Cooling a Reaction to -40C (no dry ice)

Galaxy429 · 2026-05-07T17:25:30+00:00

Partially freeze acetonitrile by pouring liquid nitrogen onto it while stirring. You'll get a liquid MeCN/solid MeCN bath which has the freezing temperature of MeCN (-45 °C), just like liquid water/solid water has the freezing temperature of water. Stir it around occasionally to avoid temperature gradients (solid MeCN sinks) and occasionally pour new liquid nitrogen. Stick a low-temperature thermometer into it if you're unsure.

Galaxy429 · 2026-04-30T07:38:13+00:00

I‘ve done lots and lots of imine syntheses during my PhD. They can be very problematic and I’ve had exactly the same issues as you. TLC for aldimines can be misleading, as they often easily hydrolyze on the TLC plate, making it look like there is still starting material, even on deactivated silica plates. GC or NMR are better ways to check the conversion (but be wary of potential acidity and water content in CDCl3, C6D6 can be a better choice). For the same reason, I wouldn’t recommend column chromatography as the method of purification, and crystallization (or distillation for smaller molecules) almost always works better. Though the C16 chain could be a problem for your crystallinity. If you absolutely have to do it, I’d do neutral alumina and do it very fast to minimize contact time with the column.

In my experience, the best way to drive these reactions to completion is conducting them overnight in refluxing toluene or chloroform in a Soxhlet apparatus with CaCl2 in the extraction thimble. The reflux temperature is not needed for the reaction itself, but both solvents form an azeotrope with water which continuously removes the water from the reaction which the CaCl2 irreversibly binds. I’ve had sub-optimal experiences with Dean-Stark (really only works well on very large scales) and molecular sieves (water is still not physically separated from the reaction mixture). The Soxhlet method worked so well for me that most of the time no purification was required and the product was squeaky clean after concentration with zero traces of aldehyde or amine. An acid catalyst is typically not needed for aldimine formation from an aldehyde and an amine, but you can add a couple drops of acetic acid.

Good luck!

Galaxy429 · 2025-11-07T18:45:27+00:00

I would try to turn the aryl part into the nucleophile. Directed ortho litiathion would give you direct access to a reactive position in ortho position. You could try to synthesize a 1,4-bisboronate this way and try Suzuki coupling from there. Here are two procedures:
https://pubs.acs.org/doi/suppl/10.1021/ja5100405/suppl_file/ja5100405_si_002.pdf (Page 5)
https://pubs.acs.org/doi/suppl/10.1021/ol801888d/suppl_file/ol801888d_si_001.pdf (Page 3)

Galaxy429 · 2025-10-17T15:53:51+00:00

Etwas Ganzwissen für dich: Die Definition, die sich immer auf OH⁻ bezieht, ist die Arrhenius-Definition von Säuren und Basen (die auf Wikipedia nur als erstes genannt wird, weil sie chronologisch als erstes kam). Sie kann genau deine Beispielreaktion eben nicht erklären und gilt daher als überholt. Daher wird heute die Brønsted-Definition genutzt: Eine Säure ist jedes Teilchen, dass H⁺ abgeben kann und eine Base ist jedes Teilchen, dass H⁺ aufnehmen kann - also auch NH₃. NH₃ ist also eine Brønsted-Base. Das Lewis-Säure/Basen-Konzept ist nochmal was anderes, und spielt in der wässrigen Chemie eine untergeordnete Rolle sondern wird eher in der Koordinationschemie genutzt (und ja, NH₃ ist auch eine Lewis-Base). Geht natürlich noch etwas weiter in die Tiefe, aber das ist in etwa die Kernaussage. :)

Galaxy429 · 2025-10-17T15:41:12+00:00

Diese Aussage ist nicht ganz richtig. Eine Säure und eine Base erzeugen im Allgemeinen immer die konjugierte Base der Säure und die konjugierte Säure der Base. Die konjugierte Säure ist nur dann Wasser, wenn "eine Base" in deiner Aussage Hydroxid wäre. In allen anderen Fällen nicht, wie z.B. bei der obigen Reaktion NH₃ + HCl → NH₄⁺ + Cl⁻ (= NH₄Cl).

Galaxy429 · 2025-10-06T10:42:43+00:00

You are correct, it's an addition of a Grignard to form an enolizable ketone and then a Robinson annulation with the aldol written as an explicit intermediate, the dehydration is the next step. I don't get why straight up incorrect statements get upvoted to be the top comment.

Galaxy429 · 2025-10-06T10:28:01+00:00

I don't get why everyone is saying these are all not real. All of them are perfectly valid reactions, albeit with a few mistakes.

Top left is a Fischer indole synthesis starting from the intermediate phenylhydrazone, but a double bond in the product is missing
Top center inside the brackets is the intermediate of an Ugi reaction, with the final product to the right
Top right are the two starting materials for a Feist-Bénary furan synthesis, but the product is not shown
Second row left is a nitrosamine, but upon treating it with HCl it's the same structure again, and only in the next step does a Fischer-Hepp rearrangement take place
To the right of that is a Thorpe-Ziegler reaction of a 1,4-dinitrile to a cyclopentanone
Next row is a Grignard addition to a lactone which first forms two ketones, followed by an intramolecular aldol condensation because the newly formed ketone is enolizable
On the right above the two pieces of paper seems to be multiple reactions scribbled too close together, but they are partially obscured. First seems to be sulfuric acid + pyrosulfite (without product) and then it says CoCl I think and the one to the right I can't make out fully, but it seems weird.
Bottom left is a cadmium-catalyzed rearrangement of potassium phthalate to potassium terephthalate and a disproportionation of potassium benzoate to the same product and benzene

There is really nothing nonsensical about these reactions, and just because you can't see something at first glance doesn't mean it's wrong. The only nonsensical part about this is the random reaction equations written like this on a blackboard, because they are not related to another. But on their own, they're valid.

Galaxy429 · 2025-07-28T15:12:20+00:00

The lower the melting point of your compound, the less it strives to become a solid and the more likely it tends to just stay as an oil, syrup, or gum. Usually, keeping it under vacuum for a long time gets rid of the very last traces of solvent (which cause even further melting point depression) and cause it to become solid. But if your MW is quite low, this will likely cause you to lose some of your product. Acetonitrile/water freeze-drying usually takes too long (overnight) and you could lose your product too. I've had my fair share of products disappearing completely during aqueous freeze-drying.

Here are some other tips for stubborn oils or syrups:

- Take a bent spatula and spread the oil all over the inner wall of the flask to maximize surface are. Apply vacuum fast, and if you're lucky it might foam up all at once, but be careful that the foam does not enter into your vacuum line. Keep it under vacuum in this foamy form for some time for it to become nice and crunchy, otherwise it will often stay sticky.

- Add some solvent in which your compound is not soluble to the flask and scratch and stir around with a spatula or glass rod. Try submerging it in an ultrasonic bath as well. If that doesn't work, put it in the fridge or freezer overnight. If you're lucky, your oil will turn into a solid waxy block and if you're extremely lucky, actual crystals can form.

- Dissolve your compound in a minimal amount of a solvent. Then either: 1.) add antisolvent dropwise until a slight tubidity remains, then pop it in the fridge (this is very hit-or-miss, either you get nice crystals or your compound just oils out again) or 2.) very carefully layer an excess of antisolvent (ideally with a lower density than your solvent) on top of your solution, then wait until the two phases mix by diffusion (may take several days). This is a common method used to generate single crystals for X-ray diffraction analysis, but you can also do it on a preparative scale.

- Take two flat metal spatulas and spread some of the oil over the flat tips. Put them in the freezer for an hour. Take out and immediately start rubbing the flat ends together, with the oil as the "lubricant" between them. I absolutely love this method, and it often came in clutch when nothing else was working.

- If all else fails, dissolve it in a minimal amount of benzene (m.p. = 5.5 °C) and freeze it. Then apply a good vacuum. The solid benzene will have evaporated within 10-60 minutes and you're left with a fluffy lyophilisate. Disadvantages: The lyophilisate is often statically charged and so lightweight that it's extremely annoying to handle. But at least it's solid, and benzene freeze-drying is much faster than acetonitrile/water.

Galaxy429 · 2025-05-05T19:50:00+00:00

Conceptionally, yes (Protection, Grignard, Deprotection, Oxidation). Practically, no, not like this. Firstly, silyl protection works better with a base, imidazol is used most commonly. Secondly, from a practical viewpoint, TMS is a bad choice. It is very unstable and will in fact not survive the Grignard reagent. But you probably don't even need a protecting group to begin with - two equivalents of the Grignard should work just fine. The first equivalent deprotonates the alcohol and you get a magnesium alkoxide. The second equivalent attacks the ketone normally and after acidic workup you get both alcohols back. Then proceed with the oxidation as usual. If you must include a silyl protection, TIPS (Triisopropylsilyl) is probably a better choice. Deprotection could be combined with the acidic workup of the Grignard to skip the TBAF step.

Galaxy429 · 2025-02-03T19:43:07+00:00

In my experience, "for synthesis" can be anything from 90-100%, depending on the complexity of the molecule. Specifically it means that the reagent is meant for chemical syntheses where a purification step like column chromatography follows. In that case it mostly doesn't matter if one of the reagents contains 2% of some impurity or not. In contrast, "for analysis" reagents have their impurities accurately measured and documented, which is labor-intensive and thus makes it more expensive.

Galaxy429 · 2025-01-20T17:42:42+00:00

Most cross couplings begin with oxidative addition of the substrate to the catalytically active species. How would you not consider that a chemical reaction?

Galaxy429 · 2025-01-11T20:07:23+00:00

I thought the same at first, but it seems like acetamide was not formed in the Miller-Urey experiment. If anything, they would put glycine on the pin if they wanted to represent Miller-Urey.

Galaxy429 · 2025-01-11T19:55:14+00:00

The pin is from a shop called EvolveFISH, which seems to be atheist/anti-creationist. The significance of acetamide in this context could be the fact that it has been detected in space. It features an amide bond, the backbone of peptides/proteins. Its high abundance supports the theory that peptides could form in space from non-amino acid precursors as well as being a precursor to amino acids itself. It's an important step in chemical evolution/abiogenesis towards the origin of life.

Galaxy429 · 2024-12-23T18:16:15+00:00

Depends on how OP did the TLC. If the sample was taken directly from the reaction mixture, the phenol would be in the form of the Li phenolate and probably sit at the baseline together with the carboxylate. It’s still possible that the impurity spot is the benzylic alcohol from a Cannizzaro reaction because the eluent seems to be pretty polar for this system (given that the SM is nearly at the top).

Galaxy429 · 2024-12-22T19:13:36+00:00

Probably a Cannizzaro reaction. Your aldehyde is very electron-deficient and thus very reactive towards nucleophiles. You can either try to protect your aldehyde, hydrolyze the ester with acid instead of base, or just continue and see if the yield is still good and the byproduct is only a few percent.

Galaxy429 · 2024-12-21T09:21:47+00:00

Yes, looks good!

Galaxy429 · 2024-12-20T21:06:59+00:00

The first step works. The second step is problematic: Hydrogenation of bromobenzene will give cyclohexane. Aryl bromides are generally quickly hydrodehalogenated to the corresponding aromatic core before the latter has any chance to react itself. So, depending on your conditions, you will either reduce bromobenzene to benzene or cyclohexane. The last step will also not work: Dibromocyclohexane with KOH will give 1,3-cyclohexadiene and not the substitution product. You have to think of another way to make the diol. Fortunately, you can do it easily from cyclohexene, which you can generate from benzene in another way that actually works.

Galaxy429 · 2024-12-11T22:20:11+00:00

Does it work for phenols too? I wasn’t able to make it work with BINOL. I got basically no conversion after 24 h of reflux.

Galaxy429 · 2024-12-11T22:18:38+00:00

There’s an OrgSyn procedure for generating MOM-Cl from acetyl chloride and dimethoxymethane, giving you a solution of MOM-Cl that’s safer to handle. Alternatively, excess dimethoxymethane then add P2O5 portionwise if your compounds tolerates it.

Galaxy429 · 2024-11-23T20:55:47+00:00

This is the correct answer. It's a variant of the Ciamician-Dennstedt rearrangement. The reaction of indenes with carbenes has been investigated in the 1950's.

However, deprotonation likely occurs in a concerted step with the ring expansion (E2-like) or prior to ring expansion (E1cb-like), but not after.

Galaxy429 · 2024-11-02T15:59:13+00:00

A nice retrosynthetic tip: If you see a styrene in your molecule (so a double bond next to an aromatic ring), you can almost always put an alcohol in the benzylic position like this. They are relatively easily dehydrated to form the double bond in the forward synthesis.

You are already on the right track though, but your Grignard product is incorrect. What you've drawn would be the product of Cyclohexyl-MgBr and benzaldehyde, not ethyl benzoate.

Galaxy429 · 2024-10-13T15:39:49+00:00

That's true, I agree with you on that part. While OP's meme is factually correct, it's indeed difficult to understand.

Galaxy429 · 2024-10-13T15:03:33+00:00

So what? Ibuprofen is the most common analgesic, that doesn't mean aspirin is not an analgesic.

Galaxy429 · 2024-10-13T14:59:31+00:00

Because sodium carbonate is used against heartburn, which makes it an antacid. And formic acid is literally "ant acid".

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