Warning: Sodium cyanide is extremely poisonous.
Para-chlorobenzyl chloride is a carcinogenic lachrymator.
Wear gloves when handling them and work in a fume hood.
Greetings fellow nerds.
We are now entering step 4 of making pyrimethamine
and to do that we need to make p-chlorophenyl acetonitrile,
also known as p-chlorobenzyl cyanide.
We'll be using the p-chlorobenzyl chloride and the sodium cyanide we made in a previous video.
First we get 50g of p-chlorobenzyl chloride.
Interesting enough today is a cold day in my lab and the p-chlorobenzyl chloride actually froze solid.
Now to this we add 7.2g of potassium iodide.
The exact quantity is not critical as this is just a catalyst.
Now we and add 19.3g of sodium cyanide.
Then we add 250 mL of acetone that has been dried overnight with molecular sieves.
Remember to add in a stir bar.
Now on top of the flask setup a reflux condenser column.
Now vigorously stir the mixture and gently raise the temperature until it starts to reflux.
Two things are happening.
First the potassium iodide is reacting with the p-chlorobenzyl chloride to form p-chlorobenzyl iodide and potassium chloride.
Now this might seem a bit odd since organochlorides are more stable than organoiodides.
But this reaction works because it's being driven forward by the very low solubility of potassium chloride in acetone.
Potassium iodide is slightly soluble so the reaction proceeds forward.
This is a useful trick in organic chemistry to make organochlorides into more reactive organoiodides.
It's such a useful reaction that it even has its own name, the Finkelstein reaction.
Usually it's done with sodium iodide since that works even better than potassium iodide.
I'm using potassium iodide because i ran out of sodium iodide.
Now if you're wondering, the aromatic para-chlorine does not react
because aromatic halides are not susceptible to Sn2 nucleophilic substitutions.
Okay, after that occurs the sodium cyanide now reacts with the newly formed p-chlorobenzyl iodide
to create p-chlorobenzyl cyanide, also known as p-chlorophenyl acetonitrile.
The sodium iodide that was produced then goes back into the original step to create more p-chlorobenzyl iodide.
So we only needed a catalytic amount of iodide.
Now unfortunately this overall reaction is very slow since it relies on salts with only weak solubility in acetone.
Even under refluxing this will take a full 24 hours or so.
I'm going to skip ahead until it's complete.
And here we are after 24 hours and then letting it cool.
Now we have to isolate our product.
First we filter over this fritted funnel.
To maximize recovery we also wash the salts with acetone.
And there is our filtrate.
Now p-chlorophenyl acetonitrile is clear but our filtrate is orange from impurities.
Anyway, set the filtrate aside and move the fritted funnel to a new collection flask.
We now dissolve the residue in water.
These salts contain unreacted cyanide and we should deal with that first.
Once it's all dissolved we add an oxidant like bleach or hydrogen peroxide.
I'm adding in sodium dichloroisocyanurate which is a highly soluble form of pool chlorine.
The idea is to convert the cyanide into relatively harmless cyanate.
Granted, you will make small amounts of chloroform due to the reaction of hypochlorite with residual acetone.
You'll also boil off the volatile products due to the heat produced.
But i'd much rather deal with that than with cyanide.
Once again, make sure sure you're doing this in a fume hood.
Now back to our acetone filtrate.
Setup a simple distillation apparatus and distill off the volatile acetone from our reaction mixture.
Set the hotplate temperature to 130 degrees celsius.
The p-chlorophenyl acetonitrile boils well above that so we won't have to worry about it distilling over.
I'm going to wrap my flask in foil to keep in the heat.
While i can easily crank the temperature higher,
I instead want to be as gentle as possible so we don't burn and decompose our product.
Now if you've been following my channel for the past year
you'd know that it's been many months since the last step of my pyrimethamine synthesis.
Why such a lengthy delay? Well i did attempt this back in august but i failed miserably.
Turns out the cyanide i made wasn't pure enough.
While it can dissolve gold and such, it wasn't pure enough for organic synthesis.
So i had to massively purify it by converting to prussian blue, filtering,
and then calcining it with sodium hydroxide to make purer sodium cyanide that i could then recrystallize from ethanol and water.
I had to also remake all my chemicals that i wasted in the august synthesis.
And then i ran into a major setback with my hotplate stirrers all breaking.
It's only now in december that i'm finally back on track.
My apologies for such delays.
I hope you guys are still onboard with the pyrimethamine synthesis.
My major blunder was using bad cyanide and not titrating it to determine purity.
Now due to the excessive dangers of cyanide i'm not sure if i'll make a video on its repurification and titration.
Okay, back to the synthesis.
Keep distilling until the temperature starts dropping, indicating everything that can boil at 130 degrees Celsius has boiled off.
And here is our residue containing our product as well as all the side products and contaminants.
Now we need to wash out any water soluble contaminants.
Add in 150 mL of water and stir.
Now the brown color is from small amounts of triiodide resulting from the oxidation of iodide ions with air.
To reduce them we add in 15 grams of sodium metabisulfite.
This dissolves in the water and reduces the triiodide ions into clear iodide ions.
This will help us wash it out.
Stir the mixture for about half an hour.
You can get even better triiodide removal the longer you react it, but i'm not going to bother.
Okay, now using a separatory funnel recover the lower organic phase and discard the upper aqueous phase.
P-chlorophenyl acetonitrile is denser than water so that's why the phase sinks rather than floats as in most organic extractions.
And there is our crude p-chlorophenyl acetonitrile.
For better purity i recommend you wash the organic phase again with 100mL of distilled water.
To increase our purity further we cool the mixture in the refrigerator to five celsius and let it crystallize.
p-chlorophenyl acetonitrile has a melting point of about room temperature so we can purify it that way.
Just pour off what doesn't solidify.
And there we have it, 44 grams of crude product.
I'm not going to give a percentage yield because we don't know yet if this material is pure.
To get even higher purity, we first remelt the product in hot water
and then we set aside the crude liquid p-chlorophenyl acetonitrile in a room at 18 degrees celsius and let it sit.
A precision temperature controlled cooler is best if you have one.
It will very slowly crystallize.
Unlike the tiny crystals from putting it in a refrigerator.
These very large crystals are much better at excluding impurities.
Wait a few days or even weeks until the crystals no longer grow and then pour off the liquid.
This should be exceptionally pure p-chlorophenyl acetonitrile.
The yield is very low though about 6 grams or 12%.
I'm hoping the leftover supernatant on the left is still pure enough for use even though it didn't crystallize at 18 celsius.
But the only way we'll know for certain is through some form of analysis.
So I sent samples of both the supernatant and the crystals for NMR spectroscopy.
Let's first look at the spectrum for the crystals which know have to be either exceptionally pure product,
or exceptionally pure crap if we failed.
And this beautifully clean spectrum proves we do have our target p-chlorophenyl acetonitrile.
This peak here corresponds to the benzylic hydrogens over here.
And these symmetrical multiplet corresponds to the aromatic hydrogens over here.
This here is water impurities since i didn't ask for dry NMR solvent.
And this is the silicon reference standard used to calibrate the scale.
We don't actually have this in our sample, it was added in by the analytical laboratory running the machine.
I'm actually impressed with just how pure this is, even my professional synthetic work didn't always meet this level of quality.
So we have successfully made high purity p-chlorophenyl acetonitrile.
Our crystallized yield was only 12% though so let's see if the uncrystallized supernatant is still good enough to use.
And this is the NMR spectrum of the supernatant liquid.
It's actually is pretty good for an amateur level synthesis.
This peak here proves we have our desired p-chlorophenyl acetonitrile in relatively high yield.
As usual these are the aromatic peaks from the benzene ring.
We have small amounts of water and the the silicon reference standard.
Interestingly enough, a significant impurity is this stuff.
This, is para-chlorobenzyl amine.
You're probably wondering how that got in there.
It's actually a side product of our reaction.
We made p-chlorophenyl acetonitrile by nucleophilic substitution of cyanide onto a benzylic halide.
But, cyanide is nucleophilic on both ends.
Both the carbon and the nitrogen are nucleophilic and either side can attack the substrate.
Now the carbon side is more reactive in water free conditions which is why we used acetone with the water removed,
but attack by nitrogen is not eliminated.
What we get as a minority product is p-chlorobenzyl isocyanide.
This stuff is actually quite reactive and when we stirred with water we hydrolyzed it to form p-chloro benzylamine and formic acid.
The formic acid is soluble in water and was washed out during our washing steps.
so what we have left is this p-chloro benzylamine impurity that now appears in our spectrum.
We can actually remove this stuff by washing again with some dilute hydrochloric acid.
This reacts with the amines and converts them to water soluble salts.
Before i do that though i'm going to spend the next few weeks making a lot more of our product
so i have extra in case i blunder again.
Additionally, the NMR laboratory that analyzed my samples is closed for the holidays
so I wasn't able to incorporate an acid washed spectra for this video.
Hopefully I'll have that ready for you next month.
Anyway, we have nonetheless successfully made p-chlorophenyl acetonitrile.
Also known as p-chlorobenzyl cyanide.
Step 4 in our synthesis of pyrimethamine.
Now at this point i should probably point out where we are in our pathway to pyrimethamine.
Something i neglected to do earlier on.
In my defence, the pathway changed as i progressed as i eliminated many dead ends before they even made it to video.
And this seems to be the final pathway i'm setting on.
Anyway, we've pretty much covered all the precursors except for guanidine.
And I'll probably make another video optimizing one or two precursors.
As for the main pathway, we have now just cleared the synthesis of p-chlorophenyl acetonitrile.
We have a few more steps to go before we reach our target.
Next we'll try and react p-chlorophenyl acetonitrile with ethyl propionate.
Until then, thanks watching.
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