Synthesis of n-butylbarbituric acid

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

Objective

To perform a two-step synthesis for the preparation of a derivative of barbituric acid. In the first step, the diethyl n-butylmalonate is prepared, which is subsequently reacted with urea in the presence of a strong base, such as NaOEt, to yield the desired compound.

Synthesis of n-butylbarbituric acid

Background

Barbiturates are drugs that are prescribed to treat severe nervous insomnia, some forms of epilepsy, and certain convulsive and psychological disorders. Structurally, they are derived from barbituric acid. They are legal substances of controlled prescription with drug action and addictive effects, and thus prescription is required for their sale. Their use leads to tolerance, and suppression causes the stop-eating syndrome. Ever since von Baeyer (Nobel Prize in Chemistry 1905) synthesized barbituric acid in 1863, which has no sedative effects, over 2,500 derivatives of the substance have been investigated. For a long period of time, barbiturates and opiates were the only substances available to relieve anxiety or agitation of some psychiatric patients.

Experimental procedure

A) Preparation of diethyl n-butylmalonate:

In a 100 ml flask place absolute EtOH (50 ml) and sodium (1.2 g). Cut sodium into small pieces or, if possible, use sodium wire. Adapt a reflux condenser and fit a drying tube. Stir, at the beginning, at r.t. (the reaction generates heat due to a strongly exothermic character), and if necessary gently heat until the sodium disappears. Cool to r.t. and then add 8 g of diethyl n-malonate. Stir for about 15 min, and add 7.5 g of 1-bromobutane. Put the mixture to reflux for 1.5 h. After the reflux time, transfer the reaction crude to a separatory funnel, sliding the remaining crude with 30 ml of water. Stir the mixture vigorously, decanting and separating the aqueous layer. Extract the aqueous layer with diethyl ether (2 × 10 ml). Combine the organic extracts in an Erlenmeyer, and dry over anhydrous sodium sulfate. The desiccant is removed by gravity filtration. Next, remove the solvent under reduced pressure (rotary evaporator). Distill the residue under vacuum. Take into account the difference in b.p. of diethyl n-malonate (199.3 ÂșC) and of ethyl n-butylmalonate (234–240 ÂșC) at atmospheric pressure.

DANGER! “Sodium reacts violently with water; therefore, all materials should be dry. At the beginning of the reaction, material projections and breaks in the flask may occur. Ensure that the ensemble (flask and reflux condenser) is firmly fixed with clamp and clamp holder.”

 

B) Preparation of n-butylbarbituric acid:

Pour 50 ml of absolute EtOH into a dry 250 ml round-bottom flask. Then add 0.46 g of sodium and adjust a reflux condenser. Maintain the mixture at r.t. until the complete dissolution of sodium. Add the solution of NaOEt formed at 4.32 g of ethyl n-butylmalonate dry, followed by a solution of 1.2 g of urea predried in 22 ml of absolute EtOH. Reflux the mixture for 2 h. Then stop the reflux, allow the crude to cool to r.t., and gradually acidify the reaction mixture with 20 ml of 10% HCl (check the pH (acidity) with indicator paper). After neutralization of EtONa, remove EtOH under reduced pressure; a precipitate will appear. Complete the crystallization by placing the flask in an ice bath. Collect crystals by vacuum filtering, and wash with hexane to remove the unreacted diethyl n-butylmalonate (detected by smell). Recrystallize the solid from water using a proportion of approximately 20 ml per gram of product. Weigh the product dry and calculate the yield.

Physico-chemical properties

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

Name Mw (g/mol) M.p. (ÂșC) B.p. (ÂșC) Density (g/ml)
1-Bromobutane137.02-112100-1041.276
Barbituric acid128.09248-252 - -
Diethyl ether74.12-11634.60.71
Diethyl malonate160.17-501991.055
Diethyl n-butylmalonate216.27 -235-2400.975
EtOH46.07-114.178.50.790
HCl 36.46-30>1001.200
Hexane86.18-95690.659
Na22.9997.88830.968
Na2SO4142.04884 -2.630
Urea 60.06132-135 -1.335

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
1-Bromobutane ghs02  Danger Warning Flammable pictogram ghs07  Warning Toxic cat. 4 Irritant cat. 2 or 3 Lower systemic health hazards pictogram ghs09  Warning (for cat. 1) (for cat. 2 no signal word) Environmental hazard pictogram
Barbituric acid Non-hazardous
Diethyl ether ghs02  Danger Warning Flammable pictogram ghs07  Warning Toxic cat. 4 Irritant cat. 2 or 3 Lower systemic health hazards pictogram
Diethyl malonate ghs07  Warning Toxic cat. 4 Irritant cat. 2 or 3 Lower systemic health hazards pictogram
Diethyl n-butylmalonate ghs05  Danger Warning Corrosive cat. 1 pictogram ghs02  Danger Warning Flammable pictogram
EtOH ghs02  Danger Warning Flammable pictogram
HCl ghs05  Danger Warning Corrosive cat. 1 pictogram ghs07  Warning Toxic cat. 4 Irritant cat. 2 or 3 Lower systemic health hazards pictogram
Hexane ghs02  Danger Warning Flammable pictogram ghs08  Danger Warning Systemic health hazards pictogram ghs07  Warning Toxic cat. 4 Irritant cat. 2 or 3 Lower systemic health hazards pictogram ghs09  Warning (for cat. 1) (for cat. 2 no signal word) Environmental hazard pictogram
Na ghs02  Danger Warning Flammable pictogram ghs05  Danger Warning Corrosive cat. 1 pictogram
Na2SO4 Non-hazardous
Urea ghs07  Warning Toxic cat. 4 Irritant cat. 2 or 3 Lower systemic health hazards pictogram

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.

1-BromobutaneMPPPKRYCTPRNTB-UHFFFAOYSA-N
Barbituric acidHNYOPLTXPVRDBG-UHFFFAOYSA-N
Diethyl etherRTZKZFJDLAIYFH-UHFFFAOYSA-N
Diethyl malonateIYXGSMUGOJNHAZ-UHFFFAOYSA-N
Diethyl n-butylmalonateRPNFNBGRHCUORR-UHFFFAOYSA-N
EtOHLFQSCWFLJHTTHZ-UHFFFAOYSA-N
HCl VEXZGXHMUGYJMC-UHFFFAOYSA-N
HexaneVLKZOEOYAKHREP-UHFFFAOYSA-N
NaKEAYESYHFKHZAL-UHFFFAOYSA-N
Na2SO4PMZURENOXWZQFD-UHFFFAOYSA-L
Urea XSQUKJJJFZCRTK-UHFFFAOYSA-N

References

Back to the Advanced Organic Synthesis Experiments page.

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