The aim of this post is to summarize several months of research and testing. It would be great if everyone could share their results and their thoughts in order to perfect this synthesis route.
All the reagents I'll be using can probably be found in any hardware store, except for helional, which can be bought quite easily from many different websites as it's not a monitored precursor. I believe it can even be bought on amazon as a flagrance.
The idea of this synthesis is to convert helional (cas:1205-17-0) to helionic acid (cas:77269-66-0, 3-(2H-1,3-benzodioxol-5-yl)-2-methylpropanoic acid), then convert the latter to helionamide (cas:858215-05-1, alpha-Methyl-1,3-benzodioxole-5-propanamide), and finally perform a Hofmann rearrangement to obtain MDA freebase.
The advantages of this synthesis are that it is OTC, and so does not require hydroxylamine, uses low-toxicity, low-cost products. In addition, the problem often encountered in the other way of doing things is to scale up the Beckmann rearrangement, which often results in an oil that is complicated to purify on a larger scale. (based on my experiences and what I've read)
This is going to be a very long post because I'm going to try to go into everything in detail, so that if you have a question or a problem, you'll probably find a solution in this post.
I'd prefer to warn you that I'm personally stuck at the last step for some reason, but that it's totally possible to succeed in getting the final product in good yield in theory, and according to the many posts by successful people.
First step, oxidation of helional to helionic acid:
61.5g helional is mixed with 216mL acetone and 80g NaHCO3 with stirring in a 1L beaker. (Tip: add NaHCO3 last and little by little, so as not to block the magnetic stirrer). Then gradually add a solution of oxone (110.8g of oxone in about 450mL of water) with stirring. You can do this drop by drop using a dropping funnel or beaker to beaker. As the reaction is exothermic, it can cause acetone to boil. If it gets too hot, stop adding the oxone and let the reaction return to room temperature. You can use an ice bath during the addition, but doing it at room temperature works just as well if you're careful.
I usually finish adding the oxone solution after 1 hour. Then I let it react for about 2h-3h. Via TLC, I was able to determine that everything had reacted after 3h.
After 3 hours, acidify the solution with HCl to precipitate the acid (the white salts at the bottom of the beaker are not our product, but potassium salts from the oxone). Add until nothing precipitates (approx. pH 1-2). Be careful, as some unreacted NaHCO3 will remain, releasing CO2. In most cases, nothing precipitated except an orange "oil" rising to the surface of the rest of the solution. It's our product that eventually solidifies. To force it to solidify, you can put it in the fridge for a few hours, but this doesn't work all the time. The best method I've found is to put the beaker in the freezer until everything solidifies, then let it come to room temperature. What remains solid is our product with potassium sulfate salts.
Filter to recover the yellow solid contaminated with potassium salts, then place the powdered solid in a beaker with 400mL to 500mL of stirring water. This will solubilize all potassium salt contamination. Then all you have to do is filter to obtain the yellow solid
You can keep the helionic acid this way, but I strongly advise you to at least perform an acid-base purification next, otherwise the amide purification step will be (even) more complicated. To do this, prepare a solution of NaOH (approx. 13g in 150mL of water). Wait until the solution has cooled before adding the acid a little at a time. If the solution gets too hot, you'll end up with a dark-brown acid instead of a white/light-brown one. Next, wash the aqueous phase (containing the conjugate base of helionic acid) with ether or DCM (gives the best results). If these are not available, naphtha or any other apolar solvent will do. Then recover your aqueous phase, and acidify it with HCl. Your acid will precipitate. If the solution turns white but you can't see any precipitates, use the same technique as above (the freezer). In general, however, placing the beaker in the fridge is sufficient. Then filter, and you've got your acid.
You can recrystallize in water or ethanol to obtain a truly pure acid, forming beautiful white crystals, but this is rather annoying as the acid is not very soluble in hot water (around 10g/L at 90°C I'd say), and this basic acid purification is enough to obtain decent results later on.
The melting point of pure helionic acid is around 77°C. Yield : 80 %-90 %
Notes on the synthesis :
-When you acidify the solution, instead of forming an “oil”, the acid can turn the solution white without precipitating, so simply freeze the solution as usual.
- The reaction mixture will turn yellow when you add the oxone, then orange/brown again. This is normal, and is due to the fact that the acid formed/impurities change color according to pH.
-I tried demineralized water, tap water, and distilled water, and it didn't seem to make any difference on the reaction (I thought that the ions in the tap water would destroy the oxone, but this was not the case).
- Always add excess NaHCO3 as recommended in my synthesis. If the pH becomes acid when all the oxone has not yet reacted, you run the risk of forming unstable and explosive TATP. Don't be afraid of that, though: if you follow everything to the letter, you'll be fine.
- The oxone is in fact a triple salt: 2KHSO5-KHSO4-K2SO4. The species of interest here is KHSO5. So we need to take this into account when calculating the moles of oxone we need (Which was done here).
-NaHCO3 will prevent the pH from becoming acidic. It will react with the acidity of the oxone, and with the helionic acid formed, converting it into its conjugate base. NaHCO3 is also a very weak base, which ensures that the pH is not too basic. In basic pH, the oxone is not stable (pH=9, the pH at which the oxone is the least stable).
-Oxone can be purchased in the swimming pool section of hardware stores. Look at the msds or the composition list on the product.
-The synthesis is easily scalable, but I'd recommend a bucket of cold water to cool the Rm down properly at larger scale.
-I've tried ethanol as a solvent three times, and it seems to form the ethyl ester of helionic acid, and other products depending on the pH. I haven't dug any deeper, so I can't tell you more. But perhaps we could form the amide from this ester, more simply than my current method (urea + boric acid + helionic acid).
Impure yellow acid:
Recrystallized acid
Second step, helionamide synthesis
I tried two ways: I first converted the helionic acid into its corresponding ammonium salt, then heated it. It was a failure.
The second way worked, although the work-up of this reaction is a nightmare, and I think this can easily be improved if you have any ideas.
I followed the procedure in the publication “SOLVENT FREE SYNTHESIS OF AMIDE A NOVEL TECHNIQUE”.
Basically, they triturate for 5min-10min a mixture of urea, carboxylic acid, boric acid, then heat the whole for 15min-30min in a beaker at 160°C-180°C. You know when the reaction is finished when it resolidifies (urea, helionic acid and boric acid melting at 180°C).
Which is strange, because helionamide melts at 123°C. I suppose this is due to the hydrogen bonds that amides can form. You'll see that it forms more of a gel than a solid. I don't think triturating is really necessary, as everything melts at 180°C. However, if you heat to around 160°C-170°C, I suppose that's advisable, as boric acid melts at 171°C. Triturate the mixture will cause melting point depression. Boric acid is not required, but is recommended as it greatly improves yields.
I've tried heating for 4 hours, and 11hours at 180°C with stirring without boric acid, and obtained yields ranging from 22% to 50%. But the work-up was a horror, because the longer you wait, the more urea forms all kinds of condensation products.
In my case, the mixture only partially solidified after about 1h30 at 180°C with stirring. However, I've found (maybe it was just a fluke) that heating to 170°C will solidify everything after 2 hours. In general, nothing, or even part of it solidifies after 30 minutes, which is why I continue the reaction even after 30min. Nevertheless, I haven't yet fully mastered this synthesis, and that's why your help in optimizing it is most welcome.
Here's how I usually do it :
g of helionic acid * 1.5 = Quantity of Urea, g of acid * 0.4 = Quantity of Boric acid.
This makes a large molar excess of urea, and I'm thinking of eventually reducing it once I'm getting good yields by following the publication procedure.
I then put the 3 in a beaker with a magnetic stirrer and heated to 170°C. When everything has solidified, or 3/4 of it (about 2 hours), I let it return to room temperature, then add about 10mL-20mL of a 15% ammonia solution and 100mL-200mL of water. I then heat the mixture until it dissolves, and let it return to room temperature to precipitate the amide, which is not very soluble when cold. And this is where I have a big problem in the Work-up. The amide doesn't want to precipitate and I have to evaporate most of the water added, but it all solidifies at once. Using ethanol isn't any better. And every time I have to get the amide to precipitate, then recrystallize it several times in water and ethanol, and only sometimes does it agree to precipitate as a solid and not as oil. I think this is due to the fact that the impurities lower the melting point of the amide enormously. In fact, the brown solid melted at around 70°C. Once purified, the white solid of roughly the same mass melted at 123°C. I think that's part of the reason for the oil when recrystallizing in ethanol/hot water.
In “A Simple Preparation of Amides from Acids and Amines by Heating of their Mixture”, it’s written:
« We have found that the optimal conditions for pyrolysis of amide-carboxylic acid mixture is 160-180°C for 10-30 minutes. Prolonged heating can cause formation of substantial amounts of tar, while heating for a short time gives incoplete reaction. »
But I had almost as much trouble with the Work Up, doing the reaction for only 30min, and not everything solidified.
Another procedure involves heating 1 mole of carboxylic acid with 0.5 moles of urea at 160°C for 4 hours. I haven't tried it, but it gives a fairly pure product according to the patent, although yields are only 50%. « UNITED STATES 2,109,941 PATENT OFFICE 2,109,94. PREPARATION OF AMIDES »
I've seen people extracting amide using a mixture of boiling naphtha and ethyl acetate. This can be interesting, but my aim is to use as little organic solvent as possible. I haven't tried it, as I don't have any ethyl acetate to hand at the moment.
If you heat for long enough (180°C), the amide will start to sublimate, making beautiful long white crystals. Unfortunately, this takes a very long time, and I only obtained 400mg of crystals after 11 hours.
I looked at the way people had to make benzamide from benzoic acid, and it doesn't differ too much from mine, yet it works very well for benzamide. There are several videos on youtube if you want to take a look.
So I think the reaction works well, but there's room for improvement in terms of the number of moles of urea used. Nevertheless, the work-up really needs to be improved. The one given in the publication doesn't work, even when using pure acid.
Reaction mixture once solidified:
White amide powder:
Recrystallized amide:
Sublimed amide:
Third step, MDA freebase
This is where I have a problem: my yields are non-existent.
I followed the TCCA procedure from the publication “Organic impurity profiling of 3,4-methylenedioxyamphetamine (MDA)
synthesised from helional” and it didn't work. I'm sure of my amide. I also tried to do the reaction at 18°C because apparently chloroamide forms too slowly at 0°C. That didn't work either. So I titrated bleach without additives and use it for my Hofmann and got nothing after all the work up.
When I synthesized using TCCA at 0°C, the solution turned orange after heating to 75°C. There was a characteristic smell no matter which synthesis route I took, but each time I ended up with nothing.
Even stranger, there is a release of CO2, but nothing afterwards. I'm sure there's no urea contamination, so it's not hydrazine forming. I let a reaction run for a week at room temperature, and we'll see if I get anything.
Perhaps a cosolvent such as ethanol is absolutely necessary. However, many people have succeeded without it, but say they need ethanol as a cosolvent when using TCCA. (You'll form a carbamate derivative, but it will subsequently hydrolyze to MDA)
From the publication :
Synthesis using trichloroisocyanuric acid. α-Methyl-1,3-benzo
dioxole-5-propanamide (0.4 g, 1.92 mmol) was dissolved in water
(14 mL), NaOH (1.45 mL, 10.61 mmol) was added dropwise and stirred
for 15 min on ice at 0 ◦ C. Trichloroisocyanuric acid (149.9 mg,
0.65 μmol) was added, and the reaction mixture was left on ice at 0 ◦ C
for an additional 1 h. The reaction mixture was then brought to room
temperature, then 75 ◦C and held for 30 min. The reaction mixture was
poured into a separating funnel and extracted with dichloromethane
(3 ×30 mL). The organic layer was washed with de-ionised water
(25 mL) and brine (25 mL), dried over anhydrous sodium sulfate and
filtered under vacuum. The organic layers were combined, and solvent
was removed using the rotary evaporator. When synthesised from crude
α-methyl-1,3-benzodioxole-5-propanamide, the final product was a
black-brown soil (270.3 – 382.2 mg). When synthesised from purified
α-methyl-1,3-benzodioxole-5-propanamide, the final product was a
brown transparent oil (286.4 – 351.5 mg)
Synthesis using sodium hypochlorite. Purified α-methyl-1,3-
benzodioxole-5-propanamide (0.4 g, 1.92 mmol) dissolved in water
(14 mL), NaOH (1.45 mL, 10.61 mmol) was added dropwise and stirred
for 15 min on ice at 0 ◦ C. Sodium hypochlorite solution (6.4 mL,
94.3 mmol) was added, and the reaction mixture was left on ice at 0 ◦ C
for an additional 1 h. The reaction mixture was then brought to room
temperature then 75 ◦ C and held for 30 min. The reaction mixture was
poured into a separating funnel and extracted with dichloromethane
(3 ×30 mL). The organic layer was then washed with de-ionised water
(25 mL) and brine (25 mL), dried over anhydrous sodium sulfate and
filtered under vacuum. The organic layers were combined, and solvent
was removed using the rotary evaporator. The final product was a black-
brown soil (248.1 – 293.3 mg).
For the work up, I tried extracting with naphtha or DCM, and either gassing with HCl, or triturating with aqueous HCl and evaporating the aqueous phase. In both cases I got nothing. If anyone has ever done this reaction, I'd love to hear from you.
So the two big problems I'm having at the moment are the work-up of the second step and the third reaction. Nevertheless, I think this synthesis is very optimizable.
That's why I hope we can improve it together.
Feel free to point out my mistakes and share your experiences if you've done this synthesis.
If you want to look for yourself, here are all the sources I used during my research:
"A Simple Preparation of Amides from Acids and Amines by Heating of their Mixture" (Branko S. Jursic* and Zoran Zdravkovski Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148)
"Analysis of Urea Pyrolysis Products in 132.5-190 °C"
" Direct Amide Formation Between Carboxylic Acids and Amines: Mechanism and Development of Novel Catalytic Solutions" (CHARVILLE, HAYLEY)
"SOLVENT-FREE SYNTHESIS OF AMIDE A NOVEL TECHNIQUE" (CHIRAGKUMAR J GOHIL1, MALLESHAPPA N NOOLVI)
"UNITED STATES 2,109,941 PATENT OFFICE2,109,94.PREPARATION OF AMIDES"
"Facile Oxidation of Aldehydes to Acidsand Esters with Oxone" (Benjamin R. Travis, Meenakshi Sivakumar, G. Olatunji Hollist, and Babak Borhan)
"Oxidation of Aldehydes with Oxone ® in Aqueous Acetone" (Kevin S. Webb and Stephen J. Ruszkay)
"Hofmann Rearrangement Yields" The Vespiary
"FACILE ONE-POT CONVERSION OF ALDEHYDES INTO AMIDES results" The Vespiary
"An unusual clandestine laboratory synthesis of 3,4-methylenedioxyamphetamine (MDA)" (Terry A. Dal Cason, Charlotte A. Corbett a, Peter K. Poole a, James A. de Haseth, David K. Gouldthorpe)
"Impurity Analysis of MDA Synthesized from Unrestricted Compounds" (Katherine Cooper)
"Isotope fractionation during the synthesis of MDMA.HCl from helional" (Justin Cormick, James F. Carter, Timothy Currie, Carney Matheson, Sarah L. Cresswell)
"Organic impurity profiling of 3,4-methylenedioxyamphetamine (MDA) synthesised from helional" (Alexandra L. Mercieca , Harrison C. Fursman , Morgan Alonzo, Scott Chadwick , AndrewM. McDonagh)
There are plenty of other sources, too, but they wouldn't be relevant here. If you can't find the publications, I can provide you with the DOIs.
All the reagents I'll be using can probably be found in any hardware store, except for helional, which can be bought quite easily from many different websites as it's not a monitored precursor. I believe it can even be bought on amazon as a flagrance.
The idea of this synthesis is to convert helional (cas:1205-17-0) to helionic acid (cas:77269-66-0, 3-(2H-1,3-benzodioxol-5-yl)-2-methylpropanoic acid), then convert the latter to helionamide (cas:858215-05-1, alpha-Methyl-1,3-benzodioxole-5-propanamide), and finally perform a Hofmann rearrangement to obtain MDA freebase.
The advantages of this synthesis are that it is OTC, and so does not require hydroxylamine, uses low-toxicity, low-cost products. In addition, the problem often encountered in the other way of doing things is to scale up the Beckmann rearrangement, which often results in an oil that is complicated to purify on a larger scale. (based on my experiences and what I've read)
This is going to be a very long post because I'm going to try to go into everything in detail, so that if you have a question or a problem, you'll probably find a solution in this post.
I'd prefer to warn you that I'm personally stuck at the last step for some reason, but that it's totally possible to succeed in getting the final product in good yield in theory, and according to the many posts by successful people.
First step, oxidation of helional to helionic acid:
61.5g helional is mixed with 216mL acetone and 80g NaHCO3 with stirring in a 1L beaker. (Tip: add NaHCO3 last and little by little, so as not to block the magnetic stirrer). Then gradually add a solution of oxone (110.8g of oxone in about 450mL of water) with stirring. You can do this drop by drop using a dropping funnel or beaker to beaker. As the reaction is exothermic, it can cause acetone to boil. If it gets too hot, stop adding the oxone and let the reaction return to room temperature. You can use an ice bath during the addition, but doing it at room temperature works just as well if you're careful.
I usually finish adding the oxone solution after 1 hour. Then I let it react for about 2h-3h. Via TLC, I was able to determine that everything had reacted after 3h.
After 3 hours, acidify the solution with HCl to precipitate the acid (the white salts at the bottom of the beaker are not our product, but potassium salts from the oxone). Add until nothing precipitates (approx. pH 1-2). Be careful, as some unreacted NaHCO3 will remain, releasing CO2. In most cases, nothing precipitated except an orange "oil" rising to the surface of the rest of the solution. It's our product that eventually solidifies. To force it to solidify, you can put it in the fridge for a few hours, but this doesn't work all the time. The best method I've found is to put the beaker in the freezer until everything solidifies, then let it come to room temperature. What remains solid is our product with potassium sulfate salts.
Filter to recover the yellow solid contaminated with potassium salts, then place the powdered solid in a beaker with 400mL to 500mL of stirring water. This will solubilize all potassium salt contamination. Then all you have to do is filter to obtain the yellow solid
You can keep the helionic acid this way, but I strongly advise you to at least perform an acid-base purification next, otherwise the amide purification step will be (even) more complicated. To do this, prepare a solution of NaOH (approx. 13g in 150mL of water). Wait until the solution has cooled before adding the acid a little at a time. If the solution gets too hot, you'll end up with a dark-brown acid instead of a white/light-brown one. Next, wash the aqueous phase (containing the conjugate base of helionic acid) with ether or DCM (gives the best results). If these are not available, naphtha or any other apolar solvent will do. Then recover your aqueous phase, and acidify it with HCl. Your acid will precipitate. If the solution turns white but you can't see any precipitates, use the same technique as above (the freezer). In general, however, placing the beaker in the fridge is sufficient. Then filter, and you've got your acid.
You can recrystallize in water or ethanol to obtain a truly pure acid, forming beautiful white crystals, but this is rather annoying as the acid is not very soluble in hot water (around 10g/L at 90°C I'd say), and this basic acid purification is enough to obtain decent results later on.
The melting point of pure helionic acid is around 77°C. Yield : 80 %-90 %
Notes on the synthesis :
-When you acidify the solution, instead of forming an “oil”, the acid can turn the solution white without precipitating, so simply freeze the solution as usual.
- The reaction mixture will turn yellow when you add the oxone, then orange/brown again. This is normal, and is due to the fact that the acid formed/impurities change color according to pH.
-I tried demineralized water, tap water, and distilled water, and it didn't seem to make any difference on the reaction (I thought that the ions in the tap water would destroy the oxone, but this was not the case).
- Always add excess NaHCO3 as recommended in my synthesis. If the pH becomes acid when all the oxone has not yet reacted, you run the risk of forming unstable and explosive TATP. Don't be afraid of that, though: if you follow everything to the letter, you'll be fine.
- The oxone is in fact a triple salt: 2KHSO5-KHSO4-K2SO4. The species of interest here is KHSO5. So we need to take this into account when calculating the moles of oxone we need (Which was done here).
-NaHCO3 will prevent the pH from becoming acidic. It will react with the acidity of the oxone, and with the helionic acid formed, converting it into its conjugate base. NaHCO3 is also a very weak base, which ensures that the pH is not too basic. In basic pH, the oxone is not stable (pH=9, the pH at which the oxone is the least stable).
-Oxone can be purchased in the swimming pool section of hardware stores. Look at the msds or the composition list on the product.
-The synthesis is easily scalable, but I'd recommend a bucket of cold water to cool the Rm down properly at larger scale.
-I've tried ethanol as a solvent three times, and it seems to form the ethyl ester of helionic acid, and other products depending on the pH. I haven't dug any deeper, so I can't tell you more. But perhaps we could form the amide from this ester, more simply than my current method (urea + boric acid + helionic acid).
Impure yellow acid:
Recrystallized acid
Second step, helionamide synthesis
I tried two ways: I first converted the helionic acid into its corresponding ammonium salt, then heated it. It was a failure.
The second way worked, although the work-up of this reaction is a nightmare, and I think this can easily be improved if you have any ideas.
I followed the procedure in the publication “SOLVENT FREE SYNTHESIS OF AMIDE A NOVEL TECHNIQUE”.
Basically, they triturate for 5min-10min a mixture of urea, carboxylic acid, boric acid, then heat the whole for 15min-30min in a beaker at 160°C-180°C. You know when the reaction is finished when it resolidifies (urea, helionic acid and boric acid melting at 180°C).
Which is strange, because helionamide melts at 123°C. I suppose this is due to the hydrogen bonds that amides can form. You'll see that it forms more of a gel than a solid. I don't think triturating is really necessary, as everything melts at 180°C. However, if you heat to around 160°C-170°C, I suppose that's advisable, as boric acid melts at 171°C. Triturate the mixture will cause melting point depression. Boric acid is not required, but is recommended as it greatly improves yields.
I've tried heating for 4 hours, and 11hours at 180°C with stirring without boric acid, and obtained yields ranging from 22% to 50%. But the work-up was a horror, because the longer you wait, the more urea forms all kinds of condensation products.
In my case, the mixture only partially solidified after about 1h30 at 180°C with stirring. However, I've found (maybe it was just a fluke) that heating to 170°C will solidify everything after 2 hours. In general, nothing, or even part of it solidifies after 30 minutes, which is why I continue the reaction even after 30min. Nevertheless, I haven't yet fully mastered this synthesis, and that's why your help in optimizing it is most welcome.
Here's how I usually do it :
g of helionic acid * 1.5 = Quantity of Urea, g of acid * 0.4 = Quantity of Boric acid.
This makes a large molar excess of urea, and I'm thinking of eventually reducing it once I'm getting good yields by following the publication procedure.
I then put the 3 in a beaker with a magnetic stirrer and heated to 170°C. When everything has solidified, or 3/4 of it (about 2 hours), I let it return to room temperature, then add about 10mL-20mL of a 15% ammonia solution and 100mL-200mL of water. I then heat the mixture until it dissolves, and let it return to room temperature to precipitate the amide, which is not very soluble when cold. And this is where I have a big problem in the Work-up. The amide doesn't want to precipitate and I have to evaporate most of the water added, but it all solidifies at once. Using ethanol isn't any better. And every time I have to get the amide to precipitate, then recrystallize it several times in water and ethanol, and only sometimes does it agree to precipitate as a solid and not as oil. I think this is due to the fact that the impurities lower the melting point of the amide enormously. In fact, the brown solid melted at around 70°C. Once purified, the white solid of roughly the same mass melted at 123°C. I think that's part of the reason for the oil when recrystallizing in ethanol/hot water.
In “A Simple Preparation of Amides from Acids and Amines by Heating of their Mixture”, it’s written:
« We have found that the optimal conditions for pyrolysis of amide-carboxylic acid mixture is 160-180°C for 10-30 minutes. Prolonged heating can cause formation of substantial amounts of tar, while heating for a short time gives incoplete reaction. »
But I had almost as much trouble with the Work Up, doing the reaction for only 30min, and not everything solidified.
Another procedure involves heating 1 mole of carboxylic acid with 0.5 moles of urea at 160°C for 4 hours. I haven't tried it, but it gives a fairly pure product according to the patent, although yields are only 50%. « UNITED STATES 2,109,941 PATENT OFFICE 2,109,94. PREPARATION OF AMIDES »
I've seen people extracting amide using a mixture of boiling naphtha and ethyl acetate. This can be interesting, but my aim is to use as little organic solvent as possible. I haven't tried it, as I don't have any ethyl acetate to hand at the moment.
If you heat for long enough (180°C), the amide will start to sublimate, making beautiful long white crystals. Unfortunately, this takes a very long time, and I only obtained 400mg of crystals after 11 hours.
I looked at the way people had to make benzamide from benzoic acid, and it doesn't differ too much from mine, yet it works very well for benzamide. There are several videos on youtube if you want to take a look.
So I think the reaction works well, but there's room for improvement in terms of the number of moles of urea used. Nevertheless, the work-up really needs to be improved. The one given in the publication doesn't work, even when using pure acid.
Reaction mixture once solidified:
White amide powder:
Recrystallized amide:
Sublimed amide:
Third step, MDA freebase
This is where I have a problem: my yields are non-existent.
I followed the TCCA procedure from the publication “Organic impurity profiling of 3,4-methylenedioxyamphetamine (MDA)
synthesised from helional” and it didn't work. I'm sure of my amide. I also tried to do the reaction at 18°C because apparently chloroamide forms too slowly at 0°C. That didn't work either. So I titrated bleach without additives and use it for my Hofmann and got nothing after all the work up.
When I synthesized using TCCA at 0°C, the solution turned orange after heating to 75°C. There was a characteristic smell no matter which synthesis route I took, but each time I ended up with nothing.
Even stranger, there is a release of CO2, but nothing afterwards. I'm sure there's no urea contamination, so it's not hydrazine forming. I let a reaction run for a week at room temperature, and we'll see if I get anything.
Perhaps a cosolvent such as ethanol is absolutely necessary. However, many people have succeeded without it, but say they need ethanol as a cosolvent when using TCCA. (You'll form a carbamate derivative, but it will subsequently hydrolyze to MDA)
From the publication :
Synthesis using trichloroisocyanuric acid. α-Methyl-1,3-benzo
dioxole-5-propanamide (0.4 g, 1.92 mmol) was dissolved in water
(14 mL), NaOH (1.45 mL, 10.61 mmol) was added dropwise and stirred
for 15 min on ice at 0 ◦ C. Trichloroisocyanuric acid (149.9 mg,
0.65 μmol) was added, and the reaction mixture was left on ice at 0 ◦ C
for an additional 1 h. The reaction mixture was then brought to room
temperature, then 75 ◦C and held for 30 min. The reaction mixture was
poured into a separating funnel and extracted with dichloromethane
(3 ×30 mL). The organic layer was washed with de-ionised water
(25 mL) and brine (25 mL), dried over anhydrous sodium sulfate and
filtered under vacuum. The organic layers were combined, and solvent
was removed using the rotary evaporator. When synthesised from crude
α-methyl-1,3-benzodioxole-5-propanamide, the final product was a
black-brown soil (270.3 – 382.2 mg). When synthesised from purified
α-methyl-1,3-benzodioxole-5-propanamide, the final product was a
brown transparent oil (286.4 – 351.5 mg)
Synthesis using sodium hypochlorite. Purified α-methyl-1,3-
benzodioxole-5-propanamide (0.4 g, 1.92 mmol) dissolved in water
(14 mL), NaOH (1.45 mL, 10.61 mmol) was added dropwise and stirred
for 15 min on ice at 0 ◦ C. Sodium hypochlorite solution (6.4 mL,
94.3 mmol) was added, and the reaction mixture was left on ice at 0 ◦ C
for an additional 1 h. The reaction mixture was then brought to room
temperature then 75 ◦ C and held for 30 min. The reaction mixture was
poured into a separating funnel and extracted with dichloromethane
(3 ×30 mL). The organic layer was then washed with de-ionised water
(25 mL) and brine (25 mL), dried over anhydrous sodium sulfate and
filtered under vacuum. The organic layers were combined, and solvent
was removed using the rotary evaporator. The final product was a black-
brown soil (248.1 – 293.3 mg).
For the work up, I tried extracting with naphtha or DCM, and either gassing with HCl, or triturating with aqueous HCl and evaporating the aqueous phase. In both cases I got nothing. If anyone has ever done this reaction, I'd love to hear from you.
So the two big problems I'm having at the moment are the work-up of the second step and the third reaction. Nevertheless, I think this synthesis is very optimizable.
That's why I hope we can improve it together.
Feel free to point out my mistakes and share your experiences if you've done this synthesis.
If you want to look for yourself, here are all the sources I used during my research:
"A Simple Preparation of Amides from Acids and Amines by Heating of their Mixture" (Branko S. Jursic* and Zoran Zdravkovski Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148)
"Analysis of Urea Pyrolysis Products in 132.5-190 °C"
" Direct Amide Formation Between Carboxylic Acids and Amines: Mechanism and Development of Novel Catalytic Solutions" (CHARVILLE, HAYLEY)
"SOLVENT-FREE SYNTHESIS OF AMIDE A NOVEL TECHNIQUE" (CHIRAGKUMAR J GOHIL1, MALLESHAPPA N NOOLVI)
"UNITED STATES 2,109,941 PATENT OFFICE2,109,94.PREPARATION OF AMIDES"
"Facile Oxidation of Aldehydes to Acidsand Esters with Oxone" (Benjamin R. Travis, Meenakshi Sivakumar, G. Olatunji Hollist, and Babak Borhan)
"Oxidation of Aldehydes with Oxone ® in Aqueous Acetone" (Kevin S. Webb and Stephen J. Ruszkay)
"Hofmann Rearrangement Yields" The Vespiary
"FACILE ONE-POT CONVERSION OF ALDEHYDES INTO AMIDES results" The Vespiary
"An unusual clandestine laboratory synthesis of 3,4-methylenedioxyamphetamine (MDA)" (Terry A. Dal Cason, Charlotte A. Corbett a, Peter K. Poole a, James A. de Haseth, David K. Gouldthorpe)
"Impurity Analysis of MDA Synthesized from Unrestricted Compounds" (Katherine Cooper)
"Isotope fractionation during the synthesis of MDMA.HCl from helional" (Justin Cormick, James F. Carter, Timothy Currie, Carney Matheson, Sarah L. Cresswell)
"Organic impurity profiling of 3,4-methylenedioxyamphetamine (MDA) synthesised from helional" (Alexandra L. Mercieca , Harrison C. Fursman , Morgan Alonzo, Scott Chadwick , AndrewM. McDonagh)
There are plenty of other sources, too, but they wouldn't be relevant here. If you can't find the publications, I can provide you with the DOIs.