1. Ch.18: Ethers and Epoxides; Thiols and Sulfides
Dr. Sivappa Rasapalli
Chemistry and Biochemistry
University of Massachusetts Dartmouth

2. Coverage and Objectives
The nomenclature of alcohols
Synthesis and Nucleophilic substitution reactions of ethers
Nucleophilic Opening reactions of epoxides
Chemistry of sulfur compounds
Learning objectives:
Provide both IUPAC and common names for ethers, sulfides.
Recognize the physical properties of ethers, epoxides and sulfides
Know the synthesis and chemistry of the functional groups
Write the reaction and electron-pushing (arrow-pushing) mechanism for the synthesis and reactions of the functional groups
Write the acid-catalyzed ring-opening of epoxides, and explain the observed stereochemistry of the products.

3. Nomenclature of Ethers, Epoxides, and Sulfides
18.1 Names and Properties of Ethers
Nomenclature of Ethers, Epoxides, and Sulfides 2

4. Ethers, Epoxides, Thiols and sulfides
•Ethers (ROR) can be regarded as derivatives of
alcohols (ROH).
•Sulfides (RSR) can be regarded as derivatives of
Thols (RSH).

5. Nomenclature: Functional Class
simple ethers are named: “alkyl alkyl ether”
name the groups attached to oxygen in alphabetical order as separate words; "ether" is last word;
“dialkyl ether” if symmetric 3

6. Nomenclature: Substituent
name as alkoxy derivatives of alkanes
CH3OCH2 CH3
CH3CH2OCH2CH2CH2Cl
methoxyethane
1-chloro-3-ethoxypropane
CH3CH2OCH2 CH3
ethoxyethane 3

7. Nomenclature: Functional Class
analogous to ethers, but replace “ether” as last word in the name by “sulfide.”
CH3SCH2 CH3
SCH3
ethyl methyl sulfide
cyclopentyl methyl sulfide
CH3CH2SCH2 CH3
diethyl sulfide 3

8. Nomenclature: Substituent
name as alkylthio derivatives of alkanes
CH3SCH2 CH3
SCH3
methylthioethane
(methylthio)cyclopentane
CH3CH2SCH2 CH3
ethylthioethane 3

9. Names of Cyclic Ethers O O O Oxirane (Ethylene oxide) Oxetane
Oxolane (tetrahydrofuran)
Oxane (tetrahydropyran)
1,4-Dioxane O O O 3

10. Names of Cyclic Sulfides
Thiirane
Thietane
Thiolane
Thiane S 3

11. Examples of Nomenclature

13. Structure and Bonding in Ethers and Epoxides8

14. Bond angles at oxygen are sensitive to steric effectsH O
(CH3)3C
C(CH3)3
112°
105°
108.5°
132°
CH3 9

15. An oxygen atom affects geometry in much the same way as a CH2 group
most stable conformation of diethyl ether resembles pentane 10

16. An oxygen atom affects geometry in much the same way as a CH2 group
most stable conformation of tetrahydropyran resembles cyclohexane 10

17. Physical Properties of Ethers11

18. • Boiling points (and melting points) of ethers are lower than corresponding alcohol – E.g. CH3CH2OH (bp 78°C) vs. CH3-O-CH3 (bp -25°C) • Why? No Hydrogen-bonding for ethers

19. Ethers resemble alkanes more than alcohols with respect to boiling point
Intermolecular hydrogen bonding possible in alcohols; not possible in alkanes or ethers.
36°C
35°C O
117°C OH 12

20. Ethers resemble alcohols more than alkanes with respect to solubility in water
solubility in water (g/100 mL)
very small
7.5
Hydrogen bonding to water possible for ethers and alcohols; not possible for alkanes. O 9 OH
• Solubility of acyclic ethers in water is less than that of corresponding alcohols of equal MW.
– Ethers can accept H-bonds, but not donate them 12

21. Physical Properties-Uses
Ethers are less dense than water and form the top layer when mixed with water.
• Note: Diethyl ether (“ether”) is a good general purpose solvent for extracting non-polar and polar organic compounds from H2O.
• Its low boiling pt (35 oC) is ideal for recovering organic solute by evaporation of ether.
Solubility of cyclic ethers in water is greater than that of acyclic ethers of equal MW.
• Compact shape more easily accommodated by H-bonding network of water ; Ex: Tetrahydrofuran 1,4-Dioxane completely miscible with water; important cosolvents

23. Solvation

24. Crown Ethers
structure cyclic polyethers derived from repeating —OCH2CH2— units
properties form stable complexes with metal ions
applications synthetic reactions involving anions O
18-Crown-6 14

25. 18-Crown-6 O K+
forms stable Lewis acid/Lewis base complex with K+ 15

26. Ion-Complexing and Solubility+ F– O O K+
benzene
18-crown-6 complex of K+ dissolves in benzene
F– carried into benzene to preserve electroneutrality 16

27. Application to organic synthesis
Complexation of K+ by 18-crown-6 "solubilizes" potassium salts in benzene
Anion of salt is in a relatively unsolvated state in benzene (sometimes referred to as a "naked anion")
Unsolvated anion is very reactive
Only catalytic quantities of 18-crown-6 are needed
CH3(CH2)6CH2Br KF
18-crown-6
benzene
CH3(CH2)6CH2F
(92%) 20

28. 18. 2 Synthesis of Ethers 21

29. Acid–catalyzed dehydration of Alcohols
Diethyl ether prepared industrially by sulfuric acid–catalyzed dehydration of ethanol – also with other primary alcohols

30. The Williamson Ether Synthesis
Reaction of metal alkoxides and primary alkyl halides and tosylates
Best method for the preparation of ethers
Alkoxides prepared by reaction of an alcohol with a strong base such as sodium hydride, NaH

31. Example
RO-, an alkoxide ion, is both a strong nucleophile (unless bulky and hindered) and a strong base. Both SN2 (desired) and E2 (undesired side product) can occur.
Choose nucleophile and electrophile carefully. Maximize SN2 and minimize E2 reaction by choosing the R’X to have least substituted carbon undergoing substitution (electrophile). Methyl best, then primary, secondary marginal, tertiary never (get E2 instead).
Stereochemistry: the reacting carbon in R’, the electrophile which undergoes substitution, experiences inversion. The alkoxide undergoes no change of configuration. 25

32. Williamson’s Ether Synthesis has Limitations
1. Alkyl halide must be primary (RCH2X)
2. Alkoxides need be derived from primary, secondary or tertiary alcohols 26

33. Origin of Reactants 26

34. What happens if the alkyl halide is not primary?27

35. Silver Oxide-Catalyzed Ether Formation
Reaction of alcohols with Ag2O directly with alkyl halide forms ether in one step
Glucose reacts with excess iodomethane in the presence of Ag2O to generate a pentaether in 85% yield

36. Addition of Alcohols to Alkenes
(CH3)2C=CH2 + CH3OH
(CH3)3COCH3
tert-Butyl methyl ether
tert-Butyl methyl ether (MTBE) was produced on a scale exceeding 15 billion pounds per year in the U.S. during the 1990s. It is an effective octane booster in gasoline, but contaminates ground water if allowed to leak from storage tanks. Further use of MTBE is unlikely. 23

37. Alkoxymercuration

38. Mechanism of Oxymercuration

39. Reactions of Ethers: 28

40. Summary of reactions of ethers
No reactions of ethers encountered to this point.
Ethers are relatively unreactive.
Their low level of reactivity is one reason why ethers are often used as solvents in chemical reactions, and as protecting groups for reactive –OH group.
Ethers oxidize in air to form explosive hydroperoxides and peroxides. 27

41. Acid-Catalyzed Cleavage of Ethers
Ethers are generally unreactive
Strong acid will cleave an ether at elevated temperature
HI, HBr produce an alkyl halide from less hindered component by SN2 (tertiary ethers undergo SN1) 31

42. Example
CH3CHCH2CH3
HBr
CH3CHCH2CH3 +
CH3Br
heat
OCH3 Br
(81%) 31

43. Mechanism CH3CHCH2CH3 Br HBr CH3 CH3CHCH2CH3 O CH3CHCH2CH3 O CH3 H + H
• • ••
CH3CHCH2CH3 O
CH3 H + •• H Br
• • •• ••
• •
CH3 Br
CH3CHCH2CH3 O H Br – ••
• • 31

44. Cleavage of Cyclic EthersHI
ICH2CH2CH2CH2I
150°C
(65%) 32

45. Mechanism O ICH2CH2CH2CH2I HI HI H O + I – H O I •• •• •• • • •• • •32

46. Claisen Rearrangement
Specific to allyl aryl ethers, ArOCH2CH=CH2
Heating to 200–250°C leads to an o-allylphenol
Result is alkylation of the phenol in an ortho position

47. Epoxides (Oxiranes)
Three membered ring ether is called an oxirane (root “ir” from “tri” for 3-membered; prefix “ox” for oxygen; “ane” for saturated)
Also called epoxides
Ethylene oxide (oxirane; 1,2-epoxyethane) is industrially important as an intermediate
Prepared by reaction of ethylene with oxygen at 300 °C and silver oxide catalyst

48. Epoxides are Extremely Reactive

49. Preparation of Epoxides Using a Peroxyacid
Treat an alkene with a peroxyacid

50. Epoxide Ring Opening reactions: 1. Epoxide Ring Opening in Acid
In acid: protonate the oxygen, establishing the very good leaving group. More substituted carbon (more positive charge although more sterically hindered) is attacked by a weak nucleophile.
Very similar to opening of cyclic bromonium ion. Review that subject.
Due to resonance, some positive charge is located on this carbon.
Inversion occurs at this carbon. Do you see it? Classify the carbons. S becomes R.

51. 2. Epoxide Ring Opening in Base
In base: no protonation to produce good leaving group, no resonance but the ring can open due to the strain if attacked by good nucleophile. Now less sterically hindered carbon is attacked.
A wide variety of synthetic uses can be made of these reactions as shown in the following slides

52. Base-Catalyzed Epoxide Opening
Strain of the three-membered ring is relieved on ring-opening
Hydroxide cleaves epoxides at elevated temperatures to give trans 1,2-diols
In base: no protonation to produce good leaving group, no resonance but the ring can open due to the strain if attacked by good nucleophile. Now less sterically hindered carbon is attacked.

53. 18.6 Reactions of Epoxides: Ring-Opening
Water adds to epoxides with dilute acid at room temperature
Product is a 1,2-diol (on adjacent C’s: vicinal)
Mechanism: acid protonates oxygen and water adds to opposite side (trans addition)

54. Halohydrins from Epoxides
Anhydrous HF, HBr, HCl, or HI combines with an epoxide
Gives trans product

55. Epoxides from Halohydrins
Addition of HO-X to an alkene gives a halohydrin
Treatment of a halohydrin with base gives an epoxide
Intramolecular Williamson ether synthesis

56. Addition of Grignards to Ethylene Oxide
Adds –CH2CH2OH to the Grignard reagent’s hydrocarbon chain
Acyclic and other larger ring ethers do not react

57. Different isomers

58. Variety of products can be obtained by varying the nucleophiles
H2O/ NaOH
Do not memorize this chart. But be sure you can figure it out from the general reaction: attack of nucleophile in basic media on less hindered carbon
LiAlH4
H2O

59. An Example of Synthetic Planning
Reactions of a nucleophile (basic) with an epoxide/oxirane ring reliably follow a useful pattern.
The epoxide ring has to have been located here
This bond was created by the nucleophile
The pattern to be recognized in the product is
–C(-OH) – C-Nu

60. Synthetic Applications
nucleophile
Realize that the H2NCH2- was derived from nucleophile: CN
N used as nucleophile twice.
Formation of ether from alcohols.

61. Epichlorohyrin and Synthetic Planning, same as before but now use two nucleophiles
Observe the pattern in the product
Nu - C – C(OH) – C - Nu. When you observe
this pattern it suggests the use of epichlorohydrin.
Both of these bonds will be formed by the incoming nucleophiles.

62. Example – Retrosynthesis Analysis
A b blocker

63. Why does Acid Catalyzed Opening Give Inversion?

64. Propose a Mechanism

65. 2 Successive SN2 Reactions

66. Provide a Mechanism

68. Sulfur-containing amino acids
• Methionine and Cysteine
Important in protein secondary and tertiary structure

69. Physical Properties
• Thiols and sulfides are more volatile (lower bp) than corresponding alcohols or ethers. Stench! Skunky! • Hydrogen bonding less important for thiols compared to alcohols • Dipoles are less pronounced Thiols are more acidic than alcohols (pKa) – Size mismatch between small hard proton and large, polarizable sulfur atom favours formation of thiolate anion.
Thiols in particular are smelly - e.g. crotyl thiol and prenyl thiol are present in excretions from skunks! But can be pleasant - as in coffee =furfuryl mercaptan ( furan with CH2SH in the 2-position).
Ethyl mercaptan is added to natural gas. The nose can detect it in concentrations as low as 1 part in 50 billion parts of air. The name mercaptan comes form the Latin, mercurium captans, which means capturing mercury.
Diminished difference in pKa due to less effective resonance stabilization of S- (3p-2p) compared to O- (2p-2p)
Note that sulfur is not very electronegative - it has the same Pauling value of electronegativity as carbon (2.5)! So a carbon-sulfur bond is not polarized.
However it is polarizable and large, with 3p orbitals (to give sp3 lone pair), so it is nucleophilic.

70. Thiols: Formation and Reaction
From alkyl halides by displacement with a sulfur nucleophile such as –SH
The alkylthiol product can undergo further reaction with the alkyl halide to give a symmetrical sulfide, giving a poorer yield of the thiol

71. Using Thiourea to Form Alkylthiols
Thiols can undergo further reaction with the alkyl halide to give dialkyl sulfides
For a pure alkylthiol use thiourea (NH2(C=S)NH2) as the nucleophile
This gives an intermediate alkylisothiourea salt, which is hydrolyzed cleanly to the alkyl thiourea

72. Preparation of Thiols Use an alkyl halide and H2S or AcSH
J. Am. Chem. Soc., 2005, 127, 15668
Excess H2S passed through the solution
Thioacetate and an alkyl halide (or can use thioacetic acid, an alcohol, PPh3, DEAD in Mitsunobu, eg 07BMCL2250)
Diazotization then potassium xanthate
J. Org. Chem., 1990, 55, 2736
For palladium coupling of AcS– and ArX, see Tetrahedron Lett., 2007, 48, 3033

73. Oxidation of Thiols to Disulfides
Reaction of an alkyl thiol (RSH) with bromine or iodine gives a disulfide (RSSR)
The thiol is oxidized in the process and the halogen is reduced

74. Sulfides
Thiolates (RS) are formed by the reaction of a thiol with a base
Thiolates react with primary or secondary alkyl halide to give sulfides (RSR’)
Thiolates are excellent nucleophiles and react with many electrophiles

75. Sulfides as Nucleophiles
Sulfur compounds are more nucleophilic than their oxygen-compound analogs
3p electrons valence electrons (on S) are less tightly held than 2p electrons (on O)
Sulfides react with primary alkyl halides (SN2) to give trialkylsulfonium salts (R3S+)

76. Sulfides as Nucleophiles

77. Oxidation of Sulfides
Sulfides are easily oxidized with H2O2 to the sulfoxide (R2SO)
Oxidation of a sulfoxide with a peroxyacid yields a sulfone (R2SO2)
Dimethyl sulfoxide (DMSO) is often used as a polar aprotic solvent

78. Oxidation of Sulfides

79. Reaction of Thiols Good nucleophiles Tetrahedron Lett., 2005, 46, 8931
TBAI probably as phase transfer cat
Tetrahedron Lett., 2005, 46, 8931
Suitable for alkyl-alkyl and aryl-alkyl thioethers
Successful for secondary alkyl iodides (iPrI) but not tertiary halides
No racemization using L-cysteine methyl ester

80. 18.9 Spectroscopy of Ethers
Infrared: C–O single-bond stretching 1050 to 1150 cm1 overlaps many other absorptions.
Proton NMR: H on a C next to ether O is shifted downfield to  3.4 to  4.5
The 1H NMR spectrum of dipropyl ether shows this signal at  3.4
In epoxides, these H’s absorb at  2.5 to  3.5 d in their 1H NMR spectra
Carbon NMR: C’s in ethers exhibit a downfield shift to  50 to  80