Improved "wet" reductive alkylation help

[XrLeap]

To a solution of the ketone in 300 ml IPA was added a solution of 25,3 g methylamine hydrochloride in 30 ml water followed by dropwise addition of 15 g NaOH dissolved in 40 ml water during 10 minutes while stirring the mixture violently.

Ketone(slightly blue tone) used was MDP2P from benzo wacker oxidation. methylamine hcl used was reagent grade, IPA used was 99.7% reagent grade, H2O used was distilled water. NaOH used was reagent grade.

After all the addition, while stirring, the color was noticed as orange.

When the addition was complete the mixture was stirred for another hour at room temperature.

A solution of 5,5 g sodium borohydride in 20 ml water containing 25 mg NaOH was then added dropwise over 30 minutes while the mixture was stirred violently.

They were all reagent grade.

The 5,5 g sodium borohydride in 20 ml water containing 25 mg NaOH solution was prepared just 20min before the addition, and it was very concentrated.
A mistake was the addition was done in less than 15 minutes.

The stirring was violent, but after completion, the solution seemed to have a layer of oil in the middle that could stir easily and another layer on the outer part wouldn't move at all, gel like..... tried to increase the speed of overhead stirrer until the whole gel would stir, violently.

When addition was complete the stirring was continued for two hours.

ok, how to define violently? SWIM tried not to splash the solution out of the 3 neck RBF(2 neck covered) while stirring with maximum rpm but there were still some part dropping here and there. wasn't that violent?(SWIM's a peace lover, thus this was classified as violent under SWIM:))

When the stirring stopped, there were 2 layers observed, in the dream. on top was a dark color thought to be oil, below was thought to be aqeous layer.

The residual borohydride was destroyed by addition of diluted hydrochloric acid (1:5 conc hydrochloric acid:water) until gas evolution ceased and pH 3 was reached.

The diluted muriatic acid was added in portions(stirred the solution to make sure the aqeous and oil layers would be acidic), till gas evolution ceased and pH3 was reached, using pH paper to test the acidity. The amount of muriatic acid(37%) used was about 350ml.


The alcohol was removed by distillation in a rotovap
The IPA distilled under simple distillation, would the be any significant here? SWIM assume there isn't. But who knows, rotovap might give some magic touch that simple distillation wouldn't have?

After distillation(stopped the distillation just at the point of 100C), there were 2 layers present, the top dark layer was now in small volume only. SWIM did not measure them, does it really matter? If yes, SWIM will dream again to report the volume.

and the aqueous solution diluted with 100 ml water, extracted once with 50 ml toluene, made strongly alkaline with 25% aq. NaOH and then extracted with 2x50 ml toluene.
SWIM dreamt that in the previous step, acid addition, a lot of water(about 400ml) was already added. so SWIM did not "dilute" the solution. The temperature of the solution was about 70C and toluene was added to extract the solution, dark color toluene solution was obtained. Added NaOH solution(the solution became milky) and tested with pH paper till the solution became alkaline, extracted with toluene 2 times.

The combined alkaline extracts was dried over MgSO4 and the solvent removed by distillation.
since there will be distillation of solvent, which BP is at 110C, SWIM did not dry the extracts over MgSO4, anyway, SWIM did not have any MgSO4, but only some silica gel. The solvent was removed, under atm pressure, simple distillation.

After distillation(stopped at temp 130C), some brown salt/crystal was present. the dark color solution was poured out for next step, the salt was kept aside, let's call them brown salt for SWIM's sake, as SWIM really could not identify what were they. The closest SWIM could think was methylamine.hcl as the weight was about 20g. COuld it be the MDMA? no, SWIM did not take them..... SWIM did not ask anyone to try as well. So swim could just stare at them interrogating with acetone, boiling IPA and they just did not give in. SWIM held them at the fridge, now, until they reveal their identification, they will not get released from SWIM's [medline]prison[/medline] fridge.

The residual oil was dissolved in 200 ml EtOAC
reagent grade was used, merck to be sure. CAS number checked, expiry date checked, seal checked, tatse, emm... not checked(SWIM got his own "spirit", so ok)

and 5N HCl/IPA was added in portions until pH 5 was reached. Several times the acid addition had to be stopped and the formed crystals removed by filtration.
the HCL/IPA was dried using silica gel. pH5 was reached easily. crystals isolated by vacuum filtration. a bit brown, dried them in oven.

The salt was then recrystallised in IPA.
oh no, SWIM now suspected all these are out there to tease SWIM, THEY just would not dissolve in boiling IPA. How could SWIM recrystallise? OMG, help, what are they? SWIM then washed them with acetone and they looked white, SWIM and FOAF was so dumb, tried the unidentified salt(tested not like shit but very salty), oh no..... up to 1 g or 2, there was no effect noted till 2 hours later. the last dose SWIM took was more than a month ago, so there should be minor effect noted even with 40mg dosage.

What can these junk be? surely not sodium borohydride as the amount weighed to be more than 10g.

Can any bee, or almighty Barium help SWIM to spot what was the problem, please? What is the critical thing(s) to note in this reaction?

ps: This was the second dream SWIM have about this reaction, both yileded 0% MDMA. Does it matter w/w or molecular % in this case?

[methyl_ethyl]

The amount of muriatic acid(37%) used was about 350ml.

I am not much of a chemist, however this sounds like an extremely large volume of conc. HCL to be used to bring the pH down to 3.

m_e

[XrLeap]

oh thanks for pointing that out, SWIM think 25mg was mistaken as 25g, in the sodium borohydride addition part, thus forming a concentrated base solution.

did this kill the reaction?

[endo1]

In SWIMS case he tried the 

Post 440288

(Barium: "PTC - imine reduction", Novel Discourse) with very low yield for mdma and also tried the 

Post 458857

(Barium: "Improved "wet" reductive alkylation", Novel Discourse) with 0% yield for mdma. Have also heard of other bee's similar findings via pm's. Try Labtops non wet amination.

[Bandil]

oh thanks for pointing that out, SWIM think 25mg was mistaken as 25g, in the sodium borohydride addition part, thus forming a concentrated base solution.

Yes I'd most definately say that it would kill the reaction! In fact i'd be suprised if you did manage to pull of the reaction with an error like that. With an enourmous amount of heavily polar ions present in the water phase your IPA becomes insoluble, thus forming two layers. The borohydride will dissolve in the water layer, effectively preventing it from reducing the immine. The immine would most likely become much more unstable in the presence of such an amount of base. Overall I would guess that you reduced most of your MDP2P to MDP2Pol (the brown gunk left after stripping the IPA).

Next time, please try a new reaction on a small scale first to prevent bloopers  

Regards
Bandil

[XrLeap]

hi Bandil,

Thanks for your reply.

SWIM would like to find out have any bee been successful with this reaction using MDP2P. SWIM has read your post about psuedo one with pF-P2P, but can this reaction be successful with MDP2P?

Thanks for your kind reply:)

[Bandil]

With MDP2P my imaginary friend has told me that it easily yields around 70%! If you run it pseudo-dry (as in using sieves), it gives over 90%  

So yes indeed; MDP2P is a mighty fine substrate for that reaction - you just need to perform it right!

Have a nice weekend,
Regards Bandil

[XrLeap]

SWIM got another question pertaining the wet dream:)

this was performed after alcohol removal, pH3 was achieved by adding HCL to kill off the excessive sodium borohydride.

and the aqueous solution diluted with 100 ml water, extracted once with 50 ml toluene, made strongly alkaline with 25% aq. NaOH and then extracted with 2x50 ml toluene.


in the first extract, assuming the desired product has been produced, extracting it with toluene will only extract away unwanted stuff as honey dissolves in H2O under acidic condition. the subsequent 2 extracts done from base solution contain the goods, SWIM assumes, as the goods tend to not dissolve in water under alkaline situation.

so can SWIM say that only the 2 extracts under alkaline contained the goods?

[endo1]

so can SWIM say that only the 2 extracts under alkaline contained the goods?

Yes. Once you have added the base to make the ph very alkaline an oil layer should fall out and this is your goods. If you don't see a healthy oil layer fall out within a half hour or so of adding the base then something probably went wrong somewhere.

[XrLeap]

and the aqueous solution diluted with 100 ml water, extracted once with 50 ml toluene, made strongly alkaline with 25% aq. NaOH and then extracted with 2x50 ml toluene.
The combined alkaline extracts was dried over MgSO4 and the solvent removed by distillation The residual oil was dissolved in 200 ml EtOAC and 5N HCl/IPA was added in portions until pH 5 was reached. Several times the acid addition had to be stopped and the formed crystals removed by filtration.

swim has another question, which he is not too sure about it.

can swim pool the 2 toluene extracts under alkaline together, then extract the honey with diluted hcl, say 3 to 4 times. pool the aq hcl extract and perform a titration? will this method be ok to crystallise the product?

[XrLeap]

SWIM had another dream

This time, all amount were followed strictly and stirring time was extended for 30 min each to ensure better reaction took place.

After the addition of borohydride, the color of the mixture was noticed to go to dark orange. There was gas thought to be methylamine gas evolved from the violent stirring, ammonia smell.

When stirring was stopped, there were 2 layers formed again, this time the bottom layer(thought to be water) was transperant yellow and the top one(IPA phase) looked very dark. SWIM believe that his water contained too much NaOH and methylamine.hcl added, but all were followed to the letters in this dream.

anyway, swim proceed to add acid to make it acidic and suddenly, the dark color spread to the yellow water. SWIM went on to trip the IPA and the whole mixture looked dark after IPA's absence.

Anyway, SWIM did not give up, thinking that there might be 15% yield as claimed by some. A/B extrations were done, np solvent used was toluene. Titration was used to crystallise, and there were a lot of salt recovered, with brown waxy looking stuff who would not disslove in acetone. Recrystallizaiton was done with boiling IPA, the salt did not dissolve, but all the brown wax did! The salt became greyish white which SWIM believed to be NaCl, as HCl + NaOH -> H2O + NaCL.

Can someone shed some light for SWIM who has had nightmare for few weeks(9 to be precise)...........  

ps endo1: how do you make easy methylamine gas? swim might give that a try.......

[Bandil]

When stirring was stopped, there were 2 layers formed again, this time the bottom layer(thought to be water) was transperant yellow and the top one(IPA phase) looked very dark. SWIM believe that his water contained too much NaOH and methylamine.hcl added, but all were followed to the letters in this dream.

anyway, swim proceed to add acid to make it acidic and suddenly, the dark color spread to the yellow water. SWIM went on to trip the IPA and the whole mixture looked dark after IPA's absence.

It's quite normal to have two layers after the addition. There are loads of salt present in the water phase, which can make the IPA:water insoluble.

In about 50% of the amination runs I too get a dark IPA:water phase. Especially after the evaporation of the IPA. Very strange indeed; I havn't figured out when out goes dark and when it does not. However, the dark colour is easily removed by washing with DCM or toluene after the IPA has been stripped. Yields also seems unaffected when it goes dark!

I don't see where you get that salt you are talking about? How do you perform the workup? I always acidify and dilute the IPA with water, strip most of the IPA. Then the acidic water:product phase is washed three times with a proper NP (usually DCM). This leaves a perfectly clear water phase, which is basified to give the water white product. After an extraction and subsequent evaoporation with the NP, a white oil is left. This is the very pure end product. So I don't see where you should get salt and brown gunk? Sounds a bit strange to me!

Regards
Bandil

[XrLeap]

hi:)

Thanks for the reply.

Afer stripping the IPA(did not dilute with water), SWIM did 2 time washes of toluene, which gave the aq water phase brown looking, the third toluene wash did not go on as the 2nd toluene wash was only light colored.

SWIM then proceed to add NaOH solution to the mixture, making it alkaline. Then extracted 3 times with toluene. The toluene extracts were combined and washed 1 time with water and another with brine. SWIM then added diluted aq  HCl solution to extract the goods, kept the water, the wash repeated another time, and the toluene phase was clean, all the dark colored monster  came to H2O phase. SWIM went on to do titration to get salt in a dish, there were brown/maroon looking oily wax covered with the salt. Scrapped them all in a beaker and dissolved in a beaker, poured in boiling IPA, the salt became gery, and the IPA became redddish brown. Kept the IPA solution in fridge overnight, nothing happened, it became very concentrated but no crystal formed. The grey salt was kept under room temperature(about 30C as it is summer ), it turned to brownish again this time, with some oil covered.

The second amination SWIM ran, the dirty looking stuff was removed easily by toluene, but SWIM followed to the letters(of the procedure), went on to combine them with the alkaline toluene phase. And the whole mixture did not crystallise at all after adding HCl. By the way, this was the third amination that SWIM failed.

[Bandil]

I have a little difficulty deducing your workup method. But it looks very non-standard.

Why not follow the given work-up to the letter? Then you are sure to get a clean product. That titration method sounds a little strange. What are you titrating with? You allready have an acidic water solution of your desired compound. So are you adding more acid or what?

Work up like this:
Acidify the IPA:water phase
Strip IPA
Wash 2-3 times with DCM or toluene
Basify
Extract with DCM or toluene
Strip solvent
Remove last bit of solvent with vacuum
(distill the amine to obtain total purity. This step can usually be omitted when using the boro red. amination though.)

Measure the amount of pure amine left in the flask.

Make the salt of this by any know methods!

Do not try to tweak the methods untill you get alot more experience! The writeups are afterall written for a reason  

Regards
Bandil

[XrLeap]

hi Bandil, thanks for the reply:)

SWiM read about Geezmeister's writeup about getting the goods and crystallisation in stim forum. It is understood that in acidic enviroment, water contains the goods whereas alkaline, non-polar contain the goods.

The difference SWIM sees is his reaction with methylamine was about 1.5 hours and borohydride reaction time was 3 hours compared to your experience of stirring for a night. There could be something wrong when SWIM's mixture temperature  went up to above 40C during borohydride stirring.

In SWIM's aminations, there were always salt(tasted very salty) present.....

Anyway, SWIM will perform this procedure 1 more time and report back.

[endo1]

Usually for mdma, IPA shouldn't be used to wash, crystalize or recrystalize in as mdma is soluble in IPA. One could preferrably distill off the toluene from the base extraction and then vacc distill the mdma freebase oil and then crystalize in acetone.  One might also just gass the toluene extracts of the base extractions. Also, one might use this gassless method:

Post 513755

(Bandil: "Easy preparation of HCl salt w/o gassing", Newbee Forum) .


P.S.
UTFSE for "methylamine gas naoh" for much info and many different options of creating methylamine gas.

[XrLeap]

Another amination carried out. The amount of each materials were added according to the writeup, with approximately 5 to 10 % allowance(SWIM's measurement equipment's tolerence). In the end of 3 hours stirring after adding NaBH4, the mixture looked very concentrated. Oops, too much spilled out(estimated about 150ml of content) of the flask during violent stirring. So, violent stirring without spilling out is an art, which SWIM has to master.

This time, the color was yellowish, something smelled good, in SWIM's mind thinking. However, when SWIM proceed to add diluted HCl to kill of the excessive NaBH4, there were a lot of gas generated, SWIM's guess was the unreacted methylamine and NaOH had started to complete their actions, meaning methylaminie gas generation. This time, about 50ml of HCl was added to make the solution reached pH3, which was higher than the previous one(about 30ml).

The IPA was stripped of and 100ml of H2O was added to dilute the solution. Toluene was used to wash the acidic water phase, it looked yellowish after 3 washes. Looked like Bandil's description, might be start of a good dream. NaOH was added to make base, there were some grey sludge and the water turned brown after basified. Oh, no, not again..... however, there was a layer of clear oil floating on top after a few minutes, but amount was too little. This might not be a bad dream after, SWIM thought. So, toluene was used to extract the clear oil, and the grey sludge was in the toluene phase. Another bad sign comming up. Emulsion, the last thing that SWIM would want to see at this stage, came to SWIM's dream, damn. The solutoin was extracted 2 more times.

Now, the toluene phase looked brown, extracting all other crap apart from the clear oil that was floating on top. They were all kept in fridge before SWIM called it a day.

SWIM would like to find out what are the grey sludge, and has anyone got experience with this? SWIM saw some clear oil floating on top and when extracted with toluene, the toluene became brown(the solutoin turned brownish after addition of NaOH), are they MDP2Pol or some other impurities? How do SWIM remove all these impurities? SWIM actually planned to distill of the MDMA oil, but it estimated to about 10ml only, how can SWIM go about it with SWIM's smallest rbf is 500ml.

""
thanks endo1:) SWIM has read some threads and found out about the methylamine gas generation. As for crystrallisation, SWIM has used variuos methods, 37% aq HCL, titration, 98% Sulphuric Acid.

The easiest would be Sulphuric acid(phospate salt), in SWIM's opinion, but read in somewhere that the "potency" is much less compared to HCl. SWIM will try to master the HCl one.

[Bandil]

The sulfate salt is by far the easiest to make! You simply have to compensate for the heavier cation attached to your product when dosing. So simply take a little more  

Measure the amount and MDMA base you have, and make an 30-40% sulfuric acid in acetone solution. The amount of sulfuric acid should be half the molar amount of MDMA, such that you make the sulfate and not the hydrogen sulfate. Dissolve the MDMA in a proper amount of acetone and stirr heavily. Drip in the sulfuric acid solution and watch the preciptate form    If you use undistilled MDMA, it is a good idea to add 50% of the acid, filter, add 50% of the remaining and filter again. Continue doing these "iteration" untill you get no more precipitate! This way you are sure to avoid forming an acidic product, which is less stable on storage.

Sulfates are somewhat harder to recrystallize in the popular solvents in my experience... Havn't really found anything thats consistently good for sulfates. For some reason almost all chlorides seems to work well with IPA/acetone, whereas sulfates are to insoluble in IPA to dissolve (this is simply empirical data, so it might not be true on several compounds). Other than that they are just as dandy as the chlorides!

Enjoy, regards
Bandil

[endo1]

are they MDP2Pol or some other impurities?
Well, it's not mdp2pol, that would be removed by your washing of the acidic solution with toluene.

How do SWIM remove all these impurities?
Distillation and or crystalize and recrystalize in methanol and or wash with acetone
etc.

how can SWIM go about it with SWIM's smallest rbf is 500ml.
Do a bigger batch or get a smaller rb flask.

The easiest would be Sulphuric acid(phospate salt),
sulfuric acid does not produce a phosphate salt, phosphoric acid does.

in SWIM's opinion, but read in somewhere that the "potency" is much less compared to HCl.

not true at all but using sulfuric acid, in swims experience, it is dificult to prevent some bisulfate from being formed.

[XrLeap]

hehe, sorry for the mixed up of phospate and sulphate:) English is not SWIM's first language and SWIM's major is not in chemistry. Anyway, there is no excuse for SWIM's mistake:) SWIM will learn from here, and SWIM's a fast and good learner.  And SWIM will try the phosphoric acid method, too.

As for this amination, SWIM has a question to ask, but a long one. Hopefully there will be answer from experience bee(s).

What is the most critical parameter(s) in this amination? Apart from correct amount and correct materials used. Assuming that A/B extraction is the basic knowledge already well practised.

1) Addition time of NaOH(10min)?

2) Stirring time for Methylamine gas generation in-situ?

3) Stirring violently for Methylamine gas generation, defination of violent?

4) Addition time for NaBH4(30min)?

5) Stirring time after NaBH4 addition(2 hours)?

6) Stirring violently after NaBH4 addition, defination of violent, again?

7) Addition of acid to kill the excessive NaBH4?

Critical, meaning that the amination will fail if it is not done to the letter. eg Stirring for 1 hr 45 min after NaBH4 will not yield any prodcut at all.

SWIM's guess is the NaBH4 addition time, must not be too fast, as too fast made SWIM's temperature shot up and ended with 0% yield(molar ). The solution always turned dark with fast addition. Anyway, SWIM has not got any yield at all so far, only kept with some toluene extract and will find out next week(SWIM has got many other commiment ).

Will report back.