Reactions of synthetic

importance
Prepared By:
Nadim M R Chhipa
Associate Professor
ASP & BRI, ADALAJ
Content

 Metal hydride reduction (NaBH4 and LiAlH4),

 Clemmensen reduction
 Birch reduction
 Wolff Kishner reduction
 Oppenauer-oxidation
 Dakin reaction
 Beckmanns rearrangement
 Schmidt rearrangement
 Claisen-Schmidt condensation
Metal hydride reduction (NaBH4 and LiAlH4),

 The most common sources of the hydride Nucleophile are lithium aluminum
hydride (LiAlH4) and sodium borohydride (NaBH4).
 Note! The hydride anion is not present during this reaction; rather, these
reagents serve as a source of hydride due to the presence of a polar metal-
hydrogen bond. Because aluminum is less electronegative than boron, the Al-H
bond in LiAlH4 is more polar, thereby, making LiAlH4 a stronger reducing agent.
Metal hydride reduction (NaBH4 and LiAlH4),

 But if both a double bond and carbonyl group is present in a structure, the
double bond may be hydrogenated, leaving the carbonyl intact or both may be
hydrogenated.
Metal hydride reduction (NaBH4 and LiAlH4),

 However, the carbonyl group cannot be catalytically hydrogenated

independently of the carbon-carbon double bond. Now to reduce a carbonyl
group and leaving a carbon-carbon double bond intact, a Metal Hydride
Reduction is the preferred method of choice.

 Hydrogen gas is inexpensive, however a hydrogenation reaction is rather

inconvenient because the apparatus usually consist of gas tanks and a metal
pressure vessel. Therefore, the use of metal hydrides are the preferred
alternative reducing agents.
Metal hydride reduction (NaBH4 and LiAlH4),

 Addition of a hydride anion (H:-) to an aldehyde or ketone gives an alkoxide

anion, which on protonation yields the corresponding alcohol. Aldehydes
produce 10-alcohols and ketones produce 20-alcohols.
Metal hydride reduction (NaBH4 and LiAlH4),

 Addition of a hydride anion (H:-) to an aldehyde or ketone gives an alkoxide

anion, which on protonation yields the corresponding alcohol. Aldehydes
produce 10-alcohols and ketones produce 20-alcohols.
Metal hydride reduction (NaBH4 and LiAlH4),

 It reacts violently with water by producing hydrogen gas. Hence it should

not be exposed to moisture and the reactions are performed in inert and
dry atmosphere. The reaction must be carried out in anhydrous non
protic solvents like diethyl ether, THF etc. It is highly soluble in diethyl
ether.

 LiAlH4 is prepared by the reaction of lithium hydride (LiH) with aluminium

chloride (AlCl3).
 Sodiumborohydride is prepared by the reaction of sodium hydride (NaH) with
trimethylborate, B(OMe)3
Metal hydride reduction (NaBH4 and LiAlH4),

 LiAlH4 is a powerful reducing agent that reduces not only aldehydes and
ketones, but also carboxylic acids, esters, amides, and nitriles.

 LiAlH4 undergoes violent reaction with water, therefore reductions are usually
carried out in a solvent such as anhydrous ether.

 Neither NBH nor LAH reduces isolated carbon-carbon double bonds, although
C═C in conjugation with a carbonyl group is sometimes attacked. Consequently,
a structure that contains both a double bond and a carbonyl group can often be
reduced selectively at the carbonyl position. In this respect, metal hydrides are
complementary to the hydrogen gas as reducing agents.
Metal hydride reduction (NaBH4 and LiAlH4),
Metal hydride reduction (NaBH4 and LiAlH4),
 Reaction Mechanism for LiAlH4 Reduction:
Metal hydride reduction (NaBH4 and LiAlH4),
 Reaction Mechanism for LiAlH4 Reduction:
Metal hydride reduction (NaBH4 and LiAlH4),
Metal hydride reduction (NaBH4 and LiAlH4),

 NBH is a milder reducing agent than LAH. Its reactions can be carried
out in water or aqueous alcohol as a solvent. For the reduction of
aldehyde or ketone, NaBH4 is the preferred reagent; it is certainly
more convenient to use because of its lower reactivity towards water.

 NaBH4 reduces aldehydes and ketones rapidly while it reduces esters

slowly. Therefore, an aldehyde or ketone carbonyl group can be reduced
without the simultaneous reduction of an ester group in the same
molecule. This selectivity is not possible with LAH.
Metal hydride reduction (NaBH4 and LiAlH4),
 Reaction Mechanism for NaBH4 Reduction:
 UNIT – V: Reactions of Synthetic Importance BP401T: PHARMACEUTICAL ORGANIC CHEMISTRY –III

- Why does LiAlH4 reduce esters, amides, or carboxylic acids, while NaBH4 cannot reduce them?
 Carboxylic acids and esters are much less reactive to reduction than are ketones and aldehydes and sodium-
borohydride, NaBH4 (aq) is too weak a reducing agent for them.
 NaBH4 is preferred for aldehydes and ketones because it does not react violently with H2O, the way LiAlH4
does and can be used as an aqueous solution, whereas the LiAlH4 must be delivered in an anhydrous solution of
diethyl-ether, Et2O, and then neutralized by water and acid to isolate the product/s. But, ultimately, LiAlH4
can be used for all of these reactions.

Sodium borohydride Lithium aluminium hydride

Boron being part of second period makes shorter and Aluminium being part of third period makes longer and
stronger bond with hydrogen weaker bond with hydrogen.

The B-H bond of NaBH4 has more covalent character The Al-H bond has more ionic character in LiAlH4

It is less reactive It is more reactive

It is a weak base It is a stronger base

Lecturer Notes_Dr. Sumanta Mondal_B. Pharm IV Sem_ GITAM (Deemed to be University) 14

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 UNIT – V: Reactions of Synthetic Importance BP401T: PHARMACEUTICAL ORGANIC CHEMISTRY –III
Metal hydride reduction (NaBH4 and LiAlH4); Clemmensen reduction; Birch reduction; Wolff Kishner reduction;
Oppenauer-oxidation reaction; Dakin reaction; Beckmanns rearrangement reaction; Schmidt rearrangement
reaction; Claisen-Schmidt condensation

 Claisen–Schmidt Condensation Reaction

- The reaction between an aldehyde or ketone having an alpha-hydrogen with an aromatic carbonyl compound
lacking an alpha hydrogen is called the Claisen–Schmidt condensation.
- In cases where the product formed still has reactive alpha hydrogen and a hydroxide adjacent to an aromatic ring,
the reaction will quickly undergo dehydration leading to the condensation product.

- Enolate ions are formed when molecules with hydrogens alpha to a carbonyl group are treated with a base like
sodium hydroxide. For example, acetone reacts with base to give an enolate.

Claisen-Schmidt condensation reaction

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Claisen-Schmidt condensation
 UNIT – V: Reactions of Synthetic Importance BP401T: PHARMACEUTICAL ORGANIC CHEMISTRY –III

 Oppenauer Oxidation Reaction

- The Oppenauer oxidation is an organic reaction used to convert a primary or secondary alcohol to a ketone using
another excess ketone reagent (such as acetone) and an aluminium triisopropoxide catalyst.
- Oppenauer oxidation, named after Sir Rupert Viktor Oppenauer

- Reaction Mechanism:

(1) Coordinates to the aluminium to form a complex.

(3) Which then, in the second step, gets deprotonated by an alkoxide ion
(4) To generate an alkoxide intermediate
(5) In the third step, both the oxidant acetone
(7) The substrate alcohol are bound to the aluminium. The acetone is coordinated to the aluminium which
activates it for the hydride transfer from the alkoxide. The aluminium-catalyzed hydride shift from the
α-carbon of the alcohol to the carbonyl carbon of acetone proceeds over a six-membered transition state
(8) The desired ketone
(9) is formed after the hydride transfer

Aluminium isopropoxide

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 UNIT – V: Reactions of Synthetic Importance BP401T: PHARMACEUTICAL ORGANIC CHEMISTRY –III

 Dakin Reaction
- Dakin Reaction is the replacement of the aldehyde group of ortho and para hydroxy and ortho amino-
benzaldehyde (or ketone) by a hydroxyl group on reaction with alkaline hydrogen peroxide.

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 UNIT – V: Reactions of Synthetic Importance BP401T: PHARMACEUTICAL ORGANIC CHEMISTRY –III

 Beckmann Rearrangement Reaction

- The Beckmann rearrangement is an organic reaction used to convert an oxime to an amide under acidic
conditions.

- Reaction mechanism

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 UNIT – V: Reactions of Synthetic Importance BP401T: PHARMACEUTICAL ORGANIC CHEMISTRY –III

IMINE
 An imine is a functional group or chemical compound containing a carbon–nitrogen double bond.

Imine
 A primary imine in which C is attached to both a hydrocarbyl and a H is called a primary aldimine.
 A secondary imine with such groups is called a secondary aldimine.
 A primary imine in which C is attached to two hydrocarbyls is called a primary ketimine; a secondary imine
with such groups is called a secondary ketamine.

Primary aldimine Secondary aldimine Primary ketimine Secondary ketimine

AZIDE
 Azide is the anion with the formula N3−. It is the conjugate base of hydrazoic acid (HN3). N3− is a linear anion.
 The dominant application of azides is as a propellant in air bags.

ENAMINE
- An ENAMINE is an unsaturated compound derived by the condensation of an aldehyde or ketone with a
secondary amine

OXIME
- An oxime is a chemical compound belonging to the imines, with the general formula RR'C=NOH, where R is an
organic side-chain and R' may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime.

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 UNIT – V: Reactions of Synthetic Importance BP401T: PHARMACEUTICAL ORGANIC CHEMISTRY –III
 Schmidt Rearrangement
- The Schmidt reaction is an organic reaction in which an azide reacts with a carbonyl group to give an amine or
amide, with expulsion of nitrogen.
- It is named after Sir Karl Friedrich Schmidt.
- Reaction Mechanism

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 UNIT – V: Reactions of Synthetic Importance BP401T: PHARMACEUTICAL ORGANIC CHEMISTRY –III

 Birch Reduction
- The reduction of aromatic substrates with alkali metals, alcohol in liquid ammonia is known as "Birch reduction".
- This reaction is named after a Australian chemist Sir Arthur John Birch.
- The Birch reduction is an organic reaction where aromatic rings undergo a 1,4-reduction to provide unconjugated
cyclohexadienes.
- The reduction is conducted by sodium or lithium metal in liquid ammonia and in the presence of an alcohol.
- The mechanism begins with a Single Electron Transfer (SET) from the metal to the aromatic ring, forming a
radical anion.
- The anion then picks up a proton from the alcohol which results in a neutral radical intermediate. Another SET,
and abstraction of a proton from the alcohol results in the final cyclohexadiene product and two equivalents of
metal alkoxide salt as a by-product.

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 UNIT – V: Reactions of Synthetic Importance BP401T: PHARMACEUTICAL ORGANIC CHEMISTRY –III

 Clemmensen Reduction Reaction

- Clemmensen reduction is a chemical reaction described as a reduction of ketones (or aldehydes) to alkanes using
zinc amalgam and hydrochloric acid.
- Clemmensen reduction is an organic reduction reaction shown by both aldehydes and ketones, But Carboxylic acid
(-COOH) group can't be reduced by this method (but the -COOH group can be reduced by treating it with soda
lime [NaOH+ CaO] and then heating).
- Here, C=O group of aldehydes and ketones is reduced to -CH2- by clemmensen reduction. Zinc amalgam and
concentrated hydrochloric acid (Zn(Hg)/conc. HCl ) is used as the reagent for Clemmensen reduction. (Note By:
alkenes and alkynes don't react with clemmensen reagent.)

- Clemmensen reduction of ethanal: Ethanal is an aldehyde. Ethanal is reduced to ethane by Clemmensen

reduction. Zinc amalgam and concentrated HCl is used as the Clemmensen reducing reagent. Ethane is an alkane
compound.

- Clemmensen reduction of Propanal: When propanal and Zn(Hg)/conc. HCl react, propane is given as the
product. Propane also an alkane.

- Clemmensen reduction of propanone: Propanone gives propane as the product with Zn(Hg)/conc. HCl. Propane
is an alkane compound.

- Benzaldehyde and Clemmensen reduction: Methylbenzene (toluene) is given when benzaldehyde is reacted with
Zn(Hg) / concentrated HCl.

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- An AMALGAM is an alloy of mercury with another metal, which may be a liquid, a soft paste or a solid,
depending upon the proportion of mercury. These alloys are formed through metallic bonding, with the
electrostatic attractive force of the conduction electrons working to bind all the positively charged metal ions
together into a crystal lattice structure. Almost all metals can form amalgams with mercury, the notable exceptions
being iron, platinum, tungsten, and tantalum. Silver-mercury amalgams are important in dentistry, and gold-
mercury amalgam is used in the extraction of gold from ore.

Preparation of zinc amalgam

- Reaction Mechanism

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 UNIT – V: Reactions of Synthetic Importance BP401T: PHARMACEUTICAL ORGANIC CHEMISTRY –III

 Wolff Kishner Reduction Reaction

- The reduction of aldehydes and ketones to alkanes. Condensation of the carbonyl compound with hydrazine
forms the hydrazone, and treatment with base induces the reduction of the carbon coupled with oxidation of the
hydrazine to gaseous nitrogen, to yield the corresponding alkane.
- Reaction of Aldehydes or Ketones with Hydrazine Produces a Hydrazone.

- Reaction with a Base and Heat Converts a Hydrazone to an Alkane

- Both Reactions Together Produces the Wolff-Kishner Reduction

- The Wolff-Kisher reduction is used to convert ketones to methylene groups, and aldehydes to methyl groups. It
cannot be used to reduce the carbonyl groups of amides and esters.
- Wolff-Kishner vs. Clemmensen Reductions
 Clemmensen reduction is done for aldehyde or ketones in presence of Zn-Hg (Zinc amalgam)/Conc. HCl to
form alkane. This reaction occurs on the zinc metal surface. There are two types of mechanism for these
reactions. A. Cabanionic mechanism, B. Cabenoid mechanism.
 WOlff-Kishner reduction is also for aldehyde/ ketones in presence of hydrazine (N2H4),KOH,H2O and 180 °C
temperature to form alkane.

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 UNIT – V: Reactions of Synthetic Importance BP401T: PHARMACEUTICAL ORGANIC CHEMISTRY –III

- Mechanism of the Wolff-Kishner Reduction

Step 1: Deprotonation of Nitrogen

Step 2: Protonation of the Carbon

Step 3: Deprotonation of Nitrogen

Step 4: Protonation of Carbon

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