1. Chemistry 250-02 Organic Chemistry I Fall, 2015 Day 19 Wed., Oct., 14, 2015 Chapter 7 Alkyl Halides R δ+ -X δ- (Ionic Substitution Lab Expt # 6) Chem Act 13 A, (B), C; D (Today)

2. R-OH -> R-Cl R-OH -> R-Br Chapter 7

3. One Step and Two Step Nucleophilic Substitution Chem Activity 13A and 13B

4. 7.4 S N 2 – a concerted mechanism How might you write a rate law for this reaction? How would you design a laboratory experiment to test this mechanism? Test yourself with conceptual checkpoint 7.6 7-4Klein, Organic Chemistry 2e

5. 7.4 S N 2 – stereochemistry What do S, N, and 2 stand for in the S N 2 name? How might we use stereochemistry to support the S N 2 mechanism for the following reaction? Practice drawing S N 2 reactions with SkillBuilder 7.2 7-5Klein, Organic Chemistry 2e

6. 7.4 S N 2 – backside attack The nucleophile attacks from the back-side –Electron density repels the attacking nucleophile from the front-side –The nucleophile must approach the back-side to allow electrons to flow from the HOMO of the nucleophile to the LUMO of the electrophile. –Proper orbital overlap cannot occur with front-side attack because there is a node on the front-side of the LUMO 7-6Klein, Organic Chemistry 2e

7. Draw the transition state for the following reaction. Use extended dotted lines to represent bonds breaking and forming Practice drawing transition states with SkillBuilder 7.3 7.4 S N 2 – backside attack Transition state symbol 7-7Klein, Organic Chemistry 2e

8. 7.4 S N 2 kinetics Less sterically hindered electrophiles react more readily under S N 2 conditions. To explain this trend, we must examine the reaction coordinate diagram ons, Inc. All rights reserved. 7-8Klein, Organic Chemistry 2e

9. 7.4 S N 2 – Rationalizing kinetic data How do we use the diagram to make a kinetic argument? How do we use the diagram to make a thermodynamic argument? 7-9Klein, Organic Chemistry 2e

10. Which reaction will have the fastest rate of reaction? WHY? 3° substrates react too slowly to measure. 7.4 S N 2 – Rationalizing kinetic data Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-10Klein, Organic Chemistry 2e

11. 7.4 S N 2 – Rationalizing kinetic data An example to consider: neopentyl bromide Draw the structure of neopentyl bromide Is neopentyl bromide a primary, secondary, or tertiary alkyl bromide? Should neopentyl bromide react by an S N 2 reaction relatively quickly or relatively slowly? WHY? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-11Klein, Organic Chemistry 2e

12. What statement about the S N 2 reaction of methyl bromide with hydroxide is incorrect? 1.The reaction kinetics is first-order in hydroxide. 2.In the transition state the carbon is sp 2 hybridized. 3.Absolute configuration is inverted from R to S. 4.The reaction is faster in HMPA than in water. 5.The reaction can be catalyzed by I –.

13. 7.5 S N 1 – a step-wise mechanism What do the S, N, and 1 stand for in the S N 1 name? 7-13Klein, Organic Chemistry 2e

14. 7.5 S N 1 – S N 2 Comparison Consider the following generic S N 2 reaction: If [Nuc: - ] were tripled, how would the rate be affected? WHY? Consider the following generic S N 1 reaction: If [Nuc: - ] were tripled, how would the rate be affected? WHY? Practice with Conceptual Checkpoint 7.13 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-14Klein, Organic Chemistry 2e

15. 7.5 S N 1 kinetics The structure-rate relationship for S N 1 is the opposite of what it was for S N 2. To explain this trend, we must examine the mechanism and the reaction coordinate diagram Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-15Klein, Organic Chemistry 2e

16. 7.5 S N 1 – Rationalizing Kinetic Data A carbocation forms during the mechanism. Recall that if a carbocation is more substituted with carbon groups, it should be more stable. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-16Klein, Organic Chemistry 2e

17. 7.5 S N 1 – Rationalizing Kinetic Data HOW do carbon groups stabilize a carbocation? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-17Klein, Organic Chemistry 2e

18. 7.5 S N 1 – Rationalizing kinetic data To explain why the 3° substrate will have a faster rate, draw the relevant transition states and intermediates. Primary substrates react too slowly to measure. Practice with SkillBuilder 7.4 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-18Klein, Organic Chemistry 2e

19. 7.5 S N 1 – stereochemistry For the pure S N 1 reaction below, predict the product(s). Pay close attention to stereochemistry. Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-19Klein, Organic Chemistry 2e

20. 7.5 S N 1 – stereochemistry The formation of ion pairs can cause inversion to occur slightly more often than retention Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-20Klein, Organic Chemistry 2e

21. 7.5 S N – stereochemistry Consider the following reaction What accounts for the 35%/65% product ratio? Is the reaction reacting more by S N 1 or S N 2? What happened to the Cl atom? Practice with SkillBuilder 7.5 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. 7-21Klein, Organic Chemistry 2e

22. Consider the reaction of (S)-(–)-1-iodo-2- methylbutane to produce (+)-2-methyl-1-butanol. What is the absolute configuration of the product? 1. R 2. S 3. R and S (racemic mixture) 4. R and S (unequal amounts-scalemic) 5.There is no chiral center in the product

23. How Nucleophiles Affect S N 2

24. Which of the following is the best nucleophile? 1.H 2 O 2.(CH 3 ) 3 N 3.(CH 3 ) 2 P – 4.(CH 3 ) 2 O 5.CH 3 O –

25. Which of the following reagents is the best nucleophile for an S N 2 reaction? 1.methanol 2.methoxide 3.acetate 4.hydroxide 5.water

26. Which of the following is the product of the S N 2 reaction between the hydroxide ion (HO–) and (R)-CH 3 –CHDI? D = 2 H (deuterium) 1. 2. 3. 4. 5.

27. Select the substrate which would react fastest in the substitution reaction. 1.2. 3. 4. 5.

28. Select the reagent and solvent combination which would result in the fastest rate of substitution (R = CH 3 in all cases). 1.R-OH, HMPA 2.R-S –, H 2 O 3.R-O –, H 2 O 4.R-S –, DMSO 5.R-SH, H 2 O

29. How Leaving Groups Affect S N 2

30. Substrate Steric Effects in S N 2

31. Which electrophile will react the fastest by the S N 2 mechanism with cyanide (:N ≡ C: – ) in DMF? 1.phenyl iodide (Ph–I) 2.vinyl tosylate (H 2 C=CH–OTos) 3.ethyl bromide 4.cyclohexyl bromide 5.benzyl tosylate (Ph-CH 2 -OTos)

32. How Solvents Affect S N 2

33. Which set of reaction conditions represents the best way to carry out the following transformation? 1.AcOH 2.NaOAc in AcOH 3.NaOAc in H 2 O 4.NaOAc in DMSO 5.AcOH in HMPA

34. Which of the following will give the fastest S N 1 reaction? 1.2. 3. 4. 5.

36. 7.5 S N – Summary 7-36Klein, Organic Chemistry 2e

38. Chem Act 13 Exercise 25, Part D, page 200

39. Problem A “Walden” cycle A B C DE What is the purpose for making B ? Why is [α] D for B positive ? What kind of reaction is B -> C and what is the mechanism ? What is the optical purity of C and what are the % ’s of the two enantiomers of C ? How could you make C from B with 100 % enantiomeric excess (i.e. optically pure) ? What kind of reaction is D -> E and what is the mechanism ? How can you convert A into CH 3 -CHCl-CH 2 -Phenyl ?

41. S N 2 It’s not always straight inversion ! R. Wester, M. Weidem-ller (U. Freiburg), W. Hase (Texas Tech) Science 2008, 319, 183

42. S N 2 With Retention ! Nucleophilic Substitution Catalyzed by a Supramolecular Cavity Proceeds with Retention of Absolute Stereochemistry Chen Zhao, F. Dean Toste *, Kenneth N. Raymond *, and Robert G. Bergman * Chemical Sciences Division, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California, Berkeley, California 94720, United States J. Am. Chem. Soc., 2014, 136 (41), pp 14409–14412 DOI: 10.1021/ja508799p Publication Date (Web): September 29, 2014 Chen ZhaoF. Dean Toste*Kenneth N. Raymond*Robert G. Bergman*