1. L18
TOPIC 6. NUCLEOPHILIC SUBSTITUTIONS (chapter 6 and parts of chapter 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
Acid-Base Chemistry

4. OVERVIEW: NUCLEOPHILIC SUBSTITUTIONS

5. PRS

6. Nucleophiles Electrophiles
Donate a pair of electrons: to an electrophile (lone pair or pi bond)
Neutral
Anionic
Electrophiles
Receive a pair of electrons: from a nucleophile
Cationic
Lacks an octet
Polar, electrophilic

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

8. Substitution: What is the Mechanism?
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 SUBSTITUTION (SN2)
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. PRS PRS HWeb Effect of Nucleophile
Rate: I– > OH– > Br– > Cl– > F– > H2O
Interpretation:
PRS
PRS
HWeb

14. Effect of Leaving Group Rate: -I > -Br > -Cl >> -F
C-L bond must be broken – weaker bonds are easier to break
Bond strengths (kcal/mole):
C-F 116
C-Cl 79
C-Br 66
C-I 52
Interpretation: A good substrate for bimolecular nucleophilic substitution should have:
Weak C-L bond
Polarizable C-L bond (ease with which the electron distribution in the bond is distorted)
Leaving group which can accommodate a pair of electrons
L19

15. Effect of Substrate Rate: methyl > 1° > 2° ( 3° unreactive)
Adjacent alkyl groups also slow the reaction

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

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

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. 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

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

21. 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?

22. (a) Ph3N or Ph3P (b) 1.0 M CH3ONa or 2.0 M CH3ONa
Problem: Which of the following would undergo the fastest reaction with 1-bromopropane?
(a) Ph3N or Ph3P
(b) 1.0 M CH3ONa or M CH3ONa

23. HWeb Synthesis of Alkynes and Alkanes: Alkylation of
Acetylide Anions (see also 4.17c)
HWeb

24. L20
SUBSTITUTION AT 3° SUBSTRATES: UNIMOLECULAR NUCLEOPHILIC SUBSTITUTION (SN1) S:
Prob: 6.16,30,35
Example
Experimental observations of kinetics, chirality, substrate structure and effect of nucleophiles for this reaction are inconsistent with the SN2 mechanism

25. 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

26. Effect of Substrate Rate: 3° > 2° (1°, methyl not reactive)
Interpretation:
Stability of Carbocations
Carbocation Relative Energy
(kcal/mol)
Methyl
Ethyl
i-Propyl
t-Butyl

27. Effect of Leaving Group
Rate: -I > -Br > -Cl (F: unreactive)
C-L bond must be broken – weaker bonds are easier to break
Bond strength: C-F > C-Cl > C-Br > C-I
Interpretation: A good substrate for unimolecular nucleophilic substitution should have:
Weak C-L bond
Polarizable C-L bond (ease with which the electron distribution in the bond is distorted)
Leaving group which can accommodate a pair of electrons
S:6.13E

28. S:6.13B
Effect of Nucleophile
Concentration of nucleophile (see slide on experimental observations)
Identity of nucleophile
Rate of reaction: I- = Br- = Cl-
Interpretation:

29. Chirality
Optically active R-L forms racemic R-Nu
S:6.12A

30. Summary
Unimolecular nucleophilic substitution mechanism explains the observations.
Effect on rate:
Nu: L:
C-L:
Chirality:
Substrate:
Solvent polarity:
PRS

31. Energetics of a Two-Step Reaction
SN1 DG
Reaction coordinate
PRS

32. PRS 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 Solvent Polarity
Increasing solvent polarity dramatically increases rate of reaction by facilitating disocciation of substrate into carbocation and anion (leaving group).
PRS

33. SUMMARY: FACTORS EFFECTING SN1 AND SN2 REACTIONS
Prob: 6.18,26
SN1
Substrate: 3°>2°>>1°or methyl
- Stability of carbocation intermediate
Nu: No effect
- Nu not involved in RDS
Rate increases by use of polar solvents
- Enhanced rate of ionization
Chirality
-Racemization
Generally only useful for solvolyses (reactions with H2O, ROH, RCO2H)
Unimolecular kinetics
SN2
Substrate: Methyl>1°>2°>>3°
- Steric bulk hinders attack of Nu
Rate depends on type of Nu
- Nu involved in RDS
Chirality
-Racemization
Rate a [nucleophile]
Often performed in polar aprotic solvents, e.g., DMF (Me2NCHO), DMSO (Me2SO) to dissolve substrate and ionic reagent, and increase reaction rate
Bimolecular kinetics

34. Why is Nucleophilic Substitution Limited to sp3 (Alkyl) Substrates?
Inaccessible carbon atom Unstable sp2 carbocation
(hinders SN2) (hinders SN1)

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

36. SUBSTITUTION REACTIONS OF ALCOHOLS
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

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 product from 1-propanol and any other starting materials?

42. SYNTHESIS AND REACTIONS OF ETHERS
Prob: 11.32
Synthesis of Ethers: Williamson Ether Synthesis
Overall Reaction and Mechanism

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

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

46. HWeb

47. A note on the use of alcohols in SN reactions
tert-butanol must be protonated to make the hydroxyl group a better leaving group
Ammonia is nucleophilic
So why doesn’t this reaction work?

48. SUBSTITUTIONS IN SYNTHESIS
L22
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.

49. ONE-STEP SYNTHESES S:
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

50. (c)
from starting materials with 7 or fewer carbon atoms

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

52. 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.

53. 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

54. Problem: How could you perform the following synthesis
Problem: How could you perform the following synthesis? [An introduction to designing multi-step syntheses]
from

55. Problem: Predict the structure of the product of the following reaction
PRS
PRS
PRS

56. HWeb 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
HWeb

57. PRS
Which of the following are primary or secondary alkyl halides, which undergo nucleophilic substitution reactions?
1 only B, C, D, F and G
2 only C, D, F and G
3 only C and D
4 only C, D and G
5 only B and E
PRS

58. PRS
Which of the following is the best leaving group in a nucleophilic substitution reaction? 1 2 3 4 5
PRS

59. PRS
Which of the following would undergo the most rapid acidolysis (e.g., substitution with acetic acid)?
1 (CH3)3CBr
2 (CH3)3CF
3 CH3Cl
4 (CH3)3CCl
5 CH3CH2Br
PRS

60. PRS
Which of the following reaction profiles corresponds to the fastest overall reaction?
Energy
Reaction Coordinate
PRS

61. PRS
If the nucleophile is used as the solvent in an SN1 reaction with tert-butyl bromide, which of the following will react fastest?
1 water, H2O
2 methanol, CH3OH
3 ethanol, CH3CH2OH
4 formic acid, HCOOH
PRS

62. PRS
Which of the following is the most reactive electrophile in SN2 reactions? 1 2
PRS

63. PRS
Which of the following reagents does not convert primary alcohols into alkyl halides?
1 HBr
2 SOCl2
3 PBr3
4 NaBr ?
PRS

64. PRS
What is the product of the reaction between (R)-2-bromopentane and potassium cyanide?
1 2-pentylpotassium
2 (2R,3S)-2-bromo-3-cyanopentane
3 trans 2-pentene
4 (S)-2-cyanopentane
PRS

65. PRS
Which statement is true regarding stereochemistry of SN1 and SN2 reactions?
1 Stereochemistry is inverted in SN2 and racemized in SN1.
2 Stereochemistry is racemized in SN2 and inverted in SN1
3 Stereochemistry is retained in SN2 and inverted in SN1.
4 Stereochemistry is retained in SN2 and racemized in SN1.
PRS

66. HWeb 15
HWeb

67. HWeb
HWeb 16
HWeb

68. HWeb
HWeb 17
HWeb

69. HWeb
HWeb 18
HWeb

70. HWeb
HWeb 19
HWeb