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Organic Chemistry

Organic Chemistry. William H. Brown & Christopher S. Foote. Nucleophilic Substitution and  -Elimination. Chapter 8. Chapter 8. Nucleophilic Substitution. Nucleophilic substitution: any reaction in which one nucleophile is substituted for another at a tetravalent carbon

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Organic Chemistry

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  1. Organic Chemistry William H. Brown & Christopher S. Foote

  2. Nucleophilic Substitution and -Elimination • Chapter 8 Chapter 8

  3. Nucleophilic Substitution • Nucleophilic substitution:any reaction in which one nucleophile is substituted for another at a tetravalent carbon • Nucleophile: a molecule or ion that donates a pair of electrons to another molecule or ion to form a new covalent bond; a Lewis base

  4. Nucleophilic Substitution • An important reaction of alkyl halides

  5. Solvents • Protic solvent: a solvent that is a hydrogen bond donor • the most common protic solvents contain -OH groups • Aprotic solvent: a solvent that cannot serve as a hydrogen bond donor • nowhere in the molecule is there a hydrogen bonded to an atom of high electronegativity

  6. Dielectric Constant • Solvents are classified as polar and nonpolar • the most common measure of solvent polarity is dielectric constant • Dielectric constant: a measure of a solvent’s ability to insulate opposite charges from one another • the greater the value of the dielectric constant of a solvent, the smaller the interaction between ions of opposite charge dissolved in that solvent • polar solvent: dielectric constant > 15 • nonpolar solvent: dielectric constant < 15

  7. Protic Solvents

  8. Aprotic Solvents

  9. Mechanisms • Chemists propose two limiting mechanisms for nucleophilic displacement • a fundamental difference between them is the timing of bond breaking and bond forming steps • At one extreme, the two processes take place simultaneously; designated SN2 • S = substitution • N = nucleophilic • 2 = bimolecular (two species are involved in the rate-determining step)

  10. Mechanism - SN2 • both reactants are involved in the transition state of the rate-determining step

  11. Mechanism - SN2

  12. Mechanism - SN1 • Bond breaking between carbon and the leaving group is entirely completed before bond forming with the nucleophile begins • This mechanism is designated SN1 where • S = substitution • N = nucleophilic • 1 = unimolecular (only one species is involved in the rate-determining step)

  13. Mechanism - SN1 • Step 1: ionization of the C-X bond gives a carbocation intermediate

  14. Mechanism - SN1 • Step 2: reaction of the carbocation with methanol gives an oxonium ion. Attack occurs with equal probability from either face of the planar carbocation • Step 3: proton transfer completes the reaction

  15. Mechanism - SN1

  16. Evidence of SN reactions 1. What is the rate of an SN reaction affected by: • the structure of Nu? • the structure of RX? • the structure of the leaving group? • the solvent? 2. What is the stereochemistry of the product if the Nu attacks at a stereocenter? 3. When and how does rearrangement occur?

  17. Kinetics • For an SN1 reaction, the rate of reaction is first order in haloalkane and zero order in nucleophile

  18. Kinetics • For an SN2 reaction, the rate is first order in haloalkane and first order in nucleophile

  19. Nucleophilicity • Nucleophilicity: a kinetic property measured by the rate at which a Nu causes a nucleophilic substitution under a standardized set of experimental conditions • Basicity: a equilibrium property measured by the position of equilibrium in an acid-base reaction • Because all nucleophiles are also bases, we study correlations between nucleophilicity and basicity

  20. Nucleophilicity

  21. Nucleophilicity • Relative nucleophilicities of halide ions in polar aprotic solvents are quite different from those in polar protic solvents • How do we account for these differences?

  22. Nucleophilicity • A guiding principle is the freer the nucleophile, the greater its nucleophilicity • Polar aprotic solvents (e.g., DMSO, acetone, acetonitrile, DMF) • are very effective in solvating cations, but not nearly so effective in solvating anions. • because anions are only poorly solvated, they participate readily in SN reactions, and • nucleophilicity parallels basicity: F- > Cl- > Br- > I-

  23. Nucleophilicity • Polar protic solvents (e.g., water, methanol) • anions are highly solvated by hydrogen bonding with the solvent • the more concentrated the negative charge of the anion, the more tightly it is held in a solvent shell • the nucleophile must be at least partially removed from its solvent shell to participate in SN reactions • because F- is most tightly solvated and I- the least, nucleophilicity is I- > Br- > Cl- > F-

  24. Nucleophilicity • Generalizations • within a period, nucleophilicity increases from left to right; that is, it increases with basicity

  25. Nucleophilicity • Generalizations • in a series of reagents with the same nucleophilic atom, anionic reagents are stronger nucleophiles than neutral reagents

  26. Nucleophilicity • when comparing groups of reagents in which the nucleophilic atom is the same, the stronger the base, the greater the nucleophilicity

  27. Stereochemistry • For an SN1 reaction at a stereocenter, the product is almost completely racemized

  28. Stereochemistry • For SN1 reactions at a stereocenter • examples of complete racemization have been observed, but • partial racemization with a slight excess of inversion is more common

  29. Stereochemistry • For SN2 reactions at a stereocenter, there is inversion of configuration at the stereocenter • Experiment of Hughes and Ingold

  30. Hughes-Ingold Expt • the reaction is 2nd order, therefore, SN2 • the rate of racemization of enantiomerically pure 2-iodooctane is twice the rate of incorporation of I-131

  31. Structure of RX • SN1 reactions governed by electronic factors; • the relative stabilities of carbocation intermediates • SN2 reactions governed by steric factors; • the relative ease of approach of the nucleophile to the site of reaction

  32. Effect of -Branching

  33. Effect of -Branching

  34. Allylic Halides • Allylic cations are stabilized by resonance delocalization of the positive charge • a 1° allylic cation is about as stable as a 2° alkyl cation

  35. Allylic Cations • 2° & 3° allylic cations are even more stable • As also are benzylic cations

  36. The Leaving Group • The more stable the anion, the better the leaving ability • the most stable anions are the conjugate bases of strong acids

  37. The Solvent - SN2 • The most common type of SN2 reaction involves a negative Nu and a negative leaving group • the weaker the solvation of Nu, the less the energy required to remove it from its solvation shell and the greater the rate of SN2

  38. The Solvent - SN2

  39. The Solvent - SN1 • SN1 reactions involve creation and separation of unlike charge in the transition state of the rate-determining step • Rate depends on the ability of the solvent to keep these charges separated and to solvate both the anion and the cation • Polar protic solvents (formic acid, water, methanol) are the most effective solvents for SN1 reactions

  40. The Solvent - SN1

  41. Rearrangements in SN1 • Rearrangements are common in SN1 reactions if the initial carbocation can rearrange to a more stable one

  42. Rearrangements in SN1 • Mechanism of a carbocation rearrangement

  43. Summary of SN1 & SN2

  44. Neighboring Groups • In an SN1 reaction, departure of the leaving group is not assisted by Nu • In an SN2 reaction, departure of the leaving group is assisted by Nu • These two types are distinguished by their order of reaction; SN2 reactions are 2nd order, and SN1 reactions are 1st order • But some reactions are 1st order and yet involve two successive SN2 reactions

  45. Mustard Gases • Mustard gases • contain either S-C-C-X or N-C-C-X • what is unusual about the mustard gases is that they undergo hydrolysis so rapidly in water, a very poor nucleophile

  46. Mustard Gases • the reason is neighboring group participation by the adjacent heteroatom • proton transfer to solvent completes the reaction

  47. SN1/SN2 Problems • Problem 1: predict the mechanism for this reaction, and the stereochemistry of each product • Problem 2: predict the mechanism of this reaction

  48. SN1/SN2 Problems • Problem 3: predict the mechanism of this reaction and the configuration of product • Problem 4: predict the mechanism of this reaction

  49. SN1/SN2 Problems • Problem 5: predict the mechanism of this reaction

  50. Phase-Transfer Catalysis • A substance that transfers ions from an aqueous phase to an organic phase • An effective phase-transfer catalyst must have sufficient • hydrophilic character to dissolve in water and form an ion pair with the ion to be transported • hydrophobic character to dissolve in the organic phase and transport the ion into it • The following salt is an effective phase-transfer catalysts for the transport of anions

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