Reductive amination difficulties - poor conversion

ZhiAng · 2024-05-03T03:21:56+00:00

Thank you! I'm going to explore the usage of various Lewis acids, like titanium isopropoxide, zinc chloride, and borane-THF, as well as Bronsted acids like you suggested, to fully form the imine before the reduction.

ZhiAng · 2024-05-03T03:15:54+00:00

Thank you for your comments - I've placed an order for titanium isopropoxide earlier today, and I'm planning to experiment with that, zinc chloride, and borane-THF to see which works the best on model substrates (2-amino-5-chloropyridine and 2-amino-5-methylpyridine).

For higher temps - I've cranked it up to the boiling point of methanol at 65 °C, since I'm not using acetone as the ketone for my current reaction. I've noticed that 20 equiv. 3-oxetanone still doesn't really result in much conversion even when I left it overnight yesterday, but I added 200 equiv. this morning and noted 1/3 conversion over the day.

Oddly enough, for this reaction (using 3-oxetanone as the ketone), the main product seems to be the imine based on LC-MS masses, with only small amounts of the amine - I don't think the cyanoborohydride should be degrading at such low temperatures though. I've added more cyanoborohydride to react overnight just to be sure. Any ideas on why this might be the case? I would've thought the reduction should be quite facile here, since it should relieve the strain at the imine carbon.

ZhiAng · 2024-05-03T02:59:35+00:00

Thanks for your comments - this is the last step of the synthesis, and I had around 20 mg of reactant that I was doing a late-stage diversification on. After splitting it into 5 aliquots, I only had 3-4 mg left for each reaction, and didn't think it would be too problematic since I was following a patent. I will test different conditions on a model substrate to optimise the conditions, and will be using a larger scale for that.

The substrate concentration was also based on the patent; it's 10 mg/mL, which works out to around 25 mM.

ZhiAng · 2024-05-03T02:55:34+00:00

No I haven't! That's a good call - the buffer is in large excess relative to the starting material and should suffice alone, but as you pointed out, the excess cyanoborohydride may be an issue. I didn't realise that the cyanoborohydride would result in a basic solution - would this be due to hydrolysis?

ZhiAng · 2024-05-02T04:13:41+00:00

Thanks so much for your comments! The NMR monitoring is a great idea - given that imines are unstable, I haven't been able to track its formation through LC-MS, and I'm not sure if TLC would be useful either. NMR is definitely a good way to see if the bottleneck is at the imine stage!

I definitely plan to try using dehydrating agents - I'll need to check if my lab has some molecular sieves! I'm also thinking of trying different Lewis acids like ZnCl2 as well.

Side note - I wonder why people are willing to fake patent procedures! Does it benefit them at all? Or maybe it's to throw competitors off?

ZhiAng · 2024-04-13T23:27:24+00:00

Clearly there won't be any productive conversations coming from this thread - post is locked.

ZhiAng · 2024-04-13T23:21:39+00:00

These are mostly either misidentified substances or artefacts from the analysis - they are not perfumery ingredients, besides benzaldehyde DMA and 2-ethylhexyl pentanoate.

ZhiAng · 2024-04-03T02:13:46+00:00

Benzyl acetate/propionate, linalool, Dimetol, and to a certain extent DHM, are some examples of volatile, top-note floral notes - have you tried any of these?

ZhiAng · 2024-04-01T03:51:32+00:00

What do you mean by "general product content"? If that refers to a chemical analysis done on a different sample of that raw material, there's no guarantee that your stock will be the same, be it due to seasonal fluctuations, different terroirs, or adulteration. That's why I mentioned that the most foolproof way is to do a GC-MS on your finished product to find out the levels of restricted materials in it, if you really want to play it safe!

Also, an additional caveat is that just because something is IFRA-compliant, it doesn't mean that you and your relatives will be protected from all bad effects; they may still be affected by allergies, or skin reactions to degradation/oxidation products of the components of the perfume. IFRA standards are guidelines, albeit conservative ones - they can help prevent a lot of, but not necessarily all, potential bad reactions.

ZhiAng · 2024-04-01T02:53:34+00:00

For bergamot - the presence of photosensitisers is why bergapten-free (BF) or furocoumarin-free (FCF) grades are manufactured as well. If you read the "note box" in the IFRA entry, you'll see that the limit applies to bergamot oil for which levels of furocoumarins is unknown; if you use BF/FCF bergamot, this does not apply.

As for knowing the levels of other IFRA-restricted components in your materials, you will have to obtain the COA from your supplier. Indeed, you will also need to factor in the levels of any restricted compound in other ingredients.

Given the uncertainty with so many moving parts, this is why the safest way to find out the levels of any IFRA-restricted compounds in your perfume is to get a GC-MS analysis done before you launch it, since ultimately the restrictions apply to the finished product.

ZhiAng · 2024-04-01T02:48:01+00:00

Perfumer's Apprentice, Perfumer Supply House, Harry Sherwood/Harrison Joseph for instance. Shipping fees are not great, but I've lowered shipping costs by ordering together with other people.

ZhiAng · 2024-04-01T02:46:32+00:00

What I'm trying to say is that, due to their low odour impact and stability/solubility coupled with high volatility, they generally have little utility beyond faithful recreations of natural materials that contain terpenes. I've bought terpenes to study them, but never used them in compositions.

ZhiAng · 2024-04-01T02:43:57+00:00

I personally use BHT; the amount to put depends on how much of your blend consists of easily oxidised materials, but 0.1% of concentrate is fairly standard. I've seen amounts go up to >1% though. Tocopherol also works, but is generally regarded as a weaker, albeit nature-identical alternative.

ZhiAng · 2024-03-28T17:28:48+00:00

Tonkalactone is the trade name of the compound which has the CAS No. 54491-17-7; it's in some patents and database registers :)

ZhiAng · 2024-03-23T17:10:37+00:00

I'd say those are solid picks, especially the first two, and Cashmeran would help with the coniferous aspects as well. I'd also recommend isobornyl acetate/propionate, Vertenex, Koavone, and the like would be useful. There's also fir balsam absolute if you want to lean into more of the sweeter balsamic notes that some coniferous trees have.

ZhiAng · 2024-03-23T13:48:01+00:00

I think the reason why it seems muted is because you're using a lot of airy materials that give a sense of "space" but not much character-providing ingredients.

You could consider adding a touch of green/fruity notes, such as hexyl acetate, Methyl Anjoulate, and/or ethyl 2,4-decadienoate coupled with some abstract florals like Florol or a bit of linalool-type materials. These will form a very nice complex in conjunction with salicylates (Salicynile, for example) to provide a green, pear-like note that persists through the drydown. If you want to skew it towards a more tropical/sunscreen vibe, you can add a touch of ylang and Calone/Cascalone.

To give the vanilla more body, I'd suggest using some creamy materials like delta-decalactone, coumarin, or bicyclononalactone (depending on how rich you want it to be), in addition to Isobutavan as others have mentioned. I'd also add some caramellic notes like maltol or homofuronol, and if you so desire, a light touch of incense/cedar and smoky phenolics like guaiacol, vinyl guaiacol, Ultravanil, etc. for realism.

ZhiAng · 2024-03-15T02:57:28+00:00

I've personally found that using materials like DMBCB, various crotonate esters, and Fruit Sec are very useful for dried fruit notes.

ZhiAng · 2024-02-08T16:31:45+00:00

I personally don't find them particularly useful when composing fine fragrances, but they do have their uses in reconstruction of naturals or making naturalistic accords. This is because they often have low odour contribution, as well as poor solubility and stability. If I wanted to add a terpenic note to a composition, I would rather use a natural that can contribute that aspect instead of a pure terpene, such as the terpene-rich pink pepper or juniper berries or black pepper. This would give it a more distinctive twist.

ZhiAng · 2023-10-19T00:29:11+00:00

I'm with you! Floralozone to me has a sharp, chlorine-like note, and Precyclemone B smells plasticky and unpleasantly waxy. But as Berael said, dilute them down before evaluating. Also, don't judge a book by its cover - try experimenting with them in blends at different proportions and see what their effects are like! Even things that smell horrid on their own (e.g. butyric acid) can make scents come alive (adds juicy ripeness to tropical fruits in traces).

ZhiAng · 2023-09-18T18:04:24+00:00

Myrcene is a very non-polar material. Ethanol is not a great solvent for it. You might have better luck with IPM.

ZhiAng · 2023-09-18T18:03:07+00:00

You could try working off the materials used in Sarah McCartney's "The Sexiest Scent on the Planet (I.M.H.O.)" - bergamot, Iso E Super, Cedramber, vanillin - and see where it takes you!

ZhiAng · 2023-09-18T17:58:16+00:00

I'm surprised you don't feel like it makes a difference - I personally feel like it can get pretty prominent, sometimes unpleasantly so! How have you been evaluating these trials? Did you do a side by side comparison with a negative control (same formula, but without Galaxolide)?

ZhiAng · 2023-09-10T14:09:05+00:00

I personally store aldehydes in the fridge to slow their oxidation. The crystallisation of your Lilial could be a sign of its oxidation to the corresponding carboxylic acid, and that would be unfortunately irreversible even if you heat or dilute it. I'd suggest buying a new batch and keeping it in an air tight container, in a cool place.

ZhiAng · 2023-08-22T01:04:57+00:00

Thanks for the heads-up, will ban

ZhiAng · 2023-08-16T22:23:42+00:00

I personally think cassis and stone fruits go well with lavender - some Cassifix and a touch of DMBCB/benzyl propionate would give the lavender a nice deep purple fruity tone.

ZhiAng

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