Warning: Sodium methoxide is corrosive.
Chloroform is carcinogenic.
Wear gloves when handling them.
Methanol is highly flammable.
Sodium metal is a highly reactive and flammable.
Fire safety protocols must be in place.
Greetings fellow nerds.
In this video we're going to revisit making trimethyl orthoformate.
I did this a few years ago but i wanted to replenish my stocks so i'm going to do again with an improved method.
Now it’s a rather unusual organic reagent so first a bit of background for those of you that never saw my old video.
The classic carboxylic acid group has carbon to which there is a double bonded oxygen and a single bonded hydroxyl group.
Now in theory if you could react this with water you would get a carbon bonded with three hydroxyl groups.
This would be called a carboxylic orthoacid.
Now as far as I know these have never actually been made or detected
and even if they could be made they would be incredibly unstable and quickly decay back into the carboxylic acid and water.
Now we know that if we condense the hydroxyl group of normal carboxylic acid with an alcohol we get an ester.
This is well known chemistry and done every day.
We ourselves did this in a previous video making ethyl propionate.
If we went a step further and did this to our hypothetical orthoacid on every hydroxyl group we would get an orthoester.
Interestingly enough, this stuff can be made using a roundabout procedure.
In a previous video i made trimethyl orthoformate using an amateur process
where i reacted sodium hydroxide with methanol and used molecular sieves to remove water and produce sodium methoxide.
This was then reacted with chloroform and fractionally distilled.
I made it in the context of a much larger project to make the antimalarial drug, pyrimethamine.
I used up most of my stocks during that project and recently i wanted to replenish them.
But original amateur process using molecular sieves was rather inefficient and only gave 20% yield.
I wanted to see if there was a better way.
In this video i want to try the professional approach using sodium metal, as well a chaser solvent to improve distillation.
First we need to prepare purified xylene.
This will be our chaser solvent to ensure a higher yielding distillation.
We get some sodium metal, about 5g that we made in a previous video, and add on top some xylene.
This is available as a cleaning solvent in most hardware stores.
I'm using about 400mL.
This is way too much but i actually have several uses for purified xylene so i'm making extra.
Now we setup a reflux column and proceed to reflux our xylene with sodium for a couple of hours.
This destroys any moisture in the xylene and reactive impurities.
Trimethyl orthoformate is water sensitive so we want to reduce that as much as possible.
Once that's done we let it cool and then rearrange our apparatus for distillation.
We distill off our xylene and save it for later use.
Now if you can't get your hands on xylene then you can also use toluene.
But since it boils much lower than xylene it's actually a bad candidate for our objective as a chaser solvent.
Now on a different note, at this point i should also emphasize that all our glassware should be meticulously dried as any water will destroy our target trimethyl orthoformate.
Anyway, in a separate flask we get 120g of chloroform.
This can be made by the haloform process as shown in a previous video.
In top we add about 300mL of anhydrous methanol.
This methanol was previously dried over molecular sieves.
So we're not forgoing molecular sieves, we're just not using them for sodium methoxide synthesis.
Now on top of the apparatus we install a reflux condenser.
Now we get 70g of sodium metal.
It's a good thing that we figured out how to make sodium metal.
This opens up so many new synthetic processes we could only dream of.
Now cut the sodium into small pieces and slowly feed them through the condensor.
What's happening is the sodium metal is reacting with methanol to create sodium methoxide.
This is a much faster and more direct way of making sodium methoxide than the molecular sieve process.
This sodium methoxide quickly reacts with chloroform to produce our target trimethyl orthoformate.
As you can see this is a whole lot simpler than our previous method of making sodium methoxide separately and then adding chloroform on top.
Unfortunately it's still very labor intensive.
We have to go slowly or the reaction boils away.
We also have to stir occasionally so the chloroform evenly distributes.
Overall i spent a good five hours feeding in sodium metal.
Let me skip ahead until we're done.
And here we are. All the sodium has been fed in.
Turn on heating and reflux the reaction mixture for two hours to ensure all the sodium methoxide is reacted.
Now setup a filter frit and vacuum filter our mixture.
Let me put a funnel on our flask here.
Now using the purified water free xylene we made earlier,
we wash out our reaction flask and stir up our salt residue to try and wash out as much of our remaining products as we can.
Let me do it one more time.
And here is our filtrate consisting of methanol, unreacted chloroform, xylene and a little bit of salt.
Now we construct on top of the flask a fractional distillation setup.
Turn on the heat and begin distilling.
What comes off first below 60 celsius is a chloroform methanol azeotrope.
This is soon followed by methanol itself at 64.7 celsius.
Finally, switch out the collection flasks at 95 celsius and start collecting our target trimethyl orthoformate which boils at around 100 celsius.
Now normally we lose some yield in the dead space of flask and distilling columns as trimethyl orthoformate is the last thing to distill in this process.
But we added xylene which has a higher boiling point than trimethyl orthoformate.
So now it will be the last thing to boil over.
In doing so it will push out all the remaining trimethyl orthoformate.
Using a higher boiling chaser solvent or tail solvent to push out the last component in a distillation is a common trick in preparative chemistry.
Although you do need to select a chaser solvent that's non-reactive and doesn't form azeotropes with any compound in your mixture.
This is why we purified our xylene earlier with sodium to remove any reactive impurities.
Anyway, once the temperature rises beyond 110 celsius we're not distilling trimethyl orthoformate anymore and we can stop our distillation.
And our yield was 35.5g or 33%.
Well i'll be honest this sucks.
Our previous process using molecular sieves to make sodium methoxide had 20% yield.
Even though we can make sodium metal now it's still a very valuable and costly reagent to the amatuer.
We would have been better off simply scaling up the molecular sieve process.
Extra chloroform, molecular sieves, methanol and sodium hydroxide is far less costly than sodium metal.
Well at least now i know.
Anyway, orthoesters are very useful for making protecting groups on carbonyl compounds.
They also have a lesser use for making esters on other carboxylic acids,
but this is a rather expensive use and more traditional ester formation reactions are preferred.
Now i don't have an immediate use for trimethyl orthoformate, but i justed wanted to replenish my stocks in case i ever do.
Thanks for watching.
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with their donations and their direction.
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then check out my patreon page here or in the video description.
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