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Warning:
This experiment uses toxic chlorine gas.
This must be performed outside or in a fume hood.
Greetings fellow nerds.
In this video we're going to make chlorotoluene.
This is the first step to making the anti-protozoal drug pyrimethamine.
There are a few approaches so i'll show a couple of them here.
First we get a liter sized flask and add some fine steel wool.
I'm using a ten gram roll but the exact quantity is not critical.
Now we add 500 mL of toluene.
This is sold as a paint thinner solvent.
I had to acquire mine by fractionally distilling some lacquer thinner.
Anyway, here is our mixture and around it we setup this chlorine generator.
I've already detailed how make chlorine gas in a previous video so i won't get into it
here.
My setup uses the trichloroisocyanuric acid and hydrochloric acid method.
Now the chlorine gas generated is first led through this flask of concentrated sulfuric
acid to dry it.
My acid is brown black because it's very low grade drain cleaner acid.
You don't need high quality acid as all it's doing is removing water and won't be a part
of the reaction.
Now the dry chlorine gas exits and through this tube
where it goes down a reflux condenser on top of our flask containing toluene.
The chlorine reacts with the toluene here and any toluene vapor is recondensed by the
condenser.
Any waste gases are sucked out by this vacuum tube on the top of the condenser and to the
right.
So let's get started.
First we drip in the hydrochloric acid and we can see the yellow chlorine gas forming.
I'm using enough reagents to produce four moles of chlorine atoms or two moles of diatomic
chlorine gas.
Go slowly as the toluene mixture can only absorb so much gas at a time.
So moving over to the toluene.
It'll take a minute or so for air to purge out of the tubes before the chlorine gets
to the toluene.
And there we go.
The reaction is very exothermic and you don't need to heat it up.
I added a stir bar previously to help mixing in my reaction.
What's happening is the chlorine is first reacting with the iron in the steel wool to
produce ferric chloride.
This ferric chloride then acts as a catalyst for the reaction of chlorine with toluene
to produce chlorotoluene and hydrogen chloride.
This is the textbook reaction of electrophilic halogenation taught in almost every university
or college organic chemistry course.
Now if you happen to have anhydrous ferric chloride you can add that directly as a catalyst.
Using steel wool is a cheaper amateur way of making ferric chloride in-situ since we're
already injecting chlorine gas.
Okay we're halfway done and the toluene seems to have dissolved the polyethylene tubing.
I'm not too worried though as we'll be distill this reaction mixture later.
You can avoid this by using polytetrafluoroethylene tubing or PTFE tubing.
I'm just going to push the tubing further into the reaction and keep going since this
tubing is cheap.
Now you'll notice a lot of steel wool remains.
Ferric chloride is an extremely active catalyst for this reaction so only a tiny amount is
needed.
It works so fast to react the chlorine with the toluene that no chlorine is left over
to dissolve more steel wool.
Looking back i probably could have gotten away with just using a couple grams of steel
wool.
Oh well.
Now i must emphasize to do this reaction in a fume hood.
As said before the byproduct is hydrogen chloride.
Hydrogen chloride has very low solubility in toluene and most of it will exit out the
top of the reflux condenser.
That's why i had the vacuum tube at the top of the condenser i showed earlier.
Nonetheless some it will likely escape so you're going to need a good fume hood or to
work outside.
Okay all the chlorine has been added.
Now we just let the mixture stir for an hour to complete the reaction and then we let it
cool completely to room temperature.
Here we are after everything is at room temperature.
Now we add 500mL of water to dissolve the iron chlorides,
any soluble impurities as well as wash out any residual hydrogen chloride.
Oh i forgot to remove the unreacted steel wool.
You can use an iron wire hook to fish it out.
Strictly speaking it isn't necessary to remove the wool,
it just makes it easier later.
Okay back to the mixture,
we add the rest of the water and give it a thorough stir to wash the chlorotoluenes.
Turn off the stirring and let the layers separate.
Now we remove the lower aqueous layer.
If you have a separatory funnel that can handle a litre of solution then use that.
I don't so i'm just going to use a tube and siphon out the bottom layer.
Here we are after most of the aqueous layer has been removed.
At this point, we now add a saturated solution of sodium bicarbonate, also known as baking
soda.
The amount you should add should bring the total solution volume to one liter again.
What we're doing here is using the alkaline sodium bicarbonate to react away any remaining
hydrogen chloride.
The hydrogen chloride must be removed to make the subsequent distillation easier.
Now once again we remove the aqueous layer by siphoning.
And here we are, our washed mixture of crude chlorotoluenes, byproducts and unreacted toluene.
To separate it we're going to use our least favorite technique, fractional distillation.
What distills off first is going to be a tiny amount of residual water from the washings
and toluene.
Then pure toluene will distill over at around 110 celsius.
Continue distilling until the temperature rises to 135 celsius then switch out the receiver
and you'll then be distilling the chlorotoluenes.
Chlorotoluenes themselves distill around 160 Celsius.
Continue distilling until nothing distills over, or if you reach a temperature of 170
Celsius.
And there you have it, chlorotoluene.
Now making chlorotoluene this way with chlorine gas is fairly clean and straightforward,
the waste products from the chlorine source remain separate from the chlorination reaction
and only hydrogen chloride gas is produced which boils away or can be easily washed out.
However you might prefer a method that doesn't involve any toxic gases and their associated
safety hazards.
I'll briefly go over another method i tried that avoids gases at the cost of more involved
separation steps.
First we start with 125 grams of anhydrous ferrous chloride.
This will serve as our catalyst for the reaction.
You can also use anhydrous ferric chloride if you happen to have it.
Do not use hydrated iron salts as water is detrimental to this reaction.
Unfortunately steel wool cannot be used for this approach.
I tried it and it doesn't work.
I'll detail how to make anhydrous ferrous chloride if there is enough interest.
Anyway, now connect a claisen adapter fitted with a reflux condenser and a funnel.
We'll be adding reagents through the funnel and then sealing it between additions.
Now to this ferrous chloride add 500 mL of dried toluene.
This toluene was dried by azeotropic distillation using a dean-stark trap as shown in a previous
video.
Now vigorously stir the reaction mixture and add to it 10g of trichloroisocyanuric acid
powder every 15 minutes
for a total of 160g over 4 hours.
Between additions, take the funnel out and stopper the claisen adapter so the vapors
go into reflux condenser instead.
What's happening is the trichloroisocyanuric acid is reacting with the toluene to directly
form chlorotoluenes and cyanuric acid.
The ferrous chloride serves as a catalyst.
As you can see no gases are produced or consumed so this requires a much simpler setup to perform
without a complicated gas generator.
Now you need to go slowly when adding the trichloroisocyanuric acid because the reaction
is very exothermic
and going too fast will result in a thermal runaway.
Trust me, i blundered quite a few times trying to speed this up.
If you notice the mixture starting to reflux or boil then stop further additions and let
it cool before continuing.
If you go slow enough, you'll never see any refluxing and infact the condenser will never
be needed.
Nonetheless i still recommend including it just in case.
Now once all the trichloroisocyanuric acid has been added
let it continue stirring for at least a couple of hours after it has reached room temperature.
I let mine continue stirring overnight.
Now we have to separate the chlorotoluenes from the cyanuric acid and ferrous chloride.
This a bit tedious because we can't just distill it as it's too thick and gooey.
Filtering it is also problematic as the particles are fine enough to clog the filter
and a lot of it remains soaked in the residues.
The most effective way i found was to add an equal volume of water and then setup a
dean-stark apparatus.
The water is the carrier fluid and will carry out the toluene and chlorotoluene.
Note that toluene is lighter than water and chlorotoluene is heavier than water.
So you'll have to change the operational mode of your dean-stark apparatus as the recovery
progresses.
Eventually i was able to fully separate the organics from the residues.
After that we then separate the water and just fractionally distill the organics to
separate toluene and chlorotoluene
just like we described previously.
As you can see, this method, while avoiding gases pays for it's reactive simplicity with
a more complicated separation step.
And there you have it, two ways of making chlorotoluene.
Now the chlorination of toluene actually forms different isomers of chlorotoluene all with
very similar properties.
Ortho-chlorotoluene where the chlorine is next to the methyl group, also known as 2-chlorotoluene.
Meta-chlorotoluene where the chlorine is another carbon over, and also called 3-chlorotoluene.
And para-chlorotoluene where the chlorine is furthest away from the methyl group, this
is also known as 4-chlorotoluene.
Now in electrophilic halogenation the methyl group actually affects the electron distribution
of aromatic ring
and meta-chlorotoluene product is negated so only trace amounts are produced.
The major products are ortho- and para-chlorotoluene.
To make pyrimethamine we want para-chlorotoluene.
Unfortunately the two methods i've shown produce ortho-chlorotoluene as the major product.
The reason why it took me two months to make this video
was because i spent most of it researching and testing other methods to make chlorotoluene
in the hopes of getting para-chlorotoluene as the major product.
They all failed.
Now you're probably wondering how i know this
and tested for the ratio of isomers if the properties of all the isomers are very similar.
I kinda cheated and sent a sample of my chlorotoluene mixture to a laboratory
that performed nuclear magnetic resonance spectroscopy analysis.
They then sent me back this printout that shows the nuclear magnetic resonance spectrum,
or NMR spectrum for my sample.
I know it all looks complicated but this spectrum tells me the ratio of chlorotoluenes produced.
The worst method i found was reacting a 50% sulfuric acid solution with toluene and trichloroisocyanuric
acid.
While it produced chlorotoluenes in good yield, only 28% was the desired para isomer.
The rest was the unwanted ortho-isomer.
Somewhat better was using chlorine gas and various forms of iron chloride catalysts.
I tried a small amount of steel wool as i showed here.
I tried huge amounts of steel wool.
I even tried anhydrous ferrous chloride all while using chlorine gas.
I got chlorotoluene with para-chlorotoluene percentages in the mid 30s.
The best method so far was the method of using ferrous chloride catalyst
and directly adding the trichloroisocyanuric acid to the toluene mixture.
This gave me a para-chlorotoluene percentage of 41%.
After two months of work and a thousand bucks of wasted chemicals and broken glassware,
I decided to stop here and just show the best and most straightforward methods in this video.
The task isn't impossible though.
Para-chlorotoluene can be made easily enough with laboratory grade chemicals in a multistep
approach.
But for amatuer synthesis the chemicals are very difficult to acquire or purify.
Perhaps in a future video i'll return to this problem and see if i can make para-chlorotoluene
in one step.
For now, we can still use this mixture of ortho- and para-chlorotoluene isomers
by adding a second separation step to isolate just the para-chlorotoluene.
I'll be showing the isolation step in an upcoming video.
Thanks for watching.
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