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Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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March 26, 2014

A New Fluorination

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Posted by Derek

BrittonF.pngNew fluorination reactions are always welcome, and there's one out in Ang. Chem. that looks really interesting. Robert Britton's group at Simon Fraser University report using tetrabutylammonium decatungstate as a photochemistry catalyst with N-fluorobenzenesulfonimide (NFSI). This system fluorinates unsubstituted alkanes, as shown at left, and apparently tolerates several functional groups in the process.

Note that the amino acids were fluorinated as their hydrochloride salts; the free bases didn't work. There aren't any secondary or tertiary amine substrates in the paper, nor are there any heterocycles, both of which are cause to wonder whenever you see a new fluorination method. But I think I'm going to order up some tungstate, turn on the lamp, and see what I get.

Update: via Chemjobber, here's an excellent process chemistry look at scaling up a trifluoromethylation reaction.

Comments (16) + TrackBacks (0) | Category: Chemical News


1. Anonymous on March 26, 2014 1:20 PM writes...

I currently work in this area (C-H fluorination), so this paper is really interesting to me. I'm not in a place where I can read the full text right now but I've got a few comments: The acyl fluoride is interesting. What's going on there is probably mechanistically different than what's going on for the aliphatic fluorinations.

I like that it tolerates the ester and hydrochloride amines, as well as the presence of water.

We're still trying to figure out what exactly it is about acetonitrile that makes these fluorination reactions work in it, almost exclusively. We try a ton of solvents whenever we're on a new method but they almost always seem to kill the reaction.

Anyways, good method, thanks for posting. We'd tried decatungstate ourselves for a while but never got it to work. I'll read the whole thing later and hopefully get some ideas from it.

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2. gippgig on March 26, 2014 2:17 PM writes...

unreacted 35? How can you have an unreacted reaction product?

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3. NaturalChemist on March 26, 2014 2:51 PM writes...

Angew. Chem.

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4. chemist on March 26, 2014 4:52 PM writes...

Really interesting, but I wish photochemistry papers gave more detail on the lamps and flasks used. Googling "15-Watt UVB-BLB lamps" gives several options, but now I'm more confused because the supplemental says "centered at 365 nm" while UVB is 315-280 nm. I believe regular Pyrex round bottomed flasks transmit >50% of 365 nm wavelength, so maybe they used regular flasks?

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5. Anonymous on March 26, 2014 4:55 PM writes...

@1 - the acyl fluoride is formed by the same mechanism. Aldehydic C-H bonds are homolytically weak, especially compared to the only competing C-H bonds in benzaldehyde. Hydrogen atom abstraction, fluorine transfer in all cases.

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6. Fluorine Chemist on March 27, 2014 6:52 AM writes...

@1 Acetonitrile is a great solvent for direct fluorinations too (using F2 gas). It is hypothesised that it takes part in the transition state of the reaction with F2 (which is just another electrophilic fluorinating reagent) Check out this review for more info: J. Fluorine Chem. 128 (2007) 90–104.

Very similar chemistry to this can be achieved using fluorine, maybe some older papers from S. Rozen and R. D. Chambers can also give you some ideas about possible role of acetonitrile.

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7. Will on March 27, 2014 9:04 AM writes...

If primary amine salts are compatible, why wouldn't there be an expectation that more highly substituted amine salts would also work?

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8. Anonymous on March 27, 2014 11:23 AM writes...

@ 4 I'm confused by that. It should be a UVA lamp. That has a major wavelength at 366 nm. BLB means black light bulb (which is UV-A) so it might be a bulb that emits both UV-B and UV-A. Shouldn't be necessary.

It also doesn't state where the lamp is placed which will make a difference. Much more efficient if the lamp is in the middle of the reactor as shown here

Pyrex absorbs wavelengths below about 275 nm so the light above that should pass through without problem.

I agree though, the SI is not helpful. But you wouldn't want people to be able to do your chemistry easily would you? That just creates more competition in your area?

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9. InfMP on March 27, 2014 11:30 AM writes...

NMR YIELDS are not acceptable. please.

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10. Hap on March 27, 2014 11:59 AM writes...

Doesn't that depend on what you want to do? If you want a comparison between methods, then using NMR makes sense - you don't want to compare the skill of the experimenter in isolating product, but the effectiveness of the reaction (particularly on small scales, where you can easily get anomalous low or high yields).

On the other hand, if I want to prepare something, then I want to know how much of it I can get out, and whether the conditions eat my product, or the catalyst or media or byproducts make my product hard to separate from what I want. Hudlicky commented in his book about how pyrrolidine alkaloid syntheses quoted extravagant yields but gave little data on the final alkaloids and their isolation because they decomposed in air and were difficult to isolate. Since the point of the papers was to make the alkaloids, and they couldn't really get them in the yields they said (at least not with the information they reported), then the authors were being dishonest. If they were comparing one method to get the products to other methods, though, then low yields might be comparing isolation procedures and experimenter skill and not the methods.

On the third hand, I kind of like looking for isolated yields from reactions, since I would not be interested in preparing CDCl3 solutions of products.

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11. Anonymous on March 27, 2014 12:45 PM writes...

It looks like they isolated them when they could- about half of the products. To their credit also, they did the reactions with one equivalent of substrate. Given the small scale these were done on and the volatility of some of the products, there was little chance of isolating some of those compounds using tools available to an academic lab.

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12. Rob on March 27, 2014 1:16 PM writes...

Thank you for the comments and critiques on our work! To be clear, "the mixture was stirred while being irradiated between two 15 Watt UVB-BLB lamps (centered at λ=365 nm)" indicates that the mixture was placed between the 2 lamps - no special glassware or setup required (see comment 8 on pyrex). 15 Watt UVB-BLB lamps are standard and purchased from local hardware store for ~$20 - BLB = blacklight blue).
It is often very difficult to isolate from a mixture of fluorinated products a single fluorinated isomer/diastereomer without significant loss in yield from repetitive chromatography (or compound volatility), for this reason many yields are reported on crude mixtures to give a better idea of the actual efficiency of the reaction (see comment 10).
Comment 8: we would be overjoyed if this became a widely adopted protocol for C-H fluorination!

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13. Anonymous on March 27, 2014 3:57 PM writes...

@12: Have you seen any dehydrofluorination on workup?

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14. exchemist on March 28, 2014 10:06 AM writes...

Why doesn't the reaction show the source of the fluorine (very first part)? Maybe it's coming from "reaction conditions", but why not show the source molecule?

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15. Hap on March 28, 2014 10:25 AM writes...

NFSI (N-fluorobenzenesulfonimide, (PhSO2)2NF) seems to be the source for the fluorine - maybe they figured it's such a common F+ source (either it or Deoxofluor is used a lot) that it didn't need to be drawn.

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16. Anton on March 30, 2014 7:33 PM writes...

This is all a bunch of crap

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