Warning: Sodium is a dangerous reactive metal.
P-chlorophenyl acetonitrile and dioxane are carcinogenic.
Wear gloves and work outside or in a fume hood.
Methanol is flammable and reactions with sodium are fire hazards.
Fire safety protocols must be in place.
Greetings fellow nerds.
I finally got the next the step of pyrimethamine synthesis to work so in this video we're going to make 2-(p-chlorophenyl)-3-oxopentanenitrile.
This is step 5 of the pyrimethamine synthesis.
First we start with 300mL of methanol dried and distilled from molecular sieves 3A as i've shown in a previous video.
Setup on top a reflux condenser.
Now get 15g of sodium metal.
I showed how to make this in a previous video using magnesium, sodium hydroxide and dioxane.
Links are in the video description.
Cut and roll the sodium into wires like this so we can drop them through the condenser.
Now one by one drop them in with the cooling water turned on.
Don't drop in too much at once or the bubbling will go out of control.
Drop in a piece at a time and let the bubbling get back under control before dropping in more.
What we're doing is reacting sodium with methanol to make sodium methoxide while generating hydrogen gas.
In previous video i showed you can also make sodium methoxide by reacting sodium hydroxide and methanol
and then removing the water with molecular sieves.
That method is much slower than using sodium metal but much safer since it never overheats.
Adding sodium to methanol is dangerous in that it can get so hot that it catches fire.
Considering that methanol and hydrogen gas are both highly flammable this can go very bad very quickly.
Nonetheless, because this is a very fast method and clean method, it's the preferred method in most laboratories.
You also don't get contamination by molecular sieve dust which can be problem for some reactions.
Eventually all the sodium will react and we'll have a solution of sodium methoxide in methanol.
Now reassemble your reflux apparatus into a distillation apparatus and distill off the methanol.
We want relatively solvent free sodium methoxide for the next step.
The reason why we started with excess methanol rather than stoichiometric is because solid sodium methoxide can precipitate out.
This blocks further reaction so it's almost impossible to perfectly react sodium and methanol in a 1:1 ratio.
So we add excess methanol and then remove it by distillation.
Don't discard this distilled methanol.
It's still pure and it's also water free which is useful for upcoming videos where we'll need it again.
Now the final amount of methanol is very hard to boil off so put a shroud around the flask and increase heating to around 250 celsius.
Keep heating until no more methanol distills over.
You can tell when you see the distillate temperature start dropping.
Now turn off the heating, stopper the flask and then let it cool.
We want to minimize the amount of moisture that gets into our sodium methoxide.
While it's cooling we can prepare our reagents.
Get 30g of p-chlorophenyl acetonitrile that we made in a previous video.
Then add 30 mL of ethyl propionate that we also made in a previous video.
All links are in the video description.
Shake it up until everything is dissolved.
Now to the cooled sodium methoxide, add the reagents.
Now add enough dioxane so the total volume is about 300mL.
We made dioxane in a previous video from sulfuric acid and antifreeze and dried it using sodium magnesium oxide aggregate.
Now assemble a reflux condenser onto the flask again and gently heat until it starts refluxing.
What we're doing is using the sodium methoxide to deprotonate the p-chlorophenyl acetonitrile and then react that with ethyl propionate to make 2-(p-chlorophenyl)-3-oxopentanenitrile.
Looking back, i forgot to break up the cake of sodium methoxide first, but eventually with enough stirring it'll break up on its own.
Now as it runs it may foam up.
Adjust heating and stirring to keep foaming under control.
But try and keep it as hot as possible.
Anyway, it's no secret i've been trying to do this reaction for the past 8 months and always failed.
I even used exotic reagents like tetrahydrofuran and potassium t-butoxide.
But i never got it to work.
I was almost ready to give up when i posted my problems here on youtube and a number of you saw right away what was causing my failures.
I was working on a too small a scale.
Even without knowing my scale you knew what the problem was.
It was so much work to make p-chlorophenylacetonitrile i tried to conserve it by working on small 300mg scale.
But for condensation type reactions like this, small scale tends to hurt the process.
Stray water from the air and walls of the glassware can contaminate the reaction and stop it from working.
Scaling up makes the reaction more reliable.
This is one of those times in chemistry where size does matter.
My performance problems for the past 8 months was because i wasn't large enough.
If i had just taken a risk and used everything in one shot this would have worked and i would have been done in january.
Oh well, hindsight is perfect as they say.
I'd like to personally thank Hovsep for emailing me and walking through the problems i was encountering. Thanks.
Anyway, keep heating for 2-3 hours.
Then turn off the heating and let it cool.
Now for aqueous workup and washing.
Get a total of 1 liter of water and fill the reaction flask as much as you can.
Mix it up with a glass stir rod and pour it out.
Wash out the reaction mixture this way.
I didn't just pour it out first because i found the mixture solidifies when cooled.
Adding water first helps make it easier to work with.
Once it's all in the beaker along with 1L of water, stir it for ten minutes or so to thoroughly suspend the chemicals.
Now add in 100mL of 30% or 10 Molar hydrochloric acid and keep stirring for another ten minutes.
Then turn off the stirring and let it settle.
What we're doing is neutralizing the sodium methoxide to sodium chloride and methanol.
The sodium chloride and methanol are very soluble in water and stay in solution while the organic products will separate out.
Most of this is done in a few hours.
But i'm going to let it go overnight.
And here we are the next day.
The organic layer on the bottom should have our product.
Now pour off most of the water and use a separatory funnel to get the rest.
I recommend washing the organic layer again with 100ml or so of water for further purification.
And here is our crude 2-(p-chlorophenyl)-3-oxopentanenitrile.
I sent a sample off for NMR analysis and got back this spectrum.
Over here are the symmetrical aromatic peaks.
This peak over here is the chloroform-d solvent peak since I asked the NMR lab to use chloroform-d for the scan.
This here is that one little proton on the trisubstituted carbon.
It's heavily shifted downfield being connected to such strongly electron withdrawing groups like nitrile, ketone and phenyl.
This spike here is left over dioxane.
It wasn't entirely washed out with the water.
But it's not going to affect our future chemistry so it's not worth putting in additional effort to remove it.
Now for interesting part, this complex multiplet is the protons right beside the ketone and this triplet is the protons at the end.
This complex multiplet is characteristic of our target compound and this is very strong evidence we were successful in making it.
Now this broad peak here is water.
For obvious reasons there is a lot of water contamination.
Overall this spectrum pretty much confirms that we have our desired product.
Our yield is 41g or 99%.
Now i don't think actual synthesis is that good, especially for a garage level synthesis performed using ghetto quality reagents.
The NMR spectrum shows numerous impurities like dioxane and they're probably inflating our numbers.
Literature yields for this procedure range from 50% to 70% so i still think we're doing pretty well.
I'm not going to bother to remove the impurities at this stage since we can remove them later in the next steps on our pyrimethamine synthesis.
So there we have it, after 8 months i finally got to the next step and the hold up was all because i was working on too small a scale.
As you can see the reaction, while very involved, is actually not that hard and if i had done it right the first time i would have been done in january.
Ah well.
Better late than never i guess.
At this point I want to thank you my viewers for believing in me and pushing me forward even though i had essentially given up.
I would have abandoned this if it weren't for you.
Now at this point we should check our map again and see where we are.
We were converting the p-chlorophenyl acetonitrile into 2-(p-chlorophenyl)-3-oxopentanenitrile and have just cleared it.
The last 8 months weren't a total wash though.
We also had to make the solvent dioxane so we can add that to our pathway as an unforeseen detour.
Interestingly enough we also figured how to make sodium metal from domestically available chemicals.
So even if we still totally fail in the upcoming steps we can still say we made a new and useful discovery that justifies our research.
Our next step is the reaction of 2-(p-chlorophenyl)-3-oxopentanenitrile with trimethyl orthoformate.
But before that I'm going to convert the rest of my p-chlorophenyl acetonitrile stock so i have a good amount to use in case I fail more in the future.
And I need to make a video on preparing a guanidine salt.
Hopefully we can finish this project before the end of the year.
Thanks for watching.
Special thank you to all of my supporters on patreon for making these science videos possible
with their donations and their direction.
If you are not currently a patron, but like to support the continued production of science videos like this one,
then check out my patreon page here or in the video description.
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