Reactions of alkyl halides: nucleophilic Substitution and elimination

1. Reactions of alkyl halides: nucleophilic Substitution and elimination Dr. Sheppard CHEM 2412 Fall 2014 McMurry (8th ed.) sections 10.1, 11.1-11.5, 11.7-11.10, 11.12

2. Alkyl Halides • Contain F, Cl, Br, or I • Widely used in: • Synthesis (electrophilic carbon and easy functional group transitions) • Solvents (CCl4, CHCl3, CH2Cl2) • Industrial applications • Structure:

3. Properties of Alkyl Halides • Bond strength • Measured by bond dissociation energy • Inversely proportional to bond length • Electronegativity and small size of F keep bonding electrons close C-F > C-Cl > C-Br > C-I short long strong weak • Which C-X bond is easier to break, C-Cl or C-Br?

4. Properties of Alkyl Halides • Polarity • Alkyl halides have substantial dipole moments • Dipole moments depend on: • Electronegativity of X • F > Cl > Br > I • C-X bond length • C-I > C-Br > C-Cl > C-F • Polarizability of electrons (ease of distribution of electron density) • I > Br > Cl > F • Since these trends oppose one another, the trend in molecular dipole moment is not periodic C-Cl > C-F > C-Br > C-I

5. Summary of Alkyl Halide Properties

6. Reactions of Alkyl Halides • Carbon bonded to X is electron-poor (electrophilic) • Will react with nucleophiles • Nucleophiles are also bases! So, there are two competing reactions: • Substitution • Nucleophile substitutes for X (the leaving group) • Elimination • Nucleophile/base removes H, eliminates HX to yield an alkene

7. Substitution vs. Elimination • How do we know which reaction will occur? • In this chapter: • Mechanisms of substitution • Mechanisms of elimination • Substitution vs. elimination

8. I. Nucleophilic Substitution • Nucleophile substitute for leaving group (X) • Example: CH3CH2CH2Br + NaOCH3→ CH3CH2CH2OCH3 + NaBr • Leaving group = • Nucleophile =

9. Stereochemistry • When the product has a stereocenter, we must consider stereochemistry • Examples: • How can we explain the observed stereochemistry? • There is more than one possible mechanism • SN2 and SN1 (differ in timing of C-X breaking and C-Nu formation)

10. The SN2 Reaction • Bimolecular nucleophilic substitution • Bimolecular = two species (RX and Nu) participate in RDS • Rate = k [RX] [Nu] • Mechanism: • Single step • No intermediates • Bonds broken and made simultaneously (concerted) • Same mechanism as acetylide ion and methyl/primary RX

11. Transition State of SN2 Reaction

12. CH3Br + NaOH→ • Products: • Mechanism:

13. SN2 Energy Diagram • One step • Exothermic E Reaction Coordinate

14. SN2 Stereochemistry • Nucleophile attacks reaction center (electrophilic carbon) from the direction opposite the leaving group • Backside attack • Causes change in configuration • Stereocenter: S↔R • Rings: cis↔trans • Ex: (S)-2-bromobutane + NaOH

15. SN2 Characteristics • Factors influencing the rate of SN2 reaction: • Alkyl halide structure • Nucleophile • Leaving group • Solvent

16. SN2 Characteristics: RX Structure • Steric effects • Nucleophile must have access to reaction center • Access is hindered with bulky substituents

17. SN2 Characteristics: RX Structure • Trends in RX reactivity: • Methyl halide most reactive • Tertiary alkyl halide not likely to react • Branched 1° and 2° alkyl halides react slower than unbranched • Vinyl and aryl halides will not react

18. SN2 Characteristics: Nucleophile • Nucleophile: contains lone pair • Some nucleophile are better than others • Better nucleophile = faster SN2 reaction • Some common nucleophiles: • What trends do you notice relating nucleophilicity and structure?

19. Trends in Nucleophile Structure • Anions are stronger nucleophiles than neutral molecules HO > H2O RO > ROH

20. Trends in Nucleophile Structure • Less stable anions are stronger nucleophiles than more stable anions RO > RCO2 • Generally, nucleophilicity increases down a group I > Br , Cl > F • Bulky anions are more likely to act as a base, rather than a nucleophile (CH3)3CO vs. CH3O base nucleophile

21. Nucleophile Structure • Some common good nucleophiles are also strong bases • HO- • RO- • H2N- • Some common good nucleophiles are weak bases • I- • -CN • RCO2- • This will be important later when comparing substitution and elimination

22. SN2 Characteristics: Leaving Group • Better LG = faster reaction • Better LG = more stable anion

23. SN2 Characteristics: Solvent • Dissolves reactants, creates environment of reaction, can affect outcome of reaction • Solvents are either protic or aprotic • Polar protic • H-bond donor • Contain NH or OH • Alcohols, carboxylic acids, amines, water • Polar aprotic • Cannot donate H-bond • Dimethyl sulfoxide (DMSO) • Acetone • Acetonitrile • N,N-Dimethylformamide (DMF)

24. SN2 Characteristics: Solvent • Polar aprotic solvents solvate cations, but not anions • Anions shielded from d+ by methyl groups • Less solvated • More available to react as nucleophiles • Good for SN2!

25. SN2 Characteristics: Solvent • Polar protic solvents solvate both cations AND anions • Anion is well-solvated • Less available to react as nucleophiles • Not good for SN2!

27. The SN1 Reaction • Unimolecularnucleophilic substitution • Unimolecular= one species (RX) participates in RDS • Rate = k [RX] • Mechanism: • Multiple steps • Carbocation intermediate • C-X bon broken before C-Nu bond formed • Which step is RDS?

28. Mechanism of SN1 Reaction

29. SN1Energy Diagram

30. SN1 Stereochemistry • Racemic mixture • 50% inversion of configuration • 50% retention of configuration • Why? Look at intermediate…

31. (R)-3-chloro-3-methylhexane + NaOAc → • Products: • Mechanism:

32. SN1 Stereochemistry • Sometimes slightly more than one enantiomer is observed • 55-60% inversion • 40-45% retention • Why? Association of leaving group with carbocation

33. SN1 Characteristics • Factors influencing the rate of SN1 reaction: • Alkyl halide structure • Nucleophile • Leaving group • Solvent

34. SN1 Characteristics: RX Structure • Electronic effects • More stable carbocation = faster reaction • Remember carbocation stability

35. SN1 Characteristics: RX Structure • Trends in RX reactivity: • Tertiary alkyl halides most reactive • Primary alkyl halides will not form unless allylic or benzylic

36. SN1 Characteristics: Nucleophile • Nucleophile is not important for SN1 reactions • Not in the rate equation • Even poor nucleophiles are OK for SN1 • H2O, ROH, etc.

37. SN1 Characteristics: Leaving Group • Better LG = faster reaction

38. SN1 Characteristics: Leaving Group • SN1 on alcohols • Need strong acid to protonate –OH and form a better LG

39. SN1 Characteristics: Solvent • Polar protic solvents = faster reaction • Solvate both cations AND anions • Speed up RDS by solvating and separating carbocation intermediate and leaving group anion • Good for SN1! • Commonly SN1 nucleophile = solvent • Solvolysis reaction

41. Summary of SN2 vs. SN1

42. Predict the substitution mechanism and products for the following reactions…

43. Carbocation Rearrangements • Carbocation intermediates can rearrange to form a more stable carbocation structure • Types of rearrangements: • Hydride shift • Alkyl shift (methyl or phenyl) • Can SN2 reactions undergo rearrangement?

44. Draw the Mechanism…

45. Outline • In this chapter: • Mechanisms of substitution • SN2 • SN1 • Mechanisms of elimination • E2 • E1 • Substitution vs. elimination

46. II. Elimination Reactions • Alkyl halide + base → alkene • X eliminated from one carbon • H eliminated from adjacent carbon • Compete with substitution reactions

47. 1-Bromobutane + t-BuOK→

48. Elimination Regiochemistry • Multiple products can be formed if there is more than one adjacent H • How do we know the major product?

49. Zaitsev’s Rule • In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates • This alkene is more stable • There are some exceptions, but this rule is generally true • Example: • Which product is major?

50. The E2 Reaction • Bimolecular elimination • Rate = k [RX] [Base] • Mechanism: • Single step • Concerted • No intermediates • Needs a strong base (NaOH, NaOR, NaNH2)