1. Chapter 10 Lecture PowerPoint
Nucleophilic Substitution
and Elimination Reactions 2

2. Nucleophilic Substitution: Converting Alcohols to Alkyl Halides
If we wish to carry out a nucleophilic substitution or elimination reaction at a carbon atom that is attached to an OH group, it is extremely useful to be able to convert that alcohol into an alkyl chloride or alkyl bromide since the halide is a much better leaving group than the hydroxide anion.

3. Mechanism for Alcohol and HBr
However, a variety of problems are often associated with this kind of reaction.
For example, there may be other functional groups in the substrate that are sensitive to strongly acidic conditions, leading to unwanted side reactions.
Carbocation rearrangements can also occur.

4. PBr3 and PCl3
A much better way to convert an alcohol to an alkyl halide is to use phosphorus tribromide, PBr3, or phosphorus trichloride, PCl3.

5. PBr3 Mechanism

6. Steric Hindrance and PBr3 and PCl3
Recall that SN2 reactions cannot take place when the leaving group is on a tertiary carbon.

7. Nucleophilic Substitution: Alkylation of Ammonia and Amines
Ammonia (NH3) is uncharged, yet it is a moderately strong nucleophile.
In an alkylation, a hydrogen atom is replaced by an alkyl group.

8. Problems with Amine Alkylation
This reaction is not an effective method of synthesizing primary amines (R-NH2).
A mixture of over-alkylated products are formed.

9. Problems with Amine Alkylation continued…
The primary amine undergoes a subsequent alkylation to produce the secondary amine.
The tertiary amine and the quaternary ammonium are produced in a similar fashion.

10. Nucleophilic Substitution: Alkylation of α Carbons
No reaction occurs when an aldehyde (RCH=O) or ketone (R2C=O) is treated with an alkyl halide alone.

11. Nucleophilic Substitution: Alkylation of α Carbons continued…
When a strong base like sodium hydride (NaH) or sodium amide (NaNH2) is included, however, alkylation can take place at the α carbon (i.e., at the C atom adjacent to the C=O group).

12. Alkylation of an α Carbon
A base is required because an α carbon is non-nucleophilic in the uncharged form of a ketone or aldehyde.
A hydrogen atom on such a carbon is weakly acidic (pKa ~ 20), so it can be deprotonated by a sufficiently strong base to generate an enolate anion.

13. Mechanism for the Alkylation of an α Carbon

14. Regioselectivity in α Alkylations
Alkylation at an α carbon is rather straightforward if there is only one distinct type of α carbon to consider.

15. Regioselectivity in α Alkylations continued…
For many ketones, however, such as methylcyclohexanone, the α carbons are distinct, so alkylation of the different C atoms leads to different products.
Regioselectivity is a concern for the alkylation of ketones that have distinct α carbons.
Regioselectivity can be controlled by the choice of base.

16. LDA and Regioselectivity

17. LDA and Regioselectivity continued…
The regioselectivity demonstrated by LDA versus RO⁻ is dictated by whether deprotonation at the α carbon takes place reversibly or irreversibly.
When LDA is used as the base, deprotonation is irreversible because Keq is much greater than 1, making DGorxn substantially negative.

18. Mechanism for LDA
LDA will predominantly deprotonate the α hydrogen that can be removed the fastest, yielding the kinetic enolate anion.

19. The Thermodynamic Enolate Anion
When (CH3)3CO⁻ is used as the base, Keq for the proton transfer step is <1, making DGorxn slightly positive.
The reaction is reversible, so it takes place under thermodynamic control and an equilibrium is established.
If two distinct enolate anions can be produced, then the more stable of the two—called the thermodynamic enolate anion—will have greater abundance prior to the SN2 step.

20. The Thermodynamic Enolate Anion continued…

21. Mechanism for a Alkylation via the Thermodynamic Enolate Ion

22. Nucleophilic Substitution: Halogenation of α Carbons
Halogenation can take place at the a carbon of a ketone or aldehyde by treatment with Cl2, Br2, or I2 under basic conditions.

23. Mechanism for α Halogenation Under Basic Conditions
Deprotonation in Step 1 produces an enolate anion, a strong nucleophile that participates in an SN2 reaction in Step 2.

24. Molecular Halogens as Substrates in SN2 Reactions
Because of the polarizability of Br2, the approach of a nucleophile creates an induced dipole.
This sets up the electron-rich to electron-poor driving force for the SN2 reaction.

25. Polyhalogenation under Basic Conditions
With each additional halogen atom, the remaining a protons become more acidic, so each subsequent halogenation speeds up.

26. Mechanism for Polyhalogenation

27. a Halogenation under Acidic Conditions
With each additional halogen atom, the remaining a protons become less acidic, so each subsequent halogenation slows down.

28. Mechanism for a Halogenation under Acidic Conditions

29. Nucleophilic Substitution: Diazomethane Formation of Methyl Esters
Treatment of a carboxylic acid with diazomethane (CH2N2) yields a methyl ester, in which the acidic H atom is replaced by a CH3 group.

30. Diazomethane Mechanism

31. Diazomethane Mechanism continued…
The leaving group is N2 gas, which is an excellent leaving group for two reasons:
N2(g) is extremely stable—one of the most inert compounds known.
It is a gas, so it bubbles out of solution as it is formed. The nitrogen product is removed permanently.

32. Nucleophilic Substitution: Formation of Ethers
One of the most convenient ways of forming an ether (R-O-R’) is via the Williamson ether synthesis.
An alkyl halide is treated with a salt of an alkoxide anion.
Can be used to synthesize both symmetric and unsymmetric ethers.

33. Nucleophilic Substitution: Formation of Ethers continued…

34. Williamson Ether Synthesis Mechanism
Can have an intramolecular ether synthesis.

35. Reactions of Epoxides under Neutral and Basic Conditions
Oxirane reacts readily under neutral and basic conditions.

36. Epoxide Mechanism

37. C-C Bonds from Oxirane

38. Regiochemistry of Epoxide Ring Opening Under Neutral or Basic Conditions

39. Mechanism for Attack on the Epoxide Under Basic Conditions

40. Reactions of Epoxides under Acidic Conditions
(R)-2-methyloxirane reacts with HBr to form the bromoalcohol.
The regioselectivity is different from that observed under neutral or basic conditions.
Under acidic conditions, a nucleophile attacks this epoxide at the more highly alkylsubstituted carbon.

41. Mechanism for the Reaction of an Epoxide under Acidic Conditions
The regioselectivity is governed by the mechanism.
The epoxide is first protonated, which creates a partial positive charge on the side of the ring with greater alkyl substitution.
The formal carbocation is not formed since the product undergoes an SN2-type inversion.

42. Reactions of Oxetanes and Cyclic Ethers
Oxetanes, which are four-membered ring ethers, can also open via nucleophilic attack under neutral or basic conditions, aided by the relief of ring strain.

43. Oxetane Reaction
Oxetanes are larger rings than epoxides, however, so they have less ring strain, giving these reactions less of a driving force.
Consequently, reactions that open oxetanes are generally limited to ones involving very strong nucleophiles, such as alkyllithium reagents (R-Li) and Grignard reagents (R-MgBr).

44. Tetrahydrofuran and Tetrahydropyran
Ethers that are part of larger rings do not readily undergo ring opening under neutral or basic conditions, because five-membered rings and larger have little or no ring strain, and thus behave much like acyclic ethers.

45. Elimination: Generating Alkynes via Elimination Reactions
The leaving group is in a vinyl position (i.e., attached to a C=C double bond).
These substrates are quite resistant to nucleophilic substitution and elimination reactions.

46. Elimination: Generating Alkynes via Elimination Reactions continued…
These reactions, therefore, are carried out under extreme conditions, often at temperatures >200 oC.

47. The Nature of the Substrate and the Choice of the Base
Depending upon the nature of the substrate, the choice of base may have a dramatic effect on the outcome of this reaction.
1-Bromopent-1-ene leads to pent-1-yne as the major product when NaNH2 is used as the base.
Pent-2-yne is the major product when NaOH is used as the base.

48. Mechanism Involving H2N⁻ as the Base
When H2N⁻ is the base and the halide is on a terminal carbon, an acid workup is required.

49. Mechanism Involving HO⁻ as the Base
Reversible deprotonation by HO⁻ allows the isomeric alkyne products to equilibrate.

50. Elimination: Hofmann Elimination
This is an example of a Hofmann elimination reaction.
The formation of a C=C double bond strongly suggests that an elimination reaction has occurred in which the leaving group contains the N atom.

51. Reconciling the Amine Leaving Group
There are two aspects of this Hofmann elimination to reconcile:
(1) Amino groups are terrible leaving groups and therefore do not participate as substrates in elimination reactions, and (2) the major product is a terminal alkene, which is the less alkyl substituted, and therefore the less stable, of two possible elimination products.

52. Hofmann Elimination Mechanism
The mechanism accounts for these observations.

53. Hofmann Mechanism Explained
The presence of CH3Br ensures that the leaving group is not simply H2N⁻.
The amine reacts with multiple equivalents of CH3Br to yield the quaternary ammonium ion.
The leaving group is a stable, uncharged amine, N(CH3)3.
HO⁻ then deprotonates at C1.
The regioselectivity of the Hofmann elimination reaction can be explained by the steric bulk of the amine leaving group.

54. Hofmann Mechanism Explained continued…
Steric hindrance makes it difficult for the H at C3 to be anti to the leaving group.

55. Summary and Conclusions
Phosphorus tribromide (PBr3) and phosphorus trichloride(PCl3) convert 1o and 2o alcohols to alkyl halides.
Ammonia and amines undergo alkylation when treated with an alkyl halide that has a good leaving group.
Alkylation can take place at an α carbon of a ketone or aldehyde.
Halogenation may occur at an α carbon under either acidic or basic conditions.
Polyhalogenation generally occurs under basic conditions.
Monohalogenation generally occurs under acidic conditions.

56. Summary and Conclusions continued…
Diazomethane (CH2N2) converts a carboxylic acid into a methyl ester (RCO2CH3).
The Williamson ether synthesis can be used to synthesize either symmetric or unsymmetric ethers via an SN2 reaction between an alkoxide anion (RO⁻) and an alkyl halide (R’X).
Epoxides and oxetanes are three- and four-membered ring ethers, respectively, that can be opened in an SN2 reaction that relieves their substantial ring strain.

57. Summary and Conclusions continued…
A vinyl halide can undergo an E2 reaction to produce an alkyne.
Hofmann elimination leads to an anti-Zaitsev elimination product.