579
CHAPTER 15
ALCOHOLS, DIOLS, AND THIOLS
T
he next several chapters deal with the chemistry of various oxygen-containing
functional groups. The interplay of these important classes of compounds—alco-
hols, ethers, aldehydes, ketones, carboxylic acids, and derivatives of carboxylic
acids—is fundamental to organic chemistry and biochemistry.
We’ll start by discussing in more detail a class of compounds already familiar to
us, alcohols. Alcohols were introduced in Chapter 4 and have appeared regularly since
then. With this chapter we extend our knowledge of alcohols, particularly with respect
to their relationship to carbonyl-containing compounds. In the course of studying alco-
hols, we shall also look at some relatives. Diols are alcohols in which two hydroxyl
groups (±OH) are present; thiols are compounds that contain an ±SH group. Phenols,
compounds of the type ArOH, share many properties in common with alcohols but are
sufficiently different from them to warrant separate discussion in Chapter 24.
This chapter is a transitional one. It ties together much of the material encountered
earlier and sets the stage for our study of other oxygen-containing functional groups in
the chapters that follow.
15.1 SOURCES OF ALCOHOLS
Until the 1920s, the major source of methanol was as a byproduct in the production of
charcoal from wood—hence, the name wood alcohol. Now, most of the more than 10
ROH
Alcohol
RORH11032
Ether
RCH
O
X
Aldehyde
RCRH11032
O
X
Ketone
RCOH
O
X
Carboxylic acid
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billion lb of methanol used annually in the United States is synthetic, prepared by reduc-
tion of carbon monoxide with hydrogen.
Almost half of this methanol is converted to formaldehyde as a starting material
for various resins and plastics. Methanol is also used as a solvent, as an antifreeze, and
as a convenient clean-burning liquid fuel. This last property makes it a candidate as a
fuel for automobiles—methanol is already used to power Indianapolis-class race cars—
but extensive emissions tests remain to be done before it can be approved as a gasoline
substitute. Methanol is a colorless liquid, boiling at 65°C, and is miscible with water in
all proportions. It is poisonous; drinking as little as 30 mL has been fatal. Ingestion of
sublethal amounts can lead to blindness.
When vegetable matter ferments, its carbohydrates are converted to ethanol and
carbon dioxide by enzymes present in yeast. Fermentation of barley produces beer;
grapes give wine. The maximum ethanol content is on the order of 15%, because higher
concentrations inactivate the enzymes, halting fermentation. Since ethanol boils at 78°C
CO
Carbon monoxide
2H
2
Hydrogen
CH
3
OH
Methanol
H11001
ZnO/Cr
2
O
3
400°C
580 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
Carbon monoxide is ob-
tained from coal, and hydro-
gen is one of the products
formed when natural gas is
converted to ethylene and
propene (Section 5.1).
CH
3
HO
CH(CH
3
)
2
HO
O
HO
HOCH
2
OH
HO
HO
H
3
C
CH
3
CH
3
CH
3
CH
3
CH
3
OH
CH
3
CH
3
CH
3
CH
3
OH
Menthol (obtained from oil of
peppermint and used to flavor
tobacco and food)
Cholesterol (principal constituent of
gallstones and biosynthetic precursor
of the steroid hormones)
Citronellol (found in rose and
geranium oil and used in perfumery)
Retinol (vitamin A, an important
substance in vision)
Glucose (a carbohydrate)
H
3
C
H
3
C
H
3
C
FIGURE 15.1 Some
naturally occurring alcohols.
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TABLE 15.1 Summary of Reactions Discussed in Earlier Chapters That Yield Alcohols
Reaction (section) and comments
(Continued)
Acid-catalyzed hydration of alkenes
(Section 6.10) The elements of water
add to the double bond in accord-
ance with Markovnikov’s rule.
General equation and specific example
Alkene
R
2
C?CR
2
H11001
Water
H
2
O
Alcohol
R
2
CHCR
2
OH
W
H
H11001
2-Methyl-2-butene
(CH
3
)
2
C?CHCH
3
2-Methyl-2-butanol (90%)
CH
3
CCH
2
CH
3
OH
CH
3
W
W
H
2
O
H
2
SO
4
15.1 Sources of Alcohols 581
and water at 100°C, distillation of the fermentation broth can be used to give “distilled
spirits” of increased ethanol content. Whiskey is the aged distillate of fermented grain
and contains slightly less than 50% ethanol. Brandy and cognac are made by aging the
distilled spirits from fermented grapes and other fruits. The characteristic flavors, odors,
and colors of the various alcoholic beverages depend on both their origin and the way
they are aged.
Synthetic ethanol is derived from petroleum by hydration of ethylene. In the United
States, some 700 million lb of synthetic ethanol is produced annually. It is relatively
inexpensive and useful for industrial applications. To make it unfit for drinking, it is
denatured by adding any of a number of noxious materials, a process that exempts it
from the high taxes most governments impose on ethanol used in beverages.
Our bodies are reasonably well equipped to metabolize ethanol, making it less dan-
gerous than methanol. Alcohol abuse and alcoholism, however, have been and remain
persistent problems.
Isopropyl alcohol is prepared from petroleum by hydration of propene. With a boil-
ing point of 82°C, isopropyl alcohol evaporates quickly from the skin, producing a cool-
ing effect. Often containing dissolved oils and fragrances, it is the major component of
rubbing alcohol. Isopropyl alcohol possesses weak antibacterial properties and is used to
maintain medical instruments in a sterile condition and to clean the skin before minor
surgery.
Methanol, ethanol, and isopropyl alcohol are included among the readily available
starting materials commonly found in laboratories where organic synthesis is carried out.
So, too, are many other alcohols. All alcohols of four carbons or fewer, as well as most
of the five- and six-carbon alcohols and many higher alcohols, are commercially avail-
able at low cost. Some occur naturally; others are the products of efficient syntheses.
Figure 15.1 presents the structures of a few naturally occurring alcohols. Table 15.1 sum-
marizes the reactions encountered in earlier chapters that give alcohols and illustrates a
thread that runs through the fabric of organic chemistry: a reaction that is characteris-
tic of one functional group often serves as a synthetic method for preparing another.
As Table 15.1 indicates, reactions leading to alcohols are not in short supply. Nev-
ertheless, several more will be added to the list in the present chapter—testimony to the
Some of the substances used
to denature ethanol include
methanol, benzene, pyri-
dine, castor oil, and gasoline.
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TABLE 15.1 Summary of Reactions Discussed in Earlier Chapters That Yield Alcohols (Continued)
Reaction (section) and comments General equation and specific example
Reaction of Grignard reagents with
aldehydes and ketones (Section 14.6)
A method that allows for alcohol
preparation with formation of new
carbon–carbon bonds. Primary, sec-
ondary, and tertiary alcohols can all
be prepared.
Aldehyde
or ketone
RH11032CRH11033
O
X
Grignard
reagent
RMgX
Alcohol
RCOH
W
W
RH11032
RH11033
H11001
1. diethyl ether
2. H
3
O
H11001
H11001
1. diethyl ether
2. H
3
O
H11001
H MgBr
Cyclopentylmagnesium
bromide
H CH
2
OH
Cyclopentylmethanol
(62–64%)
HCH
O
X
Formaldehyde
Reaction of organolithium reagents
with aldehydes and ketones (Section
14.7) Organolithium reagents react
with aldehydes and ketones in a
manner similar to that of Grignard
reagents to form alcohols.
Aldehyde
or ketone
RH11032CRH11033
O
X
Organolithium
reagent
RLi
Alcohol
RCOH
W
W
RH11032
RH11033
H11001
1. diethyl ether
2. H
3
O
H11001
H11001CH
3
CH
2
CH
2
CH
2
Li
Butyllithium 2-Phenyl-2-hexanol (67%)
CH
3
CH
2
CH
2
CH
2
±C±OH
CH
3
Acetophenone
CCH
3
O
X
1. diethyl
ether
2. H
3
O
H11001
Hydrolysis of alkyl halides (Section
8.1) A reaction useful only with sub-
strates that do not undergo E2 elimi-
nation readily. It is rarely used for
the synthesis of alcohols, since alkyl
halides are normally prepared from
alcohols.
Alkyl
halide
RX
Hydroxide
ion
HO
H11002
H11001
Alcohol
ROH
Halide
ion
X
H11002
H11001
H
3
C
CH
3
CH
2
Cl
CH
3
2,4,6-Trimethylbenzyl
chloride
H
3
C
CH
3
CH
2
OH
CH
3
2,4,6-Trimethylbenzyl
alcohol (78%)
H
2
O, Ca(OH)
2
heat
(Continued)
Hydroboration-oxidation of alkenes
(Section 6.11) The elements of water
add to the double bond with regio-
selectivity opposite to that of Mar-
kovnikov’s rule. This is a very good
synthetic method; addition is syn,
and no rearrangements are
observed.
1. B
2
H
6
2. H
2
O
2
, HO
H11002
Alkene
R
2
C?CR
2
Alcohol
R
2
CHCR
2
OH
W
1. B
2
H
6
, diglyme
2. H
2
O
2
, HO
H11002
1-Decene
CH
3
(CH
2
)
7
CH?CH
2
1-Decanol (93%)
CH
3
(CH
2
)
7
CH
2
CH
2
OH
582 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
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importance of alcohols in synthetic organic chemistry. Some of these methods involve
reduction of carbonyl groups:
We will begin with the reduction of aldehydes and ketones.
15.2 PREPARATION OF ALCOHOLS BY REDUCTION OF ALDEHYDES
AND KETONES
The most obvious way to reduce an aldehyde or a ketone to an alcohol is by hydro-
genation of the carbon–oxygen double bond. Like the hydrogenation of alkenes, the reac-
tion is exothermic but exceedingly slow in the absence of a catalyst. Finely divided met-
als such as platinum, palladium, nickel, and ruthenium are effective catalysts for the
hydrogenation of aldehydes and ketones. Aldehydes yield primary alcohols:
RCH
O
Aldehyde
H11001 H
2
Hydrogen
Pt, Pd, Ni, or Ru
RCH
2
OH
Primary alcohol
H
2
, Pt
ethanol
CHCH
3
O
O
p-Methoxybenzaldehyde
CH
2
OHCH
3
O
p-Methoxybenzyl alcohol (92%)
reducing agent
C
O
C
HOH
15.2 Preparation of Alcohols by Reduction of Aldehydes and Ketones 583
TABLE 15.1 Summary of Reactions Discussed in Earlier Chapters That Yield Alcohols (Continued)
Reaction (section) and comments General equation and specific example
Reaction of Grignard reagents with
esters (Section 14.10) Produces terti-
ary alcohols in which two of the sub-
stituents on the hydroxyl-bearing
carbon are derived from the
Grignard reagent.
RH11032CORH11033
O
X
RH11033OH2RMgX RCOH
W
W
RH11032
R
H11001H11001
1. diethyl ether
2. H
3
O
H11001
Ethyl
acetate
CH
3
COCH
2
CH
3
O
X
Pentylmagnesium
bromide
2CH
3
CH
2
CH
2
CH
2
CH
2
MgBr H11001
1. diethyl ether
2. H
3
O
H11001
6-Methyl-6-undecanol
(75%)
CH
3
CCH
2
CH
2
CH
2
CH
2
CH
3
W
W
OH
CH
2
CH
2
CH
2
CH
2
CH
3
Recall from Section 2.16 that
reduction corresponds to a
decrease in the number of
bonds between carbon and
oxygen or an increase in the
number of bonds between
carbon and hydrogen (or
both).
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Ketones yield secondary alcohols:
PROBLEM 15.1 Which of the isomeric C
4
H
10
O alcohols can be prepared by
hydrogenation of aldehydes? Which can be prepared by hydrogenation of
ketones? Which cannot be prepared by hydrogenation of a carbonyl compound?
For most laboratory-scale reductions of aldehydes and ketones, catalytic hydro-
genation has been replaced by methods based on metal hydride reducing agents. The two
most common reagents are sodium borohydride and lithium aluminum hydride.
Sodium borohydride is especially easy to use, needing only to be added to an aque-
ous or alcoholic solution of an aldehyde or a ketone:
NaBH
4
methanol
O
2
N
CH
O
m-Nitrobenzaldehyde
CH
2
OH
O
2
N
m-Nitrobenzyl alcohol (82%)
NaBH
4
water, methanol,
or ethanol
RCH
O
Aldehyde
RCH
2
OH
Primary alcohol
NaBH
4
water, methanol,
or ethanol
RCRH11032
O
Ketone
RCHRH11032
OH
Secondary alcohol
CH
3
CCH
2
C(CH
3
)
3
O
4,4-Dimethyl-2-pentanone
CH
3
CHCH
2
C(CH
3
)
3
OH
4,4-Dimethyl-2-pentanol (85%)
NaBH
4
ethanol
Sodium borohydride (NaBH
4
)
Na
H11001
H±B±H
H
W
W
H
H11002
Li
H11001
H±Al±H
H
W
W
H
H11002
Lithium aluminum hydride (LiAlH
4
)
RCRH11032
O
Ketone
H11001 H
2
Hydrogen
Pt, Pd, Ni, or Ru
RCHRH11032
OH
Secondary alcohol
H
2
, Pt
methanol
O
Cyclopentanone
OHH
Cyclopentanol (93–95%)
584 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
Compare the electrostatic
potential maps of CH
4
, BH
4
H11002
,
and AlH
4
H11002
on Learning By Mod-
eling. Notice how different the
electrostatic potentials associ-
ated with hydrogen are.
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Lithium aluminum hydride reacts violently with water and alcohols, so it must be
used in solvents such as anhydrous diethyl ether or tetrahydrofuran. Following reduc-
tion, a separate hydrolysis step is required to liberate the alcohol product:
Sodium borohydride and lithium aluminum hydride react with carbonyl compounds
in much the same way that Grignard reagents do, except that they function as hydride
donors rather than as carbanion sources. Borohydride transfers a hydrogen with its pair
of bonding electrons to the positively polarized carbon of a carbonyl group. The nega-
tively polarized oxygen attacks boron. Ultimately, all four of the hydrogens of borohy-
dride are transferred and a tetraalkoxyborate is formed.
Hydrolysis or alcoholysis converts the tetraalkoxyborate intermediate to the corre-
sponding alcohol. The following equation illustrates the process for reactions carried out
in water. An analogous process occurs in methanol or ethanol and yields the alcohol and
(CH
3
O)
4
B
H11002
or (CH
3
CH
2
O)
4
B
H11002
.
A similar series of hydride transfers occurs when aldehydes and ketones are treated
with lithium aluminum hydride.
3H
2
O
B(OCHR
2
)
3
H11002
H OH
R
2
CHO
R
2
CHOH H11001 HOB(OCHR
2
)
3
H11002
3R
2
CHOH H11001 (HO)
4
B
H11002
3R
2
C?O
H BH
3
H11002
R
2
CO
H9254H11001 H9254H11002
BH
3
H11002
R
2
CO
H
H11002
(R
2
CHO)
4
B
Tetraalkoxyborate
1. LiAlH
4
, diethyl ether
2. H
2
O
RCH
O
Aldehyde
RCH
2
OH
Primary alcohol
CH
3
(CH
2
)
5
CH
O
Heptanal
CH
3
(CH
2
)
5
CH
2
OH
1-Heptanol (86%)
1. LiAlH
4
, diethyl ether
2. H
2
O
RCRH11032
O
Ketone
RCHRH11032
OH
Secondary alcohol
1. LiAlH
4
, diethyl ether
2. H
2
O
(C
6
H
5
)
2
CHCCH
3
O
1,1-Diphenyl-2-propanone
(C
6
H
5
)
2
CHCHCH
3
OH
1,1-Diphenyl-2-propanol (84%)
1. LiAlH
4
, diethyl ether
2. H
2
O
15.2 Preparation of Alcohols by Reduction of Aldehydes and Ketones 585
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Addition of water converts the tetraalkoxyaluminate to the desired alcohol.
PROBLEM 15.2 Sodium borodeuteride (NaBD
4
) and lithium aluminum deuteride
(LiAlD
4
) are convenient reagents for introducing deuterium, the mass 2 isotope of
hydrogen, into organic compounds. Write the structure of the organic product of
the following reactions, clearly showing the position of all the deuterium atoms
in each:
(a) Reduction of (acetaldehyde) with NaBD
4
in H
2
O
(b) Reduction of (acetone) with NaBD
4
in CH
3
OD
(c) Reduction of (benzaldehyde) with NaBD
4
in CD
3
OH
(d) Reduction of (formaldehyde) with LiAlD
4
in diethyl ether, followed
by addition of D
2
O
SAMPLE SOLUTION (a) Sodium borodeuteride transfers deuterium to the car-
bonyl group of acetaldehyde, forming a C±D bond.
Hydrolysis of (CH
3
CHDO)
4
B
H11002
in H
2
O leads to the formation of ethanol, retaining
the C±D bond formed in the preceding step while forming an O±H bond.
Neither sodium borohydride nor lithium aluminum hydride reduces isolated car-
bon–carbon double bonds. This makes possible the selective reduction of a carbonyl
group in a molecule that contains both carbon–carbon and carbon–oxygen double bonds.
D
H11002
BD
3
CH
3
C O
H
CO
H11002
BD
3
D
H
CH
3
3CH
3
CH
O
X
(CH
3
CHO)
4
B
H11002
D
HCH
O
X
C
6
H
5
CH
O
X
CH
3
CCH
3
O
X
CH
3
CH
O
X
Tetraalkoxyaluminate
(R
2
CHO)
4
Al
H11002
Al(OH)
4
H11002
Alcohol
4R
2
CHOH4H
2
OH11001H11001
3R
2
C?O
H AlH
3
H11002
R
2
CO
H9254H11001 H9254H11002
AlH
3
H11002
R
2
CO
H
Tetraalkoxyaluminate
(R
2
CHO)
4
Al
H11002
586 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
H11001CH
3
CH B(OCHDCH
3
)
3
HOH
D
O
H11002
D
OH
CH
3
CH
Ethanol-1-d
3H
2
O
3CH
3
CHOH
D
B(OH)
4
H11002
OH
B(OCHDCH
3
)
3
H11002
H11001
An undergraduate labora-
tory experiment related to
Problem 15.2 appears in the
March 1996 issue of the Jour-
nal of Chemical Education,
pp. 264–266.
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15.3 PREPARATION OF ALCOHOLS BY REDUCTION OF CARBOXYLIC
ACIDS AND ESTERS
Carboxylic acids are exceedingly difficult to reduce. Acetic acid, for example, is often
used as a solvent in catalytic hydrogenations because it is inert under the reaction con-
ditions. A very powerful reducing agent is required to convert a carboxylic acid to a pri-
mary alcohol. Lithium aluminum hydride is that reducing agent.
Sodium borohydride is not nearly as potent a hydride donor as lithium aluminum
hydride and does not reduce carboxylic acids.
Esters are more easily reduced than carboxylic acids. Two alcohols are formed from
each ester molecule. The acyl group of the ester is cleaved, giving a primary alcohol.
Lithium aluminum hydride is the reagent of choice for reducing esters to alcohols.
PROBLEM 15.3 Give the structure of an ester that will yield a mixture contain-
ing equimolar amounts of 1-propanol and 2-propanol on reduction with lithium
aluminum hydride.
Sodium borohydride reduces esters, but the reaction is too slow to be useful.
Hydrogenation of esters requires a special catalyst and extremely high pressures and tem-
peratures; it is used in industrial settings but rarely in the laboratory.
15.4 PREPARATION OF ALCOHOLS FROM EPOXIDES
Although the chemical reactions of epoxides will not be covered in detail until the fol-
lowing chapter, we shall introduce their use in the synthesis of alcohols here.
1. LiAlH
4
, diethyl ether
2. H
2
O
COCH
2
CH
3
O
Ethyl benzoate
CH
2
OH
Benzyl alcohol (90%)
H11001 CH
3
CH
2
OH
Ethanol
RCORH11032
O
Ester
H11001RCH
2
OH
Primary alcohol
RH11032OH
Alcohol
1. LiAlH
4
, diethyl ether
2. H
2
O
RCOH
O
Carboxylic acid
RCH
2
OH
Primary alcohol
1. LiAlH
4
, diethyl ether
2. H
2
O
CO
2
H
Cyclopropanecarboxylic
acid
CH
2
OH
Cyclopropylmethanol (78%)
CHCH
2
CH
2
CCH
3
(CH
3
)
2
C
O
6-Methyl-5-hepten-2-one
CHCH
2
CH
2
CHCH
3
(CH
3
)
2
C
OH
6-Methyl-5-hepten-2-ol (90%)
1. LiAlH
4
, diethyl ether
2. H
2
O
15.4 Preparation of Alcohols from Epoxides 587
Catalytic hydrogenation
would not be suitable for
this transformation, because
H
2
adds to carbon–carbon
double bonds faster than it
reduces carbonyl groups.
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Grignard reagents react with ethylene oxide to yield primary alcohols containing
two more carbon atoms than the alkyl halide from which the organometallic compound
was prepared.
Organolithium reagents react with epoxides in a similar manner.
PROBLEM 15.4 Each of the following alcohols has been prepared by reaction
of a Grignard reagent with ethylene oxide. Select the appropriate Grignard
reagent in each case.
(a)
(b)
SAMPLE SOLUTION (a) Reaction with ethylene oxide results in the addition of
a ±CH
2
CH
2
OH unit to the Grignard reagent. The Grignard reagent derived from
o-bromotoluene (or o-chlorotoluene or o-iodotoluene) is appropriate here.
Epoxide rings are readily opened with cleavage of the carbon–oxygen bond when
attacked by nucleophiles. Grignard reagents and organolithium reagents react with eth-
ylene oxide by serving as sources of nucleophilic carbon.
This kind of chemical reactivity of epoxides is rather general. Nucleophiles other than
Grignard reagents react with epoxides, and epoxides more elaborate than ethylene oxide
may be used. All these features of epoxide chemistry will be discussed in Sections 16.11
and 16.12.
RCH
2
CH
2
OHR MgX
H9254H11002 H9254H11001
H
2
C
O
CH
2
R CH
2
MgX
H11001
CH
2
O
H11002
(may be written as
RCH
2
CH
2
OMgX)
H
3
O
H11001
CH
3
MgBr
o-Methylphenylmagnesium
bromide
H11001 H
2
C
O
CH
2
Ethylene oxide
1. diethyl ether
2. H
3
O
H11001
CH
3
CH
2
CH
2
OH
2-(o-Methylphenyl)ethanol
(66%)
CH
2
CH
2
OH
CH
3
CH
2
CH
2
OH
1. diethyl ether
2. H
3
O
H11001RMgX
Grignard
reagent
H11001 H
2
C
O
CH
2
Ethylene oxide
RCH
2
CH
2
OH
Primary alcohol
1. diethyl ether
2. H
3
O
H11001H
2
C
O
CH
2
Ethylene oxide
CH
3
(CH
2
)
4
CH
2
MgBr
Hexylmagnesium
bromide
H11001 CH
3
(CH
2
)
4
CH
2
CH
2
CH
2
OH
1-Octanol (71%)
588 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
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15.5 PREPARATION OF DIOLS
Much of the chemistry of diols—compounds that bear two hydroxyl groups—is analo-
gous to that of alcohols. Diols may be prepared, for example, from compounds that con-
tain two carbonyl groups, using the same reducing agents employed in the preparation
of alcohols. The following example shows the conversion of a dialdehyde to a diol by
catalytic hydrogenation. Alternatively, the same transformation can be achieved by reduc-
tion with sodium borohydride or lithium aluminum hydride.
Diols are almost always given substitutive IUPAC names. As the name of the prod-
uct in the example indicates, the substitutive nomenclature of diols is similar to that of
alcohols. The suffix -diol replaces -ol, and two locants, one for each hydroxyl group, are
required. Note that the final -e of the alkane basis name is retained when the suffix begins
with a consonant (-diol), but dropped when the suffix begins with a vowel (-ol).
PROBLEM 15.5 Write equations showing how 3-methyl-1,5-pentanediol could
be prepared from a dicarboxylic acid or a diester.
Vicinal diols are diols that have their hydroxyl groups on adjacent carbons. Two
commonly encountered vicinal diols are 1,2-ethanediol and 1,2-propanediol.
Ethylene glycol and propylene glycol are common names for these two diols and are
acceptable IUPAC names. Aside from these two compounds, the IUPAC system does not
use the word “glycol” for naming diols.
In the laboratory, vicinal diols are normally prepared from alkenes using the
reagent osmium tetraoxide (OsO
4
). Osmium tetraoxide reacts rapidly with alkenes to give
cyclic osmate esters.
Osmate esters are fairly stable but are readily cleaved in the presence of an oxi-
dizing agent such as tert-butyl hydroperoxide.
R
2
C CR
2
Alkene
H11001 OsO
4
Osmium
tetraoxide
R
2
C
Os
O
O
O
O
CR
2
Cyclic osmate ester
CH
3
CHCH
2
OH
OH
1,2-Propanediol
(propylene glycol)
HOCH
2
CH
2
OH
1,2-Ethanediol
(ethylene glycol)
H
2
(100 atm)
Ni, 125°C
HCCH
2
CHCH
2
CH
O O
CH
3
3-Methylpentanedial
HOCH
2
CH
2
CHCH
2
CH
2
OH
CH
3
3-Methyl-1,5-pentanediol (81–83%)
15.5 Preparation of Diols 589
Ethylene glycol and propy-
lene glycol are prepared
industrially from the corre-
sponding alkenes by way of
their epoxides. Some applica-
tions were given in the box
in Section 6.21.
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Since osmium tetraoxide is regenerated in this step, alkenes can be converted to vicinal
diols using only catalytic amounts of osmium tetraoxide, which is both toxic and expen-
sive. The entire process is performed in a single operation by simply allowing a solu-
tion of the alkene and tert-butyl hydroperoxide in tert-butyl alcohol containing a small
amount of osmium tetraoxide and base to stand for several hours.
Overall, the reaction leads to addition of two hydroxyl groups to the double bond
and is referred to as hydroxylation. Both oxygens of the diol come from osmium tetraox-
ide via the cyclic osmate ester. The reaction of OsO
4
with the alkene is a syn addition,
and the conversion of the cyclic osmate to the diol involves cleavage of the bonds
between oxygen and osmium. Thus, both hydroxyl groups of the diol become attached
to the same face of the double bond; syn hydroxylation of the alkene is observed.
PROBLEM 15.6 Give the structures, including stereochemistry, for the diols
obtained by hydroxylation of cis-2-butene and trans-2-butene.
A complementary method, one that gives anti hydroxylation of alkenes by way of
the hydrolysis of epoxides, will be described in Section 16.13.
15.6 REACTIONS OF ALCOHOLS: A REVIEW AND A PREVIEW
Alcohols are versatile starting materials for the preparation of a variety of organic func-
tional groups. Several reactions of alcohols have already been seen in earlier chapters
and are summarized in Table 15.2. The remaining sections of this chapter add to the list.
15.7 CONVERSION OF ALCOHOLS TO ETHERS
Primary alcohols are converted to ethers on heating in the presence of an acid catalyst,
usually sulfuric acid.
H
H
Cyclohexene
(CH
3
)
3
COOH, OsO
4
(cat)
tert-butyl alcohol, HO
H11002
cis-1,2-Cyclohexanediol
(62%)
H
H
HO
HO
CH
2
CH
3
(CH
2
)
7
CH
1-Decene
OH
CH
3
(CH
2
)
7
CHCH
2
OH
1,2-Decanediol (73%)
(CH
3
)
3
COOH, OsO
4
(cat)
tert-butyl alcohol, HO
H11002
R
2
C
Os
O
O
O
O
CR
2
H11001 2(CH
3
)
3
COOH
tert-Butyl
hydroperoxide
OHHO
R
2
C CR
2
Vicinal
diol
Osmium
tetraoxide
OsO
4
2(CH
3
)
3
COH
tert-Butyl
alcohol
H11001H11001
HO
H11002
tert-butyl
alcohol
590 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
Construct a molecular
model of cis-1,2-cyclohexanediol.
What is the orientation of the
OH groups, axial or equatorial?
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15.7 Conversion of Alcohols to Ethers 591
TABLE 15.2 Summary of Reactions of Alcohols Discussed in Earlier Chapters
Reaction (section) and comments
Reaction with hydrogen halides (Sec-
tion 4.8) The order of alcohol reactivi-
ty parallels the order of carbocation
stability: R
3
C
H11001
H11022 R
2
CH
H11001
H11022 RCH
2
H11001
H11022
CH
3
H11001
. Benzylic alcohols react readily.
Reaction with thionyl chloride (Sec-
tion 4.14) Thionyl chloride converts
alcohols to alkyl chlorides.
Reaction with phosphorus trihalides
(Section 4.14) Phosphorus trichloride
and phosphorus tribromide convert
alcohols to alkyl halides.
Acid-catalyzed dehydration (Section
5.9) This is a frequently used proce-
dure for the preparation of alkenes.
The order of alcohol reactivity paral-
lels the order of carbocation stability:
R
3
C
H11001
H11022 R
2
CH
H11001
H11022 RCH
2
H11001
. Benzylic
alcohols react readily. Rearrange-
ments are sometimes observed.
Conversion to p-toluenesulfonate
esters (Section 8.14) Alcohols react
with p-toluenesulfonyl chloride to
give p-toluenesulfonate esters. Sulfo-
nate esters are reactive substrates for
nucleophilic substitution and elimina-
tion reactions. The p-toluenesulfo-
nate group is often abbreviated
±OTs.
H
H11001
heat
Alcohol
R
2
CCHR
2
W
OH
Alkene
R
2
C?CR
2
H11001
Water
H
2
O
General equation and specific example
SOCl
2
, pyridine
diethyl ether
6-Methyl-5-hepten-2-ol
(CH
3
)
2
C?CHCH
2
CH
2
CHCH
3
W
OH
6-Chloro-2-methyl-
2-heptene (67%)
(CH
3
)
2
C?CHCH
2
CH
2
CHCH
3
W
Cl
Alcohol
ROH H11001H11001
Hydrogen halide
HX
Alkyl halide
RX
Water
H
2
O
CH
3
O
CH
2
OH
m-Methoxybenzyl alcohol
CH
3
O
CH
2
Br
m-Methoxybenzyl bromide (98%)
HBr
Alcohol
ROH H11001H11001H11001
Thionyl
chloride
SOCl
2
Alkyl
chloride
RCl
Sulfur
dioxide
SO
2
Hydrogen
chloride
HCl
Alcohol
3ROH H11001H11001
Phosphorus trihalide
PX
3
Alkyl halide
3RX
Phosphorous acid
H
3
PO
3
PBr
3
CH
2
OH
Cyclopentylmethanol
CH
2
Br
(Bromomethyl)cyclopentane (50%)
KHSO
4
heat
Br
CHCH
2
CH
3
W
OH
1-(m-Bromophenyl)-1-propanol
Br
CH?CHCH
3
1-(m-Bromophenyl)propene (71%)
H11001 SO
2
ClH
3
C
p-Toluenesulfonyl
chloride
H11001
Hydrogen
chloride
HCl
Alkyl
p-toluenesulfonate
ROS CH
3
O
X
X
O
Alcohol
ROH
Cycloheptanol
OH
Cycloheptyl
p-toluenesulfonate (83%)
OTs
p-toluenesulfonyl
chloride
pyridine
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This kind of reaction is called a condensation. A condensation is a reaction in which
two molecules combine to form a larger one while liberating a small molecule. In this
case two alcohol molecules combine to give an ether and water.
When applied to the synthesis of ethers, the reaction is effective only with primary
alcohols. Elimination to form alkenes predominates with secondary and tertiary alcohols.
Diethyl ether is prepared on an industrial scale by heating ethanol with sulfuric
acid at 140°C. At higher temperatures elimination predominates, and ethylene is the
major product. A mechanism for the formation of diethyl ether is outlined in Figure 15.2.
2CH
3
CH
2
CH
2
CH
2
OH
1-Butanol
CH
3
CH
2
CH
2
CH
2
OCH
2
CH
2
CH
2
CH
3
Dibutyl ether (60%)
H11001 H
2
O
Water
H
2
SO
4
130°C
2RCH
2
OH
Primary alcohol
RCH
2
OCH
2
R
Dialkyl ether
H11001 H
2
O
Water
H
H11001
, heat
592 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
CH
3
CH
2
O H11001 CH
2
±OH11001 ±￡ CH
3
CH
2
OCH
2
CH
3
H11001 O
Overall Reaction:
2CH
3
CH
2
OH ±±￡ CH
3
CH
2
OCH
2
CH
3
H11001 H
2
O
Step 1: Proton transfer from the acid catalyst to the oxygen of the alcohol to produce an alkyloxonium ion
CH
3
CH
2
O H11001 H±OSO
2
OH ±￡ CH
3
CH
2
O
H11001
H11001
H11002
OSO
2
OH
H
Ethyl alcohol Sulfuric acid Ethyloxonium ion Hydrogen sulfate ion
Step 2: Nucleophilic attack by a molecule of alcohol on the alkyloxonium ion formed in step 1
Ethyl alcohol
CH
3
H
H
Ethyloxonium ion Diethyloxonium ion Water
Step 3: The product of step 2 is the conjugate acid of the dialkyl ether. It is deprotonated in the final step of the
process to give the ether.
CH
3
CH
2
O
H11001
H11001
H11002
OSO
2
OH ±￡ CH
3
CH
2
OCH
2
CH
3
H11001 HOSO
2
OH
Diethyloxonium ion Hydrogen sulfate ion Diethyl ether Sulfuric acid
H
2
SO
4
140H11034C
fast
H
H
slow
S
N
2
fast
H
H
H11001
H
H
H
CH
2
CH
3
Ethanol Diethyl ether Water
FIGURE 15.2 The mechanism of acid-catalyzed formation of diethyl ether from ethyl alcohol. As an alternative in the third
step, the Br?nsted base that abstracts the proton could be a molecule of the starting alcohol.
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The individual steps of this mechanism are analogous to those seen earlier. Nucleophilic
attack on a protonated alcohol was encountered in the reaction of primary alcohols with
hydrogen halides (Section 4.13), and the nucleophilic properties of alcohols were dis-
cussed in the context of solvolysis reactions (Section 8.7). Both the first and the last
steps are proton-transfer reactions between oxygens.
Diols react intramolecularly to form cyclic ethers when a five-membered or six-
membered ring can result.
In these intramolecular ether-forming reactions, the alcohol may be primary, secondary,
or tertiary.
PROBLEM 15.7 On the basis of the mechanism for the acid-catalyzed formation
of diethyl ether from ethanol in Figure 15.2, write a stepwise mechanism for the
formation of oxane from 1,5-pentanediol (see the equation in the preceding
paragraph).
15.8 ESTERIFICATION
Acid-catalyzed condensation of an alcohol and a carboxylic acid yields an ester and water
and is known as the Fischer esterification.
Fischer esterification is reversible, and the position of equilibrium lies slightly to the side
of products when the reactants are simple alcohols and carboxylic acids. When the Fis-
cher esterification is used for preparative purposes, the position of equilibrium can be
made more favorable by using either the alcohol or the carboxylic acid in excess. In the
following example, in which an excess of the alcohol was employed, the yield indicated
is based on the carboxylic acid as the limiting reactant.
Another way to shift the position of equilibrium to favor the formation of ester is by
removing water from the reaction mixture. This can be accomplished by adding benzene
as a cosolvent and distilling the azeotropic mixture of benzene and water.
CH
3
OH
Methanol
(0.6 mol)
H11001 COH
O
Benzoic acid
(0.1 mol)
COCH
3
O
Methyl benzoate
(isolated in 70%
yield based on
benzoic acid)
H11001
Water
H
2
O
H
2
SO
4
heat
RH11032COH
O
Carboxylic acid
RH11032COR
O
Ester
ROH
Alcohol
H11001H11001H
2
O
Water
H
H11001
HOCH
2
CH
2
CH
2
CH
2
CH
2
OH
1,5-Pentanediol
H
2
SO
4
heat
O
Oxane (76%)
H11001 H
2
O
Water
15.8 Esterification 593
Oxane is also called tetrahy-
dropyran.
An azeotropic mixture con-
tains two or more substances
that distill together at a con-
stant boiling point. The ben-
zene–water azeotrope
contains 9% water and boils
at 69°C.
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For steric reasons, the order of alcohol reactivity in the Fischer esterification is
CH
3
OH H11022 primary H11022 secondary H11022 tertiary.
PROBLEM 15.8 Write the structure of the ester formed in each of the follow-
ing reactions:
(a)
(b)
SAMPLE SOLUTION (a) By analogy to the general equation and to the exam-
ples cited in this section, we can write the equation
As actually carried out in the laboratory, 3 mol of propanoic acid was used per
mole of 1-butanol, and the desired ester was obtained in 78% yield.
Esters are also formed by the reaction of alcohols with acyl chlorides:
This reaction is normally carried out in the presence of a weak base such as pyridine,
which reacts with the hydrogen chloride that is formed.
(CH
3
)
2
CHCH
2
OH
Isobutyl alcohol
H11001
O
2
N
O
O
2
N
CCl
3,5-Dinitrobenzoyl
chloride
O
2
N
O
O
2
N
COCH
2
CH(CH
3
)
2
Isobutyl
3,5-dinitrobenzoate (86%)
pyridine
RH11032CCl
O
Acyl chloride
RH11032COR
O
Ester
ROH
Alcohol
H11001H11001HCl
Hydrogen
chloride
H
2
SO
4
heat
CH
3
CH
2
CH
2
CH
2
OH
1-Butanol
H11001H11001
O
CH
3
CH
2
COH
Propanoic acid
O
CH
3
CH
2
COCH
2
CH
2
CH
2
CH
3
Butyl propanoate
H
2
O
Water
H
2
SO
4
heat
2CH
3
OH H11001 COH
O O
HOC (C
10
H
10
O
4
)
CH
3
CH
2
CH
2
CH
2
OH H11001
O
CH
3
CH
2
COH
H
2
SO
4
heat
H
H11001
benzene, heat
CH
3
COH
O
Acetic acid
(0.25 mol)
CH
3
COCHCH
2
CH
3
O
CH
3
sec-Butyl acetate
(isolated in 71%
yield based on
sec-butyl alcohol)
H
2
O
Water
(codistills
with benzene)
CH
3
CHCH
2
CH
3
OH
sec-Butyl alcohol
(0.20 mol)
H11001H11001
594 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
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Carboxylic acid anhydrides react similarly to acyl chlorides.
The mechanisms of the Fischer esterification and the reactions of alcohols with
acyl chlorides and acid anhydrides will be discussed in detail in Chapters 19 and 20 after
some fundamental principles of carbonyl group reactivity have been developed. For the
present, it is sufficient to point out that most of the reactions that convert alcohols to
esters leave the C±O bond of the alcohol intact.
The acyl group of the carboxylic acid, acyl chloride, or acid anhydride is trans-
ferred to the oxygen of the alcohol. This fact is most clearly evident in the esterification
of chiral alcohols, where, since none of the bonds to the stereogenic center is broken in
the process, retention of configuration is observed.
PROBLEM 15.9 A similar conclusion may be drawn by considering the reactions
of the cis and trans isomers of 4-tert-butylcyclohexanol with acetic anhydride. On
the basis of the information just presented, predict the product formed from each
stereoisomer.
The reaction of alcohols with acyl chlorides is analogous to their reaction with
p-toluenesulfonyl chloride described earlier (Section 8.14 and Table 15.2). In those reac-
tions, a p-toluenesulfonate ester was formed by displacement of chloride from the sul-
fonyl group by the oxygen of the alcohol. Carboxylic esters arise by displacement of
chloride from a carbonyl group by the alcohol oxygen.
15.9 ESTERS OF INORGANIC ACIDS
Although the term “ester,” used without a modifier, is normally taken to mean an ester
of a carboxylic acid, alcohols can react with inorganic acids in a process similar to the
C
6
H
5
OH
CH
3
CH
2
CH
3
(R)-(H11001)-2-Phenyl-
2-butanol
H11001 O
2
N CCl
O
p-Nitrobenzoyl
chloride
pyridine
NO
2
O
C
6
H
5
OC
CH
3
CH
2
CH
3
(R)-(H11002)-1-Methyl-1-phenylpropyl
p-nitrobenzoate (63% yield)
This is the same oxygen that
was attached to the group R in
the starting alcohol.
HOR RH11032C
O
O R
RH11032COCRH11032
O O
Carboxylic
acid anhydride
RH11032COR
O
Ester
RH11032COH
O
Carboxylic
acid
ROH
Alcohol
H11001H11001
CF
3
COCCF
3
O O
Trifluoroacetic
anhydride
C
6
H
5
CH
2
CH
2
OCCF
3
O
2-Phenylethyl
trifluoroacetate
(83%)
CF
3
COH
O
Trifluoroacetic
acid
C
6
H
5
CH
2
CH
2
OH
2-Phenylethanol
H11001H11001
pyridine
15.9 Esters of Inorganic Acids 595
Make a molecular model
corresponding to the stereo-
chemistry of the Fischer projec-
tion of 2-phenyl-2-butanol
shown in the equation and ver-
ify that it has the R configura-
tion.
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Fischer esterification. The products are esters of inorganic acids. For example, alkyl
nitrates are esters formed by the reaction of alcohols with nitric acid.
PROBLEM 15.10 Alfred Nobel’s fortune was based on his 1866 discovery that
nitroglycerin, which is far too shock-sensitive to be transported or used safely, can
be stabilized by adsorption onto a substance called kieselguhr to give what is
familiar to us as dynamite. Nitroglycerin is the trinitrate of glycerol (1,2,3-
propanetriol). Write a structural formula or construct a molecular model of nitro-
glycerin.
Dialkyl sulfates are esters of sulfuric acid, trialkyl phosphites are esters of phos-
phorous acid (H
3
PO
3
), and trialkyl phosphates are esters of phosphoric acid (H
3
PO
4
).
Some esters of inorganic acids, such as dimethyl sulfate, are used as reagents in syn-
thetic organic chemistry. Certain naturally occurring alkyl phosphates play an important
role in biological processes.
15.10 OXIDATION OF ALCOHOLS
Oxidation of an alcohol yields a carbonyl compound. Whether the resulting carbonyl
compound is an aldehyde, a ketone, or a carboxylic acid depends on the alcohol and on
the oxidizing agent.
Primary alcohols may be oxidized either to an aldehyde or to a carboxylic acid:
Vigorous oxidation leads to the formation of a carboxylic acid, but there are a number
of methods that permit us to stop the oxidation at the intermediate aldehyde stage. The
reagents that are most commonly used for oxidizing alcohols are based on high-
oxidation-state transition metals, particularly chromium(VI).
Chromic acid (H
2
CrO
4
) is a good oxidizing agent and is formed when solutions
containing chromate (CrO
4
2H11002
) or dichromate (Cr
2
O
7
2H11002
) are acidified. Sometimes it is
possible to obtain aldehydes in satisfactory yield before they are further oxidized, but in
most cases carboxylic acids are the major products isolated on treatment of primary alco-
hols with chromic acid.
RCH
2
OH
Primary alcohol
oxidize oxidize
RCH
O
Aldehyde
RCOH
O
Carboxylic acid
Dimethyl sulfate
CH
3
OSOCH
3
O
O
Trimethyl phosphite
(CH
3
O)
3
P
Trimethyl phosphate
O
H11002H11001
(CH
3
O)
3
P
HONO
2
Nitric acid
CH
3
ONO
2
Methyl nitrate (66–80%)
H
2
O
Water
CH
3
OH
Methanol
H11001H11001
H
2
SO
4
HONO
2
Nitric acid
RONO
2
Alkyl nitrate
H
2
O
Water
ROH
Alcohol
H11001H11001
H
H11001
596 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
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Conditions that do permit the easy isolation of aldehydes in good yield by oxida-
tion of primary alcohols employ various Cr(VI) species as the oxidant in anhydrous
media. Two such reagents are pyridinium chlorochromate (PCC), C
5
H
5
NH
H11001
ClCrO
3
H11002
,
and pyridinium dichromate (PDC), (C
5
H
5
NH)
2
2H11001
Cr
2
O
7
2H11002
; both are used in
dichloromethane.
Secondary alcohols are oxidized to ketones by the same reagents that oxidize pri-
mary alcohols:
Tertiary alcohols have no hydrogen on their hydroxyl-bearing carbon and do not
undergo oxidation readily:
In the presence of strong oxidizing agents at elevated temperatures, oxidation of tertiary
alcohols leads to cleavage of the various carbon–carbon bonds at the hydroxyl-bearing
carbon atom, and a complex mixture of products results.
no reaction except under forcing conditions
oxidize
C OHR
RH11032
RH11033
oxidize
RCHRH11032
OH
Secondary alcohol
RCRH11032
O
Ketone
OH
Cyclohexanol
O
Cyclohexanone (85%)
Na
2
Cr
2
O
7
H
2
SO
4
, H
2
O
1-Octen-3-ol
CHCHCH
2
CH
2
CH
2
CH
2
CH
3
CH
2
OH
PDC
CH
2
Cl
2
1-Octen-3-one (80%)
CHCCH
2
CH
2
CH
2
CH
2
CH
3
CH
2
O
CH
3
(CH
2
)
5
CH
2
OH
1-Heptanol
PCC
CH
2
Cl
2
Heptanal (78%)
CH
3
(CH
2
)
5
CH
O
PDC
CH
2
Cl
2
(CH
3
)
3
C CH
2
OH
p-tert-Butylbenzyl alcohol
(CH
3
)
3
C
O
CH
p-tert-Butylbenzaldehyde (94%)
FCH
2
CH
2
CH
2
OH
3-Fluoro-1-propanol
K
2
Cr
2
O
7
H
2
SO
4
, H
2
O
FCH
2
CH
2
COH
O
3-Fluoropropanoic acid (74%)
15.10 Oxidation of Alcohols 597
Potassium permanganate
(KMnO
4
) will also oxidize pri-
mary alcohols to carboxylic
acids. What is the oxidation
state of manganese in
KMnO
4
?
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598 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
ECONOMIC AND ENVIRONMENTAL FACTORS IN ORGANIC SYNTHESIS
B
eyond the obvious difference in scale that is ev-
ident when one compares preparing tons of a
compound versus preparing just a few grams
of it, there are sharp distinctions between “indus-
trial” and “laboratory” syntheses. On a laboratory
scale, a chemist is normally concerned only with ob-
taining a modest amount of a substance. Sometimes
making the compound is an end in itself, but on
other occasions the compound is needed for some
further study of its physical, chemical, or biological
properties. Considerations such as the cost of
reagents and solvents tend to play only a minor role
when planning most laboratory syntheses. Faced
with a choice between two synthetic routes to a par-
ticular compound, one based on the cost of chemi-
cals and the other on the efficient use of a chemist’s
time, the decision is almost always made in favor of
the latter.
Not so for synthesis in the chemical industry,
where not only must a compound be prepared on a
large scale, but it must be prepared at low cost.
There is a pronounced bias toward reactants and
reagents that are both abundant and inexpensive.
The oxidizing agent of choice, for example, in the
chemical industry is O
2
, and extensive research has
been devoted to developing catalysts for preparing
various compounds by air oxidation of readily avail-
able starting materials. To illustrate, air and ethylene
are the reactants for the industrial preparation of
both acetaldehyde and ethylene oxide. Which of the
two products is obtained depends on the catalyst
employed.
CH
2
CH
2
Ethylene
H11001 O
2
1
2
Oxygen
PdCl
2
, CuCl
2
H
2
O
Ag
300°C
O
CH
3
CH
Acetaldehyde
H
2
C CH
2
O
Ethylene oxide
Dating approximately from the creation of the
U.S. Environmental Protection Agency (EPA) in 1970,
dealing with the byproducts of synthetic procedures
has become an increasingly important consideration
in designing a chemical synthesis. In terms of chang-
ing the strategy of synthetic planning, the chemical
industry actually had a shorter road to travel than the
pharmaceutical industry, academic laboratories, and
research institutes. Simple business principles had
long dictated that waste chemicals represented
wasted opportunities. It made better sense for a
chemical company to recover the solvent from a reac-
tion and use it again than to throw it away and buy
more. Similarly, it was far better to find a “value-
added” use for a byproduct from a reaction than to
throw it away. By raising the cost of generating
chemical waste, environmental regulations increased
the economic incentive to design processes that pro-
duced less of it.
The term “environmentally benign” synthesis
has been coined to refer to procedures explicitly de-
signed to minimize the formation of byproducts that
present disposal problems. Both the National Science
Foundation and the Environmental Protection
Agency have allocated a portion of their grant bud-
gets to encourage efforts in this vein.
The application of environmentally benign prin-
ciples to laboratory-scale synthesis can be illustrated
by revisiting the oxidation of alcohols. As noted in
Section 15.10, the most widely used methods involve
Cr(VI)-based oxidizing agents. Cr(VI) compounds are
carcinogenic, however, and appear on the EPA list of
compounds requiring special disposal methods. The
best way to replace Cr(VI)-based oxidants would be to
develop catalytic methods analogous to those used in
industry. Another approach would be to use oxidizing
agents that are less hazardous, such as sodium
hypochlorite. Aqueous solutions of sodium hypochlo-
rite are available as “swimming-pool chlorine,” and
procedures for their use in oxidizing secondary alco-
hols to ketones have been developed. One is de-
scribed on page 71 of the January 1991 edition of the
Journal of Chemical Education.
—Cont.
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15.10 Oxidation of Alcohols 599
There is a curious irony in the nomination of
hypochlorite as an environmentally benign oxidizing
agent. It comes at a time of increasing pressure to
eliminate chlorine and chlorine-containing com-
pounds from the environment to as great a degree as
possible. Any all-inclusive assault on chlorine needs to
be carefully scrutinized, especially when one remem-
bers that chlorination of the water supply has proba-
bly done more to extend human life than any other
public health measure ever undertaken. (The role of
chlorine in the formation of chlorinated hydrocar-
bons in water is discussed in Section 18.7.)
NaOCl
acetic acid–water
(CH
3
)
2
CHCH
2
CHCH
2
CH
2
CH
3
OH
2-Methyl-4-heptanol
O
(CH
3
)
2
CHCH
2
CCH
2
CH
2
CH
3
2-Methyl-4-heptanone (77%)
PROBLEM 15.11 Predict the principal organic product of each of the following
reactions:
(a)
(b)
(c)
SAMPLE SOLUTION (a) The reactant is a primary alcohol and so can be oxidized
either to an aldehyde or to a carboxylic acid. Aldehydes are the major products
only when the oxidation is carried out in anhydrous media. Carboxylic acids are
formed when water is present. The reaction shown produced 4-chlorobutanoic
acid in 56% yield.
The mechanisms by which transition-metal oxidizing agents convert alcohols to
aldehydes and ketones are rather complicated and will not be dealt with in detail here.
In broad outline, chromic acid oxidation involves initial formation of an alkyl chromate:
H
2
OC
H
OH
Alcohol
H11001 HOCrOH
O
O
Chromic acid
C
H
OCrOH
O
O
Alkyl chromate
H11001
ClCH
2
CH
2
CH
2
CH
2
OH
4-Chloro-1-butanol 4-Chlorobutanoic acid
K
2
Cr
2
O
7
H
2
SO
4
, H
2
O
ClCH
2
CH
2
CH
2
COH
O
CH
3
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
OH
PCC
CH
2
Cl
2
CH
3
CHCH
2
CH
2
CH
2
CH
2
CH
2
CH
3
W
OH
Na
2
Cr
2
O
7
H
2
SO
4
, H
2
O
ClCH
2
CH
2
CH
2
CH
2
OH
K
2
Cr
2
O
7
H
2
SO
4
, H
2
O
An alkyl chromate is an ex-
ample of an ester of an inor-
ganic acid (Section 15.9).
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This alkyl chromate then undergoes an elimination reaction to form the carbon–oxygen
double bond.
In the elimination step, chromium is reduced from Cr(VI) to Cr(IV). Since the eventual
product is Cr(III), further electron-transfer steps are also involved.
15.11 BIOLOGICAL OXIDATION OF ALCOHOLS
Many biological processes involve oxidation of alcohols to carbonyl compounds or the
reverse process, reduction of carbonyl compounds to alcohols. Ethanol, for example, is
metabolized in the liver to acetaldehyde. Such processes are catalyzed by enzymes; the
enzyme that catalyzes the oxidation of ethanol is called alcohol dehydrogenase.
In addition to enzymes, biological oxidations require substances known as coen-
zymes. Coenzymes are organic molecules that, in concert with an enzyme, act on a sub-
strate to bring about chemical change. Most of the substances that we call vitamins are
coenzymes. The coenzyme contains a functional group that is complementary to a func-
tional group of the substrate; the enzyme catalyzes the interaction of these mutually com-
plementary functional groups. If ethanol is oxidized, some other substance must be
reduced. This other substance is the oxidized form of the coenzyme nicotinamide ade-
nine dinucleotide (NAD). Chemists and biochemists abbreviate the oxidized form of this
CH
3
CH
O
Acetaldehyde
CH
3
CH
2
OH
Ethanol
alcohol dehydrogenase
H11001 H
3
O
H11001
H11001 HCrO
3
H11002
CrOH
C
H
O
O
O
Alkyl chromate
H
H
O
C O
Aldehyde
or ketone
600 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
N
N
N
N
C
NH
2
O
H11001
N
NH
2
O
P
HO
HO
O
OO
H11002
P
O
O
O
H11002
O
O
HO
OH
FIGURE 15.3 Structure of NAD
H11001
, the oxidized form of the coenzyme nicotinamide adenine
dinucleotide.
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coenzyme as NAD
H11001
and its reduced form as NADH. More completely, the chemical
equation for the biological oxidation of ethanol may be written:
The structure of the oxidized form of nicotinamide adenine dinucleotide is shown
in Figure 15.3. The only portion of the coenzyme that undergoes chemical change in the
reaction is the substituted pyridine ring of the nicotinamide unit (shown in red in Fig-
ure 15.3). If the remainder of the coenzyme molecule is represented by R, its role as an
oxidizing agent is shown in the equation
According to one mechanistic interpretation, a hydrogen with a pair of electrons
is transferred from ethanol to NAD
H11001
, forming acetaldehyde and converting the positively
charged pyridinium ring to a dihydropyridine:
The pyridinium ring of NAD
H11001
serves as an acceptor of hydride (a proton plus two elec-
trons) in this picture of its role in biological oxidation.
PROBLEM 15.12 The mechanism of enzymatic oxidation has been studied by
isotopic labeling with the aid of deuterated derivatives of ethanol. Specify the
number of deuterium atoms that you would expect to find attached to the dihy-
dropyridine ring of the reduced form of the nicotinamide adenine dinucleotide
coenzyme following enzymatic oxidation of each of the alcohols given:
(a) CD
3
CH
2
OH (b) CH
3
CD
2
OH (c) CH
3
CH
2
OD
CH
3
CO
H
H
H
CNH
2
N
O
H
R
H11001
CNH
2
N
O
H
R
H
CH
3
C
H
O
H11001 H
H11001
H11001 H11001
alcohol
dehydrogenase
CH
3
CH
2
OH
Ethanol
CNH
2
N
O
H
R
H11001
NAD
H11001
CH
3
CH
O
Acetaldehyde
CNH
2
N
O
H
R
H
NADH
H11001 H
H11001
CH
3
CH
O
Acetaldehyde
CH
3
CH
2
OH
Ethanol
NAD
H11001
Oxidized form
of NAD coenzyme
H
H11001
H11001 NADH
Reduced
form of NAD
coenzyme
H11001H11001
alcohol dehydrogenase
15.11 Biological Oxidation of Alcohols 601
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SAMPLE SOLUTION According to the proposed mechanism for biological oxi-
dation of ethanol, the hydrogen that is transferred to the coenzyme comes from
C-1 of ethanol. Therefore, the dihydropyridine ring will bear no deuterium atoms
when CD
3
CH
2
OH is oxidized, because all the deuterium atoms of the alcohol are
attached to C-2.
The reverse reaction also occurs in living systems; NADH reduces acetaldehyde
to ethanol in the presence of alcohol dehydrogenase. In this process, NADH serves as a
hydride donor and is oxidized to NAD
H11001
while acetaldehyde is reduced.
The NAD
H11001
–NADH coenzyme system is involved in a large number of biological
oxidation–reductions. Another reaction similar to the ethanol–acetaldehyde conversion is
the oxidation of lactic acid to pyruvic acid by NAD
H11001
and the enzyme lactic acid dehy-
drogenase:
We shall encounter other biological processes in which the NAD
H11001
BA NADH inter-
conversion plays a prominent role in biological oxidation–reduction.
15.12 OXIDATIVE CLEAVAGE OF VICINAL DIOLS
A reaction characteristic of vicinal diols is their oxidative cleavage on treatment with
periodic acid (HIO
4
). The carbon–carbon bond of the vicinal diol unit is broken and two
carbonyl groups result. Periodic acid is reduced to iodic acid (HIO
3
).
R CC
HO OH
RH11032R
RH11032
Vicinal
diol
H11001 HIO
4
Periodic
acid
R
C
R
O
Aldehyde
or ketone
H11001
RH11032
C O
RH11032
Aldehyde
or ketone
H11001 HIO
3
Iodic
acid
H11001 H
2
O
Water
CH CCH
3
HO OH
CH
3
2-Methyl-1-phenyl-1,2-
propanediol
HIO
4
CH
O
Benzaldehyde (83%)
H11001 CH
3
CCH
3
O
Acetone
CH
3
CCOH
OO
Pyruvic acid
NAD
H11001
H
H11001
H11001 NADHH11001H11001
lactic acid dehydrogenase
Lactic acid
CH
3
CHCOHCH
O
OH
602 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
alcohol
dehydrogenase
CD
3
CH
2
OH
2,2,2-
Trideuterioethanol
H11001
CNH
2
N
H11001
R
O
NAD
H11001
CD
3
CH
O
2,2,2-
Trideuterioethanal
H11001
CNH
2
N
R
O
HH
NADH
H
H11001
H11001
What is the oxidation state
of iodine in HIO
4
? In HIO
3
?
Can you remember what re-
action of an alkene would
give the same products as
the periodic acid cleavage
shown here?
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This reaction occurs only when the hydroxyl groups are on adjacent carbons.
PROBLEM 15.13 Predict the products formed on oxidation of each of the fol-
lowing with periodic acid:
(a) HOCH
2
CH
2
OH
(b)
(c)
SAMPLE SOLUTION (a) The carbon–carbon bond of 1,2-ethanediol is cleaved by
periodic acid to give two molecules of formaldehyde:
Cyclic diols give dicarbonyl compounds. The reactions are faster when the
hydroxyl groups are cis than when they are trans, but both stereoisomers are oxidized
by periodic acid.
Periodic acid cleavage of vicinal diols is often used for analytical purposes as an
aid in structure determination. By identifying the carbonyl compounds produced, the con-
stitution of the starting diol may be deduced. This technique finds its widest application
with carbohydrates and will be discussed more fully in Chapter 25.
15.13 PREPARATION OF THIOLS
Sulfur lies just below oxygen in the periodic table, and many oxygen-containing organic
compounds have sulfur analogs. The sulfur analogs of alcohols (ROH) are thiols (RSH).
Thiols are given substitutive IUPAC names by appending the suffix -thiol to the name
of the corresponding alkane, numbering the chain in the direction that gives the lower
locant to the carbon that bears the ±SH group. As with diols (Section 15.5), the final
-e of the alkane name is retained. When the ±SH group is named as a substituent, it is
called a mercapto group. It is also often referred to as a sulfhydryl group, but this is a
generic term, not used in systematic nomenclature.
At one time thiols were named mercaptans. Thus, CH
3
CH
2
SH was called “ethyl
mercaptan” according to this system. This nomenclature was abandoned beginning with
(CH
3
)
2
CHCH
2
CH
2
SH
3-Methyl-1-butanethiol
HSCH
2
CH
2
OH
2-Mercaptoethanol
HSCH
2
CH
2
CH
2
SH
1,3-Propanedithiol
OH
OH
1,2-Cyclopentanediol
(either stereoisomer)
HIO
4
HCCH
2
CH
2
CH
2
CH
O O
Pentanedial
HIO
4
HOCH
2
CH
2
OH
1,2-Ethanediol
O
2HCH
Formaldehyde
OH
CH
2
OH
(CH
3
)
2
CHCH
2
CHCHCH
2
C
6
H
5
HO OH
WW
15.13 Preparation of Thiols 603
Thiols have a marked ten-
dency to bond to mercury,
and the word mercaptan
comes from the Latin mer-
curium captans, which means
“seizing mercury.” The drug
dimercaprol is used to treat
mercury and lead poisoning;
it is 2,3-dimercapto-1-pro-
panol.
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the 1965 revision of the IUPAC rules but is still sometimes encountered, especially in
the older literature.
The preparation of thiols involves nucleophilic substitution of the S
N
2 type on alkyl
halides and uses the reagent thiourea as the source of sulfur. Reaction of the alkyl halide
with thiourea gives a compound known as an isothiouronium salt in the first step. Hydrol-
ysis of the isothiouronium salt in base gives the desired thiol (along with urea):
Both steps can be carried out sequentially without isolating the isothiouronium salt.
PROBLEM 15.14 Outline a synthesis of 1-hexanethiol from 1-hexanol.
15.14 PROPERTIES OF THIOLS
When one encounters a thiol for the first time, especially a low-molecular-weight thiol,
its most obvious property is its foul odor. Ethanethiol is added to natural gas so that
leaks can be detected without special equipment—your nose is so sensitive that it can
detect less than one part of ethanethiol in 10,000,000,000 parts of air! The odor of thi-
ols weakens with the number of carbons, because both the volatility and the sulfur con-
tent decrease. 1-Dodecanethiol, for example, has only a faint odor.
PROBLEM 15.15 The main components of a skunk’s scent fluid are 3-methyl-1-
butanethiol and cis- and trans-2-butene-1-thiol. Write structural formulas for each
of these compounds.
The S±H bond is less polar than the O±H bond, and hydrogen bonding in thi-
ols is much weaker than that of alcohols. Thus, methanethiol (CH
3
SH) is a gas at room
temperature (bp 6°C), and methanol (CH
3
OH) is a liquid (bp 65°C).
Thiols are weak acids, but are far more acidic than alcohols. We have seen that
most alcohols have K
a
values in the range 10
H1100216
to 10
H1100219
(pK
a
H11005 16 to 19). The cor-
responding values for thiols are about K
a
H11005 10
H1100210
(pK
a
H11005 10). The significance of this
difference is that a thiol can be quantitatively converted to its conjugate base (RS
H11002
),
called an alkanethiolate anion, by hydroxide:
Thiols, therefore, dissolve in aqueous media when the pH is greater than 10.
Another difference between thiols and alcohols concerns their oxidation. We have
seen earlier in this chapter that oxidation of alcohols gives compounds having carbonyl
RS H
Alkanethiol
(stronger acid)
(pK
a
H11005 10)
H11001 OH
H11002
Hydroxide ion
(stronger base)
H11002
RS
Alkanethiolate ion
(weaker base)
H11001 H OH
Water
(weaker acid)
(pK
a
H11005 15.7)
CH
3
(CH
2
)
4
CH
2
Br
1-Bromohexane
1. (H
2
N)
2
C?S
2. NaOH
1-Hexanethiol (84%)
CH
3
(CH
2
)
4
CH
2
SH
604 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
HO
H11002
CS
H
2
N
H
2
N
Thiourea
H11001 R X
Alkyl halide
RCS
H
2
N
H11001
H
2
N
Isothiouronium salt
X
H11002
OC
H
2
N
H
2
N
Urea
H11001 HS R
Thiol
A historical account of the
analysis of skunk scent and a
modern determination of its
composition appear in the
March 1978 issue of the Jour-
nal of Chemical Education.
Compare the boiling points
of H
2
S (H1100260°C) and H
2
O
(100°C).
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groups. Analogous oxidation of thiols to compounds with C?S functions does not occur.
Only sulfur is oxidized, not carbon, and compounds containing sulfur in various oxida-
tion states are possible. These include a series of acids classified as sulfenic, sulfinic, and
sulfonic according to the number of oxygens attached to sulfur.
Of these the most important are the sulfonic acids. In general, however, sulfonic acids
are not prepared by oxidation of thiols. Arenesulfonic acids (ArSO
3
H), for example, are
prepared by sulfonation of arenes (Section 12.4).
One of the most important oxidative processes, especially from a biochemical per-
spective, is the oxidation of thiols to disulfides.
Although a variety of oxidizing agents are available for this transformation, it occurs so
readily that thiols are slowly converted to disulfides by the oxygen in the air. Dithiols
give cyclic disulfides by intramolecular sulfur–sulfur bond formation. An example of a
cyclic disulfide is the coenzyme H9251-lipoic acid. The last step in the laboratory synthesis
of H9251-lipoic acid is an iron(III)-catalyzed oxidation of the dithiol shown:
Rapid and reversible making and breaking of the sulfur–sulfur bond is essential to the
biological function of H9251-lipoic acid.
15.15 SPECTROSCOPIC ANALYSIS OF ALCOHOLS
Infrared: We discussed the most characteristic features of the infrared spectra of alco-
hols earlier (Section 13.19). The O±H stretching vibration is especially easy to iden-
tify, appearing in the 3200–3650 cm
H110021
region. As the infrared spectrum of cyclohexa-
nol, presented in Figure 15.4, demonstrates, this peak is seen as a broad absorption of
moderate intensity. The C±O bond stretching of alcohols gives rise to a moderate to
strong absorbance between 1025 and 1200 cm
H110021
. It appears at 1070 cm
H110021
in cyclo-
hexanol, a typical secondary alcohol, but is shifted to slightly higher energy in tertiary
alcohols and slightly lower energy in primary alcohols.
1
H NMR: The most helpful signals in the NMR spectrum of alcohols result from the
hydroxyl proton and the proton in the H±C±O unit of primary and secondary
alcohols.
O
2
, FeCl
3
HSCH
2
CH
2
CH(CH
2
)
4
COH
SH O
6,8-Dimercaptooctanoic acid
(CH
2
)
4
COH
OSS
H9251-Lipoic acid (78%)
2RSH
Thiol
Oxidize
Reduce
Disulfide
RSSR
RS H
Thiol
RS OH
Sulfenic acid
O
H11002
RS
H11001
OH
Sulfinic acid
O
O
H11002
H11002
RS
2H11001
OH
Sulfonic acid
15.15 Spectroscopic Analysis of Alcohols 605
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The chemical shift of the hydroxyl proton signal is variable, depending on solvent,
temperature, and concentration. Its precise position is not particularly significant in struc-
ture determination. Because the signals due to hydroxyl protons are not usually split by
other protons in the molecule and are often rather broad, they are often fairly easy to
identify. To illustrate, Figure 15.5 shows the
1
H NMR spectrum of 2-phenylethanol, in
which the hydroxyl proton signal appears as a singlet at H9254 4.5 ppm. Of the two triplets
in this spectrum, the one at lower field strength (H9254 4.0 ppm) corresponds to the protons
of the CH
2
O unit. The higher-field strength triplet at H9254 3.1 ppm arises from the benzylic
CH
2
group. The assignment of a particular signal to the hydroxyl proton can be con-
firmed by adding D
2
O. The hydroxyl proton is replaced by deuterium, and its
1
H NMR
signal disappears.
13
C NMR: The electronegative oxygen of an alcohol decreases the shielding of the car-
bon to which it is attached. The chemical shift for the carbon of the C±OH unit is
60–75 ppm for most alcohols. Compared with an attached H, an attached OH causes a
downfield shift of 35–50 ppm in the carbon signal.
CH
3
CH
2
CH
2
CH
3
Butane 1-Butanol
CH
3
CH
2
CH
2
CH
2
OH
H9254 13.0 ppm H9254 61.4 ppm
HCO H
H9254 3.3–4.0 ppm H9254 0.5–5 ppm
606 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
Wave number, cm
H110021
Transmittance (%)
O±H C±H
OH
W
C±O
FIGURE 15.4 The in-
frared spectrum of cyclo-
hexanol.
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UV-VIS: Unless there are other chromophores in the molecule, alcohols are transpar-
ent above about 200 nm; H9261
max
for methanol, for example, is 177 nm.
Mass Spectrometry: The molecular ion peak is usually quite small in the mass spec-
trum of an alcohol. A peak corresponding to loss of water is often evident. Alcohols also
fragment readily by a pathway in which the molecular ion loses an alkyl group from the
hydroxyl-bearing carbon to form a stable cation. Thus, the mass spectra of most primary
alcohols exhibit a prominent peak at m/z 31.
PROBLEM 15.16 Three of the most intense peaks in the mass spectrum of
2-methyl-2-butanol appear at m/z 59, 70, and 73. Explain the origin of these peaks.
15.17 SUMMARY
Section 15.1 Functional group interconversions involving alcohols either as reactants
or as products are the focus of this chapter. Alcohols are commonplace
natural products. Table 15.1 summarizes reactions discussed in earlier
sections that can be used to prepare alcohols.
Section 15.2 Alcohols can be prepared from carbonyl compounds by reduction of
aldehydes and ketones. See Table 15.3.
RCH
2
OH
Primary alcohol
R
H11001
CH
2
OH
Molecular ion
R
Alkyl
radical
H11001 CH
2
H11001
OH
Conjugate acid of
formaldehyde, m/z 31
15.17 Summary 607
Chemical shift (δ, ppm)
0.01.02.03.04.05.06.07.08.09.010.0
(ppm)
2.93.03.13.2
(ppm)
4.0
CH
2
CH
2
OH
ArCH
2
CH
2
O
ArH
O±H
FIGURE 15.5 The 200-MHz
1
H NMR spectrum of 2-phenylethanol (C
6
H
5
CH
2
CH
2
OH).
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Section 15.3 Alcohols can be prepared from carbonyl compounds by reduction of car-
boxylic acids and esters. See Table 15.3.
Section 15.4 Grignard and organolithium reagents react with ethylene oxide to give
primary alcohols.
Section 15.5 Osmium tetraoxide is a key reactant in the conversion of alkenes to vic-
inal diols.
(CH
3
)
3
COOH, OsO
4
(cat)
tert-butyl alcohol, HO
H11002C
CH
3
CH
2
2-Phenylpropene
CCH
2
OH
CH
3
OH
2-Phenyl-1,2-propanediol
(71%)
1. diethyl ether
2. H
3
O
H11001RMgX
Grignard reagent
H11001 H
2
C
O
CH
2
Ethylene oxide
RCH
2
CH
2
OH
Primary alcohol
1. diethyl ether
2. H
3
O
H11001H
2
C
O
CH
2
Ethylene oxide
CH
3
CH
2
CH
2
CH
2
MgBr
Butylmagnesium
bromide
H11001 CH
3
CH
2
CH
2
CH
2
CH
2
CH
2
OH
1-Hexanol (60–62%)
608 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
TABLE 15.3 Preparation of Alcohols by Reduction of Carbonyl Functional Groups
Product of reduction of carbonyl compound by specified reducing agent
Carbonyl
compound
Aldehyde RCH
(Section 15.2)
O
X
Ketone RCRH11032
(Section 15.2)
O
X
Carboxylic acid RCOH
(Section 15.3)
O
X
Carboxylic ester RCORH11032
(Section 15.3)
O
X
Lithium aluminum
hydride (LiAlH
4
)
Primary alcohol RCH
2
OH
Secondary alcohol RCHRH11032
OH
W
Primary alcohol RCH
2
OH
Primary alcohol RCH
2
OH
plus RH11032OH
Sodium borohydride
(NaBH
4
)
Primary alcohol RCH
2
OH
Secondary alcohol RCHRH11032
OH
W
Not reduced
Reduced too slowly to be
of practical value
Hydrogen
(in the presence
of a catalyst)
Primary alcohol RCH
2
OH
Secondary alcohol RCHRH11032
OH
W
Not reduced
Requires special catalyst,
high pressures and
temperatures
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The reaction is called hydroxylation and proceeds by syn addition to the
double bond.
Section 15.6 Table 15.2 summarizes reactions of alcohols that were introduced in ear-
lier chapters.
Section 15.7 See Table 15.4
Section 15.8 See Table 15.4
Section 15.9 See Table 15.4
Section 15.10 See Table 15.5
Section 15.11 Oxidation of alcohols to aldehydes and ketones is a common biological
reaction. Most require a coenzyme such as the oxidized form of nicoti-
namide adenine dinucleotide (NAD
H11001
).
Section 15.12 Periodic acid cleaves vicinal diols; two aldehydes, two ketones, or an
aldehyde and a ketone are formed.
Section 15.13 Thiols, compounds of the type RSH, are prepared by the reaction of alkyl
halides with thiourea. An intermediate isothiouronium salt is formed,
which is then subjected to basic hydrolysis.
Section 15.14 Thiols are more acidic than alcohols and are readily deprotonated by reac-
tion with aqueous base. Thiols can be oxidized to disulfides (RSSR),
sulfenic acids (RSOH), sulfinic acids (RSO
2
H), and sulfonic acids
(RSO
3
H).
CH
3
(CH
2
)
11
Br
1-Bromododecane
1. (H
2
N)
2
C?S
2. NaOH
1-Dodecanethiol (79–83%)
CH
3
(CH
2
)
11
SH
RX
Alkyl halide
1. (H
2
N)
2
C?S
2. NaOH
Alkanethiol
RSH
HIO
4
9,10-Dihydroxyoctadecanoic acid
CH
3
(CH
2
)
7
CH CH(CH
2
)
7
COH
HO OH
O
H11001 HC(CH
2
)
7
COH
O O
9-Oxononanoic acid (76%)
CH
3
(CH
2
)
7
CH
O
Nonanal (89%)
R
2
C CR
2
HO OH
Diol Two carbonyl-containing
compounds
R
2
CO O CR
2
H11001
HIO
4
NAD
H11001
enzymes
HO
OH
Estradiol
HO
O
Estrone
CH
3
CH
3
15.17 Summary 609
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610 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
TABLE 15.4 Summary of Reactions of Alcohols Presented in This Chapter
Reaction (section) and comments
Conversion to dialkyl ethers (Sec-
tion 15.7) On being heated in the
presence of an acid catalyst, two
molecules of a primary alcohol
combine to form an ether and
water. Diols can undergo an intra-
molecular condensation if a five-
membered or six-membered cyclic
ether results.
Esterification with acyl chlorides
(Section 15.8) Acyl chlorides react
with alcohols to give esters. The
reaction is usually carried out in
the presence of pyridine.
Esterification with carboxylic acid
anhydrides (Section 15.8) Carbox-
ylic acid anhydrides react with
alcohols to form esters in the same
way that acyl chlorides do.
Formation of esters of inorganic
acids (Section 15.9) Alkyl nitrates,
dialkyl sulfates, trialkyl phos-
phites, and trialkyl phosphates are
examples of alkyl esters of inor-
ganic acids. In some cases, these
compounds are prepared by the
direct reaction of an alcohol and
the inorganic acid.
Fischer esterification (Section
15.8) Alcohols and carboxylic acids
yield an ester and water in the
presence of an acid catalyst. The
reaction is an equilibrium process
that can be driven to completion
by using either the alcohol or the
acid in excess or by removing the
water as it is formed.
General equation and specific example
Alcohol
2RCH
2
OH
Dialkyl ether
RCH
2
OCH
2
R
Water
H
2
OH11001
H
H11001
heat
Alcohol
ROH
Alkyl nitrate
RONO
2
Nitric acid
HONO
2
Water
H
2
OH11001H11001
H
H11001
3-Methyl-1-butanol
2(CH
3
)
2
CHCH
2
CH
2
OH
Di-(3-methylbutyl) ether (27%)
(CH
3
)
2
CHCH
2
CH
2
OCH
2
CH
2
CH(CH
3
)
2
H
2
SO
4
150°C
Acetyl
chloride
CH
3
CCl
O
X
tert-Butyl
acetate (62%)
CH
3
COC(CH
3
)
3
O
X
tert-Butyl alcohol
(CH
3
)
3
COH H11001
pyridine
Carboxylic
acid
RH11032COH
O
X
Ester
RH11032COR
O
X
Water
H
2
O
Alcohol
ROH H11001H11001
H
H11001
Acetic acid
CH
3
COH
O
X
Pentyl acetate (71%)
CH
3
COCH
2
CH
2
CH
2
CH
2
CH
3
O
X
1-Pentanol
CH
3
CH
2
CH
2
CH
2
CH
2
OH H11001
H
H11001
Acyl
chloride
RH11032CCl
O
X
Ester
RH11032COR
O
X
Hydrogen
chloride
HCl
Alcohol
ROH H11001H11001
Carboxylic
acid anhydride
RH11032COCRH11032
O
X
O
X
Ester
RH11032COR
O
X
Carboxylic
acid
RH11032COH
O
X
Alcohol
ROH H11001H11001
H11001
CH
3
O
CH
2
OCCH
3
O
X
m-Methoxybenzyl
acetate (99%)
Acetic anhydride
CH
3
COCCH
3
O
X
O
X
pyridine
m-Methoxybenzyl
alcohol
CH
3
O
CH
2
OH
OH
Cyclopentanol Cyclopentyl
nitrate (69%)
ONO
2
HNO
3
H
2
SO
4
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Section 15.15 The hydroxyl group of an alcohol has its O±H and C±O stretching
vibrations at 3200–3650 and 1025–1200 cm
H110021
, respectively.
The chemical shift of the proton of an O±H group is variable (H9254 1–5
ppm) and depends on concentration, temperature, and solvent. Oxygen
deshields both the proton and the carbon of an H±C±O unit. Typical
NMR chemical shifts are H9254 3.3–4.0 ppm for
1
H and 60–75 ppm for
13
C
of H±C±O.
The most intense peaks in the mass spectrum of an alcohol correspond
to the ion formed according to carbon–carbon cleavage of the type
shown:
PROBLEMS
15.17 Write chemical equations, showing all necessary reagents, for the preparation of 1-butanol
by each of the following methods:
(a) Hydroboration–oxidation of an alkene
(b) Use of a Grignard reagent
(c) Use of a Grignard reagent in a way different from part (b)
(d) Reduction of a carboxylic acid
(e) Reduction of a methyl ester
(f) Reduction of a butyl ester
(g) Hydrogenation of an aldehyde
(h) Reduction with sodium borohydride
R H11001 C
H11001
OHR
H11001
C OH
Problems 611
TABLE 15.5 Oxidation of Alcohols
Aldehyde RCH
O
X
Carboxylic acid RCOH
O
X
Ketone RCRH11032
O
X
Desired productClass of alcohol
Primary, RCH
2
OH
Primary, RCH
2
OH
Secondary, RCHRH11032
OH
W
Suitable oxidizing agent(s)
PCC*
PDC
Na
2
Cr
2
O
7
, H
2
SO
4
, H
2
O
H
2
CrO
4
PCC
PDC
Na
2
Cr
2
O
7
, H
2
SO
4
, H
2
O
H
2
CrO
4
*PCC is pyridinium chlorochromate; PDC is pyridinium dichromate. Both are used in dichloromethane.
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15.18 Write chemical equations, showing all necessary reagents, for the preparation of 2-butanol
by each of the following methods:
(a) Hydroboration–oxidation of an alkene
(b) Use of a Grignard reagent
(c) Use of a Grignard reagent different from that used in part (b)
(d–f) Three different methods for reducing a ketone
15.19 Write chemical equations, showing all necessary reagents, for the preparation of tert-butyl
alcohol by:
(a) Reaction of a Grignard reagent with a ketone
(b) Reaction of a Grignard reagent with an ester of the type
15.20 Which of the isomeric C
5
H
12
O alcohols can be prepared by lithium aluminum hydride
reduction of:
(a) An aldehyde (c) A carboxylic acid
(b) A ketone (d) An ester of the type
15.21 Evaluate the feasibility of the route
as a method for preparing
(a) 1-Butanol from butane
(b) 2-Methyl-2-propanol from 2-methylpropane
(c) Benzyl alcohol from toluene
(d) (R)-1-Phenylethanol from ethylbenzene
15.22 Sorbitol is a sweetener often substituted for cane sugar, since it is better tolerated by dia-
betics. It is also an intermediate in the commercial synthesis of vitamin C. Sorbitol is prepared by
high-pressure hydrogenation of glucose over a nickel catalyst. What is the structure (including
stereochemistry) of sorbitol?
15.23 Write equations showing how 1-phenylethanol could be prepared from each
of the following starting materials:
(a) Bromobenzene (d) Acetophenone
(b) Benzaldehyde (e) Benzene
(c) Benzyl alcohol
15.24 Write equations showing how 2-phenylethanol (C
6
H
5
CH
2
CH
2
OH) could be prepared from
each of the following starting materials:
(a) Bromobenzene (b) Styrene
OH
(C
6
H
5
CHCH
3
)
W
sorbitol
H
2
(120 atm)
Ni, 140°C
HO
OH
O
H
OH
OH OH
Glucose
RH RBr ROH
Br
2
light or heat
KOH
RCOCH
3
O
X
RCOCH
3
O
X
612 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
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(c) 2-Phenylethanal (C
6
H
5
CH
2
CHO)
(d) Ethyl 2-phenylethanoate (C
6
H
5
CH
2
CO
2
CH
2
CH
3
)
(e) 2-Phenylethanoic acid (C
6
H
5
CH
2
CO
2
H)
15.25 Outline practical syntheses of each of the following compounds from alcohols containing
no more than four carbon atoms and any necessary organic or inorganic reagents. In many cases
the desired compound can be made from one prepared in an earlier part of the problem.
(a) 1-Butanethiol
(b) 1-Hexanol
(c) 2-Hexanol
(d) Hexanal, CH
3
CH
2
CH
2
CH
2
CH
2
CH?O
(e) 2-Hexanone,
(f) Hexanoic acid, CH
3
(CH
2
)
4
CO
2
H
(g) Ethyl hexanoate,
(h) 2-Methyl-1,2-propanediol
(i) 2,2-Dimethylpropanal,
15.26 Outline practical syntheses of each of the following compounds from benzene, alcohols, and
any necessary organic or inorganic reagents:
(a) 1-Chloro-2-phenylethane
(b) 2-Methyl-1-phenyl-1-propanone,
(c) Isobutylbenzene, C
6
H
5
CH
2
CH(CH
3
)
2
15.27 Show how each of the following compounds can be synthesized from cyclopentanol and
any necessary organic or inorganic reagents. In many cases the desired compound can be made
from one prepared in an earlier part of the problem.
C
6
H
5
CCH(CH
3
)
2
O
X
(CH
3
)
3
CCH
O
X
CH
3
(CH
2
)
4
COCH
2
CH
3
O
X
CH
3
CCH
2
CH
2
CH
2
CH
3
O
X
Problems 613
(a) 1-Phenylcyclopentanol
(b) 1-Phenylcyclopentene
(c) trans-2-Phenylcyclopentanol
(d)
C
6
H
5
O
(e)
(f)
(g) 1-Phenyl-1,5-pentanediol
C
6
H
5
CCH
2
CH
2
CH
2
CH
O
X
O
X
C
6
H
5
OH
OH
15.28 Write the structure of the principal organic product formed in the reaction of 1-propanol
with each of the following reagents:
(a) Sulfuric acid (catalytic amount), heat at 140°C
(b) Sulfuric acid (catalytic amount), heat at 200°C
(c) Nitric acid (H
2
SO
4
catalyst)
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(d) Pyridinium chlorochromate (PCC) in dichloromethane
(e) Potassium dichromate (K
2
Cr
2
O
7
) in aqueous sulfuric acid, heat
(f ) Sodium amide (NaNH
2
)
(g) Acetic acid in the presence of dissolved hydrogen chloride
(h) in the presence of pyridine
(i) in the presence of pyridine
(j) in the presence of pyridine
(k) in the presence of pyridine
15.29 Each of the following reactions has been reported in the chemical literature. Predict the
product in each case, showing stereochemistry where appropriate.
(a)
(b)
(c)
(d)
(e)
(f )
(g)
pyridine
OH
CH
3
H11001
O
2
N
O
2
N
CCl
O
1. LiAlH
4
, diethyl ether
2. H
2
O
O
CH
3
CCH
2
CH
O
CHCH
2
CCH
3
H
2
CrO
4
H
2
SO
4
, H
2
O, acetone
CH
3
CHC C(CH
2
)
3
CH
3
OH
1. LiAlH
4
, diethyl ether
2. H
2
O
CO
2
H
C
6
H
5
1. B
2
H
6
, diglyme
2. H
2
O
2
, HO
H11002
(CH
3
)
2
C C(CH
3
)
2
(CH
3
)
3
COOH, OsO
4
(cat)
(CH
3
)
3
COH, HO
H11002
H
2
SO
4
heat
CH
3
C
6
H
5
OH
O
O
O
C
6
H
5
COCC
6
H
5
O O
CCl CH
3
O
O
SO
2
ClCH
3
(CH
3
COH)
O
614 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
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(h)
(i)
(j)
(k)
15.30 On heating 1,2,4-butanetriol in the presence of an acid catalyst, a cyclic ether of molecular
formula C
4
H
8
O
2
was obtained in 81–88% yield. Suggest a reasonable structure for this product.
15.31 Give the Cahn–Ingold–Prelog R and S descriptors for the diol(s) formed from cis-2-
pentene and trans-2-pentene on treatment with the osmium tetraoxide/tert-butyl hydroperoxide
reagent.
15.32 Suggest reaction sequences and reagents suitable for carrying out each of the following con-
versions. Two synthetic operations are required in each case.
(a)
(b)
(c)
15.33 The fungus responsible for Dutch elm disease is spread by European bark beetles when they
burrow into the tree. Other beetles congregate at the site, attracted by the scent of a mixture of
chemicals, some emitted by other beetles and some coming from the tree. One of the compounds
given off by female bark beetles is 4-methyl-3-heptanol. Suggest an efficient synthesis of this
pheromone from alcohols of five carbon atoms or fewer.
15.34 Show by a series of equations how you could prepare 3-methylpentane from ethanol and
any necessary inorganic reagents.
C
6
H
5
OH
to
OH
C
6
H
5
OH
CH
2
OH
OH
OH
to
O to
Product of part (j)
HIO
4
CH
3
OH, H
2
O
1. LiAlH
4
2. H
2
O
H
3
C
O
CH
3
CO
O
COCH
3
CH
3
OH
H
2
SO
4
O
2
N
O
2
N
COH
O
Cl
OH
H
H11001
O
CH
3
COCCH
3
O
Problems 615
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15.35 (a) The cis isomer of 3-hexen-1-ol (CH
3
CH
2
CH?CHCH
2
CH
2
OH) has the characteristic
odor of green leaves and grass. Suggest a synthesis for this compound from acetylene
and any necessary organic or inorganic reagents.
(b) One of the compounds responsible for the characteristic odor of ripe tomatoes is the cis
isomer of CH
3
CH
2
CH?CHCH
2
CH?O. How could you prepare this compound?
15.36 R. B. Woodward was one of the leading organic chemists of the middle part of the twenti-
eth century. Known primarily for his achievements in the synthesis of complex natural products,
he was awarded the Nobel Prize in chemistry in 1965. He entered Massachusetts Institute of Tech-
nology as a 16-year-old freshman in 1933 and four years later was awarded the Ph.D. While a stu-
dent there he carried out a synthesis of estrone, a female sex hormone. The early stages of Wood-
ward’s estrone synthesis required the conversion of m-methoxybenzaldehyde to m-methoxybenzyl
cyanide, which was accomplished in three steps:
Suggest a reasonable three-step sequence, showing all necessary reagents, for the preparation of
m-methoxybenzyl cyanide from m-methoxybenzaldehyde.
15.37 Complete the following series of equations by writing structural formulas for compounds A
through I:
(a)
(b)
(c)
15.38 When 2-phenyl-2-butanol is allowed to stand in ethanol containing a few drops of sulfuric
acid, the following ether is formed:
Suggest a reasonable mechanism for this reaction based on the observation that the ether produced
from optically active alcohol is racemic, and that alkenes can be shown not to be intermediates in
the reaction.
CH
3
CH
2
OH
H
2
SO
4
OH
C
6
H
5
CCH
2
CH
3
CH
3
OCH
2
CH
3
C
6
H
5
CCH
2
CH
3
CH
3
HCl NaHCO
3
H
2
O
Na
2
Cr
2
O
7
H
2
SO
4
, H
2
O
C
5
H
7
Cl
Compound A
C
5
H
8
O
Compound B
C
5
H
6
O
Compound C
616 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
SOCl
2
pyridine
1. O
3
2. reductive
workup
NaBH
4
CH
2
OH
CHCH
2
CH
2
CHCH
3
Compound D
C
6
H
11
Cl
Compound E
C
5
H
9
ClO
Compound F
C
5
H
11
ClO
NBS
benzoyl
peroxide,
heat
H
2
O, CaCO
3
heat
PCC
CH
2
Cl
2
CH
3
Br
Compound G Compound H (C
11
H
7
BrO)
Compound I
CHCH
3
O
O
CH
2
CNCH
3
O
three steps many steps
Estrone
HO
CH
3
O
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15.39 Suggest a chemical test that would permit you to distinguish between the two glycerol
monobenzyl ethers shown.
15.40 Choose the correct enantiomer of 2-butanol that would permit you to prepare (R)-2-
butanethiol by way of a p-toluenesulfonate ester.
15.41 The amino acid cysteine has the structure shown:
(a) A second sulfur-containing amino acid called cystine (C
6
H
12
N
2
O
4
S
2
) is formed when
cysteine undergoes biological oxidation. Suggest a reasonable structure for cystine.
(b) Another metabolic pathway converts cysteine to cysteine sulfinic acid (C
3
H
7
NO
4
S), then
to cysteic acid (C
3
H
7
NO
5
S). What are the structures of these two compounds?
15.42 A diol (C
8
H
18
O
2
) does not react with periodic acid. Its
1
H NMR spectrum contains three
singlets at H9254 1.2 (12 protons), 1.6 (4 protons), and 2.0 ppm (2 protons). What is the structure of
this diol?
15.43 Identify compound A (C
8
H
10
O) on the basis of its
1
H NMR spectrum (Figure 15.6). The
broad peak at H9254 2.1 ppm disappears when D
2
O is added.
Cysteine
HSCH
2
CHCO
H11002
H11001
NH
3
O
C
6
H
5
CH
2
OCH
2
CHCH
2
OH
OH
1-O-Benzylglycerol
HOCH
2
CHCH
2
OH
OCH
2
C
6
H
5
2-O-Benzylglycerol
Problems 617
0.01.02.03.04.05.06.07.08.09.010.0
(nnm)
7.27.4
Compound A
(C
8
H
10
O)
4
2
3
1
FIGURE 15.6 The 200-MHz
1
H NMR spectrum of com-
pound A (C
8
H
10
O) (Problem
15.43).
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15.44 Identify each of the following (C
4
H
10
O) isomers on the basis of their
13
C NMR spectra:
(a) δ 31.2 ppm: CH
3
(c) δ 18.9 ppm: CH
3
, area 2
δ 68.9 ppm: C δ 30.8 ppm: CH, area 1
(b) δ 10.0 ppm: CH
3
δ 69.4 ppm: CH
2
, area 1
δ 22.7 ppm: CH
3
δ 32.0 ppm: CH
2
δ 69.2 ppm: CH
15.45 A compound C
3
H
7
ClO
2
exhibited three peaks in its
13
C NMR spectrum at δ 46.8 (CH
2
),
δ 63.5 (CH
2
), and δ 72.0 ppm (CH). What is the structure of this compound?
15.46 A compound C
6
H
14
O has the
13
C NMR spectrum shown in Figure 15.7. Its mass spectrum
has a prominent peak at m/z 31. Suggest a reasonable structure for this compound.
15.47 Refer to Learning By Modeling and compare the properties calculated for CH
3
CH
2
OH and
CH
3
CH
2
SH. Which has the greater dipole moment? Compare the charges at carbon and hydrogen
in C±O±H versus C±S±H. Why does ethanol have a higher boiling point than ethanethiol?
15.48 Construct molecular models of the gauche and anti conformations of 1,2-ethanediol and
explore the possibility of intramolecular hydrogen bond formation in each one.
15.49 Intramolecular hydrogen bonding is present in the chiral diastereomer of 2,2,5,5-tetra-
methylhexane-3,4-diol, but absent in the meso diastereomer. Construct molecular models of each,
and suggest a reason for the difference between the two.
618 CHAPTER FIFTEEN Alcohols, Diols, and Thiols
020406080100120140160180200
Chemical shift (δ, ppm)
CDCl
3
CH
2
CH
CH
2
CH
3
FIGURE 15.7 The
13
C NMR spectrum of the compound C
6
H
14
O (Problem 15.46).
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| 课件名称： | 有机化学（英文原版） |
| 课件分类： | 化学 |
| 课件类型： | 电子图书 |
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