MDA Synthesis From Helional

[DABOMB]

Excellent writeup and videos, I’ve had great success with this synthesis, so thank you! It’s cheap too, but does require a LOT of solvent.

If your aldoxime forms pure white crystals, there is no need to do the solvent extraction in stage 1 with all that DCM. You can simply filter off the liquid from the aldoxime crystals on a buchner and wash with water a few times and cold brine once (and perhaps cold ethanol if you are being careful) to remove any excess starting hydroxylamine and NaCl that forms. Only other impurities besides the CO2 that exits could be leftover helional (unlikely with the excess hydroxylamine used), maybe hydrolyzed hydroxylamine if pH gets too high and gem-diols / aldehyde hydration products if there's too much water in the system, but this shouldn't be a problem with the water. Perhaps some polymeric junk if the aldehyde reacts with itself under prolonged exposure to base, but the conditions are mild so this should be rare.

In any case, there is usually no need for all that DCM during stage one if your aldoxime crystallizes, you can just filter it and dry it & move onto the next step, but make sure you dry it somewhat well in a dessicator or vacuum chamber with dessicant as there are potential side rxns that can occur in the next Beckmann rearrangement / xylene step with too much water, but that is unlikely too. Also you can use normal xylenes (mix of the isomers instead of o-xylene) and it works fine if anyone is wondering.

If you are having trouble getting your oxime to crystallize, first add booster doses of hydroxylamine/sodium carbonate (like 4-6g HO-NH₂ + 3-4g Na₂CO₃ for each booster dose or twice that for this scale, I was doing on a 100g helional scale, dissolved in 15-25mL water), then slowly add that booster dose to the RM (over 5-10 minutes) making sure pH is between 8-9 in the RM, stir for another hour or two, and if still no crystals you can do a couple more booster doses. If still no crystals form (which is unlikely with these boosters, it worked for me multiple times after not getting crystals initially) -- then you can concentrate the RM via vacuum distillation to about 1 or 2/3rds the volume and cool again. You should be able to get nice pure white oxime crystals without those liters of DCM.

If anyone needs help with this reaction feel free to message me. As others have said, there are other ways to go about this rxn that may or may not be a bit easier, we can talk about that if anyone's interested. PEACE!

~DB <3

 

[yuvan123]

Hy bro after 40 hrs of stirred i get yellow layer on top what should i do now

 

[yuvan123]

I also added a booster doae but did not work

 

[Irving Langmuir]

Hi, I'd like to post the improvements I made for this synthesis:

For oxime synthesis, 40 hours is just insane, you can do it in just 2 hours :

10g helional + 15.35g sodium acetate tetrahydrate (or 8.16g anhydrous) + 3.88g NH3OHCl in 50mL water and 50mL EtOH. Reflux 2h. Extract 3 times 20mL DCM (You can dilute the Rm if the DCM forms an emulsion due to the ethanol) and wash the organic phase twice with 50mL water. The DCM extracts are dried using Na2SO4 and then evaporated at 110°C. You will see that the Rm becomes pink after 10min, then yellow after 30min. You'll get almost quantitative yields (96% here).

Oxime, even when vacuum-dried, is a pain in the ass to crystallize. I'd therefore advise you to use it in its “oil” form for the Beckmann rearrangement, as it makes no difference. The oil is quite viscous, so I'd advise you to heat it when you want to transfer it to another glassware. As it heats up, it becomes much less viscous.

For Beckmann, the reason GhostChemist uses so much DCM is that the amide is not very soluble in DCM. In fact, in the publication, they use DCM to triturate the amide. My advice would be to let cool the Rm, and when the brown amide precipitates, just filter it out, and recrystallize the amide in heptane, toluene or xylene (any apolar solvent with a high b.p.). When cold, apolar solvent solubilizes very badly the amide, so if you give the Rm enough time to cool down after the Beckmann rearrangement, you won't have any loss.
Also, as long as the reaction is green, it's not complete. It will start to turn light/dark brown when it's finished.

 

[Wan Jack]

Hello, can I make the synthesis according to your method?（Extract 3 times 20mL DCM）Can I directly extract three times with xylene, and then proceed to the next step of rearrangement directly without distillation?

 

[Wan Jack]

15.35g sodium acetate tetrahydrate

This should be sodium acetate trihydrate？

 

[Irving Langmuir]

If oxime is soluble enough in xylene for extraction, then yes, you can. You can use any hydrate of sodium acetate, and even anhydrous sodium acetate, just pay attention to the molar mass so that you use the right amount.

 

[Irving Langmuir]

hydroxylamine can even be simply synthesis OTC with good yields:

(You can skip the formaldehyde part if you don't have any, that works just as well).

 

[Irving Langmuir]

Your reaction takes longer because you're doing it at R°t and not at reflux. If we take the rule of thumb: reaction rates for many reactions double for every ten degrees Celsius increase in temperature, which means that my reaction takes place about 32 to 64 times faster than at R°t. Moreover, most protocols, such as for vanilin, suggest only 20 min at reflux to complete the reaction.
Even for large-scale applications, this is sufficient; for example, p-Hydroxyphenylacetaldehyde Oxime is produced in just 6h at R°t. The maximum time I've been able to find for oxime synthesis is for caprolactam, 12h at 100°C. So even though scaling up may take longer, I'm sure you can form your oxime in less than 12h if you heat at reflux, and not in 40 hours, unless there's an interest in doing the reaction at R°t, in which case I'm interested to know why.

 

[GhostChemist]

Did you carry out this reaction with an increase in scale by 10x?

 

[Irving Langmuir]

Not yet, but I'll give it a try and let you know if it works in 2 hours.

 

[GhostChemist]

This will be important information that will complement the works

 

[Irving Langmuir]

I'm sure it works because the reaction rate depends on the concentration and not on the volume, whether you're on a small scale or a large scale the concentration remains the same, your reaction will take 3 hours whether you're handling mmol or moles, otherwise industrial processes would take months.

Reaction rate - Wikipedia

en.wikipedia.org

 

[Irving Langmuir]

Your reaction lasts 40h because you do it at R°t, do a reflux set-up and you will also finish it in 2h-3h.

 

[GhostChemist]

The activation energy has not been established for this process, therefore it is incorrect to rely on empirical equations without an experimental part

 

[GhostChemist]

Ok,
Which stage of this reaction is limiting reaction?

 

[Irving Langmuir]

This is what I gathered, based on several publications:

"The rate-limiting step of oxime formation at neutral pH is the dehydration step, which is difficult due to the α-effect of aminooxy oxygen heteroatom "

"In the pH range from ca. 3 to 7, the acid-catalyzed dehydration of the tetrahedral intermediate 67/68 is typically the rate-determining step"

 

[Irving Langmuir]

I have carried out the Beckman rearrangement with several catalysts (Cu(OAc)2, ZnO, Ni(OAc)2, ZnCl2), in different solvents (toluene, xylene) and without solvent.

I noticed that each time there was an impurity melting at around 110°C after isolating the amide, which is not soluble in toluene/xylene when hot. Is it the nitrile?

Sometimes the amide precipitates as a solid, but sometimes it forms a sort of black sticky oil/goo. Occasionally the latter form a solid by adding EtOH and water, but this solid is not the amide. (amide has solubilized in EtOH). I've found many people with the same problem, especially with the xylene/Ni(OAc)2 method. Does anyone know how to extract the amide when it forms this black goo? Melting it and throwing it into cold water doesn't work either. Does anyone know what causes this?

 

[sarita123]

Can I use xylenes cas 1330-20-7 in place of o - xylene

 

[GhostChemist]

I think yes, if it bp is not low 138°C. Because the range of temperature for this synthesis is 130-140℃

 

[Gaussenberg]

First of all, thank you for a good presentation - easy to follow and good quality photos.

In the list of reagents in Scheme 1, you indicate the amount of water to dissolve the sodium carbonate in, but not the hydroxylamine hydrochloride. Also, from going over the stoichiometry, the amount of sodium carbonate used indicates that it should be the anhydrous salt, which you didn't specify. Using the more common decahydrate salt would give sadly low yields!

I had a few more questions, but they were answered in the replies.

Again, thank you ! I am hoping to start on this in a few weeks!