This post discusses the experimental synthesis of 4-Fluoroamphetamine, as well as optimization ideas. The example synthesis is on a small scale, starting with 10g 4F-P2NP, but it can be scaled by multiplication or addition if you convert to moles.
Reagents:
- 4-FluoroP2NP 10g
- NaBH4 16g
- CuCl2 dihydrate 3g, dehydrated can be used, but different molar mass has to be considered in amount
- EtOH (Alternatively i-PrOH or possible MeOH) in water, 31-35 mol% alcohol (for EtOH this is around 60-63.5 vol%). 140mL
- Distilled Water
- 37% HCl or favorably HCl gas
- Ethyl acetate (alternatively and even favorable i-PrOAc) 140mL
- NaOH (powder or solution) (If powder prepare the solution beforehand to cool down, especially at larger scale)
Equipment:
- Round Bottom flask (2 or 3 necks), for this scale 500mL are sufficient
- Mantle heater (Water bath and heating plate as alternative)
- Overhead stirrer
- pH indicator (paper or electronic)
- Thermometer
- Drip funnel (For very small scale a pippet or syringe can be used)
- 3 Beakers
- Gravity filteration system, other filteration systems are possible as well
1. Inside the round bottom flask, which is equipped with an overhead stirrer and thermometer, 16g of NaBH4 are added and dissolved in 140mL EtOH/Water as a whole, and stirring is started.
2. 10g 4-FluoroP2NP (4FP2NP) are added in small portions, especially at larger scales it is important to add it very slowly, with 1 portion not exceeding 0.5%, and ideally 0.3% of total amount of NaBH4, and frequency not exceeding 20 minute intervals. The temperature will rise, but this is delayed. It is important ti keep the temperature below 60C. it can be seen when one portion of 4FP2NP is fully reacted as soon as yellow color is absent.
3. After all 4FP2NP was added and there is an absence of yellow color and visible 4FP2NP crystals, the round bottom flask is transferred to a mantle heater, if not already in it.
4. CuCl2 dihydrate 3g is dissolved in distilled water, approximately 7mL since it is readily soluble, it is a blue solution
5. With help of drip funnel or pippet/syringe this solution is added dropwise to the RM, the reaction is exothermic, black color is visible immediately
6. Heat up to 80C, but not above it, using the mantle heater, and continue adding CuCl2 solution until you get good amont of black sediment (copper particles), that ideally is visible all throughout the reaction vessel, and ideally not clumping up. It takes about 30-50% of the solution.
7. After sufficient sediment is fomred and the RM is at 80C, it can be left at 80C for 30 minutes
8. Solution is gravity filterated into a clean flask, the solution should be slightly cloudy and slightly light brown.
9. Solution is acidified using dropwise HCl to pH 6, and then left to either dry or for at least the residual alcohol to evaporate. This will leave 4-Fluoroamphetamine HCl with the impurity boric acid (Boric acid as an impurity has a rather high LD50, but it can damage fertility and the unborn child as boron compounds are known to), assuming a full reaction of the NaBH4 (which is unlikely) you would end up qiht 1.63g of boric acid per gram NaBH4, which is in this case is about 26g.
10. Dry or fully aqueous solution of 4-Fluoroamphetamine HCl and boric acid is either left in it's water or dissolved in minimum amount of distilled water.
11. This solution is basified to pH 12 using NaOH solution, and it shold trn cloudy and white.
12. Ethyl acetate is added to this solution, and stirred and left to settle repeatedly, ntil the aqueous (bottom) layer turns clear, and the EtOAc (top) layer tunrs slightly brown, the better indicator for completion is the color of the aqueous layer.
13. Layers are seperated and top layer is kept.
14. The EtOAc layer is acidified back to pH 6 with HCl soltion or gas, if you use solution it is normal to see the newly generated aqueous layer of water to turn brown.
15. The acidified layer(s) are left to fully dry. 4-Fluoroamphetamine HCl is obtained.
This was how the synthesis was carried out eyperimentally, but there are ideas for improvement.
1. It would be possible to replace EtOH with i-PrOH, and then after the filteration step layer seperate to keep the top layer, which would make the prification easier.
2. i-PrOAc would likely have a more complete layer seperation than EtOAc.
3. It might be possible to shorten the addition intervals, but this has not been tested.
4. Other alcohols might be possible, but I choose EtOH since it would prevent the temperature from rising above 80, and boil off readily during the process, reducing time to dry/fully aqueous
5. It might be possible to use CuNPs directly instead of CuCl2 as a catalyst, reducing the total amount of NaBH4 consumed and thus impurities formed.
This synthesis was based on this synthesis for normal amphetamine:
And I thank the author of it (GhostChemist) because this synthesis wouldn't have been possible otherwise.
Reagents:
- 4-FluoroP2NP 10g
- NaBH4 16g
- CuCl2 dihydrate 3g, dehydrated can be used, but different molar mass has to be considered in amount
- EtOH (Alternatively i-PrOH or possible MeOH) in water, 31-35 mol% alcohol (for EtOH this is around 60-63.5 vol%). 140mL
- Distilled Water
- 37% HCl or favorably HCl gas
- Ethyl acetate (alternatively and even favorable i-PrOAc) 140mL
- NaOH (powder or solution) (If powder prepare the solution beforehand to cool down, especially at larger scale)
Equipment:
- Round Bottom flask (2 or 3 necks), for this scale 500mL are sufficient
- Mantle heater (Water bath and heating plate as alternative)
- Overhead stirrer
- pH indicator (paper or electronic)
- Thermometer
- Drip funnel (For very small scale a pippet or syringe can be used)
- 3 Beakers
- Gravity filteration system, other filteration systems are possible as well
1. Inside the round bottom flask, which is equipped with an overhead stirrer and thermometer, 16g of NaBH4 are added and dissolved in 140mL EtOH/Water as a whole, and stirring is started.
2. 10g 4-FluoroP2NP (4FP2NP) are added in small portions, especially at larger scales it is important to add it very slowly, with 1 portion not exceeding 0.5%, and ideally 0.3% of total amount of NaBH4, and frequency not exceeding 20 minute intervals. The temperature will rise, but this is delayed. It is important ti keep the temperature below 60C. it can be seen when one portion of 4FP2NP is fully reacted as soon as yellow color is absent.
3. After all 4FP2NP was added and there is an absence of yellow color and visible 4FP2NP crystals, the round bottom flask is transferred to a mantle heater, if not already in it.
4. CuCl2 dihydrate 3g is dissolved in distilled water, approximately 7mL since it is readily soluble, it is a blue solution
5. With help of drip funnel or pippet/syringe this solution is added dropwise to the RM, the reaction is exothermic, black color is visible immediately
6. Heat up to 80C, but not above it, using the mantle heater, and continue adding CuCl2 solution until you get good amont of black sediment (copper particles), that ideally is visible all throughout the reaction vessel, and ideally not clumping up. It takes about 30-50% of the solution.
7. After sufficient sediment is fomred and the RM is at 80C, it can be left at 80C for 30 minutes
8. Solution is gravity filterated into a clean flask, the solution should be slightly cloudy and slightly light brown.
9. Solution is acidified using dropwise HCl to pH 6, and then left to either dry or for at least the residual alcohol to evaporate. This will leave 4-Fluoroamphetamine HCl with the impurity boric acid (Boric acid as an impurity has a rather high LD50, but it can damage fertility and the unborn child as boron compounds are known to), assuming a full reaction of the NaBH4 (which is unlikely) you would end up qiht 1.63g of boric acid per gram NaBH4, which is in this case is about 26g.
10. Dry or fully aqueous solution of 4-Fluoroamphetamine HCl and boric acid is either left in it's water or dissolved in minimum amount of distilled water.
11. This solution is basified to pH 12 using NaOH solution, and it shold trn cloudy and white.
12. Ethyl acetate is added to this solution, and stirred and left to settle repeatedly, ntil the aqueous (bottom) layer turns clear, and the EtOAc (top) layer tunrs slightly brown, the better indicator for completion is the color of the aqueous layer.
13. Layers are seperated and top layer is kept.
14. The EtOAc layer is acidified back to pH 6 with HCl soltion or gas, if you use solution it is normal to see the newly generated aqueous layer of water to turn brown.
15. The acidified layer(s) are left to fully dry. 4-Fluoroamphetamine HCl is obtained.
This was how the synthesis was carried out eyperimentally, but there are ideas for improvement.
1. It would be possible to replace EtOH with i-PrOH, and then after the filteration step layer seperate to keep the top layer, which would make the prification easier.
2. i-PrOAc would likely have a more complete layer seperation than EtOAc.
3. It might be possible to shorten the addition intervals, but this has not been tested.
4. Other alcohols might be possible, but I choose EtOH since it would prevent the temperature from rising above 80, and boil off readily during the process, reducing time to dry/fully aqueous
5. It might be possible to use CuNPs directly instead of CuCl2 as a catalyst, reducing the total amount of NaBH4 consumed and thus impurities formed.
This synthesis was based on this synthesis for normal amphetamine:
And I thank the author of it (GhostChemist) because this synthesis wouldn't have been possible otherwise.