Transcript No Slide Title

Structure
• The functional group of an ether is an oxygen atom bonded
to two carbon atoms
• Oxygen is sp3 hybridized with bond angles of
approximately 109.5°. In dimethyl ether, the C-O-C bond
angle is 110.3°
• IUPAC: the longest carbon chain is the parent. Name the
OR group as an alkoxy substituent
• Common names: name the groups attached to oxygen
followed by the word ether
CH 3
CH 3 CH 2 OCH 2 CH 3
Ethoxyethane
(Diethyl ether)
• 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.
O
O
OH
CH 3 OCCH 3
CH 3
2-Methoxy-2-methylpropane
(tert-Butyl methyl ether)
Nomenclature: ethers
OCH 2 CH 3
O
Oxirane
(Ethylene
oxide)
• Sulfide: the sulfur analog of an ether
• Name the alkyl or aryl groups attached to sulfur followed
by the word sulfide
CH 3
Dimethyl sulfide
O
Oxane
(Tetrahydropyran, THP)
O
1,4-Dioxane
trans-2-Ethoxycyclohexanol
Nomenclature: sulfides
CH 3 SCH 3
Oxolane
(Tetrahydrofuran, THF)
CH 3 CH 2 SCHCH 3
Ethyl isopropyl sulfide
• The functional group of a disulfide is an
-S-S- group
• Name the alkyl or aryl groups bonded to sulfur followed
by the word disulfide
CH 3 -S-S-CH 3
Dimethyl disulfide
Preparation of Ethers
• Williamson ether synthesis: SN2
displacement of halide, tosylate, or mesylate
by alkoxide ion
CH3
SN2
+ +
CH3 I
CH3 CHO Na
Sodium
Iodomethane
isopropoxide (Methyl iodide)
CH3
+ -
CH3 CHOCH 3 + Na I
2-Methoxypropane
(Isopropyl methyl ether)
Preparation of Ethers
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 SN 2 reaction in which a poor
leaving group is converted to a better one
• Williamson ether synthesis: yields are
– highest with methyl and 1° halides,
– lower with 2° halides (competing belimination)
– fails with 3° halides (b-elimination only)
CH 3
CH 3 CBr +
CH 3
tert-Butyl
bromide
-
+
CH 3 CH2 O Na
Sodium ethoxide
2 CH 3 CH 2 OH
Ethanol
E2
O
••
CH3 CH2 -O-H + H-O-S-O-H
+
•• +
CH3 CH2 -O-H
+
••
+ CH 3 CH 2 -O-H
SN2
H
••
••
+
CH 3 CH 2 -O-CH 2 CH 3 +
••
H
A new oxonium ion
H
An oxonium ion
proton
transfe r
••
H
-
O-S-O-H
O
O-H
• Acid-catalyzed addition of alcohols to alkenes. Yields are
highest using
– an alkene that can form a stable carbocation
– methanol or a 1° alcohol
CH 3
CH 3 C=CH 2 + CH 3 OH
H
acid
catalyst
CH 3
CH 3 COCH 3
CH 3
2-Methoxy-2-methylpropane
(tert-Butyl methyl ether)
Step 3: proton transfer to solvent to complete the reaction
+
••
CH 3 CH 2 -O-CH 2 CH 3 + O-CH 2 CH 3
O
+
Preparation of Ethers
Step 2: nucleophilic displacement of OH 2 by the OH
group of the alcohol to give a new oxonium ion
••
proton
tr ansfe r
O
-
Preparation of Ethers
••
+ H2 O
••
CH 3 C=CH 2 + CH3 CH2 OH + Na Br
2-Methylpropene
••
CH 3 CH 2 OCH 2 CH 3
Diethyl ether
140oC
Step 1: proton transfer to form an oxonium ion
CH 3
CH 3 CH 2 -O-H
H 2 SO 4
Step 1: protonation of the alkene to form a carbocation
H
CH 3
••
•• +
CH 3 CH 2 -O-CH 2 CH 3 + H O-CH 2 CH 3
••
H
+
CH 3 C=CH 2 + H O CH 3
H
CH 3
CH 3 CCH 3 + O CH 3
+
H
Preparation of Ethers
Preparation of Sulfides
Step 2: reaction of the alcohol (a Lewis base) with the
carbocation (a Lewis acid)
• Symmetrical sulfides, R 2S, are prepared by treatment of 1
mol of Na2S with 2 mol of an alkyl halide. This method
can also be used to prepare five- and six-membered cyclic
sulfides
CH 3
CH 3
••
CH 3 CCH 3 + HOCH 3
••
+
CH 3 CCH 3
+
O
••
H
CH 3
2 RX
+ Na 2 S
Step 3: proton transfer to solvent to complete the reaction
RSR + 2 NaX
A sulfide
CH3
CH3 O H
+
CH3 CCH3
+
O
H •• CH3
CH3
ClCH 2 CH 2 CH 2 CH 2 Cl
1,4-Dichlorobutane
+
O H
CH3
+
••
O
••
CH3
Preparation of Sulfides
Cleavage of Ethers
• Ethers are cleaved by HX to an alcohol and
an alkyl halide
• 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)
R-O-R + H-X
-
+
CH 3 I
S
Thiolane
(Tetrahydrothiophene)
CH3 CCH3
H
+
CH 3 (CH 2 ) 8 CH 2 S Na
Sodium 1-decanethiolate
Na 2 S
SN 2
R-O-H + R-X
SN 2
CH 3 (CH 2 ) 8 CH 2 SCH 3
1-(Methylthio)decane
(Decyl methyl sulfide)
+
Na
+
I
-
– cleavage requires both a strong acid and a good
nucleophile, hence 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-
Cleavage of Ethers
Cleavage of Ethers
• The mechanism for HBr and HI cleavage of 1° and 2°
dialkyl ethers is divided into two steps
Step 1: proton transfer to the oxygen atom of the ether to
form an oxonium ion
proton
• A dialkyl ether is cleaved to two moles of
alkyl halide
••
CH 3 CH 2 -O-CH
2 CH 3 + H
••
(CH 3 CH 2 CH 2 CH 2 ) 2 O + 2 HBr
heat
Dibutyl ether
+
O H
••
transfer
H
2 CH 3 CH 2 CH 2 CH 2 Br + H 2 O
1-Bromobutane
••
O H
••
•• +
CH 3 CH 2 -O-CH 2 CH 3 +
H
An oxonium ion
H
Step 2: Nucleophilic displacement on the primary carbon
Br
-
••
••
S N2
•• +
+ CH 3 CH 2 -O-CH 2 CH 3
H
CH 3 CH 2 Br +
O-CH 2 CH 3
H
Cleavage of Ethers
Oxidation of Ethers
• 3° and benzylic ethers are particularly sensitive to
cleavage by HX
– tert-butyl ethers are cleaved by HCl at room temp
CH 3
O-CCH 3 + HCl
CH 3
SN1
• Ethers react with O 2 at a C-H bond adjacent to the ether
oxygen to form explosive hydroperoxides
OOH
CH 3
OH + Cl-C-CH
CH 3
– in this case, protonation of the ether oxygen is followed
by C-O cleavage to give the tert-butyl cation
3
CH 3 CH 2 OCH 2 CH 3
Diethyl ether
+ O2
CH 3 CH 2 OCHCH 3
A hydroperoxide
• Hydroperoxide: a compound containing the OOH group
Oxidation Sulfides
Ethers - Protecting Grps
• Sulfides can be oxidized to sulfoxides and sulfones, by the
proper choice of experimental conditions
••
S-CH 3
••
H2 O2
• 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
o
25 C
Methyl phenyl
sulfide
O
S-CH 3
••
O
HIO 4
25 o C
Methyl phenyl
sulfoxide
S-CH 3
O
Methyl phenyl
sulfone
Ethers - Protecting Grps
– The new C-C bond can be formed by alkylation of the
acetylide anion (Section 10.5)
– The OH group, however, is more acidic (pK a 16-18)
than the terminal alkyne (pK a 25)
– treating the compound with 1 mol of NaNH2 will form
the alkoxide anion rather than the acetylide
HC CCH 2 CH 2 CH 2 OH + Na + NH 2 4-Pentyn-1-ol
HC CCH 2 CH 2 CH 2 O- Na + + NH 3
HC CCH 2 CH 2 CH 2 OH
4-Pentyn-1-ol
?
CH 3 CH 2 C CCH 2 CH 2 CH 2 OH
4-Heptyn-1-ol
Ethers - Protecting Grps
• A protecting group must be
– easy to add
– easy to remove
– resistant to the reagents used to transform the
unprotected group
• In this chapter, we discuss three -OH
protecting groups
• tert-butyl ether group
• trimethylsilyl (TMS) group
• tetrahydropyranyl (THP) group
Ethers - Protecting Grps
Ethers - Protecting Grps
– the protected compound is then alkylated
• The tert-butyl protecting group
CH 3
– formed by treatment of an alcohol with 2methylpropene in the presence of an acid
catalyst
HC CCH 2 CH 2 CH 2 OH
4-Pentyn-1-ol
CH 2 =C(CH
1. Na + NH 2 2 . CH 3 CH 2 Br
HC CCH 2 CH 2 CH 2 OCCH 3
CH 3
CH 3
CH 3 CH 2 C CCH 2 CH 2 CH 2 OCCH 3
CH 3
3)2
– the tert-butyl group is removed by treatment with
aqueous acid
CH
H 2 SO 4
CH 3
3
HC CCH 2 CH 2 CH 2 OCCH 3
CH 3 CH 2 C CCH 2 CH 2 CH 2 OCCH 3
H 3 O+ /H
2O
CH 3
CH 3
CH 3
CH 3 CH 2 C CCH 2 CH 2 CH 2 OH + H 2 C C
4-Heptyn-1-ol
Ethers - Protecting Grps
Ethers - Protecting Grps
• Trimethylsilyl (TMS) group
– treat the alcohol with chlorotrimethylsilane in the
presence of a 3° amine, such as triethylamine
– the function of the 3° amine is to neutralize the HCl
• The TMS group is removed by treatment with aqueous
acid or with F - in the form of tetrabutylammonium fluoride
CH 3
CH 3
RCH 2 OH + Cl-Si-CH
(Et)
3
CH 3
Chlorotrimethylsilane
3N
CH 3
CH 3
RCH 2 O-Si-CH
CH 3
A trimethylsilyl
ether
RCH 2 O-Si-CH
3
CH 3
A trimethylsilyl
ether
3
+ H2 O
H
+
CH 3
RCH 2 OH + HO-Si-CH
CH 3
3
Epoxides
• Epoxide: a cyclic ether in which oxygen is
one atom of a three-membered ring
• Simple epoxides are named as derivatives
of oxirane.
2
3
CH 2
CH 2
H3 C
1O
• 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
1
H
O
2
H
1,2-Epoxycyclohexane
(Cyclohexene oxide)
C
C
CH 3
O
cis-2,3-Dimethyloxirane
(cis-2-Butene oxide)
Oxirane
(Ethylene oxide)
Epoxides
H
H
Synthesis of Epoxides-1
• Ethylene oxide, one of the few epoxides manufactured on
an industrial scale, is prepared by air oxidation of ethylene
2 CH 2 =CH 2 + O
Ag
2
2 CH 2
CH 2
O
Oxirane
(Ethylene oxide)
• The most common laboratory method for synthesis of
epoxides is oxidation of an alkene using a
peroxycarboxylic acid (a peracid)
O
CO OH
CO
-
O
Mg
2+
2
O
M agnesium monoperoxyphthalate
(MMPP)
CH 3 CO OH
Pe roxyacetic acid
(Peracetic acid)
Synthesis of Epoxides-2
Synthesis of Epoxides-2
• Epoxidation of cyclohexene
• Epoxidation is stereoselective:
– epoxidation of cis-2-butene gives only cis-2,3dimethyloxirane and
– epoxidation of trans-2-butene gives only trans-2,3dimethyloxirane
O
+
RCOOH
A peroxyCyclohexene carboxylic
acid
CH 2 Cl 2
H
H
O
O
+
RCOH
H
1,2-Epoxycyclohexane A carboxylic
(Cyclohexene oxide)
acid
CH 3
C
C
H3 C
H
trans-2-Butene
Synthesis of Epoxides-2
• A mechanism for alkene epoxidation must
take into account that the reaction
– takes place in nonpolar solvents, which means
that no ions are involved
H
H3 C
C
C
• A mechanism for alkene epoxidation
R
O
C
2
H
R
O
3
O
C
O
H
O
O
1
C
C
CH 3
H
O
trans-2,3-Dimethyloxirane
Synthesis of Epoxides-2
4
– is stereoselective 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
RCO 3 H
C
C
Synthesis of Epoxides-3
• A second general method involves
1. treatment of an alkene with Cl2 or Br2 in H2O to form a
halohydrin
2. treatment of the halohydrin with base, causing an
internal SN 2
Cl 2 , H 2 O
CH 3 CH CH 2
Propene
Cl
Nu
HNu
••
+
C
O
HO
CH2
O
Oxirane
(Ethylene oxide)
+
H2 O
H
Reactions of Epoxides
Step 1: proton transfer to the epoxide to form a bridged
oxonium ion intermediate
H 2 C CH 2
H 2 C CH 2
O
C
• Acid-catalyzed ring opening
– in the presence of an acid catalyst, epoxides are
hydrolyzed to glycols
CH2
1 . Cl 2 , H 2 O
CH 3 2. NaOH, H 2 O
cis-2-Butene
H
H
CH 3
H3 C
C
C
O
cis-2,3-Dimethyloxirane
C
+
HOCH2 CH2 OH
1,2-Ethanediol
(Ethylene glycol)
••
• Because of the strain associated with the three-membered
ring, epoxides readily undergo a variety of ring-opening
reactions
H
C
••
Reactions of Epoxides
C
• Each step is stereoselective
– anti stereoselective for halohydrin formation
– inversion of configuration for the S N2 reaction
• Given this stereoselectivity, show that cis-2-butene gives
cis-2,3-dimethyloxirane
H
H3 C
NaOH, H 2 O
CH 3 CH-CH 2
CH 3 CH
CH 2
HO
O
1-Chloro-2-propanol
Methyloxirane
(a chlorohydrin)
(Propylene oxide)
C
Synthesis of Epoxides-3
O+
H
+
H O H
H
Step 2: attack of H 2O from the side opposite the oxonium
ion bridge H
H
H
H
O
O
+
H2 C
CH 2
O+
H
H2 C
CH 2
O
H
Reactions of Epoxides
Reactions of Epoxides
H
Step 3: proton transfer to solvent to complete the
hydrolysis
H
H
O
H
H
O
+
H2 C
H
H2 C
CH 2
O
H
H
H2 C
CH2
O
O
CH 2 +
O
(2)
+
H O H
(1)
H2 C
O+ (2)
H
+
H O H
(1) H
H
H2 C
H
O
OH
+
H2 O
H
1,2-Epoxycyclopentane
(Cyclopentene oxide)
O
H
H
O
+
(3)
• Attack of the nucleophile on the protonated epoxide shows
anti stereoselectivity
– hydrolysis of an epoxycycloalkane gives a trans-1,2diol
H
CH2
H
Reactions of Epoxides
O
H
(3)
H
H2 C
CH 2
O
CH2 +
O
O
H
H
H
Reactions of Epoxides
• Compare the stereochemistry of the glycols formed by
these two methods
H
OH
+
RCO3 H
H
O
H2 O
H
H+
OH
trans-1,2-Cyclopentanediol
OH
OH
trans-1,2-Cyclopentanediol
+
H O H
OsO 4 , t-BuOOH
OH
cis-1,2-Cyclopentanediol
Reactions of Epoxides
Reactions of Epoxides
• Ethers are not normally susceptible to attack by
nucleophiles
• Because of the strain associated with the three-membered
epoxide ring, epoxides undergo nucleophilic ring opening
readily
• Their nucleophilic ring openings show a stereoselectivity
typical of SN2 reactions, namely inversion of configuration
at the carbon from which oxygen is displaced
-
CH 3 CH CH 2 + CH 3 OH
O
Methyloxirane
(Propylene oxide)
CH 3 O Na
+
• Reaction of epoxides with Gilman reagents is an
important method for forming new C-C bonds
– ring opening shows typical SN2 regioselectivity
O
1. (CH 2=CH) 2CuLi
CH-CH 2
2. H2O, HCl
OH
Styrene oxide
CH-CH 2 -CH=CH
1-Phenyl-3-buten-1-ol
CH 3 CHCH 2 OCH 3
OH
1-Methoxy-2-propanol
Reactions of Epoxides
Reactions of Epoxides
CH3
CH3
HSCH 2 CHOH
A b-mercaptoalcohol
HOCH 2 CHOH
A glycol
CH3
CH 3
HC CCH2 CHOH
A b-alkynylalcohol
CH2
Na + C N- /H
2O
H 2 O/H 3 O+
+
-
Na SH /H
2O
CH3
CH 2
2
CH
O
Methylo xirane
+
1 . HC C Na
2. H 2O
CH3
N CCH 2 CHOH
A b-hydroxynitrile
CH
O
Methylo xirane
1 . (R 2 Cu)Li
2. H 2O
CH3
RCH2 CHOH
An alcohol
NH 3
CH3
H2 NCH2 CHOH
A b-aminoalcohol
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:-
CH
CH 2
O
Phenyloxirane
(Styrene oxide)
1 . LiAlH 4
2. H 2O
CHCH 2 -H
OH
1-Phenylethanol