3
$\begingroup$

I want to hydrolyse a phosphonic acid diethylester to the corresponding free phosphonic acid. In the literature, it is described, that usually strongly basic or acidic conditions are utilized to achieve this.

The Hydrolysis of Phosphinates and Phosphonates: A Review. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150351/

enter image description here

Alternatively one can utilize ester cleavage by TMSBr and water workup.

In my case, however, multiple complications occur. R is a complex substituent, which will not tolerate too acidic conditions. In addition, when performing a reaction under basic conditions, the problem is, that base like NaOH or KOH would introduce a very polar species to the mixture in which the product can not separated off easyly from the free phosphonic acid that would be for sure also very polar. (I know, that one possible way get rid of the excess would be the utilization of ion exchange, but from my experience this is an extremely time consuming process when your product as well your impurities are UV inactive.) In addition to that, reaction control would be problematic due to the fact, that the product is likely to co-elute with the base, therefore the reliable reaction control by LCMS, would be problematic, also because the product is not carrying UV active groups. I am therefore wondering if there are possible other strategies to transform the diester into the acid preferably in a fashion, that does not create a problematic purification situation and work in comparison to TMSBr with milder conditions that are not too acidic.

$\endgroup$
15
  • $\begingroup$ Do you have any control over what the ester group is? Can you make it something other than Et/Me? $\endgroup$
    – Waylander
    Nov 11, 2023 at 18:28
  • $\begingroup$ The Et group is a consequence of the precursor used in the previous step, because it contains it. I thing however, it would be possible to exchange Et to a different group before hydrolysis. I did however not try this yet and Methyl is however the only one that should hydrolyse more readily. $\endgroup$
    – raptorlane
    Nov 12, 2023 at 9:08
  • $\begingroup$ I am wondering, if it would not be an idea worth testing to just try a strong organic base like DBU, DBN or a similar one in water, water/methanol mixture. And to see if the product will appear. I would also think to apply microwave conditions could be an good idea to counteract the weaker base's reaction speed in comparison to alkaline bases. In addition, if lucky, an easy DCM water extraction would be enough, to remove the excess base. $\endgroup$
    – raptorlane
    Nov 12, 2023 at 9:48
  • 1
    $\begingroup$ Is it possible to swap the phosphonate alkyl group for something that could be removed under entirely different conditions? Dibenzyl phosphonate that could be removed by hydrogenation or diallyl with Pd+Nucleophile? $\endgroup$
    – Waylander
    Nov 12, 2023 at 10:32
  • $\begingroup$ How about a resin-bound strong organic base? $\endgroup$
    – Waylander
    Nov 12, 2023 at 10:33

0

Your Answer

By clicking “Post Your Answer”, you agree to our terms of service and acknowledge you have read our privacy policy.