Reaction of 4-nitrobenzaldehyde and dimedone

Written by J.A Dobado | Last Updated on April 22, 2024

Objective

To perform a tandem aldol condensation / Michael addition reaction using an organocatalyst and to learn how to recover the organocatalyst.

Background

Organocatalysts are small organic molecules that can catalyze reactions in the absence of metals or metal ions. Proline is a chiral organic compound that can be used as a catalyst in many reactions such as aldol condensation, Mannich reactions, or Michael additions, and it should attach itself at more than one point in a symmetrical compound. Proline is nontoxic, inexpensive, and readily available in both enantiomeric forms. Reactions with proline do not require inert conditions, as do so many organometal catalysts, and most reactions carried out with this compound can be at r.t. Proline is an example of organocatalyst as a green alternative to classic organocatalysts.

On the other hand, one of the fields of interest of Green Chemistry is the use of low-environmental-impact solvents. In this sense, Polyethylene glycol (PEG-400) is a non-volatile and non-flammable solvent that possesses remarkable properties, such as recyclability, ease of work-up, thermal stability, and low cost. In addition, the solvating capability of PEG-400 often makes a reaction system homogeneous, allowing molecular interactions to be more efficient. Under the proposed reaction conditions, 4-nitrobenzaldehyde (1 mol) reacts with dimedone (2 mol). In the first step, a Knoevenagel condensation occurs, when proline reacts with the aldehyde to form an enamine to give the condensation product. In a next step, a second molecule of dimedone is added to the double bond by a Michael addition yieding 2,2′-[(4-Nitrophenyl)methylene]bis(3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one).

Experimental procedure

In a 25 ml round-bottom flask, equipped with a stir bar, place 4-nitrobenzaldehyde (151 mg, 1 mmol), 5,5-dimethylcyclohexane-1,3-dione (dimedone, 280 mg, 2 mmol), (±)-proline (57 mg, 0.5 mmol), and PEG-400 (2 ml); an automatic-delivery pipette is recommended. Stir the reaction mixture with a stirring plate for 30 min at r.t., checking the reaction by TLC (hexane/ethyl acetate, 2:1, spot visualization by UV), and continue stirring for an additional 1 h. A new TLC plate will indicate whether the reaction is complete. Once the reaction is finished, remove the flask from the magnetic stirring plate and put it in an ice-cold water until a white precipitate is formed (about 10 min). Return the flask to the stirrer/hot plate and stir for 10 min (a white precipitate will form). Collect the solid by vacuum filtration using a Hirsch funnel, rinsing any residual product from the reaction flask with no more than 5 ml of ice-water bath to avoid resolubilization. The white solid is recrystallized from absolute EtOH to give 2,2′-[(4-Nitrophenyl)methylene]bis(3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one) (typical yields 30-80 %; m.p. = 188-190 ºC.

Catalyst-solvent recovery

PEG-400/(±)-proline mixture can be recycled after the reaction. Pour the filtrate from the vacuum filtration flask of the former step into a 50 ml round- bottom flask and evaporate the water using a rotary evaporator. The residue can be placed into a vial for future use.

Physico-chemical properties

This table collects data for the molecular weight (M_w), melting point (M.p.) boiling point (B.p.) and density of the reactives and compounds used in this laboratory experiment.

GHS pictograms

Hazard pictograms form part of the international Globally Harmonized System of Classification and Labelling of Chemicals (GHS) and are collected in the followinf Table for the chemical compounds used in this experiment.

Name	GHS
(±)-Proline	Non-hazardous
Dimedone	Non-hazardous
EtOH
Ethyl acetate
Hexane
PEG-400
4-Nitrobenzaldehyde

International Chemical Identifier

The IUPAC InChI key identifiers for the main compounds used in this experiment are provided to facilitate the nomenclature and formulation of chemical compounds and the search for information on the Internet for these compounds.

References

• Isac-García, J.; Dobado, J. A.; Calvo-Flores, F. G.; and Martínez-García, H. (2015). Experimental Organic Chemistry Laboratory Manual. Elsevier Science & Technology. ISBN: 978-0-12-803893-2
• Vogel, A.I., Furniss, B.S., Hannaford, A.J., Tatchell, A.R., and Smith, P.W.G. (1989). Vogel’s Textbook of Practical Organic Chemistry (Vogel’s Textbook series). Longman. ISBN: 9780470214145
• J. M. Stacey, A. P. Dicks, A. A. Goodwin, B. M. Rush, and M. Nigam, Green Carbonyl Condensation Reactions Demonstrating Solvent and Organocatalyst Recyclability, Journal of Chemical Education 90 (2013), no. 8, 1067–1070, DOI: 10.1021/ed300819r