1. Ethers and Epoxides; Thiols and Sulfides
Chapter 18
Ethers and Epoxides; Thiols and Sulfides
Suggested Problems –
1-18, 23-28, 38-41, 44-5,54-5

2. Ethers
Ethers (R–O–R’): Organic derivatives of water, having two organic groups bonded to the same oxygen atom
Ether and THF are typically used as solvents. Ether boils around 35oC, THF at 66oC. Anisole is higher boiling and is commonly used in perfumery.

3. Names and Properties of Ethers
Simple ethers are named by identifying two organic substituents and adding the word ether
If other functional groups are present, the ether part is considered an alk-oxy substituent

4. Names and Properties of Ethers
Possess nearly the same geometry as water
Bond angles of R–O–R bonds are approximately tetrahedral
Oxygen atom is sp3-hybridized
Relatively stable and unreactive in many aspects
Very useful as solvents in the laboratory
Ethers on exposure to oxygen over long periods can form peroxides. Low molecular weight peroxides can be explosive.

5. Worked Example Name the following ethers: a) b) Solution:
a) Di-isopropyl ether
b) Allyl vinyl ether

6. Synthesis of Ethers
Prepared industrially by sulfuric-acid-catalyzed reaction of alcohols
Limited to use with primary alcohols
This acid catalyzed route to ethers is only useful with primary alcohols because secondary and tertiary alcohols dehydrate by an E1 mechanism to yield alkenes under these conditions.

7. Williamson Ether Synthesis
Reaction of metal alkoxides and primary alkyl halides and tosylates in an SN2 reaction
Best method for the preparation of ethers
Alkoxides are prepared by reaction of an alcohol with a strong base such as sodium hydride, NaH
Williamson ether synthesis is the most generally useful method of preparing ethers. Alkoxides prepared by reacting an alcohol with sodium hydride, NaH, react with an alkyl halide or a tosylate in an SN2 reaction.

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

9. Williamson Ether Synthesis
Primary halides and tosylates work best
Competitive E2 elimination with more hindered substrates
Unsymmetrical ethers best synthesized by reaction between more hindered alkoxide and less hindered halide.

10. Williamson Ether Synthesis
tert-Butyl methyl ether is best prepared by reaction of tert-butoxide ion with iodomethane rather than by reaction of methoxide ion with 2-chloro-2-methylpropane.

11. Worked Example
How are the following ethers prepared using a Williamson synthesis?
a) Methyl propyl ether
b) Anisole (methyl phenyl ether)
Solution: a) b)
Methyl propyl ether can be performed in two ways depending on which half is derived from an alcohol and which half is derived from an alkyl halide.
Because aryl halides do not undergo SN2 displacements, methyl phenyl ether must be made from the phenoxide and a methyl halide.

12. Alkoxymercuration of Alkenes
Alkene is treated with an alcohol in the presence of mercuric acetate or trifluoroacetate
Demercuration with NaBH4 yields an ether
Overall Markovnikov addition of alcohol to alkene
Note the similarities between this reaction and the Markovnikov addition of water to alkenes. The mechanism is very similar.
The principal difference is an alcohol replaces water in oxymercuration demercuration of alkenes to form an ether.
The reaction is initiated by electrophilic addition of Hg2+ to the alkene, followed by reaction of the intermediate cation with alcohol and reductionof the C-Hg bond by NaBHr.

13. Worked Example
Rank the following halides in order of their reactivity in Williamson synthesis:
a) Bromoethane, 2-bromopropane, bromobenzene
b) Chloroethane, bromoethane, 1-iodopropene
Solution:
Most reactive Least reactive a) b)

14. Reactions of Ethers: Acidic Cleavage
Cleaved by strong acids
HI, HBr produce an alkyl halide from less hindered component by SN2
Ethers are unreactive to many reagents used in organic chemistry, a property that accounts for their wide use as reaction solvents. However, ethers are cleaved by strong acids.
Acidic ether cleavages take place by either SN1 or SN2 mechanisms depending on the structure of the substrate. Ethers with only primary and secondary alkyl groups react by an SN2 mechanism, in which I- or Br- attacks the protonated ether at the less hindered site. This usually results in a selective cleavage into a single alcohol and a single alkyl halide.

15. Reactions of Ethers: Acidic Cleavage
Ethers with tertiary, benzylic, or allylic groups cleave by either an SN1 or E1 mechanism
Intermediates are stable carbocations
Tert-Butyl ethers react by an E1 mechanism on treatment with trifluoroacetic acid.

16. Worked Example Predict the product(s) of the following reaction:
Solution:
A primary alkyl group and a tertiary alkyl group is bonded to the ether oxygen
When one group is tertiary, cleavage occurs by an SN1 or E1 route to give either an alkene or a tertiary halide and a primary alcohol

17. Worked Example

18. Reactions of Ethers: Claisen Rearrangement
Specific to allyl aryl ethers and allyl vinyl ethers
Caused by heating ally aryl ether to °C
Leads to an o-allylphenol
Result is alkylation of the phenol in an ortho position
The net result of this reaction is alkylation of a phenol in the ortho position.

19. Reactions of Ethers: Claisen Rearrangement
A similar rearrangement takes place with allyl vinyl ethers
A g,d-unsaturated ketone or aldehyde results

20. Reactions of Ethers: Claisen Rearrangement
Takes place in a single step through a pericyclic mechanism
Reorganization of bonding electrons occurs in a six-membered, cyclic transition state
Mechanism is consistent with 14C labeling
Evidence for this mechanism comes from the observation that the rearrangement takes place with an inversion of the allyl group. That is, allyl phenyl ether containing a 14C label on the allyl ether carbon atom yields o-allylphenol in which the label is on the terminal vinylic carbon. (See the carbon labeled in green above.)

21. Worked Example
What products are expected from Claisen rearrangement of 2-butenyl phenyl ether?
Solution:
Six bonds will either be broken or formed in the product - Represented by dashed lines in the transition state
Redraw bonds to arrive at the intermediate enone, which rearranges to the more stable phenol

22. Worked Example

23. Cyclic Ethers
Behave like acyclic ethers with the exception of three-membered ring epoxides
Strain of the three-membered ring gives epoxides a unique chemical reactivity
Dioxane and tetrahydrofuran are used as solvents

24. Cyclic Ethers Three-membered ring compounds called epoxides
Ethylene oxide is industrially important as an intermediate
Prepared by reaction of ethylene with oxygen at 300 °C over a silver oxide catalyst
-ene ending implies the presence of a double bond in the molecule
The strain of the three-membered ring gives epoxides unique chemical reactivity.
The name, ethylene oxide, is not a systematic one because the –ene ending implies a double bond in the molecule.
The systematic name for ethylene oxide is 1,2-epoxyethane.

25. Preparation of Epoxides
By treating alkenes with a peroxyacid (RCO3H)
Also prepared from halohydrins
In the laboratory, epoxides are usually prepared by treatment of an alkene with a peroxyacid such as m-CPBA.

26. 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

27. Worked Example
Explain why reaction of cis-2-butene with m-chloroperoxybenzoic acid yields an epoxide different from that obtained by reaction of the trans isomer
Solution:
Epoxidation, in this case, is a syn addition of oxygen to a double bond
Original bond stereochemistry is retained; product is a meso compound

28. Worked Example In the epoxide product the methyl groups are cis
Reaction of trans-2-butene with m-chloroperoxybenzoic acid yields trans-2,3- epoxybutane

29. Reactions of Epoxides: Ring-Opening
Water adds to epoxides with dilute acid at room temperature
Product is a 1,2-diol
Epoxides are more reactive than other ethers because of the ring strain.
1,2-diols are also called vicinal glycols; vicinal means adjacent. A glyclol is a diol
Epoxide opening takes place by SN2-like backside attack of a nucleophile on the protonated epoxide, giving a trans-1,2-diol as product.

30. Reactions of Epoxides: Ring-Opening
Also can be opened by reaction with acids other than H3O+
Anhydrous HF, HBr, HCl, or HI combine with an epoxide
Gives a trans product
Here the product is a trans halohydrin

31. Reactions of Epoxides: Ring-Opening
Regiochemistry of acid-catalyzed ring- opening depends on the epoxide’s structure
Nucleophilic attack occurs primarily at the more highly substituted site, when one epoxide carbon atoms is tertiary
A mixture of products is often formed in the ring-opening of an epoxide.
When both epoxide carbon atoms are either primary or secondary, attack of the nucleophile occurs primarily at the less highly substituted site – an SN2-like result.
When one of the epoxide carbona toms is tertiary, however, nucleophilic attack occurs primarily at the more highly substituted site – an SN1-like result.
Thus, 1.2-epoxypropane reacts with HCl to give primarily 1-chloro-2-propanol, but 2-methyl-1,2-epoxypropane gives 2-chloro-2-methyl-1-propanol as the major product.

32. Ring-Opening of 1,2-epoxy-1-methylcyclohexane with HBr
The mechanism of epoxide opening has characteristics of both SN2 (backside attack leading to a trans product) and SN1 (attack at the more hindered tertiary carbon) reactions.

33. Worked Example Predict the major product of the following reaction:
Solution:
The rules for acid catalyzed opening of an epoxide are:
An epoxide with only primary and secondary carbons usually undergoes cleavage by SN2-like attack of a nucleophile on the less hindered carbon.
An epoxide with a tertiary carbon atom usually undergoes cleavage by backside attack on the more hindered carbon.

34. Base-Catalyzed Epoxide Opening
Epoxide rings can be cleaved by bases and nucleophiles, as well as acids
Strain of the three-membered ring is relieved on ring-opening
Hydroxide cleaves epoxides at elevated temperatures
While an ether oxygen is a poor leaving group in an SN2 reaction, the strain of the three-membered ring causes epoxides to react with hydroxide ion at elevated temperatures.
Base-catalyzed epoxide opening is a typical SN2 reaction in which attack of the nucleophile takes place at the less hindered epoxide carbon.

35. Base-Catalyzed Epoxide Opening
Amines and Grignard reagents can be used for epoxide opening
Ethylene oxide is frequently used
Allows conversion of a Grignard reagent into a primary alcohol
Many different nucleophiles can be used for epoxide opening, including amines (RNH2 or R2NH) and Grignard reagents.
The reaction of ethylene oxide with the Grignard reagent above allows for the conversion of the Grignard reagent into a primary alcohol having two more carbons than the starting alkyl halide.

36. Worked Example Predict the major product of the following reaction:
Solution:
Addition of a Grignard reagent takes place at the less substituted epoxide carbon
Note the contrast of the site of reaction here which occurs at the less substituted carbon under anionic conditions.
Under acidic conditions a nucleophile would be expected to attack at the more substituted tertiary carbon.

37. Crown Ethers Large-ring polyethers Named as x-crown-y
x is total number of atoms in the ring
y is the number of oxygen atoms
Central cavity is electronegative and attracts cations

38. Crown Ethers
Produce similar effects when used to dissolve an inorganic salt in a hydrocarbon to that of dissolving the salt in a polar aprotic solvent
18-Crown-6 chelates strongly solvates potassium cations
The anion associated with potassium is bare and therefore more nucleophilic
In solvating only the cation crown ethers are similar to polar aprotic solvents like DMF, DMSO, and HMPA in increasing the nucleophilicity of an anion.

39. Worked Example
15-Crown-5 and 12-crown-4 ethers complex Na+ and Li+, respectively
Make models of these crown ethers, and compare the sizes of the cavities
Solution:
Bases on ionic radii, the ion-to-oxygen distance in 15-crown-5 is about 40% longer than the ion-to-oxygen distance in 12-crown-4

40. Thiols and Sulfides Thiols Sulfur analogs of alcohols
Named with the suffix –thiol
–SH group is called mercapto group
Thiols are also called mercaptans.
Like alcohols, thiols are weakly acidic; unlike alcohols they don’t typically form hydrogen bonds (S is not sufficiently electronegative).
Thiols have an appalling odor. Skunk scent, for example, stems from the aroma of simple thiols. A small amount of ethanethiol is added to natural gas to permit detection of gas leaks.

41. Thiols
Prepared from alkyl halides by SN2 displacement with a sulfur nucleophile
Alkylthiol product can undergo further reaction with the alkyl halide
Gives symmetrical sulfide, a poorer yield of the thiol
The reaction shown above works poorly to produce a thiol unless an excess of the nucleophile is used because the initially generated thiol can undergo a second SN2 reaction to generate a sulfide.

42. Thiols Pure alkylthiol thiourea is used as the nucleophile
Gives an intermediate alkyl isothiourea salt, hydrolyzed by subsequent reaction with an aqueous base
The use of thiourea overcomes the problem of an initially generated thiol reacting with another equivalent of alkyl halide to form a sulfide.

43. Thiols Can be oxidized by Br2 or I2 Yields disulfides (RSSR’)
Reaction is reversible
Reduction back to thiol by zinc and acid
Oxidation and reduction are key parts of numerous biological processes
Disulfide formation is involved in defining the structure and three-dimensional conformations of proteins, where disulfide “bridges” often form cross-links between cysteine amino acid units in protein chains.
Curly hair is a result of these disulfide linkages within protein chains.

44. Sulfides Sulfur analogues of ethers
Named by rules used for ethers, with sulfide in place of ether for simple compounds and alkylthio in place of alkoxy
Thiols when treated with a base gives corresponding thiolate ion
Treatment of a thiol with a base, such as NaH, gives the corresponding thiolate ion (RS-), which undergoes reaction with a primary or secondary alkyl halide to give a sulfide. The reaction occurs by an SN2 mechanism, analoguous to the Williamson synthesis of ethers.

45. Sulfides
Thiols can undergo further reaction with the alkyl halide to give a sulfide
Sulfides and ethers differ substantially in their chemistry
Through SN2 mechanism, dialkyl sulfides react rapidly with primary alkyl halides to give sulfonium ions
Because the valence electrons on sulfur are farther from the nucleus and are less tightly held than those on oxygen, sulfur compounds are more nucleophilic than their oxygen analogs.
Dialkyl sulfides react rapidly with primary alkyl halides by an SN2 mechanism to give sulfonium ions (R3S+).

46. Oxidation of Thiols
Sulfides are easily oxidized by treatment with hydrogen peroxide at room temperature
Yields sulfoxide
Further oxidation of the sulfoxide with a peroxyacid yields a sulfone
Dimethyl sulfoxide is often used as a polar aprotic solvent
Dimethyl sulfoxide easily penetrates the skin carrying with it whatever is dissolved in this polar aprotic solvent.

47. Worked Example Name the following compound: Solution:
3-(Ethylthio)cyclohexanone

48. Spectroscopy of Ethers
Infrared Spectroscopy
C–O single-bond stretching 1050 to 1150 cm-1 overlaps many other absorptions
Nuclear magnetic resonance spectroscopy
H on a C next to ether O is shifted downfield to 3.4  to 4.5 
In epoxides, these H’s absorb at 2.5  to 3.5  in their 1H NMR spectra
Ether C’s exhibit a downfield shift to 50  to 80 

49. The Infrared Spectrum of Diethyl Ether
The C-O stretch is not easily identified.

50. The 1H NMR Spectrum of Dipropyl Ether
The electronegative oxygen shifts absorption by hydrogens on adjacent carbons downfield. Typically they occur between 2.5 and 3.5 ppm.
Ether carbon atoms also exhibit a downfield shift in the 13C NMR. They usually absorb in the ppm range.

51. Worked Example
The 1H NMR spectrum shown is that of a cyclic ether with the formula C4H8O
Propose a structure
Note there are five chemical shift positions but only four carbons. This means there must be two diastereotopic protons.
There is obviously a methyl and a methylene group. The remaining three signals correspond to methines.
Since there are no aromatic rings based on the number of carbons, draw a straight chain of four carbon atoms.
Since the methyl group is split into a triplet it must be next to the methylene. Thus one or both of the last two carbons must bear an oxygen substituent.
Three signals correponding to three hydrogen atoms on two carbons together with an oxygen mandates the oxygen be shared by two carbons, ie… an epoxide.

52. Worked Example
Solution: