Download Ethers: stable, unreactive - some ethers can form peroxides with air

Ch.18 Ethers and Epoxides; Thiols and Sulfides
Ethers: stable, unreactive
- some ethers can form peroxides with air oxygen (dangerous)
O
O
O
Diethyl ether
anesthetic agent
Anisole
Tetrahydrofuran
Thiols, Sulfides: sulfur analogues of alcohols and ethers
18.1 Nomenclature
Ethers:
simple ether: two groups + ether
O
O
O
Ethyl vinyl ether
tert-Butyl methyl ether
Cyclopropyl phenyl ether
- more than one ether linkages or other functional groups: alkoxy
2
MeO
OMe
p-Dimethoxybenzene
1
4
O
4-tert-Butoxycyclohexene
18.2 Structure, Properties, and Sources of Ethers
- ethers are H2O derivatives
- ether: no H-bonding, low b.p.
H 3C
O
CH 3
112o
- synthesis of simple symmetrical ethers: acid-catalyzed
dehydration of 1o alcohols (SN2 mechanism)
; not applicable to 2o and 3o ethers (dehydration to alkenes occur)
H2SO4
2 CH3CH2OH
O
+ H2O
CH3CH2OH
O
H
H
O
H
O
OH2
18.3 The Williamson Ether Synthesis
Williamson ethers synthesis: alkoxide + alkyl halide
ROH + NaH
+
O Na + H3C I
RONa + H2
O
CH3
+ Na+ I-
Ag2O as base for polyalkylation: in situ deprotonation
(no complete alkoxide formation)
OCH3
OH
HO
HO
Ag2O
O
H
OH
OH
CH3I
85%
H3CO
H3CO
O
H
CH3O
OCH3
SN2 reaction: 1o alkyl halides and tosylates are useful
+
O Na + H3C I
+
H3C O Na +
O
CH3
H
C Cl
+
+
Na+ I-
Na+ Cl-
+
CH3OH
18.4 Alkoxymercuration of Alkenes
oxymercuration: alcohol + alkene
; Hg(O2CCF3)2, Hg(O2CCH3)2
OCH3
OCH3
NaBH4
Hg(O2CCF3)2
HgO2CCF3
CH3OH
intramolecular oxymercuration: cyclic ether synthesis
OH
Hg(O2CCF3)2
O
HgO2CCF3
NaBH4
O
CH3
18.5 Reactions of Ethers: Acidic Cleavage
Reactions of ethers
- unreactive to many common reagents: used as solvents
- unreactive to halogens, mild acid, nucleophiles
- cleaved by strong acid: HI, HBr
CO2H
O
H-I
100oC
H2O
CO2H
OH
H-Br
O
H2O
reflux
I
+
+
OH
Br
1o, 2o alkyl ether: SN2 cleavage
X
H-I
O
I-
SN2
O
H
more hindered
OH
less hindered
+
I
3o alkyl ether: SN1 cleavage
SN1
H-Br
O
O
H
+
HO
Br-
Br
18.6 Reactions of Ethers: Claisen Rearrangement
Claisen rearrangement: sigmatropic rearrangement
O
250oC
OH
concerted mechanism: 6-membered, cyclic transition state
H
O
O
O
OH
18.7 Cyclic Ether: Epoxide
Cyclic ethers: same properties as acyclic ether, used as solvents
O
O
O
Tetrahydrofuran
(THF)
1,4-Dioxane
Epoxide (oxirane): reactive due to strain
H2C CH2
O2
Ag2O
300oC
O
H2C CH2
Ethylene oxide
Epoxidation: peroxyacid, RCO3H
O
Cl
OOH
O
H
Cl
O
+
(mCPBA)
CH2Cl2, 25oC
OH
H
concerted mechanism: syn addition
H O
O
O
R
H
O
H
O
+
HO
R
Epoxide from halohydrin
Br2
H2O
OH
Br
H
NaOH
H2O
O
H
intramolecular cyclization
OH
Br
NaOH
H2O
O
Br
H
SN2
O
H
18.8 Ring-Opening Reactions of Epoxides
Acid catalyzed epoxide opening: mild acidic conditions
OH
H3O+
O
OH
H
O
H3O
+
H
H
O H
H
O H
O H
H
H
H2O
H2O
H
H
O H
H
O H
trans-1,2-Diol
Acid catalyzed epoxide opening: HX, X= F, Br, Cl, I
H
O
OH
HX
X
H
trans
Regiochemistry of epoxide opening: a mixture of products are usually
formed
- if both carbons are 1o, 2o: attack less hindered carbon (SN2-like)
- if one carbon is 3o: attack at more hindered carbon (SN1-like)
O
HCl
Cl
OH
Cl
+
OH
90 : 10
O
HCl
Cl
OH
Cl
+
40 : 60
OH
Mechanism of acid-catalyzed epoxide opening: midway of SN1 and
SN2 ; SN2-like mechanism but SN1-like carbocation character
CH3
O H
δ+H
CH3
O
H
CH3
OH
Br
Br-
HBr
CH3
δ+
Br-
Br
CH3
O H
H
more stable
carbocation
OH
major
Base catalyzed epoxide opening: epoxides are reactive under basic
condition
O
-
OH
OH
O
H2O
OH
OH + OH
H2O
100oC
Carbon nucleophiles: Grignard reagents
O
R
1. R'MgBr
ether
2. H3O+
HO
R
R'
Base catalyzed epoxide opening:
SN2 reaction, attack at less hindered carbon
O
R
Na+-OEt
HO
EtOH
OEt
R
Biological ring opening of epoxide
OH
OH
OH
OH
OH
O
Benz[a]pyrene
DNA NH 2
HN
DNA
unreactive
18.9 Crown Ethers
C. J. Pederson: 1960s
crown ether: bind metal ions
O
O
O
O
O
O
O
O
18-Crown-6 ether
O
K+
O
MnO4O
O
KMnO4 dissolved by 18-Crown-6
soluble in hexane
18-Crown-6: selective to K+
- inorganic salts, KF, KCN, NaN3, can be dissolved in organic
solvents with the help of crown ethers
- similar solvation effect as polar aprotic solvents (DMSO,
DMF, HMPA), thus, SN2 reaction is tremendously enhanced
by crown ethers
O
O
O
K+
O
CNO
O
free CN- anion : much
more nucleophilic
18.10 Thiols and Sulfides
R-SH thiol, R-S-R' sulfide
naming: "-thiol" as in "-ol"
-SH group: referred to as a -mercapto group
SH
COOH
SH
SH
Ethanethiol
Cyclohxanethiol
m-Mercaptobenzoic acid
naming: "sulfide" as in "ether"
-SR group: referred to as a "alkylthio" as in "alkoxy"
S
S
S
Dimethyl sulfide
Methyl phenyl sulfide
3- (Methylthio)cyclohexene
Thiols
-
+
HS Na
Sodium
hydrosulfide
R-X
H S R
SN2
base
R S R
R-X
sulfide can be formed
thiourea: used for monoalkylation
S
H2N
NH2
Thiourea
R-Br
SN2
S
H2N
R
NH2
Br-
O
aq. NaOH
H S R + H2N
NH2
Urea
thiol: bad ordor
Skunk scent
SH
+
SH
Disulfide bond: RSH + I2 or Br2
Br2
2 R-SH
RS SR
+ HBr
Zn, H+
disulfide bond: stabilize 3-D structure of proteins
protein
SH
HS
protein
protein
S
S
protein
a cross-linked protein
Sulfides
thiolate ion, RS-
+
S Na
MeI
S CH3
+ NaI
Sodium
benzenethiolate
trialkylsulfonium salts (R3S+X-): sulfide is nucleophilic
H3C
S
MeI
CH3
CH3
S
H3C
CH3
I-
Trimethylsulfonium iodide
Biological alkylating reagent:
NH2
CH3
S
H
HOOC
NH2
H
N
N
H
O
H
N
N
OH OH
S-Adenosylmethionine (a sulfonium ion)
Sulfoxide, Sulfone
Ph
S
H2O2
CH3
H2O
25oC
Ph
O
S
RCO3H
CH3
a sulfoxide
O
Ph
O
S
CH3
a sulfone
- Dimethylsulfoxide (DMSO): common aprotic polar solvent
H3C
O
S
CH3
18.11 Spectroscopy of Ethers
IR Spectroscopy
C-O stretching 1050-1150 cm-1 - non hydrogen bonded alcohol
Et2O
NMR Spectroscopy
1H
NMR C-H-(O-)
13C NMR C-O-
- 2.5-3.5 ppm
- 50-80 ppm
129.5
O
58.5
23.3
74.8
120.7
114.1
O
54.8
10.7
159.9
Epoxide: slightly higher field than other ethers
; 1H NMR at 2.5-3.5 ppm
Chemistry @ Work
Epoxy Resins and Adhesives
Epoxy glue: "prepolymer" + curing agent
CH3
C
CH3
HO
O
OH
O
O
OH
O
Cl
Epichlorohydrin
Bisphenol A
CH3
C
CH3
+
O
n
"Prepolymer"
CH3
C
CH3
O
O
Chemistry @ Work
Epoxy Resins and Adhesives
Curing agent (R3N): cross-link chains by base-catalyzed epoxide
opening
O
OH
O
Middle of chain 1
O
curing
agent
O
OH
End of chain 2
"Cross-lonked" chain
Problem Sets
Chapter 18
25, 26, 27, 30, 49, 52