Org Prep Daily

September 25, 2006

Mosher Pfp ester

Filed under: procedures — milkshake @ 12:26 pm

 

mosher.gif 

 

R(+) Mosher acid 1.856g (99%ee, Aldrich, 7.926mmol) and pentafluorophenol 2.188g (11.89mmol, 1.5eq.) solution in anh. acetonitrile 12mL was cooled on ice bath. Solid DCC 1.635g (7.926mmol) was added in one portion and the mixture was stirred at 0C for 1h, the cooling bath was removed and continued at ambient temperature for 14 hours (overnight). The precipitated dicyclohexyl urea was removed by flitration, washed with acetonitrile and discarded. The combined filtrates were evaporated and the obtained semi-solid residue was dried on highvac for 6 hours to remove excess of pentafluorophenol. The crude product was dissolved in hexane 10mL, the cloudy solution was filtered through a 2g-plug of silica, the silica plug was washed with cyclohexane 30mL. The combined filtrates were evaporated and the residue was dried on highvac (for 1 hour). The residue was dissolved in hexane 15mL, allowed to crystallize in freezer for 10 hours (-20C overnight). The supernatants were decanted, the crystalline product quickly rinsed with freezer-cooled hexane (2x5mL) and dried on highvac while cold. Y=2.601g (82%) of large white crystals 

The Pfp-ester of Mosher acid is a non-hygroscopic solid that can be stored at room temperature. It is used as an inexpensive and stable alternative to Mosher acid chloride. The OH acylation with the Pfp ester is typically done in a concentrated DMF solution, with DMAP as a base. This protocol is suitable for derivatization without purification – just the DMF is evaporated by stream of nitrogen before the NMR analysis. The pentafluorophenyl signals in the 19-F spectra are far to the left so they do not interfere with the Mosher CF3 group signals. Unreacted Mosher acid Pfp ester signals can be used as internal standard. 

12 Comments »

  1. Nice prep. Thanks, it worked well. Do you have the literature reference in case I need to cite it for my thesis? Thanks! By the way, I like this blog. It’s clean, succient and w/o frivolity. Multiple golf clasps to you old boy.

    Comment by Don Mattingly — October 1, 2006 @ 8:47 pm

  2. Hi Don,

    I am glad it worked. I came to this reagent because I had to derivatise a medchem compound that had multiple reactive NHs(lactam, amide, pyrrole) besides the chiral alcohol sidechain and Mosher chloride gave me an awfull mess with the molecule. My colleague next hood – who did his PhD in Rapoport group – suggested that I try the Pfp ester and it worked well for me. I think it was from this paper: Campbell, Jeffrey A.; Lee, Won Koo; Rapoport, Henry; J. Org. Chem.; 60; 14; 1995; 4602-4616.

    Comment by milkshake — October 1, 2006 @ 9:07 pm

  3. I did not know this, we published a paper on Mosher-Bt sometime ago without knowing this.

    Comment by pmgb — May 14, 2008 @ 2:57 am

  4. I guess that the issue comes when your stuff (polyheterocyclic bis-amide) is as unsoluble (and not amenable to be purified by column chromatography, more polar than sodium chloride in TLC) as the 1,3-dicyclohexylurea junk formed in the reaction. Perhaps, DIC or EDC.

    Thanks for your preps anyway, and your generousity sharing them with us

    Comment by HOMO-LUMO — March 5, 2009 @ 6:35 pm

  5. 1. What was the source of pentafluorophenol?

    2. Did you notice any long range coupling between the CF3 fluorines and the ortho hydrogens?

    3. For 19F spectra, my favorite internal standards were CFCl3 (set to 0 ppm) and benzotrifluoride (-63.72 ppm). Our NMR guy also developed a program to broadband decouple the protons, so that our 19F spectra became that much easier to interpret.

    Comment by Vinod Jairaj — April 1, 2009 @ 2:10 am

  6. The pentafluorophenol was from Aldrich and it was quite old – not perfectly colorless…
    I have not noticed any long-range F-H couplings.
    H-decoupled 19F-NMR is now part of routine method menu on new Bruker instruments. I still like non-decoupled 19F spectra better – if not for other reasons then that I can trust the integration more, and the multiplet shape and symmetry convinces me that the spectra resolution is healthy.

    Comment by milkshake — April 1, 2009 @ 2:42 am

  7. Hello Milkshake,

    does this reaction applicable on amine?

    Comment by curiouschemistrygrad — February 2, 2010 @ 1:29 am

    • sure, the Pfp ester works great for acylating amines. You probably do not even have to add any tertiary amine to scavenge pentafluorophenol – so in this case so you would not need need DMAP (like with alcohols)

      Comment by milkshake — February 2, 2010 @ 2:29 am

  8. Dear Milkshake,

    In other paper, they used Mosher’s acid chloride to react with alcohol and amine (both functional groups on the same compound, X).

    Procedure:

    To a solution of X (6.02mmol), DMAP (3.61mmol), TEA (24.1mmol) in dry CHCl3 (15ml) was added dropwise via syringe of MTPA-Cl (13.84mmol) at room temperature, under inert atmosphere. The rx mixture was stirred overnight and quenched with EtOAc and washed with sat NHCO3. The organic layer was dried with Na2SO4 and concentrated under reduced pressure.

    My questions:

    1) Under what circumstances the reaction of Mosher’s acid with alcohol/amine is OK with or/and without converting to acid chloride?

    2) This classic reaction with alcohol need DMAP and in this case, why TEA is also used?

    Comment by curiouschemistrygrad — February 4, 2010 @ 10:15 pm

    • they probably use DMAP in catalytic amount, the stoechiometric base is NEt3. You need some activated form of the acid: acyl chloride or the Pfp ester for the reaction. I guess you can do the activation in situ but in this case it pays to make the pure acyl chloride or Pfp ester, use a small portion of it and put the rest in a bottle because chances are you will do multiple derivatizations with the reagent

      Comment by milkshake — February 5, 2010 @ 2:52 am

      • Dear Milkshake,

        This question may not have any relation to the topic above. Just out of curiosity, in what case does the DMAP works together with TEA and vice versa?

        Comment by curiouschemistrygrad — February 10, 2010 @ 8:37 pm

      • typically one would use NEt3 as a stoechiometric base and add only a small amount of DMAP as the acylation catalyst. But one can use stoechiometric DMAP alone because DMAP is nowadays cheap enough.

        If you do in situ derivatization and take the whole reaction mixture into an NMR tube, the ethyls of NEt3 will give rather broad signals which can obscure signals of your interest whereas if you use DMAP alone its signals are much sharper/narrower.

        Comment by milkshake — February 10, 2010 @ 9:08 pm


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