1. Ethers and Epoxides; Thiols and Sulfides
Organic Chemistry
Second Edition
David Klein
Chapter 14
Ethers and Epoxides; Thiols and Sulfides
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Klein, Organic Chemistry 2e

2. 14.1 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
Would the compound below be considered an ether?
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3. 14.1 Introduction to Ethers
Compounds containing ether groups are quite common
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4. 14.2 Naming Ethers Common names are used frequently Name each –R group
Arrange them alphabetically
End with the word, “ether”
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5. 14.2 Naming 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
Practice with SkillBuilder 14.1
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Klein, Organic Chemistry 2e

6. 14.2 Naming Ethers Name the following molecule
Draw the structure for (R)-1-methoxycyclohexen-3-ol
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7. 14.3 Structure and Properties of Ethers
The bond angle in ethers is very similar to that found in water and in alcohols
Is the oxygen atom in an ether sp3, sp2, or sp hybridized?
How do the –R groups affect the bond angle?
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8. 14.3 Structure and Properties of Ethers
In chapter 13, we learned that due to H-bonding, alcohols have relatively high boiling points
What is the maximum number of H-bonds an alcohol can have?
Draw an H-bond between an ether and an alcohol
What is the maximum number of H-bonds an ether can have?
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9. 14.3 Structure and Properties of Ethers
In chapter 13, we learned that due to H-bonding, alcohols have relatively high boiling points
Would you expect the boiling point of an ether to be elevated similar to alcohols?
WHY or WHY not?
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10. 14.3 Structure and Properties of Ethers
Explain the boiling point trends below using all relevant intermolecular attractions
Trend 1
Trend 2
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11. 14.3 Structure and Properties of Ethers
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. WHY is that an advantage for a solvent in many reactions?
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12. 14.4 Crown Ethers
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
Give another reason why an ether makes a good solvent in this reaction
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13. 14.4 Crown Ethers
Crown ethers have been shown to form especially strong attractions to metal atoms. WHY?
Note how many carbon atoms separate the oxygens
Why are they called CROWN ethers?
Explain the numbers found in their names
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14. 14.4 Crown Ethers
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
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15. 14.4 Crown Ethers
Normally metal ions are not soluble in low polarity solvents. WHY?
The crown ether – metal complex should dissolve nicely in low polarity solvents. WHY?
Imagine how a crown ether could be used to aid reactions between ion (especially anions) and low polarity organic substrates
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16. 14.4 Crown Ethers
The F- ion below is ready to react because the K+ ion is sequestered by the crown ether
Without the crown ether, the solubility of KF in benzene is miniscule
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17. 14.4 Crown Ethers
Generally, F- ion is not used as a nucleophile, because it is strongly solvated by polar solvents
Such solvation greatly reduces its nucleophilic strength
In the presence of the crown ether, it is soluble enough in a nonpolar solvent that it can readily attack an electrophile
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18. 14.4 Crown Ethers Smaller crown ethers bind smaller cations
Practice with conceptual checkpoint 14.4
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19. 14.5 Preparation of Ethers
Diethyl ether is prepared industrially by the acid-catalyzed dehydration of ethanol
How is it a dehydration?
Can this method be used to make asymmetrical ethers?
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Klein, Organic Chemistry 2e

20. 14.5 Preparation of Ethers
The Williamson ether synthesis is a viable approach for many asymmetrical ethers
What happens to the halide?
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21. 14.5 Preparation of Ethers
The Williamson ether synthesis is a viable approach for many asymmetrical ethers
The alkoxide that forms in step 1 is also a strong base
Are elimination products likely for methyl, primary, secondary, or tertiary alkyl halides?
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22. 14.5 Preparation of Ethers
Use the Williamson ether approach to prepare MTBE
Consider a retrosynthetic disconnect on the t-butyl side
It is better to make your retrosynthetic disconnect on the methyl side. WHY?
Practice with SkillBuilder 14.2
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Klein, Organic Chemistry 2e

23. 14.5 Preparation of Ethers
Use the Williamson ether approach to synthesize the following molecule
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24. 14.5 Preparation of Ethers
Recall from section 9.5 that oxymercuration-demercuration can be used to synthesize alcohols
Is the addition Markovnikov or anti-Markovnikov?
Is the addition syn or anti?
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25. 14.5 Preparation of Ethers
Similarly, alkoxymercuration-demercuration can be used to synthesize ethers
Is the addition Markovnikov or anti-Markovnikov?
Is the addition syn or anti?
Practice conceptual checkpoints 14.8–14.10
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26. 14.6 Reactions of Ethers
As we mentioned earlier, because they are aprotic, ethers are generally unreactive
However, ethers can react under the right conditions
Consider the ether below
Where are the most reactive sites?
Is it most likely to react as an acid, base, nucleophile, electrophile, etc.?
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27. 14.6 Reactions of Ethers Ethers can undergo acid-promoted cleavage
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28. 14.6 Reactions of Ethers
Draw a complete mechanism and predict the products for the following acid-promoted cleavage
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29. 14.6 Reactions of Ethers
To promote cleavage, HI and HBr are generally effective
HCl is less effective, and HF does not cause significant cleavage
Explain the trend above considering the relative strength of the halide nucleophiles
Why is the cleavage considered acid-promoted rather than acid-catalyzed?
Practice with conceptual checkpoint 14.11
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30. 14.6 Reactions of Ethers
Predict products for the reaction below, and draw a complete mechanism
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31. 14.6 Reactions of Ethers
Recall from section 11.9 that 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 – see next few slides
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Klein, Organic Chemistry 2e

32. 14.6 Reactions of Ethers Klein, Organic Chemistry 2e
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33. 14.6 Reactions of Ethers
Recall that the net reaction is the sum of the propagation steps
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34. 14.7 Naming Epoxides
For cyclic ethers, the size of the ring determines the parent name of the molecule
Oxiranes are also known as epoxides
Which cyclic ether system do you think is most reactive? WHY?
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35. 14.7 Naming Epoxides An epoxide can have up to 4 –R groups
Although they are unstable, epoxides are found commonly in nature
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36. 14.7 Naming Epoxides There are two methods for naming epoxides
The oxygen is treated as a side group, and two numbers are given as its locants
Oxirane is used as the parent name
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37. 14.7 Naming Epoxides
Name the molecules below by both methods if possible
Practice conceptual checkpoints and 14.13
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38. 14.8 Preparation of Epoxides
Recall from section 9.9 that epoxides can be formed when an alkene is treated with a peroxy acid
MCPBA and peroxyacetic acid are most commonly used
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39. 14.8 Preparation of Epoxides
Recall that the process is stereospecific
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40. 14.8 Preparation of Epoxides
Epoxides can also be formed from halohydrins
What is a halohydrin?
How are halohydrins formed from alkenes?
When a Halohydrin is treated with NaOH, a ring-closing reaction can occur
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Klein, Organic Chemistry 2e

41. 14.8 Preparation of Epoxides
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42. 14.8 Preparation of Epoxides
Assess the overall stereochemistry of the epoxidation that occurs through the halohydrin intermediate
Practice with SkillBuilder 14.3
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Klein, Organic Chemistry 2e

43. 14.9 Enantioselective Epoxidation
The epoxidation methods we have discussed so far are NOT enantioselective
Draw the products
racemic mixture
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44. 14.9 Enantioselective Epoxidation
The epoxidation forms a racemic mixture, because the flat alkene can react on either face
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45. 14.9 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
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46. 14.9 Enantioselective Epoxidation
The desired epoxide can be formed if the right catalyst is chosen. Note the position of the –OH group
How does the catalyst favor just one epoxide product?
Practice with conceptual checkpoint 14.16
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Klein, Organic Chemistry 2e

47. 14.10 Ring-opening of Epoxides
Because of their significant ring strain, epoxides have great synthetic utility as intermediates
Propose some reagents that might react with an epoxide to provide a specific functional group
Propose some reagents that might react with an epoxide to alter the carbon skeleton
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Klein, Organic Chemistry 2e

48. 14.10 Ring-opening of Epoxides
Strong nucleophiles react readily with epoxides
Predict whether each step is product or reactant favored, and explain WHY
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Klein, Organic Chemistry 2e

49. 14.10 Ring-opening of Epoxides
In general, alkoxides are not good leaving groups
The ring strain associated with the epoxide increases its potential energy making it more reactive– see the energy diagram on the next slide
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Klein, Organic Chemistry 2e

50. 14.10 Ring-opening of Epoxides
The epoxide reaction is both more kinetically and more thermodynamically favored. WHY?
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51. 14.10 Ring-opening of Epoxides
Epoxides can be opened by many other strong nucleophiles as well
Both regioselectivity and stereoselectivity must be considered – see next few slides
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Klein, Organic Chemistry 2e

52. 14.10 Ring-opening of Epoxides
Given that the epoxide ring-opening is SN2, predict the outcome of the following reactions
Pay attention to regio- and stereoselectivity. EXPLAIN WHY
Practice with SkillBuilder 14.4
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Klein, Organic Chemistry 2e

53. 14.10 Ring-opening of Epoxides
Acidic conditions can also be used to open epoxides
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54. 14.10 Ring-opening of Epoxides
Water or an alcohol can also be used as the nucleophile under acidic conditions
Predict the products and draw a complete mechanism
Antifreeze (ethylene glycol) is made industrially by this method
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Klein, Organic Chemistry 2e

55. 14.10 Ring-opening of Epoxides
Propose an explanation for the following regiochemical observations
Consider both steric and electronic effects (induction)
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56. 14.10 Ring-opening of Epoxides
If the nucleophile preferentially attacks the tertiary carbon under acidic conditions, is the mechanism likely SN1 or SN2?
Considering the observations below, is the mechanism likely SN1 or SN2?
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Klein, Organic Chemistry 2e

57. 14.10 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
Give reaction conditions for the following reaction
Practice with SkillBuilder 14.5
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Klein, Organic Chemistry 2e

58. 14.11 Thiols and Sulfides
Sulfur appears just under oxygen on the periodic table
Sulfur appears in thiols as an –SH group analogous to the –OH group in alcohols
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
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59. 14.11 Thiols and Sulfides Thiols are also known as mercaptans
The –SH group can also be named as part of a side group rather than as part of the parent chain
The mercaptan name comes from their ability to complex mercury
2,3-dimercapto-1-propanol is used to treat mercury poisoning. WHY? Draw its structure
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60. 14.11 Thiols and Sulfides Thiols are known for their unpleasant odor
Skunks use thiols as a defense mechanism
Methanethiol is added to natural gas (methane) so that gas leaks can be detected
Your nose is a very sensitive instrument
The hydrosulfide ion (HS-) is a strong nucleophile and a weak base
HS- promotes SN2 rather than E2
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Klein, Organic Chemistry 2e

61. 14.11 Thiols and Sulfides
Predict the outcome of the following reactions, and draw a complete mechanism
Practice with conceptual checkpoint 14.22
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Klein, Organic Chemistry 2e

62. 14.11 Thiols and Sulfides Thiols have a pKa of about 10.5
Recall that water has a pKa of 15.7
Predict whether the equilibrium below will favor products or reactants and draw the mechanism
Thiolates are excellent nucleophiles
thiolate ion
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63. 14.11 Thiols and Sulfides
A thiolate can attack Br2 to produce a disulfide
How does the oxidation number change?
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64. 14.11 Thiols and Sulfides
Disulfides can be reduced by the reverse reaction
The interconversion between thiol and disulfide can also occur directly via a free radical mechanism. Propose a mechanism
The bond dissociation energy of a S-S bond is only about 53 kcal/mol. WHY is that significant?
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Klein, Organic Chemistry 2e

65. 14.11 Thiols and Sulfides
Sulfur analogs of ethers are called sulfides or thioethers
Sulfides can also be named as a side group
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Klein, Organic Chemistry 2e

66. 14.11 Thiols and Sulfides
Sulfides are generally prepared by nucleophilic attack of a thiolate on an alkyl halide
How are thiolates generally prepared?
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67. 14.11 Thiols and Sulfides Sulfides undergo a number of reactions
Attack on an alkyl halide
The process produces a strong alkylating reagent that can add an alkyl group to a variety of nucleophiles
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Klein, Organic Chemistry 2e

68. 14.11 Thiols and Sulfides Sulfides can also be oxidized
Sodium meta-periodiate can be used to form the sulfoxide
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69. 14.11 Thiols and Sulfides Sulfides can also be oxidized
Hydrogen peroxide can be used to give the sulfone
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70. 14.11 Thiols and Sulfides
Sulfoxides and sulfones have very little double bond character
Which resonance contributor for each is the major contributor, and WHY?
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Klein, Organic Chemistry 2e

71. 14.11 Thiols and Sulfides
Because sulfides are readily oxidized, they make good reducing agents
Recall the ozonolysis reaction from section 9.11
Practice with conceptual checkpoint 14.23
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Klein, Organic Chemistry 2e

72. 14.11 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
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Klein, Organic Chemistry 2e

73. 14.12 Synthetic Strategies Involving Epoxides
Epoxides can be used to install functional groups on adjacent carbons
Give necessary reagents for the reaction below
Practice with SkillBuilder 14.6
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Klein, Organic Chemistry 2e

74. 14.12 Synthetic Strategies Involving Epoxides
By reacting an epoxide with a Grignard reagent, the carbon skeleton can be modified
You may think of an epoxide as the starting material
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Klein, Organic Chemistry 2e

75. 14.12 Synthetic Strategies Involving Epoxides
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
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Klein, Organic Chemistry 2e

76. 14.12 Synthetic Strategies Involving Epoxides
Give necessary reagents for the reaction below
Practice with SkillBuilder 14.7
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Klein, Organic Chemistry 2e

77. Additional Practice Problems
Name the following molecule
Draw the structure for (4-methylcyclohexyl)phenylether
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Klein, Organic Chemistry 2e

78. Additional Practice Problems
Fill in the missing intermediates and reagents in the scheme below
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79. Additional Practice Problems
Fill in the missing intermediates and reagents in the scheme below
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80. Additional Practice Problems
Give necessary reagents to complete the synthesis below
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