1. Ether, Epoxide, Thiol/Thioether
Preparation of Ethers
Reaction of Ethers
*Reaction of Epoxide
*Epoxide in synthesis
Preparation of Thiols and Thioethers
Reaction of Thiol as nucleophile

2. Introduction to Ethers
An ether group includes an oxygen atom that is bonded to TWO –R groups, -R groups can be alkyl, aryl, or vinyl groups
Ether in nature

3. Naming Ethers: Common Name
Common names are used frequently
Name each –R group
Arrange them alphabetically
End with the word, “ether”

4. IUPAC Nomenclature of Ethers
IUPAC systematic names are often used as well
Make the larger of the –R groups the parent chain
Name the smaller of the –R groups as an alkoxy substituent

5. Practice: Naming Ethers
Name the following molecule
Draw the structure for (R)-1-methoxycyclohexen-3-ol

6. 3 Structure and Properties of Ethers
The bond angle in ethers is very similar to that found in water and in alcohols
Ethers typically have much lower boiling point than alcohol with same formula (lack of H-bonding).
Larger R group has higher boiling point.

7. Use of Ethers in Organic Chemistry
Ethers are often used by organic chemists as solvents
Relatively low boiling points allow them to be evaporated after the reaction is complete
Their dipole moment allows them to stabilize charged or partially charged transition states. HOW?
They are NOT protic.

8. Ether as Polar Aprotic Solvent
Metal atoms with a full or partial positive charge can be stabilized by ether solvents
Ethers are generally used as the solvent in the Grignard reaction
In this reaction ether is inert to the reaction intermediates.

9. 5 Ethers from Acid Dehydration
Symmetrical ether (such as diethyl ether) can be prepared by the acid-catalyzed dehydration of alcohol (SN2)
Intermolecular dehydration
Only for symmetrical ethers

10. Williamson reaction
The Williamson ether synthesis (1. NaH; 2. R’X) is a viable approach for many asymmetrical ethers
Mechanism:
First, formation of alkoxide (nucleophile);
Then SN2 rxn of alkoxide with alkyl halide

11. Use of Williamson Reaction
R’X as primary halide: The alkoxide ion is also a strong base, so elimination rxn might occur with secondary/tertiary halides.
Use the Williamson ether approach to prepare MTBE

12. Practice: Preparation of Ethers
Use the Williamson ether approach to synthesize the following molecule

13. Ether from Oxymercuration-demercuration
Recall conversion from alkene to alcohols
Regiochemistry: Markovnikov (OH on more substituted carbon)
Stereochem: Anti addition of Hydride
Similarly, alkoxymercuration-demercuration can be used to synthesize ethers. Markovnikov; anti

14. Practice: Preparation of Ethers
Predict the alkoxymercuration-demercuration product

15. 6 Ether Reactions: Acidic Cleavage of Ether
Reaction: R-O-R’ + excess HX  R-X + R’-X
Mechanism: Protonation and SN2

16. More Acidic Cleavage of Ethers
Phenol will NOT react with HX to protonate to form Aryl halide
Cyclic ether reacts with excess HX to form dihalide

17. Nucleophilicity in Cleavage of Ethers
SN2 follows protonation, thus nucleophilicity of halide affects the reactivity
Recall the nucleophilicity of halides: I > Br > Cl F due to polarizibility of ions
HI and HBr are generally effective
HCl is less effective, and HF does not cause significant cleavage

18. Practice: Reactions of Ethers
Predict products and draw a complete mechanism

19. Autooxidation of Ethers
Ethers can undergo autooxidation
Hydroperoxides can be explosive, so laboratory samples of ether must be frequently tested for the presence of hydroperoxides before they are used
The autooxidation occurs through a free radical mechanism

20. 7 Epoxides
For cyclic ethers, the size of the ring determines the parent name of the molecule
Oxiranes are also known as epoxides
Epoxides are most reactive among the above.

21. Epoxides in nature An epoxide can have up to 4 –R groups
Although they are unstable, epoxides are found commonly in nature

22. Naming Epoxides There are two methods for naming epoxides
The oxygen is treated as a side group (epoxy), and two numbers are given as its locants
Oxirane is used as the parent name

23. Practice: Naming Epoxides
Name the molecules below by both methods if possible

24. 8 Epoxides from Alkene + MCPBA
Recall that epoxides can be formed when an alkene is treated with a peroxy acid
MCPBA and peroxyacetic acid are most commonly used

25. Syn Stereochemistry of MCPBA Addition
Recall that the process is stereospecific

26. Epoxides from Halohydrin+NaOH
Recall Halohydrin can be prepared from the addition of halogen/water to alkene:
Markovnikov regioselectivity (HOd--Xd+).
Anti stereochemistry (similar to halogenation)
When a Halohydrin is treated with NaOH, a ring-closing reaction can yield epoxide

27. Epoxide from Halohydrin: Intramolecular SN2

28. Stereochemistry of AlkeneEpoxide
Assess the overall stereochemistry of the epoxidation that occurs through the halohydrin intermediate

29. 9 Enantioselectivity in Epoxidation
The epoxidation methods we have discussed so far are NOT enantioselective
Draw the products
racemic mixture

30. 10 Ring-opening of Epoxides
Because of their significant ring strain, epoxides have great synthetic utility as intermediates
Strong nucleophiles react readily with epoxides
Predict whether each step is product or reactant favored, and explain WHY

31. Ring opening of epoxide
In general, alkoxides are not good leaving groups
The ring strain associated with the epoxide increases its potential energy making it more reactive

32. Ring-opening of Epoxides by Nucleophiles
Epoxides can be opened by many other strong nucleophiles as well, via SN2 mechanism (1>2>>3).
Both regioselectivity and stereoselectivity must be considered – see next few slides

33. Regio/Stereochemistry of Ring-opening
Given that the epoxide ring-opening is SN2, predict the outcome of the following reactions (Pay attention to regio- and stereoselectivity)

34. Acidic Ring-opening of Epoxides
Acidic ring-opening of epoxide  Halohydrin
Mechanism: Protonation  SN2
protonated RO- group as better leaving group (similar to protonated –OH group in alcohol).

35. Acidic ring-opening of Epoxides by ROH
Water or an alcohol as nucleophile under acidic conditions reacts with epoxide to form alcohol
SN1 regioselectivity (3>2>>1).
Predict the products and draw a complete mechanism
Antifreeze (ethylene glycol)

36. Ring-opening of Epoxides: Observation
Experiments:
First rxn: Nuc attack on primary over secondary, SN2
Second rxn: Tertiary carbon undergoes change. SN1

37. More on Ring-opening of Epoxides
If the nucleophile preferentially attacks the tertiary carbon under acidic conditions, the mechanism is likely SN1.
Considering the observations below:

38. Stabilized Carbocation in Ring-opening of Epoxides
When the nucleophile attacks a tertiary center of the epoxide, the intermediate it attacks takes on some carbocation character (SN1), but not completely

39. 12 Synthetic Strategies Involving Epoxides
Epoxides can be used to install functional groups on adjacent carbons
Give necessary reagents for the reaction below

40. Rxn of Epoxides with Grignard Reagent
By reacting an epoxide with a Grignard reagent (nucleophile), the carbon skeleton can be modified
Or You may think of an epoxide as the starting material

41. Synthesis from Epoxides and Grignard Reagent
An epoxide can be used to install a TWO carbon chain between an R group and an OH group
Recall that a carbonyl can be used to install a ONE carbon chain between an R group and an OH group

42. Practice: Synthesis involving Epoxides
Give necessary reagents for the reaction below

43. 11 Thiols Alcohol ROH  Thiol RSH
Thiols (–SH group) analogous to Alcohol (–OH group)
The name of a compound with an –SH group ends in “thiol” rather than “ol”
Note that the “e” of butane is not dropped in the name of the thiol

44. Naming Thiols Thiols are also known as mercaptans
The –SH group can also be named as part of a side group, mercapto, rather than as part of the parent chain
The mercaptan name comes from their ability to complex mercury (forming S-Hg-S bond)
2,3-dimercapto-1-propanol is used to treat mercury poisoning.

45. Thiols in life Thiols are known for their unpleasant odor
Skunks use thiols as a defense mechanism
Methanethiol as additive to natural gas (methane)

46. Synthesis of Thiols
Thiols can be prepared from SN2 substitution with hydrosulfide (HS-, strong nucleophile and weak base) and alkyl halide

47. Review: Preparation of Thiols
Predict the outcome of the following reactions, and draw a complete mechanism

48. Thiols: Acidity, Nucleophilicity
Thiols have a pKa of about 10.5
Recall that water has a pKa of 15.7
Review: Predict whether the equilibrium below will favor products or reactants and draw the mechanism (by comparing Ka or pKa)
Thiolates are excellent nucleophiles
thiolate ion

49. Thiols to Disulfides
A thiolate can attack Br2 to produce a disulfide. RSBr as intermediate.
The reaction is the oxidation

50. Reduction of Disulfide to Thiol
Low bond dissociation energy for S-S bond (53 kcal/mol)
Disulfides can be reduced by the reverse reaction
The interconversion between thiol and disulfide can also occur directly via a free radical mechanism.
Making curly hair: Reduction to “loosen” disulfide bonds, then oxidation to build new disulfide bonds.

51. Sulfide/Thioether
Recall: In general/inorganic chemistry, “sulfide” refers to sulfide ion or metal sulfur compound such as Al2S3
Organic chemistry, sulfide = Sulfur analogs of ethers or thioethers
Sulfides can also be named as a side group

52. Preparation of Sulfides
Nucleophilic attack of a thiolate (RS- anion) on alkyl halide
Thiolates generally are prepared from deprotonation of thiol (RSH + base, such as OH- )

53. Reaction of Sulfides
Sulfonium: The neutral sulfide is good nucleophile to attack on an alkyl halide, forming sulfonium ion.
The process produces a strong alkylating reagent that can add an alkyl group to a variety of nucleophiles

54. Oxidation of Sulfides
Sulfides can also be oxidized to form sulfoxide and sulfone. H2O2/NaHCO3 to remove skunk odor.
Sodium meta-periodate can be used to form the sulfoxide

55. S-O Bond in Sulfoxide/Sulfone
Sulfoxides and sulfones have very little double bond character, indicating the polarized resonance contributor as the major contributor

56. Sulfides as Reducing Agent
Because sulfides are readily oxidized, they make good reducing agents
Similar to the ozonolysis reaction of alkene and alkyne

57. Practice: Rxns of Thiols and Sulfides
Predict any products or necessary reagents in the reaction sequence below
Verify the formal charge on the sulfur in the final product above

58. Supplemental topics: Crown Ethers
Crown ethers have been shown to form especially strong attractions to metal atoms.
Note two carbon atoms as unit separate the oxygens

59. Size of Crown Ethers vs. Size of M+
The size of the metal must match the size of the crown to form a strong attraction
18-crown-6 fits a K+ ion just right

60. Solubility of Crown Ether-Metal Complex
Normally metal ions are not soluble in low polarity solvents.
The crown ether – metal complex should dissolve nicely in low polarity solvents because of the nonpolar section of structure
Thus crown ether could be used to aid reactions between ion (especially anions) and low polarity organic substrates

61. Crown Ether facilitate Anion rxn
Without the crown ether, KF is insoluble in benzene
The F- ion below is ready to react because the K+ ion is sequestered by the crown ether
The free F- ion readily undergo SN2 rxn despite as “poor” nucleophile:

62. Other Crown Ether-Metal Complexes
Smaller crown ethers bind smaller cations

63. *Non-enantioselective Epoxidation
The epoxidation forms a racemic mixture, because the flat alkene can react on either face

64. Enantioselective Epoxidation
To be enatioselective at least one of the reagents (or catalyst) in a reaction must be chiral
The Sharpless catalyst forms such a chiral complex with an allylic alcohol

65. Sharpless Enantioselective Epoxidation
The desired epoxide can be formed if the right catalyst is chosen. Note the position of the –OH group

66. Additional Practice Problems
Name the following molecule
Draw the structure for (4-methylcyclohexyl)phenylether

67. Additional Practice Problems
Fill in the missing intermediates and reagents in the scheme below

68. Additional Practice Problems
Fill in the missing intermediates and reagents in the scheme below

69. Additional Practice Problems
Give necessary reagents to complete the synthesis below

70. Mechanism of ether autooxidation

71. Mechanism of ether autooxidation
Recall that the net reaction is the sum of the propagation steps

72. Ring-opening of Epoxides
The epoxide reaction is both more kinetically and more thermodynamically favored, due to instability of epoxide and entropy increase