Amphetamine Synthesis From 2-Methyl-3-phenylpropanamide By Hofmann Rearrangement
Introduction
The Hofmann rearrangement is an organic reaction used to convert a primary amide to a primary amine using a halogen, base, water and heat. The reaction begins with deprotonation of the amide by the base to form an anion which then attacks the halogen to form N-haloamide. A second deprotonation by the base provides an anion that rearranges to an isocyanate intermediate and releases a halide anion. The isocyanate is then attacked by water which after a series of proton transer step results in a zwitterionic intermediate, containing ammonium cation and a carboxilate anion. Thermal conditions result in the explosion of carbon dioxide gas and quenching of ammonium cation to the amine product.
Difficulty rating: 3/10
Equipment and glassware:
- Two neck round bottom flask 2 L;
- Reflux condenser;
- Chlorine Cl2 gas making kit [watch video];
- Silicon hoses;
- Ice water bath;
- Magnetic stirrer with heating plate/mantle;
- Funnel;
- Laboratory scale (0.1 g-200 g is suitable);
- Measuring cylinders 200, 100 and 20 ml;
- Beakers 2 L; 500 ml x2; 100 ml x4; 50 ml x3;
- Pipette;
- Laboratory grade thermometer (0 °C to 100 °C) with flask adapter;
- Separating funnel 2000 ml;
- pH indicator papers;
- Buchner flask and funnel;
- Vacuum pump;
- Rotary evaporator;
Reagents:
- 2-Methyl-3-phenylpropanamide 230 g [cas 7499-19-6];
- Cl2 gas 109 g;
- Sodium hydroxide NaOH 277 g;
- Distilled water 803 ml;
- Benzene 420 ml;
- Concentrated hydrochloric acid (HCl 35-37%) 148 g;
- Sodium hydroxide aq solution 30% (NaOH);
Amphetamine Synthesis Steps From 2-Methyl-3-phenylpropanamide
1. 2-Methyl-3-phenylpropanamide 230 g (m.p. 107-108.4°C) [cas 7499-19-6] is added to sodium hypochlorite solution in 2 L two neck round bottom flask, made by passing 109 g of Cl2 gas [watch video] into a solution of NaOH 277g in 453 ml of distilled water.
2. The reaction mixture is held at 0°C for one hour.
3. It is then slowly heated to 18°C at which point considerable heat was given off and the solid went into solution.
4. After the temperature came back under control, the solution is heated to 58°C whereupon the rearrangement occurred.
5. The heating is continued until 70°C was reached.
6. The solution is cooled, the oil layer is separated and the water solution is extracted with benzene using 60 ml x 3.
7. The benzene extract is combined with amphetamine oil and the solution is washed twice with 50 ml x 3 portions of water and 148 g of concentrated HCl acid (35-37%) slowly added to it.
8. The amphetamine hydrochloride acidic solution is washed twice with 30 ml benzene.
9. The amphetamine was then basified with NaOH 30% aq solution to pH 12.
10. The basified amphetamine is extracted from water three times with 60 ml portions of benzene.
11. The benzene solution is washed twice with 100 ml of water, dried over anhydrous Na2SO4 and then vacuum distilled.
2. The reaction mixture is held at 0°C for one hour.
3. It is then slowly heated to 18°C at which point considerable heat was given off and the solid went into solution.
4. After the temperature came back under control, the solution is heated to 58°C whereupon the rearrangement occurred.
5. The heating is continued until 70°C was reached.
6. The solution is cooled, the oil layer is separated and the water solution is extracted with benzene using 60 ml x 3.
7. The benzene extract is combined with amphetamine oil and the solution is washed twice with 50 ml x 3 portions of water and 148 g of concentrated HCl acid (35-37%) slowly added to it.
8. The amphetamine hydrochloride acidic solution is washed twice with 30 ml benzene.
9. The amphetamine was then basified with NaOH 30% aq solution to pH 12.
10. The basified amphetamine is extracted from water three times with 60 ml portions of benzene.
11. The benzene solution is washed twice with 100 ml of water, dried over anhydrous Na2SO4 and then vacuum distilled.
Conclusion
The yield is 131 g of purified amphetamine free base [b.p. 105°C at 30 mm Hg], which is 69% of theoretical yield. Amphetamine free base can be converted into amphetamine sulphate in accordance with steps 9-12 of the method.
Source
- United states patent 2,413,493 https://patents.google.com/patent/US2413493A/en
This is why their law shit is so fucking stupid.
