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Substitution Reactions of Alkyl Halides: Chapter 8

Substitution Reactions of Alkyl Halides: Chapter 8. Contents of Chapter 8. Reactivity Considerations The S N 2 Reaction Reversibility of the S N 2 Reaction The S N 1 Reaction Stereochemistry of S N 2 and S N 1 Reactions Benzylic, Allylic, Vinylic & Aryl Halides

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Substitution Reactions of Alkyl Halides: Chapter 8

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  1. Substitution Reactions of Alkyl Halides:Chapter 8 Chapter 8

  2. Contents of Chapter 8 • Reactivity Considerations • The SN2 Reaction • Reversibility of the SN2 Reaction • The SN1 Reaction • Stereochemistry of SN2 and SN1 Reactions • Benzylic, Allylic, Vinylic & Aryl Halides • Competition between SN2 and SN1 Reactions • Role of the Solvent • No Biological Methylating Reagents Chapter 8

  3. Substitution and Elimination • A compound with an sp3 hybridized carbon bonded to a halogen can undergo two types of reactions • Two different mechanisms for substitution are SN1 and SN2 mechanisms • These result in diff prods under diff conditions Chapter 8

  4. SN2 Mechanism SN2 mechanism: C–X bond weakens as nucleophile approaches all in one step Chapter 8

  5. SN1 Mechanism • SN1 mechanism: C–X bond breaks first without any help from nucleophile slow step fast step • This is a two-step process Chapter 8

  6. Substitution Reactions • Both mechanisms are called nucleophilic substitutions • Which one takes place depends on • the structure of the alkyl halide • the reactivity and structure of the nucleophile • the concentration of the nucleophile, and • the solvent in which reaction is carried out Chapter 8

  7. The SN2 Reaction • Bimolecular nucleophilic substitution • rate = k [alkyl halide][nucleophile] Chapter 8

  8. The SN2 Reaction • The inversion of configuration resembles the way an umbrella turns inside out in the wind • If a single chiral enantiomer reacts a single chiral product (inverted) results. Chapter 8

  9. Steric Accessibility in the SN2 Reaction Chapter 8

  10. The SN2 Reaction: Leaving Group Stability Chapter 8

  11. The SN2 Reaction: Nucleophile Basicity stronger base weaker base better nucleophile poorer nucleophile HO– > H2O CH3O– > CH3OH –NH2 > NH3 CH3CH2NH– > CH3CH2NH2 Chapter 8

  12. The SN2 Reaction: Nucleophile Basicity Comparing nucleophiles with attacking atoms of approximately the same size, the stronger base is also the stronger nucleophile Chapter 8

  13. The SN2 Reaction: Nucleophile Size In nonpolar solvents nucleophilicity order same as basicity order- size doesn’t matter Chapter 8

  14. The SN2 Reaction: Nucleophile Size Size is related to polarizability Chapter 8

  15. The SN2 Reaction: Nucleophile Size and Type Nucleophilicity ~ both size and basicity Chapter 8

  16. ethoxide ion tert-butoxide ion better nucleophile stronger base The SN2 Reaction: Nucleophile Bulkiness • Nucleophilicity is affected by steric effects • A bulky nucleophile has difficulty getting near the back side of a sp3 carbon Chapter 8

  17. The SN1 Reaction The more stable the C+ the lower the DG‡, and the faster the rxn Chapter 8

  18. The SN1 Reaction Chapter 8

  19. The SN1 Reaction The SN1 reaction leads to a mixture of stereoisomers Chapter 8

  20. The SN1 Reaction: Factors Affecting the Rate • Two factors affect the rate of formation of the carbocation • ease with which the leaving group leaves RI > RBr > RCl > RF increasing reactivity • stability of the carbocation 3ºalkyl halide > 2º alkyl halide > 1º alkyl halide increasing reactivity Chapter 8

  21. The SN1 Reaction: Carbocation Rearrangements Chapter 8

  22. Stereochemistry of SN2 and SN1 Reactions inversion both enantiomers Chapter 8

  23. Competition Between SN2 and SN1 Reactions Chapter 8

  24. Competition Between SN2 and SN1 Reactions TABLE 9.6 Summary of the Reactivity of Alkyl Halides in Nucleophilic Substitution Reactions methyl & 1o alkyl halides SN2 only 2o alkyl halides SN2 & SN1 3o alkyl halides SN1 only vinylic & aryl halides neither SN2 nor SN1 benzylic & allylic halides SN2 & SN1 3o benzylic & allylic halides SN1 only Chapter 8

  25. Competition Between SN2 and SN1 Reactions What are the factors that determine which mechanism operates? • concentration of the nucleophile • reactivity of the nucleophile • solvent in which the reaction is carried out For SN2 rate = k2 [alkyl halide][nucleophile] For SN1 rate = k1 [alkyl halide] Chapter 8

  26. Competition Between SN2 and SN1 Reactions • An increase in the concentration of the nucleophile increases the rate of the SN2 reaction but has no effect on rate of SN1 reaction • An increase in the reactivity of nucleophile also speeds up an SN2 rxn but not an SN1 rxn Chapter 8

  27. Role of the Solvent • The solvent in which a nucleophilic substitution reaction is carried out has an influence on whether the reaction proceeds via an SN2 or an SN1 mechanism • Two important solvent aspects include • solvent polarity • whether it is protic or aprotic Chapter 8

  28. Solvent Polarity The dielectric constant is a measure of how well the solvent can insulate opposite charges from each other Chapter 8

  29. Role of the Solvent • Polar solvents have a high dielectric constant • Water • Alcohols • Dimethylsulfoxide (DMSO) • Solvents having O–H or N–H bonds are called protic solvents • Polar solventswithout O-H or N-H bonds called polar aprotic solvents Chapter 8

  30. Role of the Solvent • If charge on reactants(s) in slow step is greater than the charge on the transition state, a polar solvent will slow down rxn (by stabilizing reactants) • If all reactant(s) involved in slow step are neutral polar solvent will speed up rxn • If reactant(s) involved in slow step are charged polar solvent slows down rxn Chapter 8

  31. SN1 Reaction: Effect of Solvent • Most SN1 reactions involve a neutral alkyl halide which needs to produce a C+ • Consequently a polar solvent stabilizes the transition state more than the reactant • Increasing the polarity of the solvent speeds up such an SN1 reaction • Protic solvents stabilize the leaving group by H-bonding and thus stabilize the transition state Chapter 8

  32. SN2 Reaction: Effect of Solvent • Most SN2 reactions involve a neutral alkyl halide and a charged nucleophile • Consequently a polar solvent stabilizes the nucleophile more than the transition state and slows rxn • The nucleophiles used in SN2 reactions however are generally insoluble in nonpolar solvents - some solvent polarity is needed, but it’s best to use an aprotic solvent to avoid overstabilizing nucleophile reactant Chapter 8

  33. Competition Between SN2 and SN1 Reactions • When a halide can undergo both an SN2 and SN1 reaction: • SN2 will be favored by a high concentration of a good (negatively charged) nucleophile • SN2 will be favored in a polar aprotic solvent • SN1 will be favored by a poor (neutral) nucleophile in a polar protic solvent Chapter 8

  34. Problem-solving Info • Nucleophile strength • Protic solvent • Size most important • Look at basicity if same row of periodic table • Aprotic solvent- look at basicity only • Strength in aprotic solvent > protic solvent • First two points not strictly true but will work in this course Chapter 8

  35. Problem-solving Info • Electrophile strength • SN2 reactions • Steric accessibility • Electron withdrawing group (EWG) attached to C reaction site • Good leaving group • SN1 reactions • Carbocation stability • EWG not attached to reaction site • Good leaving group Chapter 8

  36. Problem-solving Info • Solvent polarity • Reduces rate with charged reactants • Charge on both nucleophile and electrophile important in SN2 • Only electrophile important in SN1 • Increases rate with uncharged reactants • Reduces nucleophilicity • Stabilizes leaving group for SN1 Chapter 8

  37. Problem-solving Info • Reaction speed comparisons • Increasing speed in SN1 reaction • Polar solv/uncharged electrophile, vice-versa • Relief of steric strain making C+ • More stable carbocation formed • Anything which destabilizes electrophile • Increased leaving group stability (less basic) • Increasing speed in SN2 reaction • Charge on electrophile & nuc vs. solv polarity Chapter 8

  38. Problem-solving Info • Increased leaving group stability • Less steric hindrance (both nuc & electrophile) • Switch from protic to aprotic solvent • Higher concentration of nucleophile • More basic nucleophile • Larger size of nucleophile’s attacking atom • Anything which destabilizes nuc or electrophile • Stereochemistry • SN1 reactions give both isomers at chiral C • SN2 reactions give only inversion at chiral C Chapter 8

  39. Problem-solving Info • Carbocation rearrangements • Will occur if posible with SN1 • Will not occur with SN2 • SN1 vs SN2 chemistry • Conditions which give SN1 • Tertiary C reaction center • C+ stability  2 & weak nuc (H-nuc pKa <7) • Carboxylates and sulfonates • Neutral O nucleophiles • Halides • Neutral large-atom (row >2) nucleophiles Chapter 8

  40. Problem-solving Info • Conditions which give SN2 • C+ stability index = 1 and unhindered rxn site • C+ stability  2, not 3°, strong nucleophile • Any nuc with conj acid pKa  7 (Table 10.3 pg 373) • Alkoxides and hydroxide • Ammonia and amines • Carbanions • Sulfides • Hydride • Nitrogen anions • In this text“high conc” of nuc is code for SN2 • Other conditions give SN1/SN2 mixture Chapter 8

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