Chapter 9 Ethers, Thiols, and Sulfides

I. Naming and Physical Properties of Ethers

A. Nomenclature
1) Name ethers as alkanes with an alkoxy substitutent
2) RO- = alkoxy substitutent
3) Choose the smallest part of the ether as the substituent
4) Common names: name the two R groups, followed by “ether”
O O O
CH3CH2 CH2CH3 CH3CH2 CH3 CH2CH2CH2CH3
Ethoxyethane 1-Methoxybutane
Diethyl ether 2-Ethoxy-2-methylpropane
t-Butyl ethyl ether Butyl methyl ether

5) Cyclic Ethers
a) O group is called and “oxa-” substituent: oxacycloalkanes
b) Common names are prevalent
O O
1
1 O 1
O 1 4
O
Oxacyclopropane Oxacyclopentane Oxacyclohexane 1,4-Dioxacyclohexane
Epoxide Tetrahydrofuran (THF) Tetrahydropyran 1,4-Dioxane
B. Physical Properties
1) Same molecular formula as Alcohol: CnH2n+2O
2) No Hydrogen Bonding is possible in R—O—R
3) Boiling Points are much lower than alcohols, more like haloalkanes
4) Water solubility much less than alcohols
a) MeOMe and EtOEt have some water solubility
b) Larger ethers are insoluble, very much like alkanes
5) Fairly unreactive, nonpolar solvents for organic reactions
O O
C. Metal Complexation by Crown Ethers
O O
1) Crown Ether is a cyclic polyether: --(CH2CH2O)— 6-crown-2
2) Named as: (# of total atoms in ring)-Crown-(# of oxygens) O O
3) Oxygen lone pair can be donated to M+ to form complexes
12-crown-4
4) Allows dissolution of metal salts in organic solvents
5) Size of cavity dictates which metal fits: 18-crown-6 K+ > Rb+ >Na+ etc…
O O
O O O O
+ KMnO4 K+ + MnO4
-

O O O O
O O

18-crown-6
II. Williamson Ether Synthesis
A. Alkoxides are good nucleophiles and strong bases
1) Reaction with primary, unhindered electrophile gives SN2
2) Reaction with non-primary or hindered electrophiles gives E2
RCH2I Ether
O-Na+ OCH2R
Williamson Ether
Synthesis
Alkene
Br

B. Cyclic Ethers from Intramolecular Reaction

1) Intermolecular reaction is between 2 separate molecules: A + B C
2) Intramolecular reaction is between parts of same molecule: A C
Br OH - O
Br
OH O - + Br-

slower HO
OH
3) Ring size effects rate: k3 > k5 > k6 > k4 > k7 > k8
O-
a) Ring strain says k3 slow, Entropy makes k3 fast O
b) k4 is slow because ring strain > entropy Br
 4) Intramolecular Williamson Ether Synthesis is Stereospecific
a) Like E2 elimination, the leaving group must be anti to nucleophile
b) Gauche leaving group won’t give product
- -
O D O O H
H Br
H D H
H Br R H H D
S gauche
anti

III. Other Ether Syntheses from Alcohols

A. ROH plus Strong Mineral Acid
1) Remember that ROH plus HBr gives RBr because nucleophile is present
2) Protonation by mineral acid gives good leaving group (H2O) but does not
give an interfering nucleophile

HBr H Br-
ROH R O RBr + H2O
H

H
H2SO4 H ROH -H+
ROH R O R O R O R
R
H -H2O
 3) Only makes symmetric ethers
4) Follows SN2 for primary alcohols, SN1 for 2o and 3o alcohols
5) Useful for making mixed 3o/1o ethers
H+ CH3OH
OH OH2+ OCH3

B. Ether Synthesis through Solvolysis of Haloalkanes or other Electrophiles

1) Solvolysis = nucleophilic substitution by solvent
2) Alcoholysis = solvolysis when solvent = ROH
3) Simple SN1 conditions can give complex ethers by solvolysis

MeOH MeOH
Br OMe OMe
H
IV. Reactions of Ethers
A. Peroxide formation
1) Ethers open to oxygen can form expolosive peroxide compounds
2) Never use old ethers as solvents or reactants; store ethers properly
2 R O CH + O2 2 R O C O O C O R

peroxide (explosive)
 B. Cleavage by Strong Acid
1) Reverse of Ether Synthesis by Strong Acid
2) Tertiary Ethers are most reactive to cleavage
H
+ OH + E1
H O
O

3) Secondary Ethers can be cleaved by SN2 or SN1

H -H+
+ OH2 OH +
O
H O OH2+ OH

V. Reactions of Oxacyclopropanes
A. Nucleophilic Ring Opening
1) Ether Oxygen behaves as an intramolecular leaving group
2) Anionic Nucleophiles can open the oxacyclopropane ring by SN2 attack

O O- H2O HO

CH3S- SCH3 SCH3

 3) Alkoxide usually a poor leaving group (but it doesn’t really leave here)
4) Driving force is opening of the strained 3-membered ring
5) For unsymmetric oxacyclopropanes, the Nu attacks at the least subst. C

- OH
O SN 2 O H2O
-
CH3S CH3 CH3
CH3S CH3S
CH3

6) Regioselectivity = reaction at only one of multiple sites of a molecule

B. Alcohols from Oxacyclopropanes

1) LiAlH4 attacks epoxides, but not any other ethers
O CH3 D OH
SN2
LiAlH4 + CH3 CH3 CH3
inverts
D CH3 H CH3

2) Alkylmetal reagents also react with epoxides only among the ethers
O
SN2 CH3 D OH
CH3CH2MgBr + CH3 CH3 inverts CH3
D CH3 CH3CH2 CH3
 C. Acid Catalyzed Oxacyclopropane Ring Opening
1) Mechanism
H H
O O O CH3
+ HO
H CH3
H CH3 H CH3 = H CH3 H
Nu Nu
H CH3 H CH3 H CH3 H

2) Regioselective and Stereospecific for Nu- attack at the Most Hindered C

3) Partial C+ forms only on most hindered carbon
4) Not a full carbocation, because we see stereospecific inversion
(SN2, not SN1)
5) Now we have tools to add Nu at most (H+, Nu) or least (Nu-) carbon of an
epoxide

VI. Sulfur Analogues of Alcohols and Ethers

A. Nomenclature
1) R—OH = Alcohol R—SH = Thiol
a) Name as alkanethiol CH3SH = methanethiol
b) Name as a mercapto- substituent HSCH2CH2OH =
OH > SH priority 2-mercaptoethanol
 2) R—O—R = Ether R—S—R = Sulfide (common name = thioether)
a) Name like common names for ethers
i. CH3SCH2CH3 = ethyl methyl sulfide (methylthioethane)
ii. (CH3)3CSCH3 = t-butyl methyl sulfide
iii. H2S = hydrogen sulfide
iv. RS– substituent is called alkythio
b) RS- anion is called alkanethiolate anion: CH3CH2S- = ethanethiolate

B. Properties of Thiols and Sulfides

1) RSH doesn’t Hydrogen bond very well (S is too large to match H)
2) Boiling points are lower than the analogous alcohols
3) RS—H bond is weak, so thiols are more acidic than alcohols

C. Reactivity of Thiols and Sulfides

1) RS- is more nucleophilic than RO- due to larger size
2) Synthesis of thiols and sulfides
-
R'S- R'SR + X
RX
- -
HS RSH + X
 3) Use hydroxide to deprotonate RSH
NaOH CH3CH2Br
CH3SH CH3S- CH3SCH2CH3 + Br-

4) Formation of Sulfonium Ion = R3S+ as a good leaving group

CH3SCH3 CH3CH2Br OH-

(CH3)2SCH2CH3 CH3SCH3 + HOCH2CH3
sulfonium ion
5) Valence Shell Expansion due to d orbitals is common for S compounds
O
KMnO4
CH3SH CH3 S OH
oxidation
O
6) Oxidation of Sulfides
O O
H2O2 H2O2
RSR RSR RSR
Sulfide Sulfoxide O
Sulfone
7) Disulfide formation
I2
2 RSH RS SR Disulfide

1. Li, NH3
2. H+, H2O