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Elimination Reactions of Alkyl Halides : Chapter 9

Elimination Reactions of Alkyl Halides : Chapter 9. Competition Between Substitution and Elimination. Contents of Chapter 9. The E2 Reaction The E1 Reaction Competition Between E2 and E1 Reactions Stereochemistry of Elimination Reactions Elimination from Cyclic Compounds

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Elimination Reactions of Alkyl Halides : Chapter 9

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  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

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