Alcohols, Phenols, and
Ethers
Summary of Reactions to/from
Alcohols, Phenols, and Ethers
1. Synthesis
(a) Reduction of aldehydes to give primary alcohol
(b) Reduction of ketones to give secondary alcohol
(c) Reduction of esters to give primary alcohol
(d) Reduction of carboxylic acids to give primary alcohol
2. Reaction of alcohols
(e) Dehydration to give alkenes
(f) Oxidation to give carbonyl compounds
(g) Conversion into ethers
3. Synthesis of phenols
4. Synthesis of ethers
(h) Wiliamson ether synthesis
(i) Epoxides
Summary of Reactions to/from
Alcohols, Phenols, and Ethers
5. Reaction of ethers
(a) Acidic cleavage with HBr or HI
(b) Epoxides cleavage with aqueous acids
6. Synthesis of thiols
7. Synthesis of disulfides
Nomenclature
Alcohols, Phenols, and Ethers
Nomenclature of Alcohols
Step 1: Find the longest chain with OH / Replace the parent ending –e
With –ol
Step 2: Number the parent, beginning at the end nearer the OH
Step 3: Number all substituents.
Phenols
Parent name as “-phenol”
Designate the number and name of the substituents
Ethers
Simple ether without other substituents:
Substituent1 substituent2 ether
If large functional group (substituents)
Alkoxy functional group
Nomenclature
Alcohols, Phenols, and Ethers
OH
NO2
OH
OH
OH HO OH O2N
2-Methylpentan-2-ol 3-Phenylbutan-2-ol Propane-1,2,3-triol 2,5-Dinitrophenol
H Br
O
H
OH
Propoxybenzene or (1R,2S)-2-Bromocyclopentan-1-ol
Phenyl propyl ether
Properties of alcohols, ethers, phenols
BPs of alcohols: are far higher than alkyl halide and
alkanes with the same # of carbon
= Because of hydrogen bonding
Alcohols and Phenols as acid and base
As base
H
O O+
R H + H X
R H
X-
As acid
O + H 2O RO - + H 3O +
R H
Synthesis of alcohols
1. Hydration of alkenes
OH
H 2O
H 2SO 4 catalyst
2. Reduction of carbonyl compounds
O H OH
R R' R R'
H
Synthesis of Alcohols: Reduction of Carbonyls
1. Reduction of aldehydes/ketones
H H H Primary alcohol from Aldehyde
O OH
O OH
H
Secondary alcohol from ketones
H
2. Reduction of esters and carboxylic acids
OH
O H H
O OH
O
Reagents and Hydrogen Sources in Reductive
Synthesis
Reducing reagents:
NaBH4 for aldehyde and ketones
LiAlH4 for carboxylic acid and ester
H
H 1. NaBH4 H
O 2. H3O + OH
H
O 1. LiAlH4/ether H + CH3 OH
CH3
O 2. H3O + OH
Selective Reduction to Alcohols or Esters
Notice the reactivity of reducing reagents
OH
O
?
O O
O
O ? OH
OH
NaBH4: Mild, only for ketone and aldehyde
LiAlH4: Nearly all carbonyls
Reactions of Alcohols
1. Dehydration of alcohol: Acid-catalyzed reaction
H
H O+
O
H H
H
+ H
O
C+
H H2O
H
+ H 3O+
Reactions of Alcohols
1. Dehydration of alcohol: Acid-catalyzed reaction
Note: Zaitsev’s rule following and E1 mechanism
H 2SO 4, H2 O
OH
+
Major Minor
Reactions of Alcohols
2. Oxidation of alcohol: Production of carbonyls
Alcohols Aldehydes Carboxylic acids
Alcohols Ketones
OH O O
O O
R H R H R OH
H
Primary
alcohol
OH O
O
R H R R'
R'
Secondary
alcohol
Reactions of Alcohols
2. Oxidation of alcohol: Production of carbonyls
Common oxidizing reagent:
PCC: Alcohol to aldehyde
CrO3, Na2Cr2O7: Alcohol to carboxylic acid
or Ketone
Reactions of Alcohols
3. Conversion into ethers (Williamson ether syn.)
2 ROH + 2 Na RO-Na+ + H2
CH3
O- + H3C I O
Reagent pairs of Williamson Ether Synthesis
Williamson Ether Synthesis: Reaction between Alkoxide and Alkyl halide
SN2 mechanism following / Competing E2 reaction
SN2 mechanism
CH3 CH3
H3C C O- + H 3C I H3C C O CH3 + I-
CH3 CH3
E2 mechanism
H CH3 CH3
H3C O- + H 2C C Cl
H2C + CH3 OH + Cl-
CH3
CH3
Best option for ether: Hindered Alkoxide + Less Hindered Alkyl Halide
Synthesis of Phenols
1. Sulfonation-Desulfonation of Aromatic Ring
SO3H OH
SO 3, H 2SO 4 1. NaOH, 300 oC
2. H 3O +
Reactions of Phenols
1. Alcohol-like reactions of phenols (Ether synthesis)
Similarity/difference between alcohol / phenol:
Ether formation: same reaction mechanism
but dehydration/RX formation with HX (Not possible)
OH O
K2CO3 / Acetone
+ Br
NO 2 NO2
Reactions of Phenols
2. Electrophilic Aromatic Substitution of Phenols
OH in Aromatic ring: o- and p-directing and activating
OH
Br 2/FeBr3 SO3 /H 2SO4
HNO 3
H 2SO 4
OH OH OH
Br NO2 SO3H
and and and
OH OH OH
Br O2N HO 3S
Reactions of Phenols
3. Oxidation of Phenols: Hydroquinone vs Quinone
Quinone-hydroquinone interconversion:
One of the most important reaction in biochemical reaction
OH O OH
Na2 Cr 2 O7 NaBH 4
H 3O + Na2Cr 2 O7
O OH
Benzoquinone Hydroquinone
Reactions of Phenols
3. Oxidation of Phenols: Hydroquinone vs Quinone
Quinone-hydroquinone interconversion:
Redox of Ubiquinone/hydroquinone as part of respiration
O
O
O
O
O OH
MeO CH3 MeO CH3
+ NADH + H + + NAD+
MeO R MeO R
O OH
OH O
MeO CH3 MeO CH3
+ 1/2 O2 + H2O
MeO R MeO R
OH O
Reactions of Phenols
3. Quinone-hydroquinone interconversion:
One of the most important reaction in biochemical reaction
Synthesis and Reaction of Ethers
1. Synthesis: Williamson Ether Synthesis (as described)
2. Reaction:
- In most cases, ethers are pretty stable
- But return to alcohol by strong mineral acid (HI and HBr)
H I
H
H 3C H2 H 3C H2 H 3C H2
CH O C CH3 CH O+ C CH3 CH OH + I C CH 3
H 3C H 3C H 3C
I-
Where does the oxygen go ?
- Ether with less hindered pair: more hindered, SN2
- Ether with tertiary alkyl: less hindered, SN1
Epoxides
Epoxide as cyclic ether but much more reactive
Epoxide (oxirane) is three membered oxygen heterocycle
Synthesis: Alkene/Aromatics with Peracid
O O H H
O O OH
O
+ +
H
Cl
Cl
Reactions: Cleavage to diol under acidic condition
H H
H
H OH
H3O + O+ H OH
O H
H
H O+ OH
H
H2O H2O H H
Epoxides as Mutagenic Compounds
Polycyclic aromatic hydrocarbon (e.g., benzo[a]pyrene) are potent
Mutagens through :
1) Metabolic conversion to epoxide by cytochrome P450
2) Followed by reaction of amine from DNA base to adduct
OH OH
OH OH
CYP
OH
O
HN DNA
H2N DNA
Benzo[a]pyrene
Benzo[a]pyrene
epoxides
Thiols and Sulfides
Thiols: The most notorious unforgettable smells
SH
3-Methylbutane-1-thiol
SH
But-2-ene-1-thiol
Thiols and Sulfides
Thiols: Analogues of alcohol with –SH rather than –OH
Sulfide: Analogues of ether with R-S-R’, rather than R-O-R’
Nomenclature:
Thiols: parent + thiol (rather than –ol)
Sulfide: Substituent1 substituent2 + sulfide
Synthesis
SN2
Br + NaSH SH
S+Na- SN2 S
+ CH3I
