REDUCTION OF ALDEHYDES, KETONES,TO
Aldehydes and ketones can be reduced to hydrocarbons, alcohols, and
pinacols [1, 2 diols or glycols].
[A] HYDROCARBONS
Five methods are available. The choice between them is based on the
sensitivity of other functional centers in the reactant in the reducing
conditions.
[1]Clemmsens Method
The reducing agent is amalgamated zinc and concentrated hydrochloric acid.
The probable mechanism is as follows:
The concentrated acid is apparently needed to force the initial protonation:
amalgamation of zinc raises the hydrogen-overvoltage so that hydrogen is not
produced. Only halogen acids are effective, probably because, by complexing
the initial –Zn+ specie, they provide a medium for the reduction of this species
by the second atom of zinc.
The method is particularly useful for ketones which contain phenolic or
carboxylic groups. For example, the reduction of β-benzoylpropionic acid in
toluene gives γ-phenylbutyric acid in 85% yield
This type of reduction forms one step in the extension of benzenoid systems via
Friedel-Crafts acylations.
The reagent also reduces the olefinic bond in α β–unsaturated ketones,
acids, and esters; and benzyl halides and alcohols are hydrogenolyzed. Strongly
hindered ketones give low yields and sometimes rearrangement products [e.g.
Ph3C-CO-PhPh2C=CPh2]
[2]Wolff-Kishner Method.
The hydrazones of aldehydes and ketones are reduced in vigorous basic
conditions with the evolution of nitrogen, probably as follows:
The standard procedure is the Huang-Minlon modification. The
hydrazone is formed by heating the carbonyl compound with hydrazine hydrate
and potassium hydroxide in di- or tri-ethylene glycol under a water condenser.
After completion of the formation of the hydrazone, the water condenser is
removed so that water liberated in the first reaction is distilled and the
temperature rises to about 200 oC, so bringing about decomposition of the
hydrazone.
A newly developed modification employs potassium t-butoxide as the
base and dimethyl sulphoxide as solvent. Alkoxide bases are very much more
powerful in this solvent than in water or hydroxylic solvents and reaction
occurs at room temperature in high yield. For example, benzophenone gives
about 905 of diphenylmethane:
[3]Mozingo Method.
The carbonyl compounds are converted with ethylene dithiol in the presence of
a Lewis acid into its dithiol-acetal or ketal and this is hydrogenolyzed over
Raney nickel:
Alternatively, the cyclic ditio compound is reduced by hydrogen-transfer from
hydrazine at 100-200C.
The Mozingo reaction is useful for reducing carbonyl compounds
which are sensitive to mineral acid and bases, for the Clemmensen and
Wolff-Kishner methods are then unsuitable
[4]Tosylhydrazone Method.
Reaction of carbonyl compound with toluene –p-sulphonylhydrazine gives
the tosylhydrazone which is efficiently reduced by sodium borohydride [Ar=ptolyl]:
For example, the keto group in androstan-17β-ol-3-one is reduced in this way in
about 75% yield
Reaction probably occurs as follows:
[5]Lithium aluminum hydride
Aromatic ketones are reduced by lithium aluminium trichloride. Reaction
occurs by reduction to the alcohol followed by hydrogenolysis of the benzylic
system, aided by Lewis acid:
[B]TO ALCOHOLS
Carbonyl compounds are reduced to alcohols by the variety of reagents.
Of the three general classes of reductive process, catalytic hydrogenation is
not normally chosen because it is slow, but both hydride-transfer reagents are
employed.
[I]HYDRIDE TRANSFER
The alkali-metal hydrides such as sodium hydride are unsuitable
reducing agents because of their insolubility in organic solvents and their
powerful effects as catalyst for base-catalyzed condensations. The most
commonly used hydride reducing agents are lithium aluminium hydride, sodium
[or potassium] borohydride and lithium borohydride.
[1Lithium aluminium hydride
Lithium aluminium hydride is made by treating lithium hydride with aluminium
trichloride in ether, and is generally used in very dry ether or tetra-hydrofuran
.All hydroxyl-,amino-,and thiol-containing compounds liberate hydrogen
quantitatively from it e.g.,
Each of the four hydrogen atoms in lithium aluminium hydride is
available for the transfer to carbonyl groups. e.g.
each step occurring less rapidly than the proceeding one[As result, the
replacement of two or three hydrogen atoms of aluminium hydride anion by
alkoxy groups give less reactive selective reducing agents;].Finally, hydrolysis
of the aluminum alkoxide give the alcohol.
[2]Sodium borohydride.
Sodium borohydride is much less reactive .It can be used in alcoholic
solvents and even in water ,for it decomposes only enough to make the solution
alkaline, after which it is stable.
[3]Lithium borhydride
Lithium borohydride in more reactive than sodium analogue and reacts
with hydroxylic compounds. It is usually employed in solution in
tetrahydrofuran or diethylene glycol dimethyl ether [diglyme].
These three reagents differ considerable in their reducing power.
Lithium aluminium hydride reduces not only aldehydes and ketone but also
acids, acid chlorides, esters, nitriles, imines, and nitro groups, whereas sodium
borohydride reduces only aldehydes, ketones, imines and acid chlorides.
Lithium borohydride resemble sodium borohydride except that it also
reduces esters and nitriles. None of the reagents normally reduces olefinic,
acetylenic, or N=N bonds, although the first reduces acetylenes containing αhydroxy-substituents and reduces azo compounds in the presence of Lewis acid.
Except in simple cases, therefore, sodium borohydride is the reagent of
choice. Typical examples are:
In rigid ring systems, the stereochemistry of hydride reduction appears
to be determined usually be the relative importance of competing influence;
steric hindrance to the approach of the reagent, and the stability of the final
product. Unless steric effects are particularly severe, the latter factor
dominates; for example, 10 –methyl-2-decalone-gives mainly the more stable
equatorial alcohol, although this involves approach of the reagent from the
more hindered side;
[4]Cannizarro reaction.
Aldehydes which do not have α-CH groups cannot undergo base-catalyzed
condensation. Instead they react with bases by disproportionation involving the
transfer of hydride ion e.g.
Crossed Cannizarro reaction between one such aldehyde and formaldehyde
result in the reduction of the former and the oxidation of the latter, for
formaldehyde is more reactive than other aldehyde toward nucleophiles and
rapidly gives a high concentration of the donor anion:
This fact can be exploited for reduction .For example, benzaldehyde is
reduced to formaldehyde in the presence of potash in refluxing methanol to
give 80% of benzyl alcohol. The preparation of pentaerthritol from
acetaldehyde and formaldehyde is also dependant on a crossed Cannizarro
reaction.
[5]Meerwein-Ponndorf-Verley reaction
This reaction is the reverse of the Oppenauer oxidation: equilibrium is
established between the carbonyl group to be reduced and isopropanol on the
one hand, and the required alcohol and acetone on the other hand, in the
presence of aluminium iso-peroxide .Since acetone is the lowest boiling
constituent of the mixture, it can be continuously distilled so that the
equilibrium is displaced to the right.
For example, trichloroacetaldehyde to trichloroethanol in about 80% yield.
The reaction is specific to aldehydes and ketones; in particular, the olefinic
double bond is αβ-unsaturated aldehydes or ketones is not reduced [compare
lithium aluminium hydride. However, the basic conditions may bring about
side-reaction [as in the synthesis of reserpine]. Very hindered Grignards
reagent effect reduction in similar way.
[II]ELECTRON TRANSFER REAGENTS
These reagents are less selective than sodium borohydride and the
Meerwein-Ponndorf-Verley reagent; e.g., they also reduce the olefinic double
bond in αβ-unsaturated carbonyl compounds. Nevertheless, in simple cases
they are rapid and efficient; e.g., methyl n-amyl ketone is reduced by sodium
in ethanol to 2-heptanol in over 60% yield,
and n-heptaldehyde is reduced by iron in aqueous acetic acid to n-heptanol in
80% yield.
These reductions are stereoselective. In most cases, the
thermodynamically more stable alcohol predominates: for example , 2methylcyclohexanone gives mainly trans-2-methyl-cyclohexanol. The reason is
not fully understood, but one possibility is as follows: the metal transfers one
electron to the carbonyl group to form an anion-radical, this is protonated at
carbon fro the less hindered side, and the second electron is transferred to give
the [usually less stable] alkoxide ion. This reacts with more of the ketone by a
mechanism similar to that in the Meerwein-Ponndorf-Verley reduction above,
giving an equilibrium mixture favourable to the more stable alkoxide, so that
the final hydrolysis gives the more stable alcohol.
However, if the ketone is very reactive as a result of stain ,the rate of
the direct reduction may be so much greater than that of the attainment of the
final equilibrium that the less stable alcohol is formed predominantly ,as in the
reduction of camphor:
If the ketone contains at the α-position a substituent which is good leaving
group, the intermediate anion undergoes elimination:
Zinc is often used as the electron source in these reductions. For example, αhydroxycyclodecanone gives cyclodecanone in about 75% yield when treated
with zinc in mixture of hydrochloric and acetic acid at 75-80 oC
[C] PINACOLS.
In the absence of a proton-donor, electropositive metal reduce ketones
to pinacols via the dimerization of anion-radicals:
The standard procedure employs amalgamated magnesium with benzene a
solvent; the solid magnesium salt of the pinacol is formed and is hydrolyzed to
the pinacol. For example, acetone gives pinacol itself in 45% yield after 2
hours in refluxing benzene
The reaction is generally ineffective for aldehydes because they are too
readily reduced to alcohols. Pinacols may also be formed by photochemical
dimerization
[D] REDUCTION OF EPOXIDES,
[a]Lithium aluminum hydride
Epoxides are reduced to alcohols by lithium aluminium hydride. Since
epoxides are readily obtained from olefins , the overall reaction serves to
hydrate the olefin. The procedure is complementary to the hydroboration
method since the hydride selectively attacks the less alkylated carbon of the
epoxide ring, so giving the more alkylated alcohols
The reaction has the trans stereochemistry characteristics of S N2
reaction. Thus, in a rigid cyclic systems the axial alcohol is formed, e.g.,
This therefore complements the methods for obtaining the equatorial
alcohol by reduction of the corresponding ketone with electron-transfer
reagents.
The stained ring in four-membered cyclic ether is also cleaved by lithium
aluminium hydride e.g.,
But the near-stainless five-membered ethers are resistant. They are
however, opened in the more vigorous conditions obtained by using lithium
aluminium hydride in the presence of the aluminium trichloride e.g.,
tetrahydrofuran gives n-butanol:
[b]Hydroboration
Epoxide are reduced by diborane to give mainly the less substituted
alcohols e.g.,
The method is therefore complementary to the use of lithium aluminium
hydride.
With 1-alkylcycloalkane epoxide, the main product is the cisdisubstituted alcohol, e.g.,
This therefore complements the reaction of the 1-alkycyclohexames with
diborane followed by alkaline hydrogen peroxide, which yields the trans
product.