1. Nucleophilic Substitution Reactions:SN2 Mechanism

2. The SN2 Mechanism of Nucleophilic Substitution

3. Concerted One Step - Bimolecular Reactions

5. Kinetics • Many nucleophilic substitutions follow asecond-order rate law. CH3Br + HO – CH3OH + Br – • rate = k [CH3Br] [HO – ] • What is the reaction order of each starting material? • What can you infer on a molecular level? • What is the overall order of reaction?

6. HO – CH3Br + HOCH3 + Br – Bimolecular mechanism • one stepconcerted

7. HO – CH3Br + HOCH3 + Br – Bimolecular mechanism • one stepconcerted

8. d - d - HO CH3 Br transition state HO – CH3Br + HOCH3 + Br – Bimolecular mechanism • one stepconcerted

9. Question Assuming the reaction below takes place by a concerted process, which mechanistic scheme is correct?

10. Stereochemistry of SN2 Reactions

11. Generalization • Nucleophilic substitutions that exhibitsecond-order kinetic behavior are stereospecific and proceed withinversion of configuration.

12. Inversion of Configuration nucleophile attacks carbonfrom side opposite bondto the leaving group

13. Inversion of Configuration nucleophile attacks carbonfrom side opposite bondto the leaving group three-dimensionalarrangement of bonds inproduct is opposite to that of reactant

14. Inversion of configuration (Walden inversion) in an SN2 reaction is due to back side attack

15. Stereospecific Reaction • A stereospecific reaction is one in whichstereoisomeric starting materials givestereoisomeric products. • The reaction of 2-bromooctane with NaOH (in ethanol-water) is stereospecific. • (+)-2-Bromooctane (–)-2-Octanol • (–)-2-Bromooctane (+)-2-Octanol

16. H H CH3(CH2)5 C HO Br C CH3 CH3 Stereospecific Reaction (CH2)5CH3 NaOH (S)-(+)-2-Bromooctane (R)-(–)-2-Octanol

17. CH3 CH3 Br H HO H CH2(CH2)4CH3 CH2(CH2)4CH3 • 1) Draw the Fischer projection formula for (+)-S-2-bromooctane. • 2)Write the Fischer projection of the (–)-2-octanol formed from it by nucleophilic substitution with inversion of configuration. A.) R- ? or B.) S- ?

18. A conceptual view of SN2 reactions

19. Why does the nucleophile attack from the back side?

20. Why does the nucleophile attack from the back side?

21. “Roundabout” SN2 Reaction Mechanism

22. SN2 Reaction Mechanisms: Gas Phase (2008) http://pubs.acs.org/cen/news/86/i02/8602notw1.html Roundabout Traditional Physicist Roland Wester and his team in Matthias Weidemüller's group at the University of Freiburg, in Germany, in collaboration with William L. Hase's group at Texas Tech University, provide direct evidence for this mechanism in the gas phase. However, they also detected an additional, unexpected mechanism. In this new pathway, called the roundabout mechanism, chloride bumps into the methyl group and spins the entire methyl iodide molecule 360° before chloride substitution. Data at lower collision energies support the traditional SN2 mechanism. However, at higher collision energies, about 10% of the iodide ions fell outside of the expected distribution. "We saw a group of iodide ions with a much slower velocity than the rest," says Wester. "Since energy is conserved, if iodide ions are slow, the energy has to be somewhere else." On the basis of calculations performed by their colleagues at Texas Tech, the team concluded that the energy missing from the iodide transfers to the methyl chloride product in the form of rotational excitation, supporting the proposed roundabout mechanism.

23. Roundabout SN2 Mechanism Traditional SN2 Mechanism

24. Fig. 1. Calculated MP2(fc)/ECP/aug-cc-pVDZ Born-Oppenheimer potential energy along the reaction coordinate g = RC-I - RC-Cl for the SN2 reaction Cl- + CH3I and obtained stationary points J. Mikosch et al., Science 319, 183 -186 (2008) Published by AAAS

25. Fig. 2. (A to D) Center-of-mass images of the I- reaction product velocity from the reaction of Cl- with CH3I at four different relative collision energies J. Mikosch et al., Science 319, 183 -186 (2008) Published by AAAS

26. Fig. 3. View of a typical trajectory for the indirect roundabout reaction mechanism at 1.9 eV that proceeds via CH3 rotation J. Mikosch et al., Science 319, 183 -186 (2008) Published by AAAS

27. Steric Effects in SN2 Reactions

28. Crowding at the Reaction Site The rate of nucleophilic substitutionby the SN2 mechanism is governedby steric effects. Crowding at the carbon that bears the leaving group slows the rate ofbimolecular nucleophilic substitution.

29. Reactivity toward substitution by the SN2 mechanism RBr + LiI RI + LiBr • Alkyl Class Relativebromide rate • CH3Br Methyl 221,000 • CH3CH2Br Primary 1,350 • (CH3)2CHBr Secondary 1 • (CH3)3CBr Tertiary too small to measure

30. A bulky substituent in the alkyl halide reduces the reactivity of the alkyl halide: steric hindrance

31. Decreasing SN2 Reactivity CH3Br CH3CH2Br (CH3)2CHBr (CH3)3CBr

32. Decreasing SN2 Reactivity CH3Br CH3CH2Br (CH3)2CHBr (CH3)3CBr

33. Reaction coordinate diagrams for (a) the SN2 reaction of methyl bromide and (b) an SN2 reaction of a sterically hindered alkyl bromide

34. Crowding Adjacent to the Reaction Site The rate of nucleophilic substitutionby the SN2 mechanism is governedby steric effects. Crowding at the carbon adjacentto the one that bears the leaving groupalso slows the rate of bimolecularnucleophilic substitution, but the effect is smaller.

35. Effect of chain branching on rate of SN2 substitution RBr + LiI RI + LiBr • Alkyl Structure Relativebromide rate • Ethyl CH3CH2Br 1.0 • Propyl CH3CH2CH2Br 0.8 • Isobutyl (CH3)2CHCH2Br 0.036 • Neopentyl (CH3)3CCH2Br 0.00002

36. Question • Which reaction will have the fastest rate of reaction? A) B) C)

37. Putting things together

38. IUPAC Nomenclatureof Alkyl Halides

39. IUPAC Nomenclature There are several kinds of IUPAC nomenclature. • The two that are most widely used are:functional class nomenclaturesubstituent nomenclature • Both types can be applied alkyl halides and to alcohols.

40. CH3CH2CHCH2CH2CH3 H I Br Functional Class Nomenclature of Alkyl Halides • Name the alkyl group and the halogen asseparate words (alkyl + halide). CH3F CH3CH2CH2CH2CH2Cl

41. CH3CH2CHCH2CH2CH3 H I Br Functional Class Nomenclature of Alkyl Halides • Name the alkyl group and the halogen asseparate words (alkyl + halide). CH3F CH3CH2CH2CH2CH2Cl Methyl fluoride Pentyl chloride 1-Ethylbutyl bromide Cyclohexyl iodide

42. CH3CHCH2CH2CH3 Br CH3CH2CHCH2CH3 I Substituent Nomenclature of Alkyl Halides • Name as halo-substituted alkanes. • Number the longest chain containing thehalogen in the direction that gives the lowestnumber to the substituted carbon. CH3CH2CH2CH2CH2F

43. CH3CHCH2CH2CH3 Br CH3CH2CHCH2CH3 I Substitutive Nomenclature of Alkyl Halides • Name as halo-substituted alkanes. • Number the longest chain containing thehalogen in the direction that gives the lowestnumber to the substituted carbon. CH3CH2CH2CH2CH2F 1-Fluoropentane 2-Bromopentane 3-Iodopentane

44. Cl CH3 CH3 Cl Substitutive Nomenclature of Alkyl Halides • Halogen and alkyl groupsare of equal rank when it comes to numberingthe chain. • Number the chain in thedirection that gives the lowest number to thegroup (halogen or alkyl)that appears first.

45. Cl CH3 CH3 Cl Substitutive Nomenclature of Alkyl Halides 5-Chloro-2-methylheptane 2-Chloro-5-methylheptane

46. Question • Name the compound on the right according to the IUPAC system. • A) 4-bromo-5-ethyl-2-methylheptane • B) 4-bromo-3-ethyl-6-methylheptane • C) 4-bromo-5-diethyl-2-methylpentane • D) 4-bromo-3-ethyl-6-dimethylhexane

47. Question What is the correct IUPAC name for the ABOVE structure? A. (3S,4S)-3-bromo-4-chlorohexane B. (3S,4S)-3,4-dibromochloroheptane C. (3R,4R)-3-chloro-4-bromohexane D. (3R,4R)-3-bromo-4-chlorohexane E. (3S,4S)-4-bromo-3-chlorohexane

48. Classes of Alkyl Halides

49. Classification • Alkyl halides & alcohols are classified asprimary secondary tertiaryaccording to their "degree of substitution." • Degree of substitution is determined by countingthe number of carbon atoms directly attached tothe carbon that bears the halogen or hydroxyl group.

50. Different Kinds of Alkyl Halides