinal dihalide can be prepared via halogenation of an alkene Chapter 9

40. Designing a Synthesis The alkene can be prepared from the starting material via dehydrohalogenation Chapter 9

41. Designing a Synthesis II From this analysis we might suggest the following synthesis: Chapter 9

42. Problem-solving Info • Reaction speed comparisons • Increasing speed in E1 reaction • Polar protic solvent • Relief of steric strain making C+ • More stable carbocation formed • Anything which destabilizes electrophile • Increased leaving group stability (less basic) Chapter 9

43. Problem-solving Info • Increasing speed in E2 reaction • Polar aprotic solvent • Alkene stability • Increased leaving group stability • Higher concentration of base used • Stronger base used • Anything which destabilizes electrophile • Cyclohexanes with more or more stable antiperiplanar H’s which lead to more stable products • C- stability with bad leaving group (F) Chapter 9

44. Problem-solving Info • E1 vs E2 chemistry • Conditions which give E1 • Weak base and C+ stability  2 • Polar protic solvent and C+ stability  2 • No antiperiplanar H’s in cyclohexanes • Conditions which give E2 • Primary electrophile without b hindrance • Polar aprotic solvent • Strong/concentrated base Chapter 9

45. Problem-solving Info • Unimolecular vs. bimolecular • SN1/E1 • Weak base or bad nucleophile • Protic solvent • C+ stability  2 • SN2/E2 • Concentrated strong base or good nucleophile • Polar aprotic solvent • Primary electrophile • Substitution vs. elimination • SN1 vs. E1 • Weaker base and lower temp gives SN1 • Stronger base and higher temp gives E1 Chapter 9

46. Problem-solving Info • SN2 vs. E2 • SN2 • Primary unhindered electrophile • Larger than second row anion nucleophile • Weaker base with other substitution-enhancing cond’s • E2 • b-hindered secondary electrophile • Bulky concentrated second-row base • SN1 vs. E1 • Weaker base and lower temp gives SN1 • Stronger base and higher temp gives E1 Chapter 9

47. Problem-solving Info • Product distribution • Most stable alkene formed unless: • Bad leaving group (ie. F) gives most stable C- • b H in cyclohexane trans to leaving group • Only b H in acyclic reactant which can be antiperiplanar to leaving grp leads to Z prod • Acyclic electrophile with 1 b H & chiral a C • Must use Newman projection to predict product • Product arises from antiperiplanar elimination • Stereospecific – one enantiomer gives E, other Z • C+ rearrangements with E1 reactions!!! Chapter 9