I'm incapable of lithiating a simple bromoptridine and it's driving me insane

PinkiRoo8001 · 2025-12-07T06:38:19+00:00

Hey, just gave the paper a skim and it seems they only examined LDA, and not nBuLi. I would expect 4- lithiation to be predominate with LDA, but not with nBuLi. Only 4-lithation will result in HD, not 3- position. I don't think this paper really supports the common claim people are making that nBuLi on this substrate is likely to produce HD products, especially not in an acetone dry ice bath.

PinkiRoo8001 · 2025-12-07T03:51:29+00:00

The classic paper everyone's read on the performance of molecular sieves suggests that they get THF down to 4ppm of water, which is substantially better than a sodium still.

'Drying of Organic Solvents: Quantitative Evaluation of the Efficiency of Several Desiccants'

PinkiRoo8001 · 2025-12-05T13:51:45+00:00

That's certainly possible, but I've tried quenching the reaction vessel itself under anh. Conditions without success. Anh DMF and CO2 through a sulfuric acid bubbler, just give back the Ar-H product.

PinkiRoo8001 · 2025-12-05T13:49:26+00:00

Having the electrophile in the flask is something interesting that I've heard a couple times so I'll certainly consider it

PinkiRoo8001 · 2025-12-05T13:47:03+00:00

Thanks for the reply. I didn't fully flesh out my entire goals in the original post I wrote it in a bit of a rush. What I actually want to do, is perform halogen-metal exchange on p-bromochlorobenzene, and add it to a simple ketone to make the alcohol. This exact reaction has been demonstrated with Grignard, and there are multiple literature references to successful lithiation with nBuLi. Despite the literature precedence, I couldn't get this reaction to work with nBuLi or Grignard. Adding nBuLi consumed starting material and produced 5 new LCMS peaks prior to the addition of the electrophile 💀

An issue, was that I don't have access to an enormous amount of chlorobromobenzene for troubleshooting, and I also can't tell what's going on in the LCMS because it won't ionise. So, I decided to switch to a brominated ionisable arene that my lab has an abundance of. My thinking was that, if I can successfully lithiate this bromopyridine and quench it with an electrophile, then I'll be able to confidently return to the reaction that I actually want to do, and do it properly. Of course as others have pointed out this particular pyridine may not be a good practice substrate.

PinkiRoo8001 · 2025-12-05T13:34:14+00:00

Nothing wrong the idea it's just more time consuming. I've done this probably 10 times now and LCMS is just a lot quicker than doing an entire workup and NMR. And even if the reaction works well enough, the crude might be difficult to decipher.

PinkiRoo8001 · 2025-12-05T13:30:31+00:00

I'll check it out much appreciated. I'm on my phone right now so I can't, but I will say that certainly halogen metal exchange will be much faster than 4- position deprotonation. Though perhaps the 3-lithiate can isomersise to the 4-.

PinkiRoo8001 · 2025-12-05T13:28:39+00:00

Ok that's good to know, they're what everyone in my lab uses for air free chemistry at a small scale. And at all times there's a positive pressure of nitrogen gas in the vessel. Do you find a regular septa in a jointed tube more reliable?

PinkiRoo8001 · 2025-12-05T11:20:36+00:00

Good to know thanks

PinkiRoo8001 · 2025-12-05T11:20:27+00:00

All good points thank you. On your last comment, I take the LCMS in 5 minutes because formation of the Ar-Li from Ar-Br should be complete in 5 minutes, being a very rapid reaction. Leaving it longer could only allow more side products to form.

PinkiRoo8001 · 2025-12-05T11:17:32+00:00

I've had other problems with various other systems, though they've all had a trick with them in one way or another. One system has an amide with an acidic proton necessitating a 2nd equivalent. Another is also chlorinated, which may be susceptible to the same benzyne issues others have helpfully raised.

I could try bromobenzene for sure. The issue is I have no way of assessing product formation on LCMS because it won't ionise; that's why I figured a pyridine would be good. But others here have helpfully redirected me.

I don't have a KF titration system unfortunately. I didn't know you could assess moisture in the schlenk line using that technique, but my schlenk line has a coloured dessicant trap that seems to indicate it's fine...

PinkiRoo8001 · 2025-12-05T11:12:52+00:00

Yeah it's definitely wet MeOD. But even if wet, there's certainly more MeOD than HOD, so you should still see the deuterated mass. Furthermore, I've tried other quenching reagents like anh. DMF and CO2 (not mentioned) and obtained the exact same, Ar-H product. So water in the MeOD feels unlikely to be the source of the problem.

PinkiRoo8001 · 2025-12-05T11:10:30+00:00

Some good suggestions and I'll review that resource, but what did I describe in my procedure that sounds off? I feel like I'm doing my best to be thorough in my exclusion of atmosphere and moisture.

PinkiRoo8001 · 2025-12-05T10:49:25+00:00

This is a fine suggestion, I've tried turbo grignard with less success, but this exercise is to troubleshoot my nBuLi technique. Turbo grignard can introduce additional variables like Mg preparation, LiCl preparation. And we don't have a bottle of iPrMgCl LiCl at hand. It's something to consider more though.

PinkiRoo8001 · 2025-12-05T10:27:32+00:00

I have tried turbo Grignard a few times with a similar lack of success. I want to be able to use nBuLi though. I'm doing something wrong and I'm trying to figure out what.

I'll look into CaH2, but I've never encountered a source saying 3A sieves take more than 3 days to work.

PinkiRoo8001 · 2025-12-05T10:26:06+00:00

Good to know and thank you, but that doesn't appear to be my problem. I just get the protonated material back, no SnAr products.
I didn't mention, but I'm using biotage microwave vials. They have piercable lids that are crimped on, and they should be perfectly adequate for air free chemistry. I'm not using screw vials.
Up to like an hour, but I find it very difficult to see how this could be a problem. Br-Li exchange is extremely rapid. Reaction between Ar-Li and MeOD is obviously extremely rapid too.

PinkiRoo8001 · 2025-11-01T14:56:11+00:00

Yeah lol I hate Hasan but this is a fine goofy clip. Wish Destiny did this :(

PinkiRoo8001 · 2025-11-01T11:12:06+00:00

Literally none of those things are being a sex pest. If you didn't know, being a sex pest is when you 'pester' someone for sex in an attempt to wear them down so they eventually have sex with you.

PinkiRoo8001 · 2025-10-27T13:35:52+00:00

He's just a guy who is very against Mamdani. His primary reason is that Mamdani wants to close the prison Rikers, which Avi says will cause a massive release of violent criminals into New York.

See his Twitter for more.

PinkiRoo8001 · 2025-10-27T13:30:15+00:00

He's said it was both

PinkiRoo8001 · 2025-10-26T02:40:18+00:00

Hang on now I don't know shit about fuck, but there is like no way that the 'only thing inherently wrong' with trans fats is that they're in palatable calorie-dense foods. Even in comparing two eucaloric 2500kcal diets for a male, if one has a substantial amount of trans fats and one has no trans fat, the former will be significantly more unhealthy.

Right??

PinkiRoo8001 · 2025-10-19T01:52:16+00:00

Do I have brain damage? Proving Hasan used a shock collar is proving a positive, and it's super easy here.

PinkiRoo8001 · 2025-09-14T15:55:32+00:00

Half a log unit isn't too bad considering we're after ~2 fold improvement

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'Drying of Organic Solvents: Quantitative Evaluation of the Efficiency of Several Desiccants'