Organic Chemistry Second Edition

1. Organic Chemistry Second Edition David Klein Chapter 7 Substitution Reactions Klein, Organic Chemistry 2e

2. 7.1 Substitution reactions • One group of atoms is replaced with another • Generic example • Specific example • Label the nucleophile and electrophile Klein, Organic Chemistry 2e

3. 7.1 Substitution reactions • Which side do you think will be favored in the dynamic equilibrium? WHY? • Draw a reaction coordinate diagram that illustrates your equilibrium prediction Klein, Organic Chemistry 2e

4. 7.1 Substitution reactions • During the substitution, one group ATTACKS and one group LEAVES. Can you label them in the reaction? • A leaving group always takes a pair of electrons with it. • In the reaction below, fill in arrows to show the mechanism and label the leaving group. Klein, Organic Chemistry 2e

5. 7.1 Substitution reactions To encourage substitution a good leaving group must fulfill two criteria: • The electronegative leaving group creates a partial charge on the site of attack to attract the negative charge of the nucleophile • The Leaving Group must be able to stabilize the electrons it leaves with Klein, Organic Chemistry 2e

6. 7.1 Substitution reactions Can you give some examples of groups of atoms that qualify as good leaving groups according to the two key criteria? • Create a positive charge to attract the nucleophile. • Be able to stabilize the electrons it leaves with Klein, Organic Chemistry 2e

7. 7.2 Alkyl Halides • Alkyl halides are compounds where a carbon group (alkyl) is bonded to a halide (F, Cl, Br, or I) • Recall from section 4.2 the steps we use to name a molecule • Identify and name the parent chain • Identify the name of the substituents • Assign a locant (number) to each substituents • Assemble the name alphabetically • The halide group is the key substituent we will name and locate Klein, Organic Chemistry 2e

8. 7.2 Alkyl Halide Nomenclature • For each of these examples, convince yourself that they are numbered in the most appropriate way. Klein, Organic Chemistry 2e

9. 7.2 Alkyl Halide Nomenclature • Some simple molecules are also recognized by their common names. • the alkyl group is named as the substituent, and the halide is treated as the parent name Methylene chloride is a commonly used organic solvent Klein, Organic Chemistry 2e

10. 7.2 Alkyl Halide Nomenclature • Give reasonable names for the following molecules • Try more examples with conceptual checkpoint 7.1 Klein, Organic Chemistry 2e

11. 7.2 Alkyl Halide Structure • Greek letters are often used to label the carbons of the alkyl group attached to the halide • Substitutions occur at the alpha carbon WHY? • The amount of branching at the alpha carbon affects the reaction mechanism. There are three types of alkyl halides Klein, Organic Chemistry 2e

12. 7.2 Alkyl Halide Structure • Some alkyl halides are used as insecticides. For the insecticides below… • Label each halide as either primary, secondary, or tertiary • For the circled atoms, label all of the alpha, beta, gamma, and delta carbons. Klein, Organic Chemistry 2e

13. 7.2 Alkyl Halide Structure • Halides appear in a wide variety of natural products and synthetic compounds • The structure of the molecule determines its function, and functions include… • Insecticides (DDT, etc.) • Dyes (tyrian purple, etc.) • Drugs (anticancer, antidepressants, antimicrobial, etc.) • Food additives (Splenda, etc.) • Many more Klein, Organic Chemistry 2e

14. 7.2 Alkyl Halide Structure HOW does a molecule’s structure affect its function and properties? Klein, Organic Chemistry 2e

15. 7.3 Substitution Mechanisms • Recall from chapter 6 the FOUR arrow pushing patterns for ionic processes Klein, Organic Chemistry 2e

16. 7.3 Substitution Mechanisms • Recall from chapter 6 the arrow pushing patterns for ionic processes Klein, Organic Chemistry 2e

17. 7.3 Substitution Mechanisms • EVERYnucleophilic substitution reaction will involve nucleophilic attack and the loss of a leaving group • The order that these steps occur can vary • The inclusion of a proton transfer or rearrangement can also vary Klein, Organic Chemistry 2e

18. 7.3 Substitution Mechanisms • Draw mechanisms for each possibility and critique their likelihood • Nucleophilic attack first then loss of leaving group. • Loss of leaving group first then nucleophilic attack • Both happen simultaneously • Practice arrow pushing with SkillBuilder 7.1 Klein, Organic Chemistry 2e

19. 7.4 SN2 – 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 Klein, Organic Chemistry 2e

20. 7.4 SN2 – stereochemistry • What do S, N, and 2 stand for in the SN2 name? • How might we use stereochemistry to support the SN2 mechanism for the following reaction? • Practice drawing SN2 reactions with SkillBuilder 7.2 Klein, Organic Chemistry 2e

21. 7.4 SN2 – 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 Klein, Organic Chemistry 2e

22. 7.4 SN2 – backside attack • 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 Transition state symbol Klein, Organic Chemistry 2e

23. 7.4 SN2 kinetics • Less sterically hindered electrophiles react more readily under SN2 conditions. • To explain this trend, we must examine the reaction coordinate diagram Klein, Organic Chemistry 2e

24. 7.4 SN2 – 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? Klein, Organic Chemistry 2e

25. 7.4 SN2 – Rationalizing kinetic data • Which reaction will have the fastest rate of reaction? • WHY? • 3° substrates react too slowly to measure. Klein, Organic Chemistry 2e

26. 7.4 SN2 – 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 SN2 reaction relatively quickly or relatively slowly? WHY? Klein, Organic Chemistry 2e

27. 7.4 SN2 – Rationalizing kinetic data • If you memorize rules, you will probably miss questions about exceptions to rules • It is better to understand the concepts than to memorize rules Klein, Organic Chemistry 2e

28. 7.5 SN1 – a step-wise mechanism • If kinetic experiments were performed to determine the rate law, you would find that… Klein, Organic Chemistry 2e

29. 7.5 SN1 – reaction coordinate • A two-step mechanism gives a diagram with two transitions states. Where on the diagram is the intermediate? Klein, Organic Chemistry 2e

30. 7.5 SN1 – reaction coordinate • What is happening to the molecule in each transition state? Klein, Organic Chemistry 2e

31. 7.5 SN1 – reaction coordinate • Which step is the RDS and WHY? • Why does the rate depend only on [electrophile] and NOT [nucleophile]? Klein, Organic Chemistry 2e

32. 7.5 SN1 – a step-wise mechanism • What do the S, N, and 1 stand for in the SN1 name? Klein, Organic Chemistry 2e

33. 7.5 SN1 – SN2 Comparison • Consider the following generic SN2 reaction: • If [Nuc:-] were tripled, how would the rate be affected? WHY? • Consider the following generic SN1 reaction: • If [Nuc:-] were tripled, how would the rate be affected? WHY? • Practice with Conceptual Checkpoint 7.13 Klein, Organic Chemistry 2e

34. 7.5 SN1 kinetics • The structure-rate relationship for SN1 is the opposite of what it was for SN2. • To explain this trend, we must examine the mechanism and the reaction coordinate diagram Klein, Organic Chemistry 2e

35. 7.5 SN1 – 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. Klein, Organic Chemistry 2e

36. 7.5 SN1 – Rationalizing Kinetic Data • HOW do carbon groups stabilize a carbocation? Klein, Organic Chemistry 2e

37. 7.5 SN1 – 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 Klein, Organic Chemistry 2e

38. 7.5 SN1 – stereochemistry • For the pure SN1 reaction below, predict the product(s). Pay close attention to stereochemistry. Klein, Organic Chemistry 2e

39. 7.5 SN1 – stereochemistry • The formation of ion pairs can cause inversion to occur slightly more often than retention Klein, Organic Chemistry 2e

40. 7.5 SN – stereochemistry • Consider the following reaction • What accounts for the 35%/65% product ratio? • Is the reaction reacting more by SN1 or SN2? • What happened to the Cl atom? • Practice with SkillBuilder 7.5 Klein, Organic Chemistry 2e

41. 7.5 SN – summary Klein, Organic Chemistry 2e

42. 7.6 SN1 Complete Mechanisms • In SN1, proton transfer steps often occur before the substitution process. • Why would a proton transfer sometimes be necessary before the substitution reaction? For example… • If the OH is protonated first though… Klein, Organic Chemistry 2e

43. 7.6 SN1 Complete Mechanisms • Would it also be helpful to protonate an OH group in an SN2 substitution? Klein, Organic Chemistry 2e

44. 7.6 SN1 Complete Mechanisms • Lets look at the complete mechanism. • Practice with conceptual checkpoint 7.18 Klein, Organic Chemistry 2e

45. 7.6 SN1 Complete Mechanisms • In SN1, proton transfer steps often occur after the substitution process. Examine the following example • The leaving group is good, but what about the nucleophile? • Draw a complete mechanism. Each step is an equilibrium. Which side will the equilibrium favor? • If the nucleophile were used as the solvent (a solvolysis reaction), would that shift the equilibrium one way or the other? • Practice with Conceptual Checkpoint 7.19 Klein, Organic Chemistry 2e

46. 7.6 SN1 Complete Mechanisms • Rearrangements sometimes occur In SN1 reactions • Example: • After the leaving group leaves, the resulting carbocation may rearrange. What type of rearrangements are likely? WHY? • Predict the product(s), and explain why the carbocation rearrangement is likely to occur before the nucleophile has a chance to attack. • Check your work with Conceptual Checkpoint 7.20 Klein, Organic Chemistry 2e

47. 7.6 SN1 Complete Mechanisms Summary of considerations to make • Will proton transfers be necessary? • look at the quality of the leaving group • Look at the stability of the final product • Will the mechanism be SN1 or SN2? • look at how crowded the electrophilic site is • Look at how stable the resulting carbocation would be • Are rearrangements likely? • look for ways to improve the stability of the carbocation • Will the product have inversion or racemization? • SN1=racemization while SN2=inversion Klein, Organic Chemistry 2e

48. 7.6 SN1 Complete Mechanisms • Use the considerations from the previous slide to solve this problem • Predict the reagents necessary to complete this substitution. • Draw a complete mechanism • Draw a complete reaction coordinate diagram including drawings for all transition states. • Practice more with SkillBuilder 7.6 Klein, Organic Chemistry 2e

49. 7.7 SN2 Complete Mechanisms • Proton transfer steps occur often in SN2 reactions for the same reasons they occur in SN1 reactions. Klein, Organic Chemistry 2e

50. 7.7 SN2 Complete Mechanisms • Proton transfer steps occur often in SN2 reactions for the same reasons they occur in SN1 reactions. Klein, Organic Chemistry 2e