Amphetamine "White-Box" synthesis
Amphetamine synthesis using zinc is a classic method. Proton donors in these reactions are acids (hydrochloric, sulfuric, acetic), ammonium compounds (ammonium chloride and acetate), and in some cases, water. Zinc can also be substituted with other metals (such as iron, tin, or aluminum), but it possesses the highest reactivity.
All variations of this method are not designed for maximum yield or reaction speed, but are used when alternative reagents are unavailable (for synthesis via amalgam, expensive catalysts under high pressure, or due to certain complexities in reduction with sodium borohydride and metal salts.
Gradually, we will explore and highlight various variations of these classic methods, specifically focusing on the solvents used, optimal reaction conditions, catalysts, and scaling. We will begin our overview with a small-scale variation that is loosely similar to the classic amalgam method.
Reagents:
- 1-phenyl-2-nitropropene (P2NP) - 10g
- Isopropyl alcohol (IPA) - 100 mL
- Zinc dust (Zn) - 20g
- Food vinegar 70% ~70 mL
- Sodium hydroxide (NaOH) 25% aq. soln
- H2SO4 98%
Equipment:
- Beakers
- Syringe
- Magnetic stirrer
Synthesis of amphetamine:
1. We’re using a 250 mL beaker with a magnetic stir bar on a magnetic stirrer. We’re using the “White Box” setup in this case, so don’t be surprised by how we’re mixing the reaction mixture.2. We add 10g of P2NP to our beaker. It’s best if your P2NP is of good quality and appears crystalline. If your product looks like cotton candy, it may hinder effective mixing. In that case, it’s better to recrystallize it from alcohol to obtain a HQ precursor.
3. 100 mL of isopropyl alcohol (ethanol can also be used) was added and stirring was initiated. The stirring speed was adjusted to ensure the mixture was as homogeneous as possible without splashing. A synthesis protocol is possible without using alcohol in the reaction process, but more on that later.
4. Add 20g of zinc dust. It should be added in portions, and the stirring should not be stopped until the very end of the reaction to prevent the zinc from clumping. If the zinc dust has lumps before addition, it is better to crush them for improved reactivity. There are options to replace zinc with iron, tin, or aluminum powder (dust). However, zinc dust is the preferred choice.
5. We begin adding acetic acid. We could use glacial acetic acid, but in this case, we used 70% food-grade acetic acid. The presence of some water allows for better control of the reaction’s exotherm, and helps dissolve zinc derivatives that can passivate the activated metal surface.
This step is the most critical. At the beginning of the reaction, we need to add the acid in minimal portions, or the entire contents of the beaker will end up on all the walls of our “White Box.” The reaction can start quite quickly. Therefore, after each added portion of acid, we wait about a minute to control the heating and the amount of hydrogen produced.
You can check the heating by hand. When the beaker becomes warm to the touch, the reaction has started. If the beaker feels hot to the touch, you need to wait before adding the next portion. However, you should strive to maintain an acidic environment, ensuring that an excess of unreacted acid is always present in the mixture.
If you can use a thermometer, the acceptable temperature range is from 40 to 60 *C, with the latter being more optimal. However, the temperature can rise quite quickly, so aim to maintain around 50 degrees Celsius. Brief overheating to 70-80 *C may not be detrimental, but prolonged exposure to these temperatures can lead to byproducts and a reddish discoloration of the reaction mixture (though this doesn’t necessarily mean the product is ruined).
If you need to add small portions, remember that towards the middle of the reaction, not as much heat will be generated, and you can safely add the remaining required amount of acid. If possible, you can use an ice bath (preferably after the zinc has been activated, i.e., after the mixture has initially warmed up) and add all the necessary acid at once (approximately 70 mL for 70% food-grade acetic acid and approximately 50 mL for glacial acetic acid). However, if you use cooling in the subsequent process, you should ideally use heating or extend the stirring time. This method will be better. A method without cooling and with slow addition and stirring will give you the product, but you can achieve better quality with initial cooling and subsequent heating of the mixture.
6. After adding all the acid, the mixture becomes somewhat lighter in color. The zinc reacts, releasing hydrogen, and the P2NP is reduced to an amine through intermediate stages. At this point, if you want to minimize byproducts or incompletely reduced products, you should use additional stirring time or forced heating (no more than 60 *C) for several hours. The specific time depends on a number of parameters, making it difficult to say without analytical methods. However, you can base your decision on the change in the reaction color and the amount of reacted zinc.
Additionally, you can use litmus paper to monitor the acidity of the reaction mixture. The reaction mixture should be weakly acidic for complete reduction. If the mixture is neutral, it is advisable to add an additional excess of acid during the additional stirring or forced heating process.
7. After some time has passed, we stop stirring, resulting in a mixture with a precipitate. We can decant this into a separate beaker if you don’t have a filtration system. Alternatively, we can filter the liquid phase from the solid suspension, which would be the better option for the following steps. If you do not use filtration, you will need a larger amount of sodium hydroxide solution to obtain the final product.
8. To the obtained filtrate (or decanted mixture), we add a 25% solution of sodium hydroxide until the pH is > 10. This is necessary to convert the resulting amphetamine acetate into its free base form.
9. We stop stirring and allow the mixture to separate into two layers. The layer we need is on top. We can separate this using a syringe or use a separatory funnel if you have one. For the separated top layer, we start stirring again. However, don’t forget that it’s best to cool the separated layer before the next step, as this will affect the purity and yield.
10. While stirring, we begin adding concentrated sulfuric acid dropwise. It is advisable to use litmus indicator paper, adding the acid until the pH reaches 6. The approximate amount is 1.5 mL, but this can vary depending on how your reaction proceeded. When enough acid has been added, your mixture will thicken and be ready for filtration.
11. If the mixture has heated up during the acidification process, cool it further and then filter. The yield obtained using this method is approximately 6g of amphetamine sulfate.
12. Dry the obtained product at room temperature in a dry place until a constant weight is achieved. Use as intended.
Conclusion:
A positive aspect of this protocol is the easy extraction of the free base from the reaction mixture. A negative aspect is the more complex control of the reaction temperature and the required acidity of the medium during the process.
There are similar protocols that don’t use alcohol and are conducted in aqueous conditions. Under these conditions, we can use 25% acetic acid without having to worry about the reaction’s acidity and it’s easier to control the temperature (either forced heating is needed or just a long period of stirring at room temperature). These methods yield approximately the same amount of product (around 6g of amphetamine sulfate), but the purity of the product is higher due to the milder conditions.
We will definitely publish this method in aqueous conditions for comparison, so you can choose the best approach for you. Additionally, catalysts can be used for this type of reaction, which may reduce reaction time and improve yield, but require some adjustments to the synthesis protocol.
Furthermore, scaling up the process from hundreds of grams to kilogram-scale reactions in reactors may have its own specific challenges, which we will try to show you in the near future.
Thank you for your interest in this material. If you require further details, please contact our experts via DM or leave a post in this thread. We can provide product purity spectra privately.
Last edited: