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Organic Chemistry, 7th Edition
L. G. Wade, Jr.
Chapter 10
Structure and Synthesis
of Alcohols
Copyright © 2010 Pearson Education, Inc.
Structure of Water and Methanol
• Oxygen is sp3 hybridized and tetrahedral.
• The H—O—H angle in water is 104.5°.
• The C—O—H angle in methyl alcohol is 108.9°.
Chapter 10
2
Examples of Classifications
OH
CH3
CH3
CH3
CH CH2OH
*
Primary alcohol
CH CH2CH3
*
Secondary alcohol
CH3
CH3
C* OH
Tertiary alcohol
CH3
Chapter 10
3
IUPAC Nomenclature
• Find the longest carbon chain containing the
carbon with the —OH group.
• Drop the -e from the alkane name, add -ol.
• Number the chain giving the —OH group the
lowest number possible.
• Number and name all substituents and write
them in alphabetical order.
Chapter 10
4
Examples of Nomenclature
OH
CH3
CH3
3
CH3
CH CH2OH
2
1
1
2-methyl-1-propanol
2-methylpropan-1-ol
2
CH3
CH3
1
C OH
CH3
CH CH2CH3
2
3
4
2-butanol
butan-2-ol
2-methyl-2-propanol
2-methylpropan-2-ol
Chapter 10
5
Alkenols (Enols)
• Hydroxyl group takes precedence. Assign the
carbon with the —OH the lowest number.
• End the name in –ol, but also specify that there is
a double bond by using the ending –ene before -ol
OH
CH2
5
CHCH2CHCH3
4
3
2 1
4-penten-2-ol
pent-4-ene-2-ol
Chapter 10
6
Naming Priority
Highest ranking
Lowest ranking
1. Acids
2. Esters
3. Aldehydes
4. Ketones
5. Alcohols
6. Amines
7. Alkenes
8. Alkynes
9. Alkanes
10. Ethers
11. Halides
Chapter 10
7
Hydroxy Substituent
• When —OH is part of a higher priority class of
compound, it is named as hydroxy.
carboxylic acid
OH
CH2CH2CH2COOH
4
3
2
1
4-hydroxybutanoic acid
also known as g-hydroxybutyric acid (GHB)
Chapter 10
8
Common Names
• Alcohol can be named as alkyl alcohol.
• Useful only for small alkyl groups.
OH
CH3
CH3
CH CH2OH
isobutyl alcohol
CH3
CH CH2CH3
sec-butyl alcohol
Chapter 10
9
Naming Diols
• Two numbers are needed to locate the two
—OH groups.
• Use -diol as suffix instead of -ol.
1
2
3
4
5
6
hexane-1,6- diol
Chapter 10
10
Glycols
• 1, 2-diols (vicinal diols) are called glycols.
• Common names for glycols use the name of the
alkene from which they were made.
ethane-1,2- diol
ethylene glycol
propane-1,2- diol
propylene glycol
Chapter 10
11
Phenol Nomenclature
• —OH group is assumed to be on carbon 1.
• For common names of disubstituted phenols,
use ortho- for 1,2; meta- for 1,3; and para- for
1,4.
• Methyl phenols are cresols.
OH
OH
H3C
Cl
3-chlorophenol
(meta-chlorophenol)
4-methylphenol
(para-cresol)
Chapter 10
12
Solved Problem 1
Give the systematic (IUPAC) name for the following alcohol.
Solution
The longest chain contains six carbon atoms, but it does not contain the carbon bonded to the hydroxyl
group. The longest chain containing the carbon bonded to the —OH group is the one outlined by the
green box, containing five carbon atoms. This chain is numbered from right to left in order to give the
hydroxyl-bearing carbon atom the lowest possible number.
The correct name for this compound is 3-(iodomethyl)-2-isopropylpentan-1-ol.
Chapter 10
13
Boiling Points of alcohols
• Alcohols have higher boiling points than ethers and
alkanes because alcohols can form hydrogen bonds.
• The stronger interaction between alcohol molecules
will require more energy to break them resulting in a
higher boiling point.
Chapter 10
14
Solubility in Water
Small alcohols are miscible in
water, but solubility decreases as
the size of the alkyl group
increases.
Chapter 10
15
Table of Ka Values
Chapter 10
16
Formation of Alkoxide Ions
• Ethanol reacts with sodium metal to form sodium
ethoxide (NaOCH2CH3), a strong base commonly
used for elimination reactions.
• More hindered alcohols like 2-propanol or tert-butanol
react faster with potassium than with sodium.
Chapter 10
17
Formation of Phenoxide Ion
The aromatic alcohol phenol is more acidic than
aliphatic alcohols due to the ability of aromatic rings
to delocalize the negative charge of the oxygen within
the carbons of the ring.
Chapter 10
18
Charge Delocalization on the
Phenoxide Ion
• The negative charge of the oxygen can be delocalized over four
atoms of the phenoxide ion.
• There are three other resonance structures that can localize the
charge in three different carbons of the ring.
• The true structure is a hybrid between the four resonance forms.
Chapter 10
19
Grignard Reagents
•
•
•
•
Formula R—Mg—X (reacts like R:- +MgX).
Ethers are used as solvents to stabilize the complex.
Iodides are most reactive.
May be formed from any halide.
Chapter 10
20
Reactions with Grignards
Br
+
Mg
ether
Cl
CH3CHCH2CH3
+
Mg
ether
Chapter 10
MgBr
MgCl
CH3CHCH2CH3
21
Organolithium Reagents
• Formula R—Li (reacts like R:- +Li)
• Can be produced from alkyl, vinyl, or
aryl halides, just like Grignard reagents.
• Ether not necessary, wide variety of
solvents can be used.
Chapter 10
22
Reaction with Carbonyl
Chapter 10
23
Formation of Primary Alcohols
Using Grignard Reagents
• Reaction of a Grignard with formaldehyde will
produce a primary alcohol after protonation.
Chapter 10
24
Synthesis of 2º Alcohols
• Addition of a Grignard reagent to an aldehyde
followed by protonation will produce a
secondary alcohol.
Chapter 10
25
Synthesis of 3º Alcohols
• Tertiary alcohols can be easily obtained by
addition of a Grignard to a ketone followed by
protonation with dilute acid.
Chapter 10
26
Solved Problem 2
Show how you would synthesize the following alcohol from compounds containing no more than five
carbon atoms.
Solution
This is a tertiary alcohol; any one of the three alkyl groups might be added in the form of a Grignard
reagent. We can propose three combinations of Grignard reagents with ketones:
Chapter 10
27
Solved Problem 2 (Continued)
Solution (Continued)
Any of these three syntheses would probably work, but only the third begins with fragments containing
no more than five carbon atoms. The other two syntheses would require further steps to generate the
ketones from compounds containing no more than five carbon atoms.
Chapter 10
28
Reaction of Grignards with
Carboxylic Acid Derivatives
Chapter 10
29
Mechanism
Step 1: Grignard attacks the carbonyl forming the tetrahedral
intermediate.
CH3
H3C
R
MgBr
C O
R C O
Cl
MgBr
Cl
Step 2: The tetrahedral intermediate will reform the carbonyl and form
a ketone intermediate.
CH3
R C O
CH3
R C
MgBr
Cl
Chapter 10
+
MgBrCl
O
30
Mechanism continued
Step 3: A second molecule of Grignard attacks the carbonyl of the
ketone.
CH3
CH3
R MgBr
+
R C
R C O
O
MgBr
R
Step 4: Protonation of the alkoxide to form the alcohol as the product.
CH3
R C O
HOH
MgBr
CH3
R C OH
R
R
Chapter 10
31
Addition to Ethylene Oxide
• Grignard and lithium reagents will attack epoxides (also called
oxiranes) and open them to form alcohols.
• This reaction is favored because the ring strain present in the
epoxide is relieved by the opening.
• The reaction is commonly used to extend the length of the
carbon chain by two carbons.
Chapter 10
32
Limitations of Grignard
• Grignards are good nucleophiles but in
the presence of acidic protons it will
acts as a strong base.
• No water or other acidic protons like
O—H, N—H, S—H, or terminal alkynes.
• No other electrophilic multiple bonds,
like C═N, CN, S═O, or N═O.
Chapter 10
33
Reduction of Carbonyl
• Reduction of aldehyde yields 1º alcohol.
• Reduction of ketone yields 2º alcohol.
• Reagents:
 Sodium borohydride, NaBH4
 Lithium aluminum hydride, LiAlH4
 Raney nickel
Chapter 10
34
Sodium Borohydride
• NaBH4 is a source of hydrides (H-)
• Hydride attacks the carbonyl carbon,
forming an alkoxide ion.
• Then the alkoxide ion is protonated by
dilute acid.
• Only reacts with carbonyl of aldehyde or
ketone, not with carbonyls of esters or
carboxylic acids.
Chapter 10
35
Mechanism of Hydride Reduction
• The hydride attacks the carbonyl of the aldehyde or
the ketone.
• A tetrahedral intermediate forms.
• Protonation of the intermediate forms the alcohols.
Chapter 10
36
Lithium Aluminum Hydride
• LiAlH4 is source of hydrides (H-)
• Stronger reducing agent than sodium
borohydride, but dangerous to work with.
• Reduces ketones and aldehydes into the
corresponding alcohol.
• Converts esters and carboxylic acids to 1º
alcohols.
Chapter 10
37
Reduction with LiAlH4
• The LiAlH4 (or LAH) will add two hydrides to
the ester to form the primary alkyl halide.
• The mechanism is similar to the attack of
Grignards on esters.
Chapter 10
38
Reducing Agents
• NaBH4 can reduce
aldehydes and
ketones but not
esters and
carboxylic acids.
• LiAlH4 is a stronger
reducing agent and
will reduce all
carbonyls.
Chapter 10
39
Catalytic Hydrogenation
• Raney nickel is a hydrogen rich nickel powder that is
more reactive than Pd or Pt catalysts.
• This reaction is not commonly used because it will
also reduce double and triple bonds that may be
present in the molecule.
• Hydride reagents are more selective so they are used
more frequently for carbonyl reductions.
Chapter 10
40
Thiols (Mercaptans)
• Sulfur analogues of alcohols are called
thiols.
• The —SH group is called a mercapto
group.
• Named by adding the suffix -thiol to the
alkane name.
• They are commonly made by an SN2
reaction so primary alkyl halides work
better.
Chapter 10
41
Synthesis of Thiols
• The thiolate will attack the carbon displacing
the halide.
• This is an SN2 reaction so methyl halides will
react faster than primary alkyl halides.
• To prevent dialylation use a large excess of
sodium hydrosulfide with the alkyl halide.
Chapter 10
42
A better way into thiols
Thiol Oxidation
Thiols can be oxidized to form disulfides. The disulfide bond
can be reduced back to the thiols with a reducing agent.
Chapter 10
44
Reactions
Reactions
Oxidation States of Carbons
Chapter 11
47
Oxidation States of Carbons
Chapter 11
48
Oxidation of 2° Alcohols
• 2° alcohol becomes
a ketone.
• Oxidizing agent is
Na2Cr2O7/H2SO4.
• Active reagent
probably is H2CrO4.
• Color change is
orange to greenishblue.
Chapter 11
49
Oxidation Mechanism
Chapter 11
50
Oxidation of 1° Alcohols to
Carboxylic Acids
• Chromic acid reagent oxidizes primary
alcohols to carboxylic acids.
• The oxidizing agent is too strong to stop at
the aldehyde.
Chapter 11
51
Pyridinium Chlorochromate (PCC)
• PCC is a complex of chromium trioxide,
pyridine, and HCl.
• Oxidizes primary alcohols to aldehydes.
• Oxidizes secondary alcohols to ketones.
Chapter 11
52
3° Alcohols Cannot Be Oxidized
• Carbon does not have hydrogen, so oxidation is
difficult and involves the breakage of a C—C bond.
• Chromic acid test is for primary and secondary
alcohols because tertiary alcohols do not react.
Chapter 11
53
Example of the Swern Oxidation
Chapter 11
54
Swern Oxidation
Chapter 11
55
Solved Problem 1
Suggest the most appropriate method for each of the following laboratory syntheses.
(a) cyclopentanol ––––––> cyclopentanone
Solution
Many reagents are available to oxidize a simple secondary alcohol to a ketone. For a laboratory
synthesis, however, dehydrogenation is not practical, and cost is not as large a factor as it would be in
industry. Most labs would have chromium trioxide or sodium dichromate available, and the chromic
acid oxidation would be simple. PCC and the Swern oxidation would also work, although these
reagents are more complicated to prepare and use.
Chapter 11
56
Solved Problem 1 (Continued)
Suggest the most appropriate method for each of the following laboratory syntheses.
(b) 2-octen-l-ol ––––––> 2-octenal (structure below)
Solution
This synthesis requires more finesse. The aldehyde is easily over-oxidized to a carboxylic acid, and the
double bond reacts with oxidants such as KMnO4. Our choices are limited to PCC or the Swern
oxidation.
Chapter 11
57
Enzymatic Oxidation
Alcohol dehydrogenase catalyzes an oxidation: the removal of two
hydrogen atoms from an alcohol molecule. The oxidizing agent is called
nicotinamide adenine dinucleotide (NAD+).
Chapter 11
58
Alcohol as a Nucleophile
H
C
O
R X
• ROH is a weak nucleophile.
• RO- is a strong nucleophile.
• New O—C bond forms; O—H bond breaks.
Chapter 11
59
Alkoxide Ions: Williamson Ether
Synthesis
• Ethers can be synthesized by the reaction of alkoxide ions with
primary alkyl halides in what is known as the Williamson ether
synthesis.
• This is an SN2 displacement reaction and as such, works better
with primary alkyl halides to facilitate back-side attack.
• If a secondary or tertiary alkyl halide is used, the alkoxide will
act as a base and an elimination will take place.
Chapter 11
60
Substitution and Elimination
Reactions Using Tosylates
Chapter 11
61
SN2 Reactions with Tosylates
• The reaction shows the SN2 displacement of the
tosylate ion (-OTs) from (S)-2-butyl tosylate with
inversion of configuration.
• The tosylate ion is a particularly stable anion, with its
negative charge delocalized over three oxygen
atoms.
Chapter 11
62
Summary of Tosylate
Reactions
Chapter 11
63
Reduction of Alcohols
• Dehydrate with concentrated H2SO4, then
add H2.
• Make a tosylate, then reduce it with LiAlH4.
OH
CH3CHCH3
H2SO4
alcohol
OH
CH3CHCH3
alcohol
CH2
CHCH3
alkene
TsCl
OTs
CH3CHCH3
tosylate
Chapter 11
H2
Pt
LiAlH4
CH3CH2CH3
alkane
CH3CH2CH3
alkane
64
Reaction of Alcohols with Acids
• The hydroxyl group is protonated by an acid
to convert it into a good leaving group (H2O).
• Once the alcohol is protonated a substitution
or elimination reaction can take place.
Chapter 11
65
Reaction with HBr
•
•
•
•
–OH of alcohol is protonated.
–OH2+ is good leaving group.
3° and 2° alcohols react with Br- via SN1.
1° alcohols react via SN2.
+
R O H
H3O
H
R O H
Chapter 11
-
Br
R Br
66
Reaction with HCl
• Chloride is a weaker nucleophile than
bromide.
• Add ZnCl2, which bonds strongly with
–OH, to promote the reaction.
• The chloride product is insoluble.
• Lucas test: ZnCl2 in concentrated HCl:
 1° alcohols react slowly or not at all.
 2 alcohols react in 1-5 minutes.
 3 alcohols react in less than 1 minute.
Chapter 11
67
SN2 Reaction with the Lucas
Reagent
• Primary alcohols react with the Lucas reagent
(HCl and ZnCl2) by the SN2 mechanism.
• Reaction is very slow. The reaction can take
from several minutes to several days.
Chapter 11
68
SN1 Reaction with the Lucas
Reagent
Secondary and tertiary alcohols react with the Lucas
reagent (HCl and ZnCl2) by the SN1 mechanism.
Chapter 11
69
Solved Problem 2
When 3-methyl-2-butanol is treated with concentrated HBr, the major product is 2-bromo-2methylbutane. Propose a mechanism for the formation of this product.
Solution
The alcohol is protonated by the strong acid. This protonated secondary alcohol loses water to form a
secondary carbocation.
Chapter 11
70
Solved Problem 2 (Continued)
Solution (Continued)
A hydride shift transforms the secondary carbocation into a more stable tertiary cation. Attack by
bromide leads to the observed product.
Chapter 11
71
Reactions with
Phosphorus Halides
•
•
•
•
Good yields with 1° and 2° alcohols.
PCl3 for alkyl chlorides (but SOCl2 better).
PBr3 for alkyl bromides.
P and I2 for alkyl iodides (PI3 not stable).
Chapter 11
72
Mechanism with PBr3
• Oxygen attacks the phosphorus, displacing one of the
halides.
• Br- attacks back-side (SN2).
Chapter 11
73
Reaction of Alcohols with Thionyl
Chloride
• Thionyl chloride (SOCl2) can be used to
convert alcohols into the corresponding alkyl
chloride in a simple reaction that produces
gaseous HCl and SO2.
Chapter 11
74
Mechanism of Thionyl Chloride
Reaction
Chapter 11
75
Appel reaction
Also CBr4, or Br2
Appel reaction Mechanism
Dehydration of Cyclohexanol
• The dehydration of cyclohexanol with H2SO4 has
three steps: Protonation of the hydroxide, loss of
water, and deprotonation.
• Alcohol dehydration generally takes place through
the E1 mechanism. Rearrangements are possible.
• The rate of the reaction follows the same rate as the
ease of formation of carbocations: 3o > 2o > 1o.
Chapter 11
78
Energy Diagram, E1
Chapter 11
79
Pinacol Rearrangement
• In the pinacol rearrangement, a vicinal diol converts
to the ketone (pinacolone) under acidic conditions
and heat.
• The reaction is classified as a dehydration since a
water molecule is eliminated from the starting
material.
Chapter 11
80
Mechanism of the Pinacol
Rearrangement
• The first step of the rearrangement is the
protonation and loss of a water molecule to
produce a carbocation.
Chapter 11
81
Mechanism of the Pinacol
Rearrangement (Continued)
• There is a methyl shift to form a resonancestabilized carbocation, which upon
deprotonation by water, yields the pinacolone
product.
Chapter 11
82
Periodic Cleavage of Glycols
• Glycols can be oxidatively cleaved by periodic acid (HIO4) to
form the corresponding ketones and aldehydes.
• This cleavage can be combined with the hydroxylation of
alkenes by osmium tetroxide or cold potassium permanganate
to form the glycol and the cleavage of the glycol with periodic
acid.
• Same products formed as from ozonolysis of the corresponding
alkene.
Chapter 11
83
Periodic Acid Cleavage
• Periodic acid cleaves vicinal diols to
give two carbonyl compounds.
• Separation and identification of the
products determine the size of the ring.
Chapter 23
84
=>
Fischer Esterification
• Reaction of an alcohol and a carboxylic acid
produces an ester.
• Sulfuric acid is a catalyst.
• The reaction is an equilibrium between starting
materials and products, and for this reason, the
Fischer esterification is seldom used to prepare
esters.
Chapter 11
85
Reaction of Alcohols with Acyl
Chlorides
• The esterification reaction achieves better results by
reacting the alcohol with an acyl chloride.
• The reaction is exothermic and produces the
corresponding ester in high yields with only HCl as a
by-product.
Chapter 11
86
Nitrate Esters
• The best known nitrate ester is nitroglycerine, whose
systematic name is glyceryl trinitrate.
• Glyceryl nitrate results from the reaction of glycerol
(1,2,3-propanetriol) with three molecules of nitric
acid.
Chapter 11
87
Phosphate Esters
Chapter 11
88
Phosphate Esters in DNA
Chapter 11
89