Proline Catalyzed Aldol Reaction(Organo-catalysis)

By :

Hemanta Sarmah(09MS001)

Soumalya Sinha(09MS006)

Debtanu Chakraborty(09MS031)

Aldol Reaction :

It is the type of reaction that produces a β-hydroxy carbonylcompound from a mixture to two or more carbonyl compounds , inpresence of a suitable catalyst.

The catalyst could be either of the following:

Base or Acid

Other organic catalysts ( If the reaction is organocatalytic )

The product formed is called an aldol.

(Aldol = Aldehyde + Alcohol)

An example : (of Aldol Condensation)

Enol/enolate ion + a carbonyl compound β- hydroxyaldehyde /

β-hydroxyketone

What’s Organo-catalysis ?

Organocatalysis (or metal –free catalysis ) uses small organic molecules predominantly composed of C, H, O, N, S and P to accelerate chemical reactions.

In simple words, Organocatalysis refers to a form of catalysis, whereby the rate of a chemical reaction is increased by an organic catalyst.

For Example :

CH3CHOCN—CN ----------------> CO(NH2)—CO(NH2)

H2O (rt)

: PROS and CONS :

Advantages :

It gives us enantio-selective product

A very little amount( equivalent) of catalyst is needed to carry the reaction

Low cost

Lack of sensitivity to moisture and oxygen

No metal contamination

Multiple stereocenter formation

Disadvantages :

It’s no CHEMICAL STUNT ! Requires Time and patience

Slower than metal catalyzed reactions

Enantio-selective ! But why ?

Different enantiomers or diastereomers of a molecule often have different biological activity

Synthesis of chiral drugs : $18 billion annually (growing @ 9% p.a)

Predicted that 75% of the drugs will be sold as single enantiomers in the coming years.

One day-to-day life example :

How many of you still take Cetirizine or Cetirizine Hypochlorite ?

Today we have the levorotary enantiomer of cetirizine, known as levocetirizine, that is far more effective and less damaging to the body.

Enzyme

recognition

Natural Epinephrin(adrenaline)

UnnaturalEpinephrin

Organo-catalysts are generally low molecular weight compounds.

Basically they can be classified as chiral and achiral ones. Here are few:

Organo-catalysts are generally low molecular weight compounds.

Basically they can be classified as chiral and achiral ones. Here are few:

Our Project :

Aldol condensation of Cyclohexanone and Nitro-

substituted benzaldehyde in presence of L-Proline.

Materials Used : 15ml Glass Vial (for carrying out the reactions)

Round Bottom Flask

Magnetic Bead and Stirrer

Rotavapour (for removing excess solvent from solution)

Testube , Capillary tube, TLC film, pencil and scale

UV lamp

Apparatus for Flash Chromatography

Reagents Used :

Acetone

DMSO

Ethyl Acetate

Here’s the reaction ingredients !!

Starting Compound(s) :

Cyclohexanone 98.150 g/mol

3-nitro benzaldehyde 151.12 g/mol

4-nitro benzaldehyde 151.12 g/mol

Organocatalyst :

L-proline 115.13 g/mol

Solvent :

PtsOH 190.22 g/mol

Procedure:

In a vial, we mixed 7.61mg of L-Proline, 12.57mg of PtsOH,0.6613mmol(100mg) of 3-Nitrobenzaldehyde and 300 mg of Cyclohexanone all together.

In another vial, 0.6613mmol(100mg) of 4-Nitrobenzaldehyde was taken while all the other ingredients (of vial 1) were repeated with the exact amounts.

Now, both the vials were stirred with the magnetic bar for 3 days.

The solution was then run on a TLC plate and it resulted in formation of at least 3 distinct bands for both the reactions when viewed in UV light chamber.

To purify the product, Flash Chromatography was undertaken. All the products were isolated, solidified using Rotavapour and sent for NMR Spectroscopy.

(1)

Reaction of Cyclohexanone with 4-nitrobenzaldehyde

O

NO2C

O

H

Reaction Mechanism :

(2)

Reaction of Cyclohexanone with 3-nitrobenzaldehyde

O

C

O

H

No2

`

Calculations :

Sl.No

Substrate Formula wt. Mass(gm)

No. of milimoles

No. of equivalents

1 3-nitro benzaldehyde

151.12 100 0.6613 1

2 4-nitrobenzaldehyde

151.12 100 0.6613

Analysis with Chromatography :

TLC analysis :

1H NMR spectra for 4-nitrobenzaldehyde:

OOH

N+

O

O-

2.27;2.17

1.81;1.78

1.85;1.75

1.88;1.63

2.68

7.45 8.12

8.127.45

4.72

2.0

1H NMR spectra for 3-nitrobenzaldehyde:

Acknowledgements :

We are extremely grateful to

Dr. Debasish Haldar and

Dr. Jyotirmayee Dash for

having allowed us this

wonderful opportunity as a

part of the lab course.

Acknowledgements :

We are extremely grateful to Mr.

Sushovan Paladhi (PhD student)

and Mr. Ganesh Midya (PhD

student) for their immense help

and support throughout the

semester and specially during the

project tenure.

Thank you !!