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Chapter 17: Alcohols and Phenols
Dr. Sivappa Rasapalli
Chemistry and Biochemistry
University of Massachusetts Dartmouth
Coverage and Objectives
Coverage:
1. Structure and Bonding; Physical Properties of Alcohols
2. Acidity of Alcohols and Phenols
3. Formation of Alkoxides and Phenoxides
4. Preparation of Alcohols including Review Reactions
and Ring-opening Reactions of Epoxides (+ Mechanisms).
5. Reactions of Alcohols + Mechanisms
Objectives:
1. Know all mechanisms discussed in class.
2. Know how to predict the relative acidities of substituted alcohols and phenols.
3. Know reactions and reagents for preparation of alcohols including review reactions.
4. Know reactions of alcohols and mechanisms.
Alcohols and Phenols
H3C
OH
Methanol
CO + 2H2  CH3OH
H3C
OH
Ethanol
Oldest known synthesis: fermentation
Sugar
+
yeast

ethyl alcohol + CO2
Role of Hydroxy group in Antitumor Agents
Me
HO
N
O
O
HO
HO
O
HO
O
HO
O
O
Tropine
(toxic alkaloid present
in several plant species)
O
O
Taxus brevifolia
Epothilone B
inhibits tubulin aggregation
Me
Me
O
OH O O
OH
Me
Me
O
O
OH
(high concetrations of this sugar in
the tissue of certain insects and
desert plants allows them to survive
under conditions of water deficiency
and cold)
OH
NH
OH
OH
H
Trehalose
OH
O
Me
O
Me
Me
OH
S
Me
Geraniol
H
(present in oil of geranium,
roses and citronella)
H
Cholesterol
HO
OH
N
H
O
H
O
21
O
CH3O
O
O
O
O
OH
N
H
AcO
H
N
10
HO
Azinomycin B
Streptomyces sahachiroi
OH
OH
O
N
CH3
O
OH
O
OCH3 O
OH
O
CH3
NH2
Doxorubicin (adriamycin)
OH
Binds to DNA and inhibits the enzyme topoisomerase II
OH
O
Problem 1: Classify each of the following either as a phenol, or as a 1º, 2º, 3º, or vinyl alcohol
IUPAC Rules for Naming Alcohols
HO
7
5
6
4
2
1
3
6-methyl-3-propyl-2-heptanol
3-hydroxycyclohexanone
6
5
4
OH
3
2
1
OH
5-methyl-2,4-hexanediol
Nomenclature of Phenols
Problem 2: Name the following using IUPAC system
Structure and Bonding of Alcohols
17.2 Physical Properties:
miscible
miscible
0.6% soluble
Acidity of Alcohols and Phenols
Acidity of Alcohols
pKa
~15.5
~15.5
~19.0
H2O
CH3OH
H3C
CH OH
H2O
H2O
H2O
~12.4
CH3 CH2OH
CF3 CH2OH
stronger acid
+
H3O+
CH3O
+
H3O+
+
H3O
+
+
H3O+
+
+
H3C
CH O
CH3
~15.9
HO
donating groups
destabilize anion
CH3
H2O
H2O
CH3 CH2O
CF3 CH2O
H3O
electron withdrawing (inductive) group
stabilizes the anion
.
Acidity of Phenols
weaker
acid
stronger
acid
HO
HO
O
O
O
O
Acidity of Phenols
HO
HO
NMe2
HO
CF3
increasing acidity
Summary of EDG/EWG Substituents on p-Bonding Systems
• donating and withdrawing ability measured relative to hydrogen
increasing electron donating ability
increasing electron withdrawing ability
F3C
N C
HO3S
O2N
+
R4N
O
R C
O
F
RO C
Cl
O
Br
R2N C
R
H
Ar
CH CH2
O
NH C R
O
O C R
NH2
NR2
OH
OR
Problem 3: Write the products of the following reactions
Preparation of Alcohols: an Overview
1. Hg(OAc)2 / H2O
HO
2. NaBH4
(±)
H CH3
.
1. BH3 THF
Syn
Addition
HO
H
-
2. OH/H2O2
(±) trans-2-methylcyclohexanol
OsO4 / H2O2
or
HO
–
dil. KMnO4 / OH
1. MCPBA
+
2. H3O
O
H2
Pd/C
H
HO
OH
H
H
H
OH
cis-diol
OH
(±)
Racemic
Retrosynthesis
R
H
C
R
OH
C
H:–
H
H
R
H
C
R'
O
R
OH
H:–
C
R'
O
Oxidation-Reduction Reactions in Organic Chemistry
19
Alcohols by Reduction of Carbonyl Compounds
Reducing agents
both reagents act as donors of hydride (H-) donors
H
Na
+
H
B
i-Butyl
H
–
H
Sodium
borohydride
H
Li
+
H
Al
–
H
H
Lithium
aluminum hydride
H
Al
iButyl
Diisobutyl
aluminum hydride
Sodium borohydride
Aldehydes are reduced to 1° alcohols
Ketones are reduced to 2° alcohols
The reagent adds the equivalent of hydride to the carbon of C=O and polarizes the group as well
NaBH4 Vs LiAlH4
synthons
R1
C
R2
R1
C
R2
OH
H
OH
precursors
+
R1
=
H:
C
O
+
NaBH4
R2
NaBH4 reduces aldehydes to primary alcohols
O
O2N
H
NaBH4
H H
O2N
OH
HOCH2CH3
NaBH4 reduces ketones to secondary alcohols
O
H
NaBH4
OH
HOCH2CH3
ketones
2° alcohols
NaBH4 does not react with esters or carboxylic acids
HO H
O
NaBH4
H3CH2CO
HOCH2CH3
O
H3CH2CO
O
23
NaBH4 Vs LiAlH4
Preparation of Diols
Preparation of Diols
Recap of the reduction and examples
Alcohols via Grignard
Grignard reactions
Grignard reaction of Aldehydes and Ketones
Mechanism
Organometallics
Order of the reactivity
Grignard + Ester
Grignard attacks the carbonyl and OEt ion leaves.
Ketone intermediate
Grignard + Acid Chloride
Grignard attacks the carbonyl and Chloride ion leaves.
Ketone intermediate
How would you synthesize...
Using an aldehyde or ketone.
Using an acid chloride or ester.
Grignard with epoxides
Draw the mechanism and the products for the following?
Problems
Propose a synthetic route
Grignard Reagents and Other Functional Groups in the Same Molecule
Which Solvents (if any) Would be OK for Handling RMgBr?,
Which substrates could be converted into RMgBr, and Subsequently reacted with CH3CHO?
Combining Grignard Reactions with Other Reactions
Some Reactions of Alcohols
Two general classes of reaction
– At the carbon of the C–O bond
– At the proton of the O–H bond
Dehydration of Alcohols
Conversion to halides
Solve the following?
Tosylates are Pseudohalides!
R
O
Cl
H
O
S
O
CH3
R
O
H
O
S
O
O
R O S
O
CH3
Base
HO
+
TsO
TsCl
+
-
Na Br
+-
Na
Br
N
C
CN
Na
NH3
H2N
+-
OCH3
H3CO
CH3
Oxidation of Alcohols
Can be accomplished by inorganic reagents, such as KMnO4,
CrO3, and Na2Cr2O7 or by more selective, expensive reagents
Oxidation of Alcohols
Typical Oxidizing Agents
High-oxidation state metal salts are useful
oxidizing agents, which are soluble in water.
Mn(VII)
Cr(VI)
Chromic acid is formed when chromate (CrO4-) or dichromate
(Cr2O72-) are exposed to aqueous acid which is an oxidizing agent
Mechanism of Chromic Acid Oxidation
Alcohol forms a chromate ester followed by elimination with electron transfer to give ketone
The mechanism was determined by observing the effects of isotopes on rates
Why doesn’t it stop aldehyde stage?
Non-aqueous Sources of Cr(VI)
Oxidation of Primary Alcohols with PCC or PDC
To aldehyde: pyridinium chlorochromate (PCC, C5H6NCrO3Cl) in
dichloromethane
Other reagents produce carboxylic acids
Oxidation of Secondary Alcohols
Oxidation of Alcohols-Review
Identify the products?
Synthesis problems?
Recognizing Oxidizing versus Reducing Agents
Oxidizing Agents: Often have:
Highly Oxidized Metals or
Nonmetals
Extra Oxygen
OsO4 (+8)
KMnO4 (+7)
CrO4 (+6)
H2CrO4 (+6)
HNO3 (+5)
H2O2 H2O
RCO3H RCO2H
O3 O2
Reducing Agents: Often involve:
Hydrides in Formulas
Highly Reduced Metals
Metals + H2
Metals + acid
LiAlH4
NaBH4
Li, Na, K, Mg, Zn, Al, etc.
Pd/H2, Pt/H2, Ni/H2 etc.
Zn/HCl, Fe/HCl, Zn/Hg/HCl, etc..
Protection of Alcohols
Methods to Protect Alcohols
Reaction with chlorotrimethylsilane in the presence of base yields
an unreactive trimethylsilyl (TMS) ether
The ether can be cleaved with acid or with fluoride ion to
regenerate the alcohol
Protection-Deprotection
An example of TMS-alcohol protection in a synthesis
Reactions of Phenols
Ar-OH
Reactions:
alcohols
phenols
1. HX
NR
2. PX3
NR
3. dehydration
NR
4. as acids
more acidic
5. ester formation
similar
6. oxidation
NR
1.
as acids
2.
ester formation
3.
ether formation
4.
EAS
Preparation and Uses of Phenols
Special Reactions of Phenols
Summary - Phenols
Much more acidic (pKa  10) than alcohols
Substitution of the aromatic ring by an electron-withdrawing
group increases phenol acidity
Substitution by an electron-donating group decreases acidity
Oxidized to quinones
Quinones are reduced to hydroquinones
Spectroscopy of Alcohols and Phenols
Summary - Alcohols
Synthesis:
– Reduction of aldehydes and ketones
– Addition of Grignard reagents to aldehydes and ketones
Protection of OH as TMS) ether:
Reactions:
– Conversion to alkyl halides
– Dehydration
– Oxidation
Reactions of Alcohols: A Review
Conversion to alkyl halides
1. Reaction with hydrogen halides
2. Reaction with thionyl chloride
3. Reaction with phosphorous trihalides
Acid-catalyzed dehydration to alkenes
Conversion to p-toluenesulfonate esters
Conversion to ethers
Conversion to esters
Esters of inorganic acids
Oxidation to carbonyl compounds
Cleavage of vicinal diols to ketones and aldehydes
Important Reactions
Important Reactions
Design the synthesis for the following?
Retrosynthesis Problems
Draw the mechanisms for the following?
Important Concepts
1.
2.
Alcohols are alkanols (IUPAC) - Names derived from stem prefixed by alkyl and halo substitutents.
Alcohols Have Polar and Short O-H Bond •
Hydroxy group is hydrophilic (hydrogen bonding)
•
Unusually high boiling points
•
Appreciable water solubility
•
Alkyl part is hydrophobic
3.
Alcohols Are Amphoteric –
•
Deprotonation by bases whose conjugate acids are weaker than the alcohol.
•
Protonation yields alkyloxonium ions
•
Acidity: primary > secondary > tertiary alcohol
•
Electron withdrawing substituents increase acidity.
4.
Reverse Polarization - ie – Conversion of the alkyl group in a haloalkane, Cδ+-Xδ-, into its nucleophilic analog in an organometallic compound, C δ--Mδ+.
5.
Aldehyde and Ketone Carbonyl Carbons are Electrophilic - C=O carbon is subject to attack by hydride hydrogens or organometallic alkyl groups. Aqueous workup yields alcohols.
6.
Oxidation of Alcohols – Yields aldehydes and ketones (Chromium IV reagents).
7.
Protection of alcohols is required in order to mask them participating in unwanted reactions.
8.
Phenols are acidic in nature, and can be oxidized to quinones.
9. Alcohols upon reaction with HX provide alkyl halides.
10. An alkyl halide = an alkyl group with a halogen
11. Haloalkane Properties – Strongly affected by the C-X bond polarization and the polarizability of X.
12. Alcohols and alkyl halides are produced via each other, and also they participate in some common type of reactions . 13. Nucleophilic substitution and eliminations – When a lone pair of electrons
on a reagent attacks a positively polarized (or electrophilic) center. If a substituent is replaced, the reaction is termed a nucleophilic substitution. The substituent replaced is called the
leaving group. If the neucleophile picks up a proton and leads to elimination of leaving group on adjacent atom it is called elimination.