I have a synthetic problem in my PhD thesis, in which I synthesize a phosphonate ester. To be more precise, it is a phosphonofluoridic compound. In my specific case, the fluorine attached to the phosphorus is the result of the acidic reaction conditions successfully applied in the previous step. I do not want to have a fluorine atom at this position in the final molecule and want to replace it by oxygen. Until now, I was not able to remove this fluorine. I tried to use base, but until now, to no avail.

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In the literature I found during the similarity research, that compounds with a methyl group (like the toxic organofluor esters) attached to the phosphorus are in contrast hydrolyzed quite easyly. Here, only water is utilized to remove the fluorine.

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In my case in contrast to that behaviour, the removal by base seems to be inhibited by the partly deprotonation of the oxygen in proximity to the fluorine. Seemingly, the compound has a small pka-value (strong acid), therefore the proton in neighboring position is likely to be fully deprotonated and therefore the negative charge will stabilize the fluorine in this position. My idea was now, when I can't get the hydrolysis to work to attach a protective group so that the discussed fluorine is not introduced in the first place, perform all the reactions that form "R" and than as the last step perform a deprotection reaction to release the free acid/ the salt. In the Greens book on protective groups in organic chemistry unfortunately, most strategies show only monodeprotection when not too acidic conditions are utilized:

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I am wondering, what could be a valid approach, to achieve full deprotection to receive the free acid? The protective group should be stable under acidic conditions and in the presence of fluoride ions.

Currently I would say the following groups would be most interesting: Benzyl and 1,2-Phenylene

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However, the protective chemistry for phosphate offers many different options. Maybe you would have a better possible route to solve this problem and recommend a different group? Do you have another idea how to kick out that fluorine?

  • $\begingroup$ How does the compound, and the base, really look? $\endgroup$
    – Mithoron
    Feb 3 at 19:47
  • $\begingroup$ For the compound, currently I am not at liberty to disclose, but for the base I utilized ammonia up to pH 12 because its a polar structure and utilizing a non volatile base like NaOH would bring challages in terms of purification. I did additional research recently, and it is maybe possible to remove excess base by HILIC chromatography, so I might try this again with stronger base up to pH 14. $\endgroup$
    – raptorlane
    Feb 3 at 19:52
  • $\begingroup$ sigh Is it phosphonic acid or ester that gets hydrolysed? Your post is unclear. $\endgroup$
    – Mithoron
    Feb 3 at 19:56
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    $\begingroup$ O-Allyl is another possibility. Can you silylate the P-OH group then run the hydrolysis? The fluoride released by hydrolysis may then cleave the silyl group. $\endgroup$
    – Waylander
    Feb 4 at 7:59
  • 1
    $\begingroup$ TMSDEA might work, but consider Bis(trimethylsilyl)acetamide (BSA) for silylating the P-OH $\endgroup$
    – Waylander
    Feb 4 at 9:22


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