Laboratory-Scale Preparation Method of Cyclobutanone

English Name: Cyclobutanone

CAS No.: 1191-95-3

Synonyms: Cyclobutanone

Molecular Formula: C₄H₆O

Molecular Weight: 70.09

EINECS Number: 214-745-6

Solubility: Insoluble in water

Density: 0.938 g/mL at 25 °C (lit.)

Importance of Cyclobutanone in Pharmaceutical Intermediates

Cyclobutanone is an organic compound that plays a vital role in pharmaceutical chemistry. Due to its unique chemical structure, it is widely used as a key intermediate in the synthesis of various drugs, particularly antibiotics, antiviral agents, and anticancer drugs. Below are several key aspects highlighting the importance of Cyclobutanone in pharmaceutical intermediate applications:

This article introduces a laboratory method for the preparation of Cyclobutanone via the oxidation of cyclopropanol. The process uses oxalic acid and chromium trioxide as oxidants in an acidic aqueous medium, and the volatile product is captured through a condensation system. This method is suitable for small-scale laboratory synthesis and can yield high-purity cyclobutanone.

Procedure

1. Reaction Initiation

In a 2-liter, three-neck round-bottom flask equipped with a reflux condenser, add 250 mL of water, 48 mL of concentrated hydrochloric acid (approx. 0.55 mol), and 49.5 g of cyclopropanol (0.65 mol). Heat the mixture under reflux for about 100 minutes. The formation of cyclobutanol can be observed almost immediately, as it is only partially soluble in water and separates quickly.

2. Cooling and Condensation Setup

Place the flask in an ice bath. Install a mechanical stirrer, thermometer, and a dropping funnel using a three-way adapter. Replace the reflux condenser with a U-tube condenser immersed in a dry ice–ethanol bath to capture the volatile Cyclobutanone.

3. Addition of Oxalic Acid

To the flask, add another 48 mL of concentrated hydrochloric acid (approx. 0.55 mol) dissolved in 200 mL of water, followed by 440 g of oxalic acid dihydrate (approx. 3.5 mol). Stir the heterogeneous mixture for about 15 minutes until the solution becomes saturated with oxalic acid.

4. Oxidant Addition

While stirring, slowly add a solution of 162 g of chromium trioxide (approx. 1.62 mol) in 250 mL of water. Maintain the temperature between 10°C and 15°C (using a NaCl–ice bath, -5°C to -10°C) to ensure the gentle release of carbon dioxide. The addition should take 1.5 to 2 hours, during which the oxalic acid dissolves gradually, forming a deep blue solution of Cr(III) salts.

5. Introduction of Condensed Product

Before the oxidation completes (when about 10 mL of the chromium trioxide solution remains), pour the Cyclobutanone (possibly containing a small amount of cyclobutanol) collected in the U-tube condenser back

 into the reaction mixture.

6. Post-Reaction Stirring

Remove the ice bath and continue stirring for approximately 1 hour to allow the mixture to reach room temperature and reduce the amount of dissolved CO₂.

7. Extraction and Drying

Transfer the reaction mixture to a 2-liter separatory funnel and extract with four portions of 200 mL dichloromethane. Combine the organic layers (bottom phase), dry over anhydrous magnesium sulfate with a small amount of anhydrous potassium carbonate to remove traces of HCl, then filter.

8. Distillation and Purification

Concentrate the filtrate by vacuum distillation using a silver-plated insulated column (20 cm long, 1 cm inner diameter) packed with 2.3 mm glass helices and equipped with an adjustable distillation head. Heat until the pot temperature reaches 80°C. Transfer the crude product to a 100 mL flask and redistill using the same column at a 10:1 reflux ratio. Collect 14–16 g (0.20–0.23 mol) of Cyclobutanone , corresponding to a 31–35% yield based on pure cyclopropanol. The product boils at 98–99°C and reaches a purity of 98–99%, sufficient for most applications.