Книга_5852_Библиотеки_им_академика_М_И_Перельмана

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C H A P T E R 12 u Alcohols

12.4 GENERAL METHODS OF PREPARATION OF ALCOHOLS

Monohydric alcohols can be prepared by the following methods.

1. From alkenes

a. By hydration of alkenes in the presence of acids (addition of water): Hydration of alkenes can be

carried out indirectly by the addition of H with hot water gives an alcohol. The addition of H

to furnish hydrogen sulphate, which on hydrolysis

2SO4

to alkene is an electrophilic addition and

2SO4

takes place through the formation of a carbocation.

431

—

−

— —

The mechanism of this reaction is shown below:

—

— — —

—

Alkyl hydrogen sulphates on hydrolysis yield alcohols.

—

i. In case of unsymmetrical alkenes, addition of H2SO4 takes place according to Markownikoff's rule.

—

Propylene

(Propene)

M.Rule

—

— —

Isopropyl hydrogen

sulphate

—

Isopropyl

alcohol

ii. Reactive alkenes directly add a molecule of water in the presence of mineral acids as catalysts to

form alcohols.

—

Isobutylene

— —

Markownikoff’s

—

tert-Butyl alcohol

Isobutylene accepts a proton from the mineral acid to from a stable tert-butyl carbocation, which is attacked by H2O (nucleophile) to form protonated tert-butyl alcohol, which then loses a proton to form tert-butyl alcohol.

This method is used for the industrial preparation of alcohols because the alkenes can be obtained on a commercial scale by cracking of petroleum. Except ethyl alcohol, no other primary alcohol can be prepared by this method as the addition H

to alkene follows Markowinkoff's rule.

2SO4

b. By oxo process: This involves treatment of alkenes with carbon monoxide and hydrogen in the pres-

ence of cobalt carbonyl [Co(CO) formed on catalytic reduction (Ni/H

catalyst at high temperature and under high pressure. The aldehyde

4]2

) gives a primary alcohol. Thus

432

CH CH CHO

3 2

CH CH CH OH

3 2 2

Ni/H

-Propanol

Propanal

—

Isopropyl alcohol

PH A R M A C EUT I C A L O R G ANIC C H E MIST RY

CH CH + CO + H

2 2

Ethene

[Co(CO) ]

High temp.,

High pressure

4 2

Propanal

1-Propanol

c. By hydroboration–oxidation of alkenes: Alkenes react with diborane to form trialkyl boranes, which

upon treatment with alkaline H

—

Propylene

(Propene)

, give alcohols giving anti-Markownikoff's addition of water.

2O2

-propyl borane

The alkenes, which give secondary and tertiary alcohols by the method discussed in the hydration of alkenes, however, can be converted into primary alcohol by this method.

d. Oxymercuration–demercuration reaction: Alkenes can also be converted to alcohols by oxymercura-

tion–demercuration reaction. In this reaction, alkene is treated with mercuric acetate in THF (tetrahydrofuran) water solution to yield a produce, which on reduction with NaBH

gives alcohol. In this

reaction addition occurs according to Markownikoff's rule.

—

— —

—

NOTEWORTHY POINTS

1. Hydroboration–oxidation reaction, the addition of water to an alkene is syn anti-Markownikoff's and free from rearrangement.

—

CH CH

—

–

—

H BH

—

3 2

H BH

—

CH CH

—

3 2

H BH

–

H O /OH

2 2

—

CH CH

3 2

—

H OH

2. In oxymercuration–demercuration reaction, the addition of water to an alkene is anti-Markownikoff's and free from rearrangement.

2. From alkyl halides By the hydrolysis of alkyl halides: Alcohols are obtained by treating alkyl halides with aq. sodium or

potassium hydroxide or moist silver oxide (AgOH), or aqueous potassium carbonate, e.g.

C H A P T E R 12 u Alcohols

433

—

Alkyl

bromide

—

Ethyl bromide

KOH

ROH

Alcohol

Ethyl alcohol

Secondary alkyl halides give mixture of alcohols and alkenes while tertiary alkyl halides are converted

mainly into alkenes.

—

2-Bromopropane

−

—

2-Propanol

—

This method is not of much use for preparing alcohols because haloalkanes are themselves obtained from alcohols. However, this method can be effectively used for the preparation of aromatic alcohols. For example,

HCl

Toluene Benzyl chloride

KCl

Benzyl alcohol

3. From carbonyl compounds

a. By reduction of carbonyl compounds: Alcohols can be easily prepared by the reduction of alde-

hydes, ketones and esters. The commonly used reducing agents are as follows:

i. Nascent hydrogen obtained by the action of sodium on ethanol ii. Complex metal hydrides such as sodium borohydride (NaBH4) or lithium aluminium hydride

(LiAlH4)

iii. Hydrogen in the presence of a catalyst such as nely divided Ni, Pt or Pd.

—

H C + H

C O

—

3 2

Ethanal

—

H C + 2H

C CH

Propanone

Pt or Ni

Na/C H OH

2 5

Ethanol (1º alcohol)

—

— —

C OH

H C

—

H C3 C CH

—

2-Propanol (2º alcohol)

434

PH A R M A C EUT I C A L O R G ANIC C H E MIST RY

—

H C C H + 4H

C O

3 5

Ethyl ethanoate Ethanol

LiAIH

H C

3 2

—

H OH

Aldehydes are reduced to primary alcohols while ketones are reduced to secondary alcohols. Esters are

also reduced to corresponding alcohols. Reduction by nascent hydrogen obtained by the action of sodium on ethanol

—

From aldehyde

From ketone

From ester

—

Aldehyde

—

Ketone

——

Ester

— —

Primary alcohol

—

Secondary alcohol

′

The reduction of aldehydes, ketones and esters with sodium and alcohol is commonly known as Bou-

veault–Blanc reduction. A tertiary alcohol cannot be prepared by this method.

Reduction by complex metal hydrides such as sodium borohydride (NaBH4) or lithium alu-

minium hydride (LiAlH

From aldehyde

From ketone

—

— —

R C OR + 4 (H)

Ester

)

C O + 2 [H]

—

Aldehyde

C O + 2 [H]

—

Ketone

LiAlH

— —

R CH OH

Primary alcohol

LiAlH

′ ′

—

CH OH

—

Secondary alcohol

RCH OH + ROH

It may be noted that LiAIH4 is more powerful reducing agent than NaBH4. It may not only reduce aldehydes and ketones but also reduces esters, acids and nitrile as well. But NaBH only C LiAIH

—

O double bond but not C

—

normally does not reduce olenic double bond, although exceptions are known. For instance, cinna-

—

C double bond, which can otherwise be reduced by the use of H2/Ni.

—

maldehyde (a,b-unsaturated carbonyl compound) when treated with excess of LiAlH

is so specic that it reduces

(lithium aluminum

hydride) gives an excellent yield of 3-phenyl propanol.

C H A P T E R 12 u Alcohols

Cinnamyl alcohol

Alcohol

H /Ni

—

C H CH CH C H

6 5

—

— —

Cinnamaldehyde

or excess LiAlH

NaBH

C H CH CH CH OH

6 5 2 2 2

3-Phenyl propanol

—

6 5 2

Note: LiAlH4 is used in anhydrous ether while NaBH4 can be used in protic solvents like ROH and H2O. Carbonyl compounds may be reduced to alcohols by catalytic hydrogenation (Pt, Pd or Ni and H2)

—

— —

—

Similarly acid chlorides, acid anhydride can also be reduced to primary alcohols by Na/alcohol or LiAlH4 or H

in the presence of Pd or Pt or Ni.

b. Meerwein–Ponndorf reduction: Ketones can also be reduced to secondary alcohols with alumini-

um isopropoxide in 2-propanol solution.

435

—

4. From esters By hydrolysis of esters: When esters are reuxed with dilute solution of an alkali they hydrolyzed to

yield alcohol and sodium salt of carboxylic acid. This reaction is called saponication reaction.

—

— —

The mechanism of this reaction is

—

Ester

—

Salt

—

— —

—

Alcohol

The mechanism suggested above is supported by the fact that rst it involves nucleophilic attack of

hydroxide ion on ester, which is consistent with the second-order kinetics of this reaction, with the rate depending on the concentration of both the ester and the hydroxide.

436

Ethanol

PH A R M A C EUT I C A L O R G ANIC C H E MIST RY

Hydrolysis of esters can also be carried out by dilute acid.

Unlike acid hydrolysis, the alkaline hydrolysis is essentially irreversible as the carboxylate anion ob-

tained is resonance stabilized more than carboxylic acid (obtained in acid hydrolysis) and thus show little

tendency to react with an alcohol or a phenol.

5. From aliphatic primary amines On treatment with HNO2, primary aliphatic amines give primary alcohols. Nitrous acid, being un-

stable, is prepared in the reaction mixture by adding sodium nitrite and sulphuric or hydrochloric acid (in situ).

—

Ethylamine

Ethyl alcohol

Ethanol

Note: a. Under similar conditions, methylamine does not yield methyl alcohol. The product formed is

methyl nitrite or ether.

—

b. Secondary and tertiary alcohols cannot be obtained by this method.

c. This reaction is often employed in the estimation of primary amino groups, particularly in amino

acids and proteins, by making use of the quantitative evolution of nitrogen.

6. From Grignard reagent 1º, 2º and 3º alcohols can be prepared by the reaction of Grignard reagent and carbonyl compound in

dry ether followed by hydrolysis with water or dilute mineral acid.

—

Alcohol

—

a. i. 1º alcohols are obtained by treating the Grignard reagent with formaldehyde.

—

H C

Formaldehyde

—

+ CH MgI

—

H C OMgI

—

H O/H

—

H C

OH + Mg(OH)

—

C H A P T E R 12 u Alcohols

ii. 1º alcohols having two methylene groups attached with alkyl group of the RMgX can be obtained

by treating ethylene oxide with RMgX followed by acid hydrolysis.

437

—

−

—

— —

−

iii. 1º alcohols can also be synthesized by treating the Grignard reagent with dry oxygen and decom-

posing the adduct with water or dilute mineral acid.

— —

b. i. 2º alcohols are obtained by treating the Grignard reagent with aldehydes other than formaldehyde.

Thus

—

— —

—

ii. Secondary alcohols can also be prepared by addition of a suitable Grignard reagent (two moles) to

esters of formic acid and followed by acid hydrolysis.

—

— —

—

— —

—

— —

—

c. i. Tertiary alcohols are produced by treating Grignard reagent with ketones.

H O/H

(CH

—

C O + CH MgI (CH )

)

—

C OMgI

3 2

—

(CH )

CHOH + MgOHI

3 2

—

ii. Tertiary (3º) alcohols can also be prepared by the addition of Grignard reagent (two moles) to an

ester other than formic ester followed by acid hydrolysis.

—

MgI

Note: CH3OH cannot be prepared by this method.

—

MgI

—

— —

—

MgI

—

438

7. From hydrolysis of ethers

Ethers when heated with dil. H

PH A R M A C EUT I C A L O R G ANIC C H E MIST RY

under pressure are hydrolysed to corresponding alcohols.

2SO4

—

dil.

—

dil.

NOTEWORTHY POINTS

1. Lithium aluminium hydride (LiAIH4) and sodium borohydride (NaBH4) are highly speciﬁc reducing agents. The most important advantage of LiAIH (like esters, carboxylic acids, aldehydes, ketones, ozonides, etc.) to the corresponding alcohols but without attacking the double bond. Thus unsaturated aldehydes, ketones, etc., can be reduced to an unsaturated alcohol. However, when a phenyl group is attached to the

unsaturated carbonyl group, double bond is also attacked.

—

2. Reduction converts

3. 3º alcohol cannot be prepared by reduction of aldehydes and ketones.

4. On the other hand, sodium borohydride is a much milder reducing agent than LiAIH reduce aldehydes, ketones and acid chlorides without attacking other reducible groups namely esters, carboxylic acids, double bond, triple bond, etc.

C O

—

+ 2[H]

—

5. Grignard reagent (RMgX) converts

—

6. CH3OH cannot be prepared by using Grignard reagent and aldehyde or ketone.

7. CH

8. In the use of Grignard reagent,

(i) HCHO gives 1º alcohol (ii) RCHO gives 2º alcohol (iii) RCOR′ gives 3º alcohol

OH can however be prepared from CH3MgBr by treatment with O2.

is its ability to reduce a variety of organic compounds

-carbon atom of

—

C O

—

. It can effectively

—

a,b

12.5 STRUCTURE OF ALCOHOL

The general formula of the alcohols is R—O

—

H, where R— is some alkyl or substituted alkyl group. In alcohols, the oxygen atom of the hydroxyl group carries two bond pairs and two lone pairs of electrons. Therefore, alcohol has a bent structure.

—

Methanol (H = 1.71 D)

—

C H A P T E R 12 u Alcohols

439

Further, the electrons of the C — O and O — H bonds are slightly displaced towards the oxygen atom because oxygen is more electronegative than both carbon and hydrogen. As a result, in an alcohol molecule, the oxygen atom carries a partial negative charge (–d ) and both carbon and hydrogen atoms carry partial positive charges (+d ). Due to this, alcohols are polar in nature.

12.6 PHYSICAL PROPERTIES

1. Physical state: At ordinary temperature, lower members are colour-

less liquids with burning taste and a pleasant smell. Higher members

1. 3º alcohol cannot be prepared

2. Methyl alcohol cannot be pre-

3. NaBH4 is a speciﬁc agent as it re-

REMEMBER

by reduction of aldehydes and ketones.

pared by using Grignard reagent and aldehyde/ketone.

duces only C O double bond while LiAlH4 reduces both C C

and C O double bonds.

are colourless waxy solids. Generally, the smell and taste diminishes with the increase in the molecular mass.

2. Boiling point:

a. The boiling points of alcohols are higher as compared to the boiling points of the corresponding

hydrocarbons. This property is due to intermolecular association of a large number of alcohol molecules through hydrogen bonding. Thus, large amount of energy is required to break these hydrogen bonds and have high boiling points.

—

For example, boiling points of methanol (molecular mass 32) and ethane (molecular mass 30) are 337

and 184.4 K, respectively.

b. The boiling points of alcohols increase with an increase in their molecular mass. Among isomeric

alcohols, the boiling points decrease in the order.

1º > 2º > 3º

c. The boiling points of alcohols are higher as compared to the boiling points of alkyl halides of com-

parable molecular masses. Hydrogen bonding in alcohols is stronger than dipole–dipole interactions in alkyl halides.

For example, boiling points of n-butyl alcohol and n-propyl chloride are 391 K and 320 K, respectively.

3. Solubility: The rst three members of alcohols are soluble in water. However, solubility goes on

decreasing with an increase in the molecular mass. The solubility of alcohol in water is due to the association of these substances by hydrogen bonding.

—

440

PHARMACEUTICAL ORGANIC CHEMISTRY

The extent of solubility of an alcohol in the water depends upon the capability of its molecule to form hydrogen bonds with the water molecule. As the molecular mass increases, the large nonpolar hydrocarbon portion (i.e. alkyl group) resists the formation of hydrogen bonds with water molecules and consequently the solubility decreases. Moreover, this H-bonding also gets weakened in higher alcohols as the –OH group

is less polarized due to +I effect of the alkyl groups and hence have less tendency to form hydrogen bonds

with water and therefore less soluble. Similarly alcohols are soluble in organic solvents such as ethers.

Among isomeric alcohols, the solubility in water increases with branching of the chain. It is because the surface area of the nonpolar part in the molecule decreases, i.e. it becomes compact. This increases the

solubility.



Learning Plus

1. The name fermentation has been

ferver

derived from Latin word meaning 'to boil', as during this process there is lot of frothing due to evolution of CO appearence of boiling liquid.

2. Favourable conditions for fermentation are (a) optimum temperature (25º–30ºC), (b) low concentration of solution, (c) presence of inorganic compounds such as (NH

3. Tincture of iodine is 2–3% alcoholic solution of iodine.

4. Alcohols cannot be dehydrated using anhydrous CaCl addition compound CaCl

and this gives the

because it forms an

4)2SO4

·4CH3OH.

4. Density: Alcohols are lighter than water, however the den-

sity increases with the increase in molecular mass.

5. Solvation phenomenon: Lower alcohols form solid deriva-

tives with some metallic chlorides.

CaCl24CH3OH MgCl26CH3OH

CaCl24CH3CH2OH MgCl26CH3CH2OH

That is why methyl alcohol and ethyl alcohol cannot be dehydrated with anhydrous calcium chloride as it forms an additional crystalline compound, CaCl

4CH

OH and CaCl

OH, respectively,

2H5

with it.

6. Physiological effect: Alcohols are intoxicating, when tak-

en internally. Out of all the alcohols, ethyl alcohol is least toxic. Methyl alcohol, for example, is quite toxic. Drinking it, breathing its vapours for a prolonged period, or allowing it to skin can lead to blindness or death.

12.7 CHEMICAL PROPERTIES

The chemical reactions of alcohols are of three types:

—

OH bond

—

H bond or active hydrogen

1. Reactions involving the cleavage of RO

2. Reaction involving cleavage of R

3. Other reactions (involving both the alkyl and hydroxyl groups)

Reactions involving the cleavage of RO—H bond or active hydrogen

Note: The energy required to break the O—H bond is 110.0 kcal/mol.

1. Reaction with electropositive or active metals (acidic nature): With electropositive or active met-

als like Na, Mg and Ca, alcohols form alkoxides with the liberation of hydrogen gas.

2ROH + 2Na (2 Moles) Sodium alkoxide (1 Mole)

2RONa + H

– +

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