NUCLEOPHILIC SUBSTITUTION REACTIONS Part 1

1. NUCLEOPHILIC SUBSTITUTION REACTIONSPart 1 CHEM 2101 Module 6 Susan Morante

2. 1. Some Definitions • Nucleophile (symbol Nu): • Electrophile (symbol E): • Leaving Group (symbol L): • R Group (symbol R):

3. 2. The General Reaction Nu:¯ + R – L  Nu – R + :L¯ • Example of an R – L (a substrate):

4. 2. The General Reaction • C is sp3 hybridized (tetrahedral) • Cl is more electronegative than C making the C electrophilic and the C-Cl bond polar • Nu is attracted to the electron-deficient site and becomes bonded to it in the product

5. 2. The General Reaction • In general, we use Nu:¯ to indicate a strong Nucleophile and Nu: (without the negative charge) to indicate a weak Nucleophile • Halides are the most common leaving groups in substrates used for Nucleophilic substitution reactions • We can use alkyl halides as examples to explore some more terminology

6. 2. The General Reaction

7. 2. The General Reaction

8. 2. The General Reaction

9. 2. The General Reaction

10. 2. The General Reaction • There are two possible mechanisms for the substitution reaction which will be discussed in detail later in these notes • Bimolecular Nucleophilic substitution (SN2) • Unimolecular Nucleophilic substitution (SN1)

11. 3. Possible Stereochemistry of Substitution Reactions • Retention of configuration: • Not usually seen • inversion of configuration: • seen in all SN2 reactions involving chiral reactants and products • racemization • seen in all SN1 reactions involving chiral reactants and products

12. 4. Bimolecular Nucleophilic substitution (SN2) • Generic Reaction: Nu:¯ + R – L  Nu – R + :L¯

13. 4. Bimolecular Nucleophilic substitution (SN2) • Specific Example: HO:¯+CH3CH2Cl→CH3CH2OH+Cl¯ • Rate Equation: Rate = k [EtCl] [OH¯]

14. 4. Bimolecular Nucleophilic substitution (SN2) • For any SN2: Rate = k [substrate] [Nu] • The reaction rate depends on the concentration of the nucleophile and the substrate • Second order rate law (In general, the order of a reaction is equal to the sum of the exponents in the rate equation.) • Reaction is bimolecular (two species involved in rate-determining step)

15. 4. Bimolecular Nucleophilic substitution (SN2) • Concerted reaction –

16. 4. Bimolecular Nucleophilic substitution (SN2) • Energy diagram –

17. 4. Bimolecular Nucleophilic substitution (SN2) • Mechanism of the reaction: • SN2 occurs through a back side attack

18. 4. Bimolecular Nucleophilic substitution (SN2) • Mechanism of the reaction cont’d: • The nucleophile must approach the carbon from the side opposite to the leaving group

19. 4. Bimolecular Nucleophilic substitution (SN2) • Mechanism of the reaction: • HOMO of Nu attacks LUMO of E

20. 4. Bimolecular Nucleophilic substitution (SN2) • Mechanism of the reaction cont’d: • Bond between Nu and E strengthens • Bond between E and L weakens

21. 4. Bimolecular Nucleophilic substitution (SN2) • Mechanism of the reaction cont’d: • Inversion of configuration

23. 4. Bimolecular Nucleophilic substitution (SN2) • Mechanism of the reaction cont’d: • During transition state – C becomes sp2 hybridized • Transition state – a fleeting arrangement (one molecular vibration, 10-12s) of atoms

24. p. 262

25. The Hammond Postulate • The structure of the transition state for a reaction step is most similar to (or looks most like) the structure of the species (reactant or product) to which it is closer in energy.

26. The Hammond Postulate • For an exergonic step: if a bond is forming in the step, that bond is less than half formed in the transition state, and if a bond is breaking, it is less than half broken (i.e. TS resembles reactants). • the transition state is closer in energy to the reactants thus the transition state most resembles the reactants

27. The Hammond Postulate

28. The Hammond Postulate • For an endergonic step this means that if a bond is forming in the step, that bond is more than half formed in the transition state, and if the bond is breaking, it is more than half broken (i.e. TS resembles products). • the transition state is closer in energy to the products thus the transition state most resembles the products

29. The Hammond Postulate

30. Effect of Substituents on the Rate of the SN2 reaction • The rate of the SN2 reaction decreases dramatically each time one of the hydrogens of the electrophilic carbon of the substrate is replaced by an alkyl group.

31. Effect of Substituents on the Rate of the SN2 reaction • This result of the larger size of the alkyl group on the rate of reaction, as compared to the size of hydrogen, is called steric effect. • Steric effect – the effect on the rate caused by space-filling properties of parts of the molecule near the reacting site.

33. Fig. 8-5, p. 267

34. Table 8-1, p. 264

35. Effect of Substituents on the Rate of the SN2 reaction • Exceptions • neopentyl substrates – react many times slower than other primary substrates because the tert-butyl group attached to the electrophilic carbon hinders the back – side attack of the Nu

36. Effect of Substituents on the Rate of the SN2 reaction • Exceptions • allylic and benzylic substrates – react faster than other primary substrates because there is resonance stabilization of the transition state possible

37. Effect of Substituents on the Rate of the SN2 reaction • Exceptions • Vinylic and aryl substrates – do not undergo nucleophilic substitution reactions • No good direction of approach for Nu • Inability to form the transition state • C-L bond not easily broken

38. Intramolecular Nucleophilic substitution reactions using SN2 • An example of an SN2 reaction and a lesson in how to make alkoxides • An alkoxide is an alcohol (ROH) that has had the H removed to form (RO‾) ROH + Na(s) → RO¯Na+ + ½ H2(g) Alcohol Alkoxide

39. Intramolecular Nucleophilic substitution reactions using SN2

40. Intramolecular Nucleophilic substitution reactions using SN2 • Intramolecular reactions tend to be faster than intermolecular reactions because collisions between the Nu and the E happen more rapidly.

41. p. 293

42. 4. Bimolecular Nucleophilic substitution (SN2) • Various examples:

43. 4. Bimolecular Nucleophilic substitution (SN2) • Various examples:

44. 5. Unimolecular Nucleophilic Substitution (SN1) • Generic Reaction: R – L → R+ + L¯ R+ + :Nu → R – Nu • Proceeds with racemization if electrophilic C is chiral

45. 5. Unimolecular Nucleophilic Substitution (SN1) • Carbocation formation is the rate determining step because it is slightly endothermic and thus very slow

46. 5. Unimolecular Nucleophilic Substitution (SN1) • Mechanism:

47. 5. Unimolecular Nucleophilic Substitution (SN1) • Specific Example: • Rate Equation: Rate = k [t-BuCl]

48. 5. Unimolecular Nucleophilic Substitution (SN1) • Rate Equation cont’d: For any SN1 Rate = k [substrate] • This is a first order reaction • The reaction rate depends only on the concentration of the substrate • Only the substrate is present in the transition state for the rate determining step

49. 5. Unimolecular Nucleophilic Substitution (SN1) • Non – Concerted reaction –

50. 5. Unimolecular Nucleophilic Substitution (SN1) • Energy diagram –