1. 6. NUCLEOPHILIC SUBSTITUTIONS (and an introduction to elimination reactions)

2. OBJECTIVES
1. Describe two pathways (mechanisms) to account for substitution at sp3 carbons bearing an electronegative atom (leaving group)
2. Discuss the effect of starting material (substrate), leaving group, reagent (a nucleophile), and reaction conditions on the course of a reaction.
3. Introduce elimination reactions, which might compete with substitutions.

3. REACTIONS TO DATE

4. OVERVIEW: NUCLEOPHILIC SUBSTITUTIONS

5. Nucleophiles
Electrophiles
Leaving Groups

6. TWO CLASSES OF REACTION
Nucleophilic substitution reactions can be classified as one of two types, based on experimental observations.
Characteristics which allow this classification are listed on the next slide, and will be studied in greater detail in the next two sections.
In order to develop predictive tools, we need to understand reasons why these observations are important. That is, we need to develop proposals for two different mechanisms which are consistent with the two sets of data and which we can use to predict the outcome of other reactions.

7. Classifying Nucleophilic Substitutions
Rate is proportional to concentration of electrophile (substrate) and is independent of the concentration and type of the nucleophile
Chiral substrates give racemic products
3° react faster than 2° substrates (1° or methyl substrates are unreactive)
Class 2
Rate is proportional to concentration of electrophile and nucleophile
Chiral substrates give products with inverted stereochemistry
Methyl and 1° substrates react faster than 2° (3° substrates are unreactive)
For example, if it is found that Me-L reacts faster than Et-L, i-Pr-L, t-Bu-L under the same conditions, then it is also found that the rate of the reaction is proportional to [E] and [Nu] (i.e., Class 2). On the other hand, for reactions in which t-Bu-L reacts fastest, it is found that the rate is independent of [Nu] (i.e., Class 1).

8. CLASS 2: BIMOLECULAR NUCLEOPHILIC SUBSTITUTIONS
S: Prob: , 17a-j,20,27,31,33,36
Examples

9. Class 2: Some observations
Rate: Rate = k[R-L][Nu]
Stereochemistry: Chiral R-L forms R-Nu with opposite stereochemistry (“inversion of stereochemistry”)
Effect of substrate:
Rate: methyl > 1° > 2° (3° not reactive)
Effect of Nucleophile:
Rate: I– > OH– > Br– > Cl– > H2O
Effect of Leaving Group:
Rate: -I > -Br > -Cl >> -F
Effect of Solvent:
Increasing solvent polarity: anionic nucleophiles: rate  neutral nucleophiles: rate 

10. Experimental validation
Rate = k[R-L][Nu]

11. HWeb Answer HWeb Answer HWeb 20
Question 1. In the nucleophilic displacement reaction below, identify the correct components of the reaction; (i) starting material, (ii) product, (iii) nucleoplile, (iv) leaving group.
1. i - B, ii - A, iii - C, iv - D
2. i - A, ii - D, iii - B, iv - C
3. i - A, ii - C, iii - B, iv - D
4. i - C, ii - A, iii - D, iv - B
HWeb Answer

12. HWeb Answer HWeb Answer HWeb 20
Question 2. For a SN2 reaction, what would be the effect on the rate of the reaction of doubling the concentration of both the starting material and the nucleophile?
1. One fourth the rate
2. No change in the rate
3. Twice the rate
4. Four times the rate
HWeb Answer

13. Chiral R-L forms R-Nu with opposite stereochemistry (inversion of stereochemistry, “Walden Inversion”)

14. Effect of substrate:
Rate: methyl > 1° > 2° ( 3° unreactive) Adjacent groups slow the reaction

15. Effect of Nucleophile:
Rate: I– > OH– > Br– > Cl– > F– > H2O
Effect of Leaving Group:
Rate: -I > -Br > -Cl >> -F

16. Conclusion
Bimolecular nucleophilic substitution mechanism explains the observations

17. Increasing solvent polarity: anionic nucleophiles: rate  neutral nucleophiles: rate 

18. Energetics of one-step (i.e., concerted) reactionDG
Reaction coordinate

19. Alcohols as Substrates in SN2 reactions
Hydroxide, being a relatively strong base, is a poor leaving group in SN2 reactions. Alcohols are converted to tosylates, which are better electrophiles for SN2 reactions (tosylate is a weak base, why?)

20. Synthetic Utility of SN2 Reactions

21. HWeb Answer HWeb Answer HWeb 21
Question 1. Which statement is true about the transition state of a reaction?
1. The transition state must be stable enough to be isolated at room temperature.
2. The transition state corresponds to the highest energy point in going from reactants to products.
3. If the free energy of activation of the transition state is very high, the reaction will bevery fast.
4. If a reaction is highly exothermic, it will have a very low free energy of activation of the transition state.
HWeb Answer

22. HWeb Answer HWeb Answer HWeb 21
Question 2. In the reaction shown below, the stereochemistry of the product A will be:
1. R
2. S
3. R and S
4. Cannot be determined
HWeb Answer

23. CLASS 1: UNIMOLECULAR NUCLEOPHILIC SUBSTITUTIONS
S6:10-13 Prob:6.28,30,34,
Example

24. Class 1: Some observations
Rate Rate = k[R-L], independent of [Nu]
Stereochemistry Chiral R-X forms racemic R-Nu (“racemization”)
Effect of substrate:
Rate: 3° > 2° (1°, methyl unreactive)
Effect of Nucleophile:
Rate is independent of type of nucleophile
Effect of Leaving Group:
Rate: -I > -Br > -Cl >> -F
Effect of Solvent:
Increasing solvent polarity dramatically increases rate of reaction

25. Experimental validation
Rate = k[R-L] independent of concentration of Nu

26. Optically active R-L forms racemic R-Nu

27. Effect of substrate:
Rate: 3° > 2° (1°, methyl not reactive)

28. Effect of Leaving Group:
Rate: -I > -Br > -Cl
Effect of Solvent:
Increasing solvent polarity dramatically increases rate of reaction

29. Conclusion
Unimolecular nucleophilic substitution mechanism explains the observations

30. Energetics of two-step reactionDG
Reaction coordinate

31. FACTORS AFFECTING SN1 and SN2 REACTIONS
Substrate: 3°>2°>>1°,methyl
- Stability of carbocation intermediate
Nu: No effect
- Nu not involved in RDS
Rate increases by use of polar solvents
- Enhanced rate of ionization
SN2
Substrate: Methyl>1°>2°>>3°
- Steric bulk hinders attack of Nu
Rate a [nucleophile]
Rate depends on type of Nu
- Nu involved in RDS
Often performed in polar aprotic solvents, e.g., DMF (Me2NCHO), DMSO (Me2SO) to dissolve substrate and ionic reagent.

32. HWeb Answer HWeb Answer HWeb 22
Question 1. Arrange the following carbocations in order of increasing stabilty.
1. D<A<C<B
2. C<A<D<B
3. C<D<B<A
4. D<C<B<A
HWeb Answer

33. HWeb Answer HWeb Answer HWeb 22
Question 2. Which of the following statements is true?
1. For an SN2 substitution reaction the rate depends only on the concentration of nucleoplile.
2. For an SN1 substitution reaction the rate depends only on the concentration of nucleoplile.
3. For an SN2 substitution reaction a highly reactive intermediate is formed.
4. For an SN1 substitution reaction a highly reactive intermediate is formed.
HWeb Answer

34. ELIMINATIONS FROM ALKYL HALIDES

35. The E2 Reaction

36. The E1 Reaction

37. FACTORS FAVORING SUBSTITUTION AND ELIMINATION
S:6.19 Prob:6.21, 23,29
Substitution and elimination mechanisms might be competitive pathways in a reaction mixture. The outcome of a reaction depends on:
i. the structure of the substrate,
ii. basicity of the nucleophile

38. R–L nucleophile/base Mechanism
In general:
3° substrates only undergo substitution with weakly basic nucleophiles (ROH, H2O, RCO2H). Stronger bases promote elimination. 1° substrates generally undergo substitution unless the base itself is sterically crowded (e.g., t-BuO-).
R–L nucleophile/base Mechanism 3° 2° 1° Me
ROH, H2O, RCO2H
Anionic bases, NH3
Less basic than HO –
(e.g.., HS –, RS –, NH3, CN, RCO2–)
More basic than HO –
ROH, H2O
All except t-BuO–
t-Bu-O–
all
SN1 (some E1 on heating) E2
SN2

39. SUBSTITUTIONS AND ELIMINATIONS IN SYNTHESIS
Prob:6.32

42. HWeb Answer HWeb Answer HWeb 23
Question 1. Which of the following would be most reactive to SN displacement?
1. A
2. B
3. C
4. D
HWeb Answer

43. HWeb Answer HWeb Answer HWeb 23
Question 2. Which of the following statements is true?
1. An E2 elimination involves the formation of a carbocation.
2. An E1 elimination involves the formation of a carbocation.
3. The transition state for an E2 elimination has a carbon-carbon double bond.
4. The transition state for an E1 elimination has a carbon-carbon double bond.
HWeb Answer

44. CHAPTER 6 ON EXAM 3 Types of Questions Preparing for Exam 3
- Recognize factors which influence the mechanism of nucleophilic substitutions
- Predict outcomes of substitution reactions
- The problems in the book are good examples of the types of problems on the exam.
Preparing for Exam 3
- Work as many problems as possible.
- Work in groups.
- Do the “Learning Group Problem” at the end of the chapter.
- Work through the practice exam