Hydratropic Aldehyde Synthesis Approaches

[G.Patton]

Introduction​

In this topic, there are two the simplest methods of hydratropic aldehyde (2-Phenylpropanal) synthesis, which is direct P2P (phenylacetone; BMK) precursor. In these methods common reagents as benzene, 2-Chloropropanal and Ethyl methylphenylglycidate are used to make hydratropic aldehyde with pretty hight yields. Both of them need simple glassware and equipment, which is easy to get.​

Hydratropic Aldehyde (2-Phenylpropanal) in a Beaker​

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Hydratropic Aldehyde Synthesis From Benzene and 2-Chloropropanal​

Difficulty rating: 2/10

Equipment and glassware:

• Round bottom flask 2 L (preferably with two necks);
• Reflux condenser;
• Magnetic stirrer with heating plate;
• Funnel;
• Spatula;
• Laboratory scale (0.1 g-200 g is suitable);
• Measuring cylinders 100 ml and 20 ml;
• Beakers 2 L; 500 ml x2; 100 ml x4; 50 ml x3;
• Pipette;
• Drip funnel 100 ml;
• Laboratory grade thermometer (0 °C to 100 °C) with flask adapter;
• Retort stand and clamp for securing apparatus;
• Separating funnel 2000 ml;
• pH indicator papers;
• Pyrex dish or similar;
• Buchner flask and funnel;
• Vacuum pump;
• Round-bottom flask 50 mL;
• Magnetic stirrer with stir bar;
• Separatory funnel;
• Ice bath;
• Rotovap or distillation setup (optional);

Reagents:

• Benzene 20 mL;
• 2-Chloropropanal 0.005 mmol, ~0.37 g CAS 683-50-1;
• Aluminum chloride (AlCl₃, anhydrous) 7 mmol (~0.94 g);
• Dichloromethane (DCM, dry) 20 mL;
• Hydrochloric acid 10% (HCl) 15 mL;
• Saturated brine solution (NaCl) 15 mL;
• Anhydrous sodium sulfate (Na₂SO₄);

Hydratropic Aldehyde Synthesis From Benzene and 2-Chloropropanal Scheme​

Hydratropic Aldehyde Synthesis From Benzene and 2-Chloropropanal
1. In a 50 mL round-bottom flask, add aluminum chloride (0.94 g, 7 mmol) to 20 mL of dry dichloromethane (DCM).
2. While maintaining the temperature at 0°C (ice bath), slowly add 2-chloropropanal (0.37 g, 5 mmol) to the reaction mixture.
3. Gradually add 20 mL of dry benzene at 0°C. Keep stirring the mixture continuously.
4. After adding all the reactants, allow the temperature to rise to room temperature (25°C).
5. Stir the reaction mixture for 2 hours to ensure completion.
6. Quenching the reaction is carried out by slowly adding of hydrochloric acid 10% 15 mL solution to decompose the aluminum chloride complex.
7. Transfer the mixture into the separatory funnel and separate the organic phase (dichloromethane layer).
8. Wash the organic phase twice with 15 mL of saturated brine solution.
9. Dry the organic phase over anhydrous sodium sulfate.
10. Then, distill off the solvent. Hydratropic aldehyde can be purified by distillation.​

Yield is ~65%-68%​

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Hydratropic Aldehyde Synthesis From Ethyl Methylphenylglycidate​

Difficulty rating: 2/10

Equipment and glassware:

• Pear shaped flask 50 ml;
• Reflux condenser;
• Magnetic stirrer with heating plate;
• Funnel;
• Spatula;
• Laboratory scale (0.1 g-200 g is suitable);
• Measuring cylinders 10 ml and 50 ml;
• Beakers 100 ml x2; 50 ml x3;
• Pipette;
• Drip funnel 100 ml (optional);
• Laboratory grade thermometer (0 °C to 150 °C);
• Retort stand and clamp for securing apparatus;
• Separating funnel 250 ml;
• pH indicator papers;
• Filter paper;
• Vacuum pump;
• Rotovap or distillation setup (optional);

Reagents:

• Ethyl methylphenylglycidate 3.2065 g, 15.55 mmol CAS 77-83-8;
• Sodium hydroxide solution 40% (w/w) 7.0 mL, 8.4 g;
• Water 25 mL;
• Hydrochloric acid 32% w/w (HCl aq);
• Sodium carbonate water solution Na2CO3;
• Dichloromethane (DCM) 45 mL;
• Anhydrous sodium sulfate (Na₂SO₄);

Hydratropic Aldehyde Synthesis From Ethyl methylphenylglycidate Scheme​

1. Ethyl methylphenylglycidate (3.2065 g, 15.55 mmol) is slowly added to 40% (w/w) sodium hydroxide water solution (7.0 mL, 8.4 g) at 23°С with the constant stirring in 50 ml pear shaped flask equipped with reflux condenser.​

2. Then, the reaction mixture is heated up to 110°С.
3. After 30 min, water 25 mL is slowly added and heated for 15 min before cooling to 23°С.
4. Next, the reaction mixture is acidified by 32% w/w hydrochloric acid (HCl), neutralised by saturated Na2CO3 aq solution and extracted with DCM 3 x 15 mL.
5. The DCM layer is dried over anhydrous Na2SO4.
6. After that, the reaction solution is filtered and the solvent is removed under vacuum to provide crude hydratropic aldehyde as a yellow-green oil 2.3638 g (yield is 88%). Hydratropic aldehyde can be purified by distillation.

Sources​

• @Ranof ‘s method; <<== Special thanks indeed from BB Forum community to this guy.​
• Biddle, Timothy J., et al. "Potential forensic markers from synthetic pathways to 1-phenyl-2-propanone from uncontrolled and controlled substances." Forensic Chemistry 28 (2022): 100410. https://www.sciencedirect.com/science/article/abs/pii/S2468170922000133​