CHEM-332

Rahman S. Z. Saleem
Department of Chemistry & Chemical Engineering, SBASSE
Lahore University of Management Sciences

Lecture

07
Sep 26, 2019
 Addition of Organometallic Reagents to Aldehydes & Ketones
(organolithium & organomagnesium)

Li-C and Mg-C bonds in organolithium and organomagnesium reagents are highly polarized due
to electropositive nature of metals.
 Addition of Organometallic Reagents to Aldehydes & Ketones
(organolithium & organomagnesium)

2 steps

Low temp.

Aprotic solvent

What if it is present in the beginning?

The addition of water, or sometimes dilute acid or ammonium chloride, at the end of the
reaction is known as the work-up
 Addition of Organometallic Reagents to Aldehydes & Ketones

PhLi & nBuLi are other common commercially available organolithium compounds
Addition to aldehyde and ketone results in secondary & tertiary alcohol respectively.

Organomagnesium reagents are called Grignard’s reagents

Grignard’s reagents also react similarly with aldehydes and ketones to form C-C bond.
 Addition of Organometallic Reagents to Aldehydes & Ketones

organolithiums and organomagnesiums are strong bases as well as powerful nucleophiles

• Addition of organometallic reagents cannot be used with molecules that contain both a carbonyl
group and N—H or O—H bonds.

• Carbonyl compounds that also contain N—H or O—H bonds undergo an acid-base reaction with
organometallic reagents, not nucleophilic addition.
 Addition of Water to Aldehydes and Ketones

Weak nucleophiles may also attack the carbonyl carbon but the reaction is reversible and the
equilibrium position depends on the structure of carbonyl compound.
 Addition of Water to Aldehydes and Ketones

sp3 orbital of oxygen and π* of carbonyl group are involved in the interaction

Sterics play critical role in the position of the equilibrium

sp2 (120⁰) sp3 (109⁰)

Formaldehyde having no bulky group reacts rapidly with water & the equilibrium lies more
towards the right side. The aqueous solution of formaldehyde exists as a hydrated polymer.
Problem in water sensitive reactions???
Thermal cracking of
paraformaldehyde
to give
formaldehyde
 A problem to solve

Checking purity of the compounds before setting up the reactions is very important

Trichloroacetaldehyde (chloral) Chloral hydrate- a crystalline stable product

 Addition of Water to Aldehydes and Ketones

Steric hindrance & more alkyl substituents make carbonyl compounds less reactive towards Nu:

How about the ring size?

VS

small ring size make them more reactive

 Addition of Alcohol to Aldehydes and Ketones

Like water, alcohols also add to aldehydes and ketones to form hemiacetal/hemiketal or
acetal/ketal. The reaction is catalyzed both by acids and bases & it is a reversible reaction.
 Addition of Alcohol to Aldehydes and Ketones

Intramolecular addition is also possible to form cyclic hemiacetals.

Cyclic hemiacetals are more stable.

Stability depends on the ring size (6,5 membered vs 3,4-membered)

in solution
 Cyclic Acetals – Common Examples

In solution, fructose exists as an equilibrium mixture of 70% fructopyranose and about 22%
fructofuranose, as well as small amounts of three other forms, including the acyclic structure
 Addition of Alcohol to Aldehydes and Ketones – Acid Catalysis

We have seen alcohol act as base and then acid as:

Strong acids or strong bases increase the rate of hemiacetal or hydrate formation because they
allow these proton-transfer steps to occur before the addition to the carbonyl group.
 Addition of Alcohol to Aldehydes and Ketones – Base Catalysis

Base deprotonates the alcohol to increase into nucleophilicity

For nucleophilic additions to carbonyl groups:

• Acid catalysts work by making the carbonyl group more electrophilic
• Base catalysts work by making the nucleophile more nucleophilic
Cyclic Acetals/Ketals as Protecting Groups
Some Common Protecting Groups
 Addition of Bisulfite to Aldehydes and Ketones

The lone pair of electron on sulfur attacks the carbonyl carbon of aldehydes and ketones to form
a crystalline bisulfite-addition compound.

The reaction is reversible like the addition of other weak nucleophiles

 Bisulfite Adducts as Intermediates for Other Compounds

Due to the reversible nature of such reactions and the crystalline nature of adducts (that can be
hydrolyzed to aldehyde and ketones), these adducts are used to
• purify such carbonyl compounds and
• as intermediates in the reactions of carbonyl compounds

In this way no dangerous HCN is released as would have happen in direct cyanohydrin formation
in the presence of acids.
 Making Dapsone – An Antileprosy Drug Water Soluble

difficult to work Water soluble

with as monomer monomeric form
Rongalite (trade mark name by BASF)

Formaldehyde reacts with sodium bisulfite to form a crystalline addition product which reacts
with Dapsone to make it water soluble.
Nucleophilic addition of hydrazine: Wolff Kishner reduction
Nucleophilic addition of hydrazine: Wolff Kishner reduction