Warning: Sodium hydroxide and sodium methoxide are corrosive. Chloroform is carcinogenic.
Wear gloves when handling them. Methanol is highly flammable. Fire safety protocols should be in place.
Greetings fellow nerds.
In this video we're going to make trimethyl orthoformate.
Now it's a rather unusual organic reagent so first a bit of background.
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.
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.
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 and we're going to do just that in this video.
We're going to focus on making trimethyl orthoformate because I want to use it to make an antiprotozoal drug.
It's also the simplest of the orthoesters and is thus a good demonstration reaction.
It uses the simplest carboxylic acid which is formic acid, and the simplest alcohol which is methanol.
To start get 200mL of methanol and add 40 g of sodium hydroxide.
Then we stir until completely dissolved.
This might take awhile as sodium hydroxide dissolves very slowly in methanol.
What we're trying to do is make sodium methoxide.
But this reaction doesn't go to completion since it's easily reversible as the water reacts with sodium methoxide again.
Professional labs make sodium methoxide by reacting sodium metal with methanol.
This avoids the water issue entirely.
But obviously this reaction is very dangerous since the methanol can easily catch fire.
Sodium metal is also somewhat difficult to obtain domestically.
To force the equilibrium to the right we add 100g of molecular sieves 3A.
Make sure they were previously dried per the manufacturer's instructions.
Now seal up the flask to prevent evaporation of the methanol out but more importantly to prevent moisture getting in.
Now mark off the starting level of the flask and let it sit for a few days.
As demonstrated in a previous video, molecular sieves are very good at removing water from solvents.
By pulling the water out of the system we force the equilibrium toward to the formation of sodium methoxide.
As this happens the liquid level will go down as the water is removed.
It's pretty slow and i'm timelapsing this video over twenty four hours.
Everyday give the flask a good shake to prevent dead pockets of molecular sieves.
Now when the liquid level stops decreasing over a twenty four hour period,
we're ready to use the solution of water free sodium methoxide in methanol.
Now set up a flask and stir bar with a vertical condenser column for reflux.
I should emphasize that at this point all subsequent apparatus should be meticulously dried before use, preferably in an oven.
Any water that comes into contact with the reaction mixture will destroy the trimethyl orthoformate we intend to make.
This is because orthoesters are very water sensitive chemicals
and irreversibly react with water to release their alcohols and normal esters they are made from.
So be as dry as you can.
Now transfer the sodium methoxide solution to the reflux flask.
Try not to transfer any of the molecular sieves but a few pellets is not a problem.
Now turn on the cooling water and start heating the mixture until it starts to reflux.
When it starts refluxing, turn off the heating and get 30mL of chloroform.
We made this chloroform in a previous video on the haloform reaction and it's also been dried over molecular sieves.
Now add the chloroform 1mL at a time through the top of the condenser to the hot sodium methoxide solution.
Do not add it all at once or the reaction will go into thermal runaway.
Add in at rate to maintain constant reflux.
The reaction is very exothermic and will boil quite vigorously with every addition.
What's happening is the chloroform is reacting with sodium methoxide to produce trimethyl orthoformate and sodium chloride salt.
The sodium chloride has low solubility in methanol and precipitates out as a white powder that you can see here.
Now even though the reaction is very exothermic we started with a hot sodium methoxide solution
because the reaction proceeds very slowly at cold temperatures.
The false sense that the reaction is under control can lead you to add more chloroform than the apparatus can handle
and when it does start up the self heating leads to thermal runaway.
I'll admit I made this exact blunder and spent my Christmas cleaning my fume hood of the resulting chemical waste.
Anyway, once all the chloroform has been added and the refluxing has stopped,
turn the heating back on and reflux the mixture for one hour.
This is to ensure the reaction is finished.
Then let it cool to room temperature.
Now we need to remove the salt so to do that we vacuum filter over a fritted funnel.
Don't take too long though as the trimethyl orthoformate is being destroyed by the moisture in the air.
Here is our filtrate, about 150mL worth. To recover the small quantity of trimethyl orthoformate we use fractional distillation.
We're going to do this in two phases with the first one using the full sized 24/40 fractional distillation setup.
What boils off first under 60 celsius is an azeotrope of methanol and excess chloroform.
This azeotrope has a boiling of around 53 degrees Celsius.
Then we boil off the next 100 mL of methanol at around 64.7 degrees Celsius.
We're not going to boil down all the way to the trimethyl orthoformate because even with perfect yield we're expecting only about 36 mL of it.
The sheer size of the full distillation setup means that there is a lot of dead space that the product must fill first before it can distill over.
Our recovery would be terrible if we got anything at all.
Professional chemists solve this problem using a chaser solvent, also called a pusher solvent or tail solvent.
The chaser solvent is a very high boiling liquid that distills last.
As we get down to our product, which is now the second last liquid,
the chaser boils and fills the dead space in the distillation apparatus, pushing out the product.
Since the boiling point is much higher, it's easy to observe and separate and only traces end up in the product.
I didn't do that for this procedure because for a very sensitive chemical like trimethyl orthoformate
the chaser solvent itself must be meticulously purified and dried so it doesn't destroy our product.
I wanted to see how far i would get without a chaser solvent and if the yield was useable.
So after distilling off most of the methanol we now stop the distillation and let all the apparatus cool.
Here is the residue containing side products, decomposition products,
sodium chloride by products, methanol and our trimethyl orthoformate.
This much smaller volume of material means we can now transfer over to a much smaller 14/20 sized distillation apparatus.
Being smaller there is much less dead space than the full sized apparatus.
You'll notice i'm using an unconnected condenser column as the fractionating column.
As i said before in my fractional distillation video, you can use an unconnected condenser with some loss of performance.
Fortunately the boiling of trimethyl orthoformate is much higher than methanol so even this condenser should be able to give good separation.
So start the heating and there it goes.
First methanol will distill over.
Trimethyl orthoformate boils at around 101 degrees Celsius
so when the vapor temperature rises above 75 degrees Celsius change out the receiver and start collecting the product.
And there it is, trimethyl orthoformate. I only managed to get 7g of an expected 35g for a yield of 20%.
While this is very low, I think it's easy to fix by using even more molecular sieves for my original preparation of sodium methoxide.
I think the original sodium methoxide was not as dry as it could be and using extra molecular sieves is a cheap and easy solution.
Also maybe i should consider using a chaser solvent to squeeze out the last drops of product from the distillation apparatus.
Nonetheless for a first successful run I think this was pretty good.
Now some of your might wonder why didn't i use magnesium and react that with methanol to make magnesium methoxide to in turn react with chloroform.
I actually did try that first but I got no yield at all.
So i had to use the sodium hydroxide and molecular sieve method.
Now orthoesters are used in organic chemistry to make acetals from carbonyl groups.
I'm going to try and use this to make an antiprotozoal drug.
Thanks for watching.
And remember to add the chloroform slowly so it doesn't go into thermal runaway like my not so successful attempts.
If you would like to support the continued production of science videos like this one.
Please support the channel on patreon.
Links are in the video description.