1. L19
TOPIC 6. NUCLEOPHILIC SUBSTITUTIONS (chapter 6 and parts of chapters 7 and 11)

2. OBJECTIVES
1. Describe two pathways (mechanisms) to account for substitution at sp3 carbons bearing an electronegative atom (leaving group)
Discuss the effect of starting material (substrate), leaving group, reagent (a nucleophile) and reaction conditions on the course of a reaction
Recognize functional group transformations and synthesis of new molecules in one step by substitution of an appropriate material
Explore the substitution chemistry of alcohols and ethers

3. REACTIONS TO DATE Hydrogenation and Alkylation of Alkynes
Acid-Base Chemistry

4. OVERVIEW: NUCLEOPHILIC SUBSTITUTIONS

6. Nucleophiles Electrophiles Donates a pair of electrons
Receives a pair of electrons

7. Effect of Leaving Groups on Electrophilicity
C-L bond must be polarizable
Must break C-L bond
Needs to be able to accommodate a pair of electrons
 Good leaving groups are weak bases

8. substitute /’sêb-,stê,t(y)üt/ vb: to put in the place of another
What are the rules?
                              
                               
                               
                      
                      

9. TWO CLASSES OF REACTION
Substitution reactions can be performed under different conditions which give rise to dramatically different outcomes. Nucleophilic substitution reactions can be classified as one of two types, based on these 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.

10. SUBSTITUTION AT 1° SUBSTRATES: BIMOLECULAR NUCLEOPHILIC SUBSTITUTIONS
S: Prob: , 17a-j,25,27,31,33,36
Examples

11. Experimental Observations Kinetics
[CH3CH2Br] [NaOMe] relative rate
0.01 M 0.01 M
0.02 M 0.01 M
0.01 M 0.02 M
0.02 M 0.02 M
Conclusion: Rate = k[R-L][Nu]
Interpretation:

12. Chirality
Chiral R-L forms R-Nu with opposite stereochemistry (inversion of stereochemistry, “Walden Inversion”)
Interpretation:

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

14. Conclusion
Bimolecular nucleophilic substitution mechanism explains the observations
Effect on rate:
Nu: L:
C-L:

15. Energetics of One-Step (i.e., concerted) Reaction SN2DG
Reaction coordinate

16. More Observations Which Confirm the SN2 Mechanism Effect of substrate
L20
More Observations Which Confirm the SN2 Mechanism
Effect of substrate
Rate: methyl > 1° > 2° ( 3° unreactive)
Adjacent alkyl groups also slow the reaction

17. Common Solvents in Organic Chemistry H2O HCO2H MeOH EtOH (CH3)2SO - DMSO CH3CN - AN (CH3)2NCHO - DMF CH3COCH3 CH2Cl THF
Et2O – “ether” CH3(CH2)4CH3

18. Effect of Solvent on SN2 Reactions
Generally need a polar solvent to dissolve the source of the nucleophile (i.e., a salt of an anionic nucleophile). However, protic solvents solvate anionic nucleophiles, lowering their reactivity. Thus, polar aprotic solvents are soften used. Such as DMSO, DMF, CH3CN, THF, Et2O.
Anionic Nucleophile:
Solvent polarity 
enhances stability of  rate
Neutral Nucleophile: ‡ ‡

19. Practical Applications of SN2 Reactions: Functional Group Transformations at 1o and 2o Carbons

20. Problem: How would you prepare 2-phenylethanethiol from 1-iodo-2-phenylethane?
Problem: How would you make the following compound from 1-bromopropane and any other starting materials?

21. Synthesis of Alkynes: Alkylation of Acetylide Anions
(see also 4.18c)
S:7.12

22. Problem: Which of the following would undergo the fastest reaction with 1-bromopropane?
Ph3N or Ph3P
1.0 M CH3ONa or M CH3ONa

23. SUBSTITUTION AT 3° SUBSTRATES: UNIMOLECULAR NUCLEOPHILIC SUBSTITUTIONS
S6:10-13 Prob:6.16,30,35
Example

24. Experimental Observations Kinetics
Result: Rate = k[R-L] independent of concentration of Nu
Interpretation:
[t-BuBr] [H2O] relative rate
0.01 M 0.01 M 1
0.02 M 0.01 M 2
0.01 M 0.02 M 1
0.02 M 0.02 M 2

25. Chirality
Optically active R-L forms racemic R-Nu

26. Effect of Substrate Rate: 3° > 2° (1°, methyl not reactive)
Interpretation:
Stability of Carbocations

27. Effect of Nucleophile Concentration of nucleophile (see above)
Identity of nucleophile
Rate of reaction: I Br Cl-
Interpretation:

28. Effect of Leaving Group
Rate: -I > -Br > -Cl (F: unreactive)

29. Conclusion
Unimolecular nucleophilic substitution mechanism explains the observations.
Effect on rate:
Nu: L:
C-L:
Substrate:
Solvent polarity:

30. Energetics of Two-Step Reaction SN1DG
Reaction coordinate

31. Practical Applications of SN1 Reactions: Solvolysis
The only practical SN1 reactions are solvolyses, reactions in which the solvent also acts as the nucleophile. These reactions arise because solvents which are polar enough to facilitate dissociation of the substrate are also nucleophilic
S-H = HOH, RCO2H, ROH
Effect of Polarity
Increasing solvent polarity dramatically increases rate of reaction by facilitating disocciation of substrate into carbocation and anion (leaving group).

32. Problem: Which of the following would undergo the most rapid hydrolysis (substitution with water)?
(CH3)3CBr or (CH3)3CCl
Problem: Which of the following would undergo the fastest SN1 reaction?
(CH3)3CCl + H2O or (CH3)3CCl + EtOH

33. SUMMARY: FACTORS AFFECTING SN1 and SN2 REACTIONS
L21
SUMMARY: FACTORS AFFECTING SN1 and SN2 REACTIONS
S:6.14 Prob:6.18,26
SN1
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
Generally only useful for solvolyses (reactions with H2O, ROH, RCO2H)
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, and increase reaction rate

34. Why is Nucleophilic Substitution Limited to sp3 (Alkyl) Substrates?
Inaccessible Carbon Atom Unstable sp2 Carbocation
(hinders SN2) (hinders SN1)

35. A Limitation to Reactions of Alkyl Halides with Nucleophiles
Elimination competes with substitution is the nucleophile is too basic or if the electrophile is too crowded (we will explore this further in Topic 7) S:

36. ALCOHOLS AS ACIDS AND BASES
Alcohols are weak acids and weak bases. However, acid-base chemistry is important in activating the electrophilic and nucleophilic character of alcohols, respectively.

37. CONVERSION OF ALCOHOLS TO ALKYL HALIDES
Alcohols do not react with sodium halides to give alkyl halides!
Alcohol + H-Hal
3o Alcohols: SN1

38. 1o Alcohols: SN2

39. Other reagents
S11.14

40. MESYLATES AND TOSYLATES IN SN2 REACTIONS
R’ = Me: mesylate (Ms) methylphenyl: tosylate (Ts)

41. Problem: How would you prepare 2-phenylethanethiol from 2-phenyl-1-ethanol?
Problem: How would you make the following compound from 1-propanol and any other starting materials?

42. SYNTHESIS AND REACTIONS OF ETHERS
S Prob:11.38
Synthesis of Ethers: Williamson Ether Synthesis
Overall Reaction and Mechanism

43. Designing Williamson Ether Syntheses
You could suggest making either C-O bond of the ether.

44. Synthesis: Dehydration of Alcohols
At higher temperature a competing reaction predominates (elimination of water to form an alkene, see Topic 7)

45. Acid Catalyzed Hydrolysis of Ethers

47. SUBSTITUTIONS IN SYNTHESIS
L23
Prob:6.17,20,32a-h,33
You should prepare a chart of all of the types of reactions that have been covered so far…
….we’ll add more later.

48. ONE STEP SYNTHESES
It is important to recognize transformations which can be performed in a single step.
Problem: How would you prepare the following from appropriate alkyl chlorides?
(a) CH3CH2SH
(b) (CH3)2CHCN
(c)

49. Problem: Why does the following reaction not take place?
CH3CH2CH3 + HO— CH3CH2CH2OH + H—

50. Problem: Explain why reaction of 1-bromopropane with potassium cyanide gives a mixture of CH3CH2CH2CN (major product) and CH3CH2CH2NC (minor)? Draw Lewis structures of the products and nucleophiles.

51. Problem: How can you prepare the following two compounds from the appropriate alkyl bromide?
(a) Methyl phenyl ether, Me-O-Ph
(b) (S)-2-Pentanol, CH3CH(OH)CH2CH2CH3

52. Problem: Predict the structure of the product of the following reaction

53. TOPIC 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