Organic Chemistry

1
Organic Chemistry

• William H. Brown
• Christopher S. Foote
• Brent L. Iverson

2

• Ethers Epoxides

Chapter 11
3
Structure

• The functional group of an ether is an oxygen
  atom bonded to two carbon atoms
• in dialkyl ethers, oxygen is sp3 hybridized with
  bond angles of approximately 109.5.
• in dimethyl ether, the C-O-C bond angle is 110.3

4
Structure

• in other ethers, the ether oxygen is bonded to an
  sp2 hybridized carbon
• in ethyl vinyl ether, for example, the ether
  oxygen is bonded to one sp3 hybridized carbon and
  one sp2 hybridized carbon

5
Nomenclature ethers

• IUPAC the longest carbon chain is the parent
• name the OR group as an alkoxy substituent
• Common names name the groups bonded to oxygen in
  alphabetical order followed by the word ether

6
Nomenclature ethers

• Although cyclic ethers have IUPAC names, their
  common names are more widely used
• IUPAC prefix ox- shows oxygen in the ring
• the suffixes -irane, -etane, -olane, and -ane
  show three, four, five, and six atoms in a
  saturated ring

7
Physical Properties

• Although ethers are polar compounds, only weak
  dipole-dipole attractive forces exist between
  their molecules in the pure liquid state

8
Physical Properties

• Boiling points of ethers are
• lower than alcohols of comparable MW
• close to those of hydrocarbons of comparable MW
• Ethers are hydrogen bond acceptors
• they are more soluble in H2O than are hydrocarbons

9
Preparation of Ethers

• Williamson ether synthesis SN2 displacement of
  halide, tosylate, or mesylate by alkoxide ion

10
Preparation of Ethers

• yields are highest with methyl and 1 halides,
• lower with 2 halides (competing ?-elimination)
• reaction fails with 3 halides (?-elimination
  only)

11
Preparation of Ethers

• Acid-catalyzed dehydration of alcohols
• diethyl ether and several other ethers are made
  on an industrial scale this way
• a specific example of an SN2 reaction in which a
  poor leaving group (OH-) is converted to a better
  one (H2O)

12
Preparation of Ethers

• Step 1 proton transfer gives an oxonium ion
• Step 2 nucleophilic displacement of H2O by the
  OH group of the alcohol gives a new oxonium ion

13
Preparation of Ethers

• Step 3 proton transfer to solvent completes the
  reaction

14
Preparation of Ethers

• Acid-catalyzed addition of alcohols to alkenes
• yields are highest using an alkene that can form
  a stable carbocation
• and using methanol or a 1 alcohol that is not
  prone to undergo acid-catalyzed dehydration

15
Preparation of Ethers

• Step 1 protonation of the alkene gives a
  carbocation
• Step 2 reaction of the carbocation (an
  electrophile) with the alcohol (a nucleophile)
  gives an oxonium ion

16
Preparation of Ethers

• Step 3 proton transfer to solvent completes the
  reaction

17
Cleavage of Ethers

• Ethers are cleaved by HX to an alcohol and a
  haloalkane
• cleavage requires both a strong acid and a good
  nucleophile therefore, the use of concentrated
  HI (57) and HBr (48)
• cleavage by concentrated HCl (38) is less
  effective, primarily because Cl- is a weaker
  nucleophile in water than either I- or Br-

18
Cleavage of Ethers

• A dialkyl ether is cleaved to two moles of
  haloalkane

19
Cleavage of Ethers

• Step 1 proton transfer to the oxygen atom of the
  ether gives an oxonium ion
• Step 2 nucleophilic displacement on the 1
  carbon gives a haloalkane and an alcohol
• the alcohol is then converted to an haloalkane by
  another SN2 reaction

20
Cleavage of Ethers

• 3, allylic, and benzylic ethers are particularly
  sensitive to cleavage by HX
• tert-butyl ethers are cleaved by HCl at room temp
• in this case, protonation of the ether oxygen is
  followed by C-O cleavage to give the tert-butyl
  cation

21
Oxidation of Ethers

• Ethers react with O2 at a C-H bond adjacent to
  the ether oxygen to give hydroperoxides
• reaction occurs by a radical chain mechanism
• Hydroperoxide a compound containing the OOH group

22
Silyl Ethers as Protecting Groups

• When dealing with compounds containing two or
  more functional groups, it is often necessary to
  protect one of them (to prevent its reaction)
  while reacting at the other
• suppose you wish to carry out this transformation

23
Silyl Ethers as Protecting Groups

• the new C-C bond can be formed by alkylation of
  an alkyne anion
• the OH group, however, is more acidic (pKa 16-18)
  than the terminal alkyne (pKa 25)
• treating the compound with one mole of NaNH2 will
  give the alkoxide anion rather than the alkyne
  anion

24
Silyl Ethers as Protecting Groups

• A protecting group must
• add easily to the sensitive group
• be resistant to the reagents used to transform
  the unprotected functional group(s)
• be removed easily to regenerate the original
  functional group
• In this chapter, we discuss trimethylsilyl (TMS)
  and other trialkylsilyl ethers as OH protecting
  groups

25
Silyl Ethers as Protecting Groups

• Silicon is in Group 4A of the Periodic Table,
  immediately below carbon
• like carbon, it also forms tetravalent compounds
  such as the following

26
Silyl Ethers as Protecting Groups

• An -OH group can be converted to a silyl ether by
  treating it with a trialkylsilyl chloride in the
  presence of a 3 amine

27
Silyl Ethers as Protecting Groups

• replacement of one of the methyl groups of the
  TMS group by tert-butyl gives a
  tert-butyldimethylsilyl (TBDMS) group, which is
  considerably more stable than the TMS group
• other common silyl protecting groups include the
  TES and TIPS groups

28
Silyl Ethers as Protecting Groups

• silyl ethers are unaffected by most oxidizing and
  reducing agents, and are stable to most
  nonaqueous acids and bases
• the TBDMS group is stable in aqueous solution
  within the pH range 2 to 12, which makes it one
  of the most widely used -OH protecting groups
• silyl blocking groups are most commonly removed
  by treatment with fluoride ion, generally in the
  form of tetrabutylammonium fluoride

29
Silyl Ethers as Protecting Groups

• we can use the TMS group as a protecting group in
  the conversion of 4-pentyn-1-ol to 4-heptyn-1-ol

30
Epoxides

• Epoxide a cyclic ether in which oxygen is one
  atom of a three-membered ring
• simple epoxides are named as derivatives of
  oxirane
• where the epoxide is part of another ring system,
  it is shown by the prefix epoxy-
• common names are derived from the name of the
  alkene from which the epoxide is formally derived

H
H
1
H
2
3
O
C
C
O
O
2
1
H
31
Synthesis of Epoxides

• Ethylene oxide, one of the few epoxides
  manufactured on an industrial scale, is prepared
  by air oxidation of ethylene

2

O
32
Synthesis of Epoxides

• The most common laboratory method is oxidation of
  an alkene using a peroxycarboxylic acid (a
  peracid)

O
O
O
O
2
33
Synthesis of Epoxides

• Epoxidation of cyclohexene

34
Synthesis of Epoxides

• Epoxidation is stereospecific
• epoxidation of cis-2-butene gives only
  cis-2,3-dimethyloxirane
• epoxidation of trans-2-butene gives only
  trans-2,3-dimethyloxirane

35
Synthesis of Epoxides

• A mechanism for alkene epoxidation must take into
  account that the reaction
• takes place in nonpolar solvents, which means
  that no ions are involved
• is stereospecific with retention of the alkene
  configuration, which means that even though the
  pi bond is broken, at no time is there free
  rotation about the remaining sigma bond

36
Synthesis of Epoxides

• A mechanism for alkene epoxidation

37
Synthesis of Epoxides

• Epoxides are can also be synthesized via
  halohydrins
• the second step is an internal SN2 reaction

38
Synthesis of Epoxides

• halohydrin formation is both regioselective and
  stereoselective for alkenes that show cis,trans
  isomerism, it is also stereospecific (Section
  6.3F)
• conversion of a halohydrin to an epoxide is
  stereoselective
• Problem account for the fact that conversion of
  cis-2-butene to an epoxide by the halohydrin
  method gives only cis-2,3-dimethyloxirane

H
H
H
H
C
C
C
C
O
39
Synthesis of Epoxides

• Sharpless epoxidation
• stereospecific and enantioselective

40
Reactions of Epoxides

• Ethers are not normally susceptible to attack by
  nucleophiles
• Because of the strain associated with the
  three-membered ring, epoxides readily undergo a
  variety of ring-opening reactions

41
Reactions of Epoxides

• Acid-catalyzed ring opening
• in the presence of an acid catalyst, such as
  sulfuric acid, epoxides are hydrolyzed to glycols

O
42
Reactions of Epoxides

• Step 1 proton transfer to oxygen gives a bridged
  oxonium ion intermediate
• Step 2 backside attack by water (a nucleophile)
  on the oxonium ion (an electrophile) opens the
  ring
• Step 3proton transfer to solvent completes the
  reaction

43
Reactions of Epoxides

• Attack of the nucleophile on the protonated
  epoxide shows anti stereoselectivity
• hydrolysis of an epoxycycloalkane gives a
  trans-1,2-diol

44
Reactions of Epoxides

• Compare the stereochemistry of the glycols formed
  by these two methods

45
Epoxides

• the value of epoxides is the variety of
  nucleophiles that will open the ring and the
  combinations of functional groups that can be
  prepared from them

46
Reactions of Epoxides

• Treatment of an epoxide with lithium aluminum
  hydride, LiAlH4, reduces the epoxide to an
  alcohol
• the nucleophile attacking the epoxide ring is
  hydride ion, H-

O
1-Phenylethanol
47
Ethylene Oxide

• ethylene oxide is a valuable building block for
  organic synthesis because each of its carbons has
  a functional group

48
Ethylene Oxide

• part of the local anesthetic procaine is derived
  from ethylene oxide
• the hydrochloride salt of procaine is marketed
  under the trade name Novocaine

49
Epichlorohydrin

• The epoxide epichlorohydrin is also a valuable
  building block because each of its three carbons
  contains a reactive functional group
• epichlorohydrin is synthesized from propene

50
Epichlorohydrin

• the characteristic structural feature of a
  product derived from epichlorohydrin is a
  three-carbon unit with -OH on the middle carbon,
  and a carbon, nitrogen, oxygen, or sulfur
  nucleophile on the two end carbons

51
Epichlorohydrin

• an example of a compound containing the
  three-carbon skeleton of epichlorohydrin is
  nadolol, a b-adrenergic blocker with vasodilating
  activity

52
Crown Ethers

• Crown ether a cyclic polyether derived from
  ethylene glycol or a substituted ethylene glycol
• the parent name is crown, preceded by a number
  describing the size of the ring and followed by
  the number of oxygen atoms in the ring

53
Crown Ethers

• The diameter of the cavity created by the
  repeating oxygen atoms is comparable to the
  diameter of alkali metal cations
• 18-crown-6 provides very effective solvation for
  K

54
Thioethers

• The sulfur analog of an ether
• IUPAC name select the longest carbon chain as
  the parent and name the sulfur-containing
  substituent as an alkylsulfanyl group
• common name list the groups bonded to sulfur
  followed by the word sulfide

55
Nomenclature

• Disulfide contains an -S-S- group
• IUPAC name select the longest carbon chain as
  the parent and name the disulfide-containing
  substituent as an alkyldisulfanyl group
• Common name list the groups bonded to sulfur and
  add the word disulfide

56
Preparation of Sulfides

• Symmetrical sulfides treat one mole of Na2S with
  two moles of a haloalkane

57
Preparation of Sulfides

• Unsymmetrical sulfides convert a thiol to its
  sodium salt and then treat this salt with an
  alkyl halide (a variation on the Williamson ether
  synthesis)

58
Oxidation Sulfides

• Sulfides can be oxidized to sulfoxides and
  sulfones by the proper choice of experimental
  conditions

59

• Ethers
• Epoxides

End of Chapter 11