High yielding trans-2,5-Dimethoxy-beta-nitrostyrene synthesis (detailed description)

[Rabidreject]

I’ll try is again…not the end of the world…

It was just the fact I stupidly added the GAA all at once and the fact I went 4mins over on time for reflux that I differed my procedure from the 10g example you gave.

Oh and I weighed everything - I didn’t go by ml OTHER THAN for the MeOH

 

[Rabidreject]

Also tbf RT for me is essentially always going to be different as I’m working from my flat…

Can I ask, why is it that ammonium acetate is quite often used as a catalyst that works for quite a few Henry reactions using a pretty wide range. Iv seen It used with benzaldehyde to more exotic things - I think even shulgin used it for this synth or maybe it was his mescaline synth. One of the two…just seems like it’s used along with GAA for a lot of Henry reactions that’s all.
I get what your saying about each aldehyde needing a diff catalyst though…

I just realised I went 9 mins over not 4.
I got a bit overexcited when I got a big watch glass full of crystals I think, not realising how light they are…

As I say, I was previously working with DMT which was a bit of a bastard to get nice crystals so seeing that for the first time was incredible!

 

[FENTAMAS]

I don't think that too quick addition of GAA can ruin your yield so much, the reason is probably in filtering/washing step, or in your aldehyde quality.
You can try to make dry bisufite adduct from it and calculate how much you get.

Next time you do it again, try to take even less solvent, for example x5-x6 v/w of abs. IPA, so just enough to dissolve your 2,5-DMBA at RT or with a slight preheating.
As I assume you haven't yet good skills of quick vacuum filtering and good sintered glass filters and/or cold enough freezer.
Also I recommend skip washing step for now, better just filter, dry and weight to calculate your yield, later you can recrystallize it to increase purity.
So that you can more easily figure out what was the reason of poor output. Washing is just for removing of last traces of possible unreacted material and salts.

Anyway here are some notes for washing step to clarify it for your next runs.
When I told "wash it with a minimum amount of cold 1:1 v/v IPA:Water" I meant:

1. You should prepare 50% solution of IPA and distilled water by volume, for example 20ml + 20ml, place it in freezer at least 1h before washing procedure.
2. Prepare you filtering setup with sintered glass funnel.
3. Take out your post-reaction mixture from the freezer and quickly break crystalline lumps with spatula or so.
4. Immediately start your pump, and pour everything on filter.
5. Press your crystalline mass on filter with something inert to evenly distribute it and collect as much filtrate as possible. Turn it off.
6. Take your IPA:Water solution from freezer and pour on filter (you can first pour it in RBF if there something left to wash everything out, but quickly). Pour JUST enough to wet your mass and cover it 1-3mm more. Brake wetted mas with spatula and stir to evenly mix. Start pump and again press it. Turn off and collect it for drying. Preferably get sintered funnel with pore sizes not too large, so that without vacuum there is almost no flow.

 

[Rabidreject]

Yes this is actually what I concluded had happened.
I don’t think I realised that it would obviously get stuck in the RB so it took time to break it all up.
Next time, I firstly would pre chill the solvent to wash it with but mainly I’d transfer it to a suitable beaker instead of letting it crystallise in the round bottom.

That way, when I’m transferring it from the beaker to the vacuum filter, I can do it MUCH quicker.

I got a little jar full of it - looks like more than it is as they are such fine crystals, the consistency is a little like fibreglass!

I do actually have one of those super fine vacuum filters that’s held together with a blue clamp - it doesn’t work for gravity filtration so I’ll use that next time also.

Thanks a lot for your help. I’ll try again soon and this time actually keep the filtrate until after iv weighed the crystals!

 

[Rabidreject]

Oh also; I told this to the guy who was helping me to the finish line of the n,n-DMT synthesis via reductive animation - bare in mind everything iv learned about chemistry has been whilst iv been in pretty bad benzodiazepine withdrawal.
So sometimes I may make silly mistakes or not be quick enough or just generally be inexperienced.
I’m not stupid though- I do learn the mechanics of what I’m doing each time but when you are in bad withdrawal your mind is just fog….so yeah.
I appreciate your help…But am sorry when I make silly mistakes - like letting it go 9 mins too long!

 

[Rabidreject]

At least I have NO DESIRE to synthesise anything addictive!

 

[Rabidreject]

Oh also with regards to re-x’ing - I figured I would worry about that and do that in a beaker when I actually plan to reduce it…

Also, now I think about it - it seemed like there were a lot more crystals in the RB before I had to take time to go grab my glass rod and break it up - then probably used solvent that was way too warm to try and wash it out - melting yet more…duh. Idiotic really. It’s not like I haven’t done freeze precip’s hundreds of times at this point.

I suppose I could re-x the aldehyde but honestly, it came from the same dude with the Smokey as fuck ethylenediamine as well as the nitromethane and I asked, it was fresh from china so I doubt it was bad quality to be fair…

I think you are right in that I didn’t properly prep the washing solvent and probably dissolved a load that were already there…see that’s one of them duh withdrawal fogginess…

I’ll get there and tbf, I have no REAL plans of yet other than to reduce it to 2c-h. Maybe I’ll brominate it? Seems like one of the easier ones to start with even if I don’t love the final product…I also don’t hate it lol

 

[Rabidreject]

Okay I tried it again and was strict about the timing and it didn’t crystallise nearly as easily for some reason…

Had to really cool it with an ice bath to induce crystallisation this time.

I personally think it seemed to work better last time but I guess I can’t say that until iv done a decent vacuum filtration after it’s been cool for quite a while and then obviously weighed it.
We’ll c…it’s all been logged in my spreadsheet…

 

[Rabidreject]

I know you already accounted for excess nitromethane within your numbers so that it goes to completion but last time I thought I would add a tiiiiny bit extra, just in case it was less pure than I figured so I think instead of 4.5g i added 5 or something like I that (I do have it written down just not in front of me) but I feel like either that, or the extra time I gave it last time made it crystallise more readily.

I have some better vacuum hose now and so can use my finer vacuum filter as well this time.

I’ll leave it in the freezer over night and then tomorrow crush it up with a rod quickly then put it back in the fridge while I set up the vacuum pump etc…

Should be interesting actually…

 

[Rabidreject]

Oh and I have a load of 70% Ipa In the fridge to wash it QUICKLY!

 

[FENTAMAS]

So you done it 10mins in 30ml MeOH or 1h in 50ml(?) IPA this time?

70% IPA?) Man, where do you get these numbers?) I thought I clearly indicated a few times about 1:1 v/v that's 50% IPA (or 1:2 v/v for methanol that's 33% MeOH).
Do you realize that water is for decreasing solubility of nitrostyrene product in it? The more water - the less product you will wash out.
Better place 50%(!) IPA in freezer at -20C.
Even better, as I already said - skip this step for now, as I see you can find the way to make something differently anyway)

If you intend to do it step-wise, place it back in freezer at -20C again for at least 30mins before filtering.
Don't forget to save your filtrate(s).
There is different approach of work-up for this type of syntheses where you pour your reaction mixture in big excess of cold water and then filter it,
but in that case sometimes it can crash out as an oil or as a fine powder that is hard to filter and after drying become very irritant.

 

[Rabidreject]

No I used the same solvent again so 30ml MeOH, I observed it between 5-10 mins for any colour change then pulled it straight off at 10mins.

Sorry I didn’t read the IPA numbers too clearly as I didn’t use it….other than using cold IPA to wash stuff out…

So this time I set everything up first (the vacuum filter), filtered it - looked like a similar amount, however, I did what you said and was very quick and skipped the washing step - figuring I’ll just re-x it all before I reduce to 2c-h.

This time, yes I kept everything, put it straight back in the freezer (other than what’s drying in my desiccator) and almost straight away can see it crystallising again.

When I do my next filtering I shall use the finer Büchner funnel I have, just in case what is crystallising now was too fine and passed through the filter paper (may well have been the case but then it was translucent by the time it got to the vacuum erhlenmeyer I used to filter this time.

I fucked up one number - once during one synthesis. Okay I may have said a few random numbers but was going from memory. I have already said iv been in Benzo withdrawal and it destroys your memory so I appologise. When I performed the syntheses I had your write up in front of me and just followed the 10g synthesis using scales as opposed to ml (other than the MeOH).

As I say; if anyone wants my spreadsheets with notes, pictures, videos and actual the exact timings and quantities - they are more than welcome and I’ll upload…

 

[FENTAMAS]

Dilute your filtrate with water (at least x3 of its volume) and then place it in freezer before filtering again.
I wonder what you will get.

"As I say; if anyone wants my spreadsheets with notes, pictures, videos and actual the exact timings and quantities - they are more than welcome and I’ll upload…"
Yes, please.

 

[Rabidreject]

Oh also 70 because….well that’s what I had in my cupboard and a lot of it -70% iso…as opposed to the 100% stuff iv got.

yeah the water thing you mention earlier is what I tried the first time I tried this RXN and didn’t realise I needed GAA. Sorry ‘the water thing’ - not a great description!
I meant crystallisation by throwing the RM into really ice cold water to lower the solubility.
That IS exactly what happened I got a yellow oil…mind you I guess it should have been orange just looking at these x’stals.

So this time, first filtration gave me the same as last time - actually slightly more.

I got 2 grams on the first attempt and then 2.1g on the second attempt but I also put the RM back in the freezer after the first filtration and got a bit more.

Hang on….spreadsheets r on my tablet - I’m on my phone! I’ll just switch

 

[Rabidreject]

Okay - as I say, I’m not organised, I’m learning as I go and I take (s)-crappy notes!

okay it won’t let me attach either a ‘numbers’ file or an excell file….thats weird…

 

[Rabidreject]

No idea how to upload it to you then….I know there is a way because I simply modified or at least based my spreadsheets on one sent to me for the DMT synthesis, so I know it can be uploaded just don’t know how….maybe in direct messages?….nope

thats so odd…if You can help me work out how to upload either a numbers or excel format but would rather send the numbers documen as the excel save moved everything about a bit…

 

[Rabidreject]

Also, I shall dilute it and try it now….

edit: ah interesting - added a load of water to it (cold water from the fridge) and it did basically what happened when I disposed of the last lot but didn’t keep it.
Soon as I started pouring in the water, it went from dark red to looking like orange juice with a small amount of oils stuck around the bottom that looks darker than the surrounding orange/yellow colour…iv set it in the freezer again for a bit but I won’t let it freeze as I assume the water may do if left in…

 

[Rabidreject]

So do I separate the oil and re-x it from MeOH? Obviously a small amount of it?

 

[Rabidreject]

Wow okay, it’s gone like a slushy again after adding water and a while in the freezer - interesting

 

[Rabidreject]

Ah yes okay - after having re-chilled, 2nd filter, then added water: froze it solid by accident haha brought it back up to 0–2c then re-filtered for a third time. Got a decent amount but most of the ‘goodies’ were stuck (probably when it froze) to the sides and edges of the RB, tried to flush it through using cold water but water doesn’t want to move it very well so I grabbed a tiny bit of iso I had leftover in the freezer (70%) - probably 10ml and could see it def moved it about just wasn’t enough.
So iv put what I already gained into the vacuum desiccator as always and then I added 5-7ml of warm MeOH into the RB (kind of with the intentions of dissolving it and re-crashing it out, however, all it did was dislodge the mass from the edge of the RB and so I put it straight back into the fridge and when the iso is cool will flush the flask through - looks like quite a lot there to be fair…I have definitely at very least doubled my yield - even if the actual crystals weren’t as good - doesn’t matter it’s all getting re-x’d before I do anything with it all anyway.
It’s just interesting - I see what you mean now. You add water it dilutes it and makes it less soluble in solution. Of course…

I did get a TINY bit of oil on the bottom. Dunno if this is impure product or some sort of impurity but hey, I’m chuffed with myself

Thanks very much for all the help…I really do appreciate it. I’m pretty dam ill atm and so am very dopey and just have flu brain so I’m sorry I misremembered numbers.
Again, if you can tell me how to upload a spreadsheet I’ll do so, maybe if I tried on an actual computer….ill see