1. Alcohols and Ethers Part 2
ROHAZITA BAHARI
School of Bioprocess Engineering
University Malaysia Perlis (UniMAP)

2. Reaction of Alcohol Others OXIDATION ALKYL HALIDE ALKENE SUBSTITUTION
ELIMINATION
(DEHYDRATION)
OXIDATION
SUBSTITUTION
Others
ALKYL HALIDE
SULFONATE ESTER
KETONE
ALDEHIDE
CARBOXILIC ACID
ALKENE

3. Substitution Reactions of Alcohols
Alcohols are not reactive in nucleophilic substitution
or elimination reactions since hydroxide is a strong base,
poor leaving group.
SN1
SN2
strong
base
poor leaving
group
no reaction in
either case

4. Substitution Reactions of Alcohols
The situation improves under acid conditions. We change the leaving group to water, a neutral group.
neutral
neutral

5. Electrophiles
Molecules that contain atoms with empty orbital, which can accommodate electrons. Typically, these are positively charged.
Examples:
Boron has only 6 valence electrons.
BF3 is a Lewis acid.

6. Nucleophiles Examples:
Molecules that contain atoms with lone pairs, which can donate electrons. Often these are negatively charged. Almost all the time they contain elements from groups 15–17 of the periodic table, since those have lone pairs.
Examples:

7. Nucleophilic substitution of Alcohol
An alcohol has a strongly base leaving group (HO-) therefore alcohol cannot undergo a nucleophilic substitution reaction
Convert the strongly basic leaving group (OH–) into the good leaving group, H2O (a weaker base):

8. Primary, secondary, and tertiary alcohols all undergo nucleophilic substitution reactions with HI, HBr, and HCl:

9. SN1 reaction
The SN1 reaction is a substitution reaction in organic chemistry. "SN" stands for nucleophilic substitution and the "1" represents the fact that the rate-determining step is unimolecular.
It involves a carbocation intermediate and is commonly seen in reactions of secondary or tertiary alkyl halides or, under strongly acidic conditions, with secondary or tertiary alcohols.

10. SN2 reaction
The SN2 reaction (known as bimolecular substitution nucleophilic) is a type of nucleophilic substitution, where a lone pair from a nucleophilic attacks an electron deficient electrophilic center and bonds to it, expelling another group called a leaving group. Thus the incoming group replaces the leaving group in one step.
Since two reacting species are involved in the slow, rate-determining step of the reaction, this leads to the name bimolecular nucleophilic substitution, or SN2.
The somewhat more transparently named analog to SN2 among inorganic chemists is the interchange mechanism.

11. Nucleophilic Substitution

12. Examples

13. Mechanism of Substitution
Secondary and tertiary alcohols undergo SN1 reaction.

14. Mechanism of Substitution
Primary alcohols undergo SN2 reaction. Primary carbocations are too unstable to be formed.
Attack from back-side

15. SN1 REACTION OF ALCOHOL
Secondary and tertiary alcohols undergo SN1 reactions with hydrogen halides:

16. Look out for rearrangement product in the SN1 reaction of the secondary or tertiary alcohol:

17. SN2 REACTION OF ALCOHOL
Primary alcohols undergo SN2 reactions with hydrogen halides:

18. When HCl is used; SN2 reaction is slower, but the rate can be increased using ZnCl2 as catalyst . ZnCl2 functions as a Lewis acid that complexes strongly with the lone-pair electrons on oxygen:

19. Other Methods for Converting Alcohols into Alkyl Halides
Utilization of phosphorus tribromide:
Other phosphorus reagents can be used:
PBr3, phosphorus tribromide
PCl3, phosphorus trichloride
PCl5, phosphorus pentachloride
POCl3, phosphorus oxychloride

20. SUMMARY
When treated with HBr or HCl alcohols typically undergo a nucleophilic substitution reaction to generate an alkyl halide and water
Alcohol relative reactive order : 30>20>10>methyl
Hydrogen halide reactively order: Hi>HBr>HCl>HF (paralleling acidity order)
Reaction usually proceeds via an SN1 mechanism which proceeds via a carbocation intermediate, that can also undergo rearrangement.

21. SUMMARY
Methanol and primary alcohols will proceed via an SN2 mechanism since these have highly unfavorable carbocations
The reactions of alcohols with HCl in the presence of ZnCl2 (catalyst) forms the basis of the Lucas test for alcohols.

22. Reactions of Alcohols with other Halogenating agents (SOCl2, PX3)

23. Alcohols can also be converted to alkyl cloride using thionyl chloride,SOCl2, or phosphorous trichloride, PCl3.
Alkyl bromides can be prepared in a similar reaction using PBr3
Used mosty for 10 and 20 ROH
In each case a base is used to ‘mop-up’ the acidic by-product

24. Common bases are tiethylamine,Et3N, or pyridine, C6H5N
In each case the –OH reacts first as a nucleophile, attacking the electrophilic center of the halogenating agent
A displaced halide ion then completes the substitution displacing the leaving group

25. Activation by SOCl2
Pyridine is generally used as a solvent and also acts as a base:

27. Summary: Converting of Alcohols to Alkyl Halides
Recommended procedures:

28. Converting Alcohols into Sulfonate Esters

29. Several sulfonyl chlorides are available to activate OH groups:

30. The elimination of water from an alcohol is called DEHYDRATION.

31. Elimination
Elimination of water, dehydration, is commonly obtained using sulfuric acid (H2SO4) as a catalyst.
The acid is mandatory to convert the poor leaving group OH– into a good leaving group H2O.

32. ELIMINATION REACTION OF ALCOHOL (DEHYDRATION)
Dehydration of alcohol requires acid catalyst and heat
Dehydration of Secondary and Tertiary Alcohols by an E1 Pathway

33. Elimination First step is protonation of the hydroxyl group.
Loss of water leads to a carbocation.

34. Elimination
Second, a base removes a proton b to the carbocation center.
Notice that this reaction is an E1 reaction.
Rate-determining step is the formation of the carbocation.

35. Mechanism of E1 Dehydration of an Alcohol

36. The major product is the most stable alkene product: The most stable alkene product has the most stable transition state

37. Elimination
In case we have a choice between several b-hydrogens, the most stable alkene is formed preferentially.
84 % 16 %

38. Elimination
As a result of the E1 mechanism, the ease of dehydration follows the order:
That directly reflects the stability of the
intermediate carbocations.

39. The rate of dehydration reflects the ease with which the carbocation is formed:

40. Look out for carbocation rearrangement:

41. Pinicol Rearrangement
Protonate alcohol:
Eliminate water:
Rearrange carbocation:
Deprotonate:
Resonance-stabilized
oxocarbocation

42. Ring Expansion and Contraction
Mechanism for this reaction:
Protonate the alcohol.
Eliminate water.
Rearrange carbocation to afford the more stable cyclohexane ring.
Deprotonate.

43. Elimination Primary alcohols undergo dehydration by an E2 pathway.
First, however, we generate the good leaving group.
The subsequent steps, removal of water and
deprotonation, take place simultaneously.

44. Primary Alcohols Undergo Dehydration by an E2 Pathway

45. A Milder Way to Dehydrate an Alcohol

46. ETHER

47. Nucleophilic substitution reaction of Ether
Ethers, like alcohols, can be activated by protonation:
Ether can undergo nucleophilic substitution with HBr and HI only (HCl cannot be used because Cl- too poor nucleophile

48. Substitution of Ethers
The mechanism involves first a protonation step.
The subsequent steps are determined by the stability of the intermediates.
Stable carbocation  SN1
Unstable carbocation  SN2

49. Substitution of Ethers
Examples
attack of nucleophile
stable carbocation

50. Substitution of Ethers
Primary carbocations are unstable;
thus, reaction proceeds via SN2.
Reaction takes place on the less hindered of the
two alkyl groups.

51. Ether cleavage: an SN1 reaction:

52. Reagents such as SOCl2 and PCl3 can activate alcohols but not ethers
Ethers are frequently used as solvents because only they
react with hydrogen halides

53. Ethers Only hydrogen halides react with ethers
Ethers commonly used as solvents
Often used solvents are:

54. Epoxides A special group of ethers are epoxides.
Here the oxygen is incorporated into a three- membered ring.
We name epoxides commonly by using the name
of the parent alkene followed by oxide.

55. Epoxides
Alternatively we can use the name of the parent alkane with an “epoxy” prefix
Formation of epoxides can be accomplished
by a reaction of a peracid with an alkene

56. Epoxides
Reaction with hydrogen halides proceeds as with other ethers.

57. Epoxides
Reaction with water and alcohols can be accomplished via acid catalysis.

58. Epoxides
For unsymmetrical epoxides we have to inspect the individual steps in the reaction more carefully.
acidic conditions
basic conditions
We obtain different results depending on the
reaction conditions used.

59. Epoxides Acidic conditions:
First step is the formation of an oxonium species.
Attack of the nucleophile can take place
at two positions.

60. Epoxides
For the process of breaking the C-O bond of the epoxide we have to assume that the oxygen is keeping the bonding electrons, thus creating a partial positive charge on the neighboring carbon.
secondary
carbocation
tertiary
carbocation
Now we have carbocation-type carbons that can
be distinguished via their stability.

61. Epoxides
Reaction proceeds at the tertiary center

62. Epoxides Under basic reaction conditions the situation changes.
First we generate an alcoholate anion
Attack takes place on the less hindered side.

63. Epoxides
Finally, the reaction is completed by taking up a proton.

64. Epoxides
Ring opening of epoxides is an important reaction in organic chemistry. A wide variety of nucleophiles can be used for this reaction.

65. Nucleophilic Substitution
Reactions of Epoxides
Acidic condition;
HBr:
Aqueous acid:

66. Reaction of an epoxide in different substituent
Regioselectivity:
Mechanism:

67. Neutral or Basic condition:
When a nucleophile attacks an unprotonated epoxide,the reaction is a pure SN2 reaction:
Therefore: