alcool synthèse

463
A: R
 S
16
16.1
OVERVIEW OF
ALCOHOL REACTIONS
In some reactions in which either the CO or the OH bond breaks, a CH bond also breaks.
at CH bond may be on the b carbon atom or on the atom bearing the hydroxyl group. e de-
hydration reaction of alcohols results in the cleavage of both the CO bond and the CH bond of
the b carbon atom. We discussed this process, a b-elimination reaction that results in net dehydration,
in Section 9.20.
e reaction of the oxygen atom with the electrophilic center of alkyl groups bonded to good leaving
groups yields ethers. We will discuss the synthesis of ethers in Chapter 17. Many of the reactions of
alcohols yield an ester either as a reaction intermediate or as a stable product. Ester-forming reac-
tions fall into three broad classes:
1. e synthesis of esters of inorganic or organic acids.
2. e formation of ester intermediates that contain a transition metal.
3. e formation of ester intermediates in the conversion of alcohols into alkyl halides.
We will begin with a brief review of the conversion of alcohols into alkyl halides that we discussed in
Chapter 9. e conversion of alcohol to alkyl chlorides and alkyl bromides is accomplished using thio-
nyl chloride and phosphorus tribromide, respectively. e CO bond breaks in these nucleophilic
substitution reactions.
Alcohols can be converted into many classes of oxygen-containing compounds including ethers,
esters, aldehydes, ketones, and carboxylic acids. ey can also be converted into haloalkanes by
substitution reactions, and into alkenes by elimination reactions.
We will classify the reactions of alcohols by the bonds that are formed or broken. Considering
only the bonds of the hydroxyl oxygen atom, two types of reactions occur: the OH bond can break
or the CO bond can break. We have already considered the loss of a proton from the OH bond
in acid–base reaction. Acid-base reactions are not synthetic reactions. However, replacing the hydrogen
atom of the OH bond by a carbon-containing group is a synthetic procedure used to form more
complex structures.
CCO
HH e carbon-oyxgen bond breaks in a nucleophilic
substitution reaction, which is often acid-catalyzed.
H
CCO
HH
Replacing the alcohol hydrogen with an alkyl group gives an ether.
Replacing it with a carbonyl carbon atom yields an ester.
H
Citronellol
Organic Chemistry. https://doi.org/10.1016/B978-0-12-812838-1.50016-5 Copyright © 2018 Elsevier Inc. All rights reserved.

464
Dimethyl sulfate, a diester of sulfuric acid, is a commercially available liquid used as a methylating
agent. Nucleophiles readily attack the electrophilic methyl carbon atom by an SN2 reaction to give
methylated products. e methyl sulfate ion is an excellent leaving group because it is resonance sta-
bilized, and only weakly basic.
Esters of Nitric, Sulfuric, and Phosphoric Acid
e structures of nitric, sulfuric, and phosphoric acid are shown below. e polyprotic acids, sulfuric
acid and phosphoric acid, contain two and three hydroxyl groups, respectively. us, mono- and
diesters can form from sulfuric acid and mono-, di-, and triesters from phosphoric acid.
16.2
CONVERTING ALCOHOLS
INTO ESTERS
CCO
HH
H
e oxygen–hydrogen and carbon–hydrogen bonds break
in an oxidation reaction, an α-elimination,
α
β
HO S
O
OH
O
sulfuric acid
HO
N
O
O
nitric acid
HO P
O
OH
OH
phosphoric acid
Cl S
O
OH
O
chlorosulfuric acid sulfuryl chloride
Cl S
O
Cl
O
e reaction of an oxyacid, represented as HOA, with an alcohol can yield an ester. e ester forms
by the nucleophilic attack of the alcohol oxygen atom on the central atom of the oxyacid bearing the
hydroxyl group. us, the ester contains the oxygen atom of the alcohol.
Although esters can be formed by direct reaction of an acid with an alcohol, they are more commonly
formed using a derivative of an acid called an acid chloride or acyl chloride. Two acid chlorides of
sulfuric acid—chlorosulfonic acid and sulfuryl chloride— are used to prepare esters.
Breaking both the OH bond and the CH bond at the carbon atom bearing the hydroxyl
group is an oxidation reaction. We will consider this a-elimination reaction in detail in this chapter.
e oxidation reactions convert alcohols into aldehydes and ketones or, by further oxidation, into
carboxylic acids.
CCO
HH
H
e carbon–oxygen and carbon–hydrogen bonds break
in a dehydration reaction, often acid-catalyzed.
α
β
Water comes from here.
+
R
OHHOAROA+H2O
(an ester)
(an alcohol)
(an oxyacid)
Part of the original alcohol.
Part of the original acid.

465
OS
O
O
O
dimethyl sulfate
CH3
C
H
H
H
Nu
Nu CH3+OS
O
O
O
CH
3
methyl sulfate
CC
OTs
H
CC
OTs
H
Nu
SN2
CC
NuH
Nu
E2
+ OTs
+HB
+ OTs
CC
Highly active methylating agents such as dimethyl sulfate must be used with great care because they
react with cellular molecules, which all contain nucleophilic sites. Some alkylating agents act as anti-
neoplastic agents, slowing the growth of some cancers. For example, myleran is used in the treatment
of myelogenous leukemia.
We recall that alcohols react with sulfonyl chlorides—the acid chlorides of sulfonic acids—to form
sulfonates (Section 9.3). We now recognize that these alcohol derivatives are esters of an organic analog
of sulfuric acid.
Alcohols react with p-toluenesulfonyl chloride to give useful synthetic intermediates called p-toluene-
sulfonates, or tosylates. e p-toluenesulfonate ion, a weak base, is an excellent leaving group. Methyl,
primary, and secondary tosylates undergo SN2 displacement reactions with nucleophiles. ey also
react with strong bases in E2 reactions.
CH3 S
HO
O
O
p-toluenesulfonic acid
CH
3
SCl
O
O
p-toluenesulfonyl chloride
(tosyl chloride)
CH3 SRO
O
O
alkyl p-toluenesulfonate
(alkyl tosylate)
OS
O
O
Omyleran
CH2CH2CH2CH2
CH
3OS
O
O
O
CH
3
Esters of Carboxylic Acids
If the nucleophilic oxygen atom of an alcohol attacks the carbonyl carbon atom of the carboxylic
acid, the result is an ester that contains the oxygen atom of the alcohol.

466
RCNu
O
+
nucleophilic addition
C
O
LR
Nu
C
L
Nu
R
O
tetrahedral intermediate
elimination L
e reaction of an alcohol with an acid chloride produces an organic ester. e reaction releases HCl,
which is neutralized with a base such as pyridine.
is reaction, in which a halide ion is formally replaced by an alkoxy group, is an example of nucleo-
philic acyl substitution. A general representation of this mechanism using Nu:– as the nucleophile
and Nu:– as the leaving group is shown below.
e net result is a substitution reaction in which the stoichiometry resembles that of an SN2 sub-
stitution reaction of haloalkanes. However, an SN2 reaction occurs in a single step in which the
nucleophile bonds to the carbon atom as the leaving group leaves. Nucleophilic acyl substitution
occurs in two steps, and the rate-determining step is usually nucleophilic attack at the carbonyl
carbon atom to form a tetrahedral intermediate. e loss of the leaving group occurs in a second,
faster step.
We recall that the size of the nucleophile strongly aects the rate of an SN2 reaction. us,
tert-butoxide is a poorer nucleophile than ethoxide ion (Section 9.1). For the same steric reasons,
the order of reactivity of an alcohol with an acyl chloride (or carboxylic acid) decreases in the order
primary > secondary > tertiary.
e chemistry of organic esters diers substantially from that of inorganic esters. e con-
jugate base of a carboxylic acidthe carboxylate ionis a stronger base than the conjugate bases of
inorganic acids. Hence, a carboxylate ion is not a good leaving group, and the alkyl carbon atom is not
nearly as susceptible to nucleophilic substitution reactions. Also, the carbonyl carbon atom of the ester
is much more susceptible to attack by a nucleophile (Chapter 21).
As in the case of inorganic acids, an acyl chloride is often the preferred reagent to form esters.
Water comes from here.
+
RCOH HOR+H2
O
(an alcohol)
Part of the original alcohol.
O
RCO
(an ester)
O
(a carboxylic acid)
R
CH3CO
O
CH2CH3
CH
3CCl
O
+OCH2CH3
H+H
Cl
N
ethanoyl chloride
(acetyl chloride)
pyridine
+HCl
N
pyridinium chloride
H
Cl
ethanol ethyl ethanoate
(ethyl acetate)
R
CO
O
HRC
Cl
acyl group
O

467
Problem 16.1
Write the Lewis structure of phosphorus oxychloride (POCl), which is the acid chloride of phos-
phoric acid. Write the structure of the product formed when excess methanol reacts with phosphorus
oxychloride.
Problem 16.2
Write the structure of the product formed in the reaction of chlorosulfonic acid with (S)-2-butanol.
What is the conguration of this product?
Problem 16.3
Silicic esters, (RO)Si, form in the reaction of alcohols with SiCl. ey react with water to form silica,
Si(OH)4, and an alcohol. Mechanisms for the hydrolysis can be written that involve SN2 attack of wa-
ter on silicon or at the carbon atom of the R group. Suggest an experiment using isotopes that would
distinguish between these two possible mechanisms.
(RO)Si + 4 HO → 4 ROH + Si(OH)
Problem 16.4
e rates of reaction of ethanoyl chloride CHCOCl (acetyl chloride) with exo- and endo-bicyclo[2.2.1]
heptan-2-ol, are dierent even though both are secondary alcohols. Examine molecular models of these
compounds to determine why. Which compound reacts at the faster rate?
Sample Solution
e hydroxyl group of the endo compound is in a more sterically crowded environment. ere are 1,3
diaxial interactions, much like those in the axial position of a cyclohexane ring.
H
O
H
H
H
We recall that the rate of reaction of nucleophiles decreases with increased steric size of the nucleophile
(Section 9.1). us, the endo compound reacts at a slower rate than the exo compound.
H
OH
OH
H
endo-bicyclo-[2.2.1]heptan-2-ol exo-bicyclo-[2.2.1]heptan-2-ol
16.3
CONVERSION OF
ALCOHOLS TO
HALOALKANES
Alcohols are starting materials for the synthesis of many functional groups, and a synthetic scheme
might very well begin with conversion of an alcohol to a chloroalkane. e reaction of an alcohol
with a hydrogen halide, however, often produces carbocations that undergo elimination reactions that
compete with substitution reactions. To avoid this competing reaction, synthetic methods have been
developed that do not use strongly acidic reagents.
Reaction of Alcohols with Thionyl Chloride
We recall that alcohols react with HCl to give alkyl chlorides. e negatively charged hydroxide ion,
a strong base, is a poor leaving group. e rst step in these reactions is protonation of the alcohol to
give its conjugate acid. Protonation of the alcohol converts the OH group into a good leaving group,
water. Substitution of water by chloride or bromide ion occurs by an SN2 process for primary and sec-
ondary alcohols and an SN1 process for tertiary alcohols. e order of reaction rates for alcohols is 3° >
2° > 1°. We also recall that primary and secondary alcohols react readily with thionyl chloride (SOCl2) to
give alkyl chlorides. e reaction of thionyl chloride gives the by-products hydrogen chloride and sulfur
dioxide, which are released from the reaction as gases. e chloroalkane remains in solution.
1,3- diaxial
interaction