Hi, after receiving many requests via PM, I am posting my final, fully optimised and OTC protocol for synthesising MDA from helional. This post is the result of more than two years of optimisation and testing.
The synthesis takes place in three steps:
- Oxidation of helional to helionic acid
- Formation of the amide with boric acid as the activating agent
- Hofmann rearrangement of the amide
Oxidation of helional to helionic acid :
I had to try more than 20 different oxidation methods (air oxidation with/without catalyst, oxidation with H2O2 with/without phase catalyst, oxidation with nickel and bleach, oxidation with TBHP, ester formation followed by ammonolysis, oxidation in DMF, 4Na2SO42H2O2NaCl adduct etc.). and the best method remains the one using oxone in acetone (the other methods yielding little or no results.).
In this method, I use less NaHCO3 than theory would suggest, but experimentally this is sufficient. As I said, I tried to optimise the procedure as much as possible. I tried this method with 200g of helional and it works perfectly, so it scales up rather well.
61.5g of helional and 216mL of acetone (170g) are poured in a 1L beaker. 70g of sodium bicarbonate is added little by little with stirring, so that the magnetic bar does not get stuck. In a 1L beaker, 110.8g of oxone (triple salt, CAS 37222-66-5) is mixed with 600mL of tap water, or more if all the oxone is not dissolved. The oxone solution is then gradually added to the helional solution. Once everything has been added, the mixture is left for 1 hour at room temperature with stirring. Then add 100g of 23% HCl to the Rm until pH <2 (You can use any strong acid such as H2SO4, regardless of its concentration. The goal is simply to achieve a low pH.). Then add 1L of water (you can use a larger beaker or divide the RM into two equal parts).
This will dilute the Rm, allowing the acetone to solubilise the acid less. Then either the acid will precipitate immediately, or it will form an orange oil. The best method I have found to push it to form a solid is to decant the acetone/water/HCl mixture from the orange oil, add water to this oil, mix, decant the added water and repeat this operation two or three times to wash the acetone mixed with the oil, which prevents the acid from crystallising. Generally, after the third wash, I leave it aside and it crystallises in 1-2 minutes. Otherwise, you can just wait a few hours or days and it will crystallise without washing. Once the acid has precipitated, filter it and wash it with water.
Meanwhile, prepare a solution of 14g of NaOH in 200mL of tap water. Allow it to cool and gradually add the acid (which is usually yellow/orange) to this solution. Then filter this solution into a separating funnel and wash it with 2x20mL of a non-polar solvent (toluene, naphtha, etc.). Keep the aqueous phase and add it to a solution of 71 g of 23% HCl while stirring. This will form white/beige/light brown crystals. Wait 1 hour for everything to precipitate and filter/wash the crystals with water.
Then heat the acid to 110°C for 1 hour and 30 minutes with stirring (the acid will melt) in order to remove all the water, generally 10%-20% of the mass of the acid was water. This step is MANDATORY to obtain a good yield for the amide synthesis. The yield is generally 60%-70%.
Tips and further information :
- When adding oxone, the acetone may boil because the addition is exothermic. If this happens, wait for the temperature of the RM to drop. You can use a cold or ice water bath during the addition. If you manage to maintain a cold temperature throughout the addition, you will be able to obtain a white acid directly. However, based on my experience, you still need to perform acid-base purification and dry it properly before moving on to the next step.
- Drying the acid and performing acid-base purification is mandatory before proceeding to the next step. A perfectly pure, white acid is not mandatory for the next step. Therefore, there is no need to recrystallise the acid obtained from this synthesis.
- You can use DCM or ether instead of a non-polar solvent during acid-base purification. This does not change much for the synthesis of the amide, and I personally prefer to use a non-polar solvent because it is more OTC.
Waste management:
- The aqueous phases contain acetone, so you can evaporate it before disposing it down the drain, or you can dispose of it directly down the drain by diluting it with a large amount of water (at least 10 litres of water for 100 ml of acetone).
- For the organic phase (acid-base purification), you can put it in a waste container, let it evaporate, distil it or burn it outside, as you wish.
Formation of the amide with boric acid as the activating agent :
For this method, I also tried several protocols, including the one described in the paper ‘SOLVENT-FREE SYNTHESIS OF AMIDE: A NOVEL TECHNIQUE OF GREEN CHEMISTRY,’ which worked quite well, but only on a small scale, and used too much urea and boric acid for my liking. I also tried methods using H3PO4 and Mg(NO3)2 as catalysts, with and without solvents...
Here is the best method:
15.66g of urea, 1.3g of boric acid and 17.4 g of helionic acid are placed in an erlenmeyer flask. The hotplate is set to 180°C, and when everything has melted, the stirring is turned on. A condenser is placed on the Erlenmeyer flask and an inverted funnel trap is placed at the end to neutralise the NH3 vapours formed in a beaker of HCl. The erlenmeyer flask is covered with aluminium foil to retain as much heat as possible. The condenser is mainly used to trap any amide that may sublimate during the process. The mixture is left at 180°C for 3½ hours. Then the mixture is left to cool. 430 mL of water is added with 20 mL of 13% NH3 (the pH must be basic to make the unreacted acid soluble in water) to the RM and the mixture is heated with stirring. Once the water temperature is close to 100°C, the mixture must be filtered while hot (use 2 coffee filter papers, as a single one tends to break even when wet). The amide will already begin to precipitate in the receiving beaker. Leave for several hours to cool to room temperature. Cooling to temperatures close to 0°C did not precipitate any more amide for me, so leaving it to cool to room temperature was sufficient.
Filter, wash with water and dry the amide (it generally absorbs 10%-20% water). The yield is generally 50%-60%, sometimes 40%. The amide will generally be pink in colour, but works perfectly for the Hofmann reaction. If you wish, you can recrystallise it in water. (200mL of hot water for 11g of amide).
Tips and further information :
- This synthesis will produce a brown goo that is insoluble in water and stick to the magnetic bar. It is mainly due to the condensation products of urea and impurities in the helionic acid. It can be easily removed with acetone.
- This method requires the acid to be dry and undergoes acid-base purification to achieve good yields. Recrystallisation of the acid does not significantly alter the yields but produces a slightly purer amide.
- The best OTC catalyst is boric acid, but others such as Mg(NO3)2 or H3PO4 can also be used.
Waste management:
- The aqueous phase can be disposed down the drain.
Hofmann rearrangement of the amide :
I have never had good results using bleach or TCCA. The best way for me is to use NaDCC because it is much more soluble in water than TCCA, and therefore less troublesome to handle. Unlike bleach, you know what's in it and you know its exact concentration. (https://en.wikipedia.org/wiki/Sodium_dichloroisocyanurate)
This allows for excellent yields while obtaining an almost pure product at the end of the synthesis. In fact, with my method, we do not use 2eq of Cl+ but about 1.1eq. Visually, you can see a difference because the freebase obtained is yellow and not brown/orange, and above all, the Rm will turn yellow and not orange like in the video on the forum.
Yields vary from 70% to 80% depending on the purity of the amide (and how dry it is when you weigh it).
1.55g of NaDCC (dihydrate) is dissolved in 90 ml of water with 7g of NaOH (the solution MUST be clear and not cloudy, add a little more water if necessary.). This solution is then placed in the freezer/ice bath until its temperature is below 5°C. Then 2.3 g of cold amide is added to the solution (placed in an ice bath) with stirring.
Then it is left at <5°C for 1 hour with stirring and then placed in a water bath at 80°C-85°C for 1 hour. The Rm is left to cool and then extracted with 3x20mL of DCM or non-polar solvent. (EtOAc only works well if the Rm has been saturated with NaCl beforehand). The extraction solvent is washed twice with water, then evaporated. For DCM, I like to evaporate at 110°C because this does not damage the product and removes any traces of water.
Next, acetone is added to dissolve the freebase (5mL-10mL), and a few drops of HCl are added until the pH is acidic. The mixture is evaporated at 110°C. The solid obtained is washed with cold acetone, giving a 76% yield. I found that with this synthesis, performing acid-base purification directly after extraction with DCM and then washing the product obtained with glacial acetone is perfect for obtaining a very pure product and avoids recrystallisation in IPA. This results in better yield because recrystallisation generally causes more product loss.
Tips and further information :
- A temperature below 5°C is essential for the synthesis, so please be patient before adding the amide.
Waste management:
- The aqueous phase can be disposed down the drain.
If you have any questions or would like clarification on any point, please do not hesitate to contact me.
The synthesis takes place in three steps:
- Oxidation of helional to helionic acid
- Formation of the amide with boric acid as the activating agent
- Hofmann rearrangement of the amide
Oxidation of helional to helionic acid :
I had to try more than 20 different oxidation methods (air oxidation with/without catalyst, oxidation with H2O2 with/without phase catalyst, oxidation with nickel and bleach, oxidation with TBHP, ester formation followed by ammonolysis, oxidation in DMF, 4Na2SO42H2O2NaCl adduct etc.). and the best method remains the one using oxone in acetone (the other methods yielding little or no results.).
In this method, I use less NaHCO3 than theory would suggest, but experimentally this is sufficient. As I said, I tried to optimise the procedure as much as possible. I tried this method with 200g of helional and it works perfectly, so it scales up rather well.
61.5g of helional and 216mL of acetone (170g) are poured in a 1L beaker. 70g of sodium bicarbonate is added little by little with stirring, so that the magnetic bar does not get stuck. In a 1L beaker, 110.8g of oxone (triple salt, CAS 37222-66-5) is mixed with 600mL of tap water, or more if all the oxone is not dissolved. The oxone solution is then gradually added to the helional solution. Once everything has been added, the mixture is left for 1 hour at room temperature with stirring. Then add 100g of 23% HCl to the Rm until pH <2 (You can use any strong acid such as H2SO4, regardless of its concentration. The goal is simply to achieve a low pH.). Then add 1L of water (you can use a larger beaker or divide the RM into two equal parts).
This will dilute the Rm, allowing the acetone to solubilise the acid less. Then either the acid will precipitate immediately, or it will form an orange oil. The best method I have found to push it to form a solid is to decant the acetone/water/HCl mixture from the orange oil, add water to this oil, mix, decant the added water and repeat this operation two or three times to wash the acetone mixed with the oil, which prevents the acid from crystallising. Generally, after the third wash, I leave it aside and it crystallises in 1-2 minutes. Otherwise, you can just wait a few hours or days and it will crystallise without washing. Once the acid has precipitated, filter it and wash it with water.
Meanwhile, prepare a solution of 14g of NaOH in 200mL of tap water. Allow it to cool and gradually add the acid (which is usually yellow/orange) to this solution. Then filter this solution into a separating funnel and wash it with 2x20mL of a non-polar solvent (toluene, naphtha, etc.). Keep the aqueous phase and add it to a solution of 71 g of 23% HCl while stirring. This will form white/beige/light brown crystals. Wait 1 hour for everything to precipitate and filter/wash the crystals with water.
Then heat the acid to 110°C for 1 hour and 30 minutes with stirring (the acid will melt) in order to remove all the water, generally 10%-20% of the mass of the acid was water. This step is MANDATORY to obtain a good yield for the amide synthesis. The yield is generally 60%-70%.
Tips and further information :
- When adding oxone, the acetone may boil because the addition is exothermic. If this happens, wait for the temperature of the RM to drop. You can use a cold or ice water bath during the addition. If you manage to maintain a cold temperature throughout the addition, you will be able to obtain a white acid directly. However, based on my experience, you still need to perform acid-base purification and dry it properly before moving on to the next step.
- Drying the acid and performing acid-base purification is mandatory before proceeding to the next step. A perfectly pure, white acid is not mandatory for the next step. Therefore, there is no need to recrystallise the acid obtained from this synthesis.
- You can use DCM or ether instead of a non-polar solvent during acid-base purification. This does not change much for the synthesis of the amide, and I personally prefer to use a non-polar solvent because it is more OTC.
Waste management:
- The aqueous phases contain acetone, so you can evaporate it before disposing it down the drain, or you can dispose of it directly down the drain by diluting it with a large amount of water (at least 10 litres of water for 100 ml of acetone).
- For the organic phase (acid-base purification), you can put it in a waste container, let it evaporate, distil it or burn it outside, as you wish.
Formation of the amide with boric acid as the activating agent :
For this method, I also tried several protocols, including the one described in the paper ‘SOLVENT-FREE SYNTHESIS OF AMIDE: A NOVEL TECHNIQUE OF GREEN CHEMISTRY,’ which worked quite well, but only on a small scale, and used too much urea and boric acid for my liking. I also tried methods using H3PO4 and Mg(NO3)2 as catalysts, with and without solvents...
Here is the best method:
15.66g of urea, 1.3g of boric acid and 17.4 g of helionic acid are placed in an erlenmeyer flask. The hotplate is set to 180°C, and when everything has melted, the stirring is turned on. A condenser is placed on the Erlenmeyer flask and an inverted funnel trap is placed at the end to neutralise the NH3 vapours formed in a beaker of HCl. The erlenmeyer flask is covered with aluminium foil to retain as much heat as possible. The condenser is mainly used to trap any amide that may sublimate during the process. The mixture is left at 180°C for 3½ hours. Then the mixture is left to cool. 430 mL of water is added with 20 mL of 13% NH3 (the pH must be basic to make the unreacted acid soluble in water) to the RM and the mixture is heated with stirring. Once the water temperature is close to 100°C, the mixture must be filtered while hot (use 2 coffee filter papers, as a single one tends to break even when wet). The amide will already begin to precipitate in the receiving beaker. Leave for several hours to cool to room temperature. Cooling to temperatures close to 0°C did not precipitate any more amide for me, so leaving it to cool to room temperature was sufficient.
Filter, wash with water and dry the amide (it generally absorbs 10%-20% water). The yield is generally 50%-60%, sometimes 40%. The amide will generally be pink in colour, but works perfectly for the Hofmann reaction. If you wish, you can recrystallise it in water. (200mL of hot water for 11g of amide).
Tips and further information :
- This synthesis will produce a brown goo that is insoluble in water and stick to the magnetic bar. It is mainly due to the condensation products of urea and impurities in the helionic acid. It can be easily removed with acetone.
- This method requires the acid to be dry and undergoes acid-base purification to achieve good yields. Recrystallisation of the acid does not significantly alter the yields but produces a slightly purer amide.
- The best OTC catalyst is boric acid, but others such as Mg(NO3)2 or H3PO4 can also be used.
Waste management:
- The aqueous phase can be disposed down the drain.
Hofmann rearrangement of the amide :
I have never had good results using bleach or TCCA. The best way for me is to use NaDCC because it is much more soluble in water than TCCA, and therefore less troublesome to handle. Unlike bleach, you know what's in it and you know its exact concentration. (https://en.wikipedia.org/wiki/Sodium_dichloroisocyanurate)
This allows for excellent yields while obtaining an almost pure product at the end of the synthesis. In fact, with my method, we do not use 2eq of Cl+ but about 1.1eq. Visually, you can see a difference because the freebase obtained is yellow and not brown/orange, and above all, the Rm will turn yellow and not orange like in the video on the forum.
Yields vary from 70% to 80% depending on the purity of the amide (and how dry it is when you weigh it).
1.55g of NaDCC (dihydrate) is dissolved in 90 ml of water with 7g of NaOH (the solution MUST be clear and not cloudy, add a little more water if necessary.). This solution is then placed in the freezer/ice bath until its temperature is below 5°C. Then 2.3 g of cold amide is added to the solution (placed in an ice bath) with stirring.
Then it is left at <5°C for 1 hour with stirring and then placed in a water bath at 80°C-85°C for 1 hour. The Rm is left to cool and then extracted with 3x20mL of DCM or non-polar solvent. (EtOAc only works well if the Rm has been saturated with NaCl beforehand). The extraction solvent is washed twice with water, then evaporated. For DCM, I like to evaporate at 110°C because this does not damage the product and removes any traces of water.
Next, acetone is added to dissolve the freebase (5mL-10mL), and a few drops of HCl are added until the pH is acidic. The mixture is evaporated at 110°C. The solid obtained is washed with cold acetone, giving a 76% yield. I found that with this synthesis, performing acid-base purification directly after extraction with DCM and then washing the product obtained with glacial acetone is perfect for obtaining a very pure product and avoids recrystallisation in IPA. This results in better yield because recrystallisation generally causes more product loss.
Tips and further information :
- A temperature below 5°C is essential for the synthesis, so please be patient before adding the amide.
Waste management:
- The aqueous phase can be disposed down the drain.
If you have any questions or would like clarification on any point, please do not hesitate to contact me.