[Matt67230]

Hi everyone

This week we tried to synthesize atenolol in class. Except, we couldn't follow the planned protocol due to a timetable issue, and everyone's experiments failed.

Protocol was :

Add 5g gram of 4-hydroxyphenylacetamid to 20mL of water containing 2,5g of solubilized NaOH, using an erlenmeyer. Then add 20mL of ethanol and 25mL of epichlorhydrine and heat it (180°C) for an hour under reflux. Cool the erlenmeyer and use a Büchner funnel to keep the solid formed during the cooling process.
Let it rest in the heat chamber put at 50°C for the night to eliminate the excess of water.

Second part

Solid is put in an erlenmeyer containing 15mL of water and 30mL of isopropylamine are slowly poured in. Reaction is heated under reflux again ; solid will dissolve. After 30 minutes the medium is compared to commercial atenolol using TLC. After an hour reaction medium is put in a round-bottom flask on a rotatory evaporator. Isopropylamine is distillated and a white precipitate can be seen. Afterward medium is acidified using 15mL of 6M HCl while the flask is put in ice. Test the pH that should be acid. Using a Büchner funnel filter the white precipitate that has formed (impurities). Filtrate is cooled down. Add 30% NaOH until precipitation stops (precipitate = atenolol). Filter using a Büchner funnel then put it in the heat chamber at 60°C overnight.


What happened

First part went well. We had 25g of solid but deemed it was full of water.

Second part is where it went wrong. We could only let it in the heat chamber for about 2 hours, so we still had around 23g of solid. We tried the experiment anyway.
No problem during the heating procedure, TLC result of the medium even matched the commercial atenolol. But that's when we had to use the rotatory evaporator that troubles began.

No precipitate could be seen. We were expected to use it for 5 minutes but after 30 minutes and still no white precipitate, we stopped the equipment and carried on. What was liquid turnt to a viscous, thick, limpid gel. Professors realized 2 hours in the heat chamber clearly wasn't enough to eliminate the excess of water, and couldn't explain what would happen starting from now.

We managed to solubilize the gel with the 15mL of HCl but pH was 9. Professors told us to add acid until pH paper turnt to red (pH=3), which took us another 25mL of HCl (for a total of 40mL hence).
No precipitate in sight, it was plain liquid. They told us to filter anyway to see what would happen. As expect, everything went through the Büchner funnel. We added a bit of sodium hydroxyde anyway. It started heating and smoking quite a lot for a minute. We poured the whole thing in the funnel again.
A thick gel appeared ; it was white but went limpid/yellowish when using a rod. After a while (5-10 minutes), it decanted into 2 distinct phases : a thick, yogurt-like white precipitate, floating above a limpid liquid.

So my question here is : what happened in the medium? What are your hypothesis, what reaction could explain such a result?

We thought with my duo it could be the excess of water interfering with the reaction, some think the first solid we had contained NaOH as well as water, but we can’t clearly verify nor identify what occured during the process.
So I was getting curious and wondered what were your thoughts on that?

Thanks in advance for your proposals and ideas!

[rolnor]

The first step you wright 180°? Maybe you mean 80°C?.
Its important to follow procedure, an epoxide or alkyl chloride is not very reactive so long reaction time is required. I suggest you do it again or use chromatography to purify your product.

[Matt67230]

No, that's indeed 180°C.
I've seen online the melting point is 175-178°C so it must be about that (we haven't been told why we would use this temperature). 4-hydroxyphenylacetamide boiling point is about 344°C so I guess it isn't the matter here. Moreover that's how every other groups before us did and there wasn't any problem, thus I'm not sure that is where we should be looking.
I haven't thought about any of the heating process though, so I'll make sure this isn't where the problem resides with my professors tomorrow. Thanks!

[rolnor]

But you have water and ethanol in the mix, you say reflux?
You have TLC so you can monitor the reaction and also check your product. That something does not chrystalize does not mean its useless, you can still have a lot of product in the mixture.

[kriggy]

Evaporating water on rotovap is pain in the ass and possibly what happened is that you did not distill enough of it to cause precipitation. Your TLC matched the product, therefore its just matter of isolating the product.

[rolnor]

I get the impression that you did not follow the procedure for the reaction and the reaction therefore was not complete, this leaves residues of reactants in your product wich interferes with the crystalization.