[Babcock_Hall]

I am trying to oxidize a sulfide to a sulfone.  I am following the procedure in Blumenkopf T., Synthetic Communications (1986) 16(2) 139-146.  Blumenkopf had a phenyl ring, and I have a methyl group but otherwise the molecules are identical (both are phosphonates--see diagram).  The active oxidant in Oxone, KHSO₅ is present in 3-fold greater quantity than the β-sulfonylphosphonate.  Oxone is in water and the substrate is in methanol (equal in volume to the water), and the ozone solution is added to the methanol solution.  Blumenkopf wrote, "A white precipitate forms and the resulting slurry is stirred overnight. The mixture is then concentrated in vacuo to remove most of the methanol. The concentrate is diluted with water until all the white powder dissolves, and the resulting mixture is extracted three times with methylene chloride."  I set the reaction up yesterday, and the white precipitate began to form immediately.  Owing to the smaller scale at which I am working, I was thinking about replacing the distillation step that follows the extraction with a silica column.

My first question is what is the precipitate?  I would guess K₂SO₄, which is present in a mole ratio of 1.5 to 1 with respect to the substrate.

My second question is how should I sample for P-31 NMR to test for completeness?  I plan to take a 150-200 µL of the reaction mixture and add deuterated chloroform and filter.  As long as the reactant or product is not the precipitate, I think that I will be OK, but sampling something heterogeneous always raises this sort of question.  The first oxidation (from the sulfide to the sulfoxide) should change the chemical shift by about 5 ppm upfield, and the second oxidation (to the sulfone) should shift by about the same increment.

My third question is should I adjust the extraction to account for the presumably greater water solubility when R = methyl than when R = phenyl? 

[rolnor]

How about running TLC? You can se the RF going down and you can dipp the plates in KMnO4, the sulphone should have no reaction but the sulphide and sulphoxide should.
You can also see if you have any product left in the water-phase. You need a polar mobile-phase, maybe 5%MeOH in EtOAc.

[Babcock_Hall]

My starting material P-31 signal was at 24.5 ppm, and my first first time point (overnight) was at 11.75 ppm, which is close to what I expected for the sulfone.  If I can easily lay my hands on the reference values that I have used in the past, I will post them.  If I have to run a column, I will try the TLC.  I have used 2-6% methanol or ethanol in DCM or chloroform, but I have not tried alcohols in ethyl acetate.  Sounds good.

[rolnor]

Its a simple reaction, I think hydrogen peroxide i MeOH would work, then just evaporate.

[Babcock_Hall]

Some time ago, we did some analogous reactions with water-soluble β-phosphono derivatives of cysteine or homocysteine and found that the first oxidation (to the sulfoxide) needed only one equivalent of hydrogen peroxide and was pretty facile.  On the other hand, the full oxidation to the sulfone required an excess of hydrogen peroxide, went pretty slowly, and did not always go to completion.  With respect to β-phosphonosulfides that are soluble in organic solvents, I have seen mCPBA used to perform either oxidation (dx.doi.org/10.1021/jm401788m | J. Med. Chem. 2014, 57, 1473−1487), but I have also seen one report of a yield of 28% when employing this oxidant (https://onlinelibrary.wiley.com/doi/epdf/10.1002/cber.19741070425).  Blumenkopf did not obtain a good yield with permanganate.  The yield was 81% when hydrogen peroxide was used with selenium dioxide as a catalyst (Drabowicz _{et al}., Phosphorus Sulfur Silicon 1983 17(2) 169-172).  A different group attempted the reaction with per-acetic acid took two days and gave a yield of 69%.

[rolnor]

An advantage with hydrogen peroxide or peracetic acid is that you can evaporate and possibly crystalize without chromathography. The product should be crystalline, or?

[Babcock_Hall]

That is a very interesting question.  Blumenkopf wrote, "The permanganate oxidation of sulfide phosphonates appears to work well if the product sulfonyl phosphonates can be isolated by crystallization.  Solid arylsulfonylphosphonates such as 4b⁹ [PhSO_2-] may be obtained in reasonable yield and purity by this procedure. However, compound 4a [4BromophenylSO₂-] is a high-boiling oil..."  Drabowicz and collaborators apparently used crystallization and the substrate had a methyl group on sulfur.  However, they did not provide their recrystallization solvent, or I missed it when I read their paper.  Wegener W, Courault K. Z. Chem. 1980 20:337 used per-acetic acid, and their substrate had a methyl group.  I attempted to obtain their paper from our interlibrary loan service, but what I received was an abstract, and I do not have certain details of their procedure.

[wildfyr]

I gotta say, in my book the value of an easy workup (evaporate the reagent) can really outweigh a higher lit yield. If its small scale you can recover the starting material anyways for reuse. Oxone is a really easy one if its working though, since it partitions into water.

Babcock, I found the Wegener paper... in German. I've emailed it to the email you used to sign up for this forum, god speed. Maybe post the useful information you find after translation?

P.S. I guess this proves I'm better at, or at least care more about, finding literature for scientists than your librarians 

[Babcock_Hall]

Methylsulfonylmethan-phosphonsaure-diethylester( 2 ) : Zu einer Losung von 30 g (0,15 mol) 1 in 100 ml abs. Ether wird bei einer Reaktionstemperatur von 20°C in abs. Ether geloste etwa 13%ige Peressigsaure getropft, bis sich angefeuchtetes Kaliumiodid-Starkepapier blaut. Man laDt die Mischung zwei Tage stehen und engt dann im Vakuum bis zur Trockne ein. Ausbeute: 24 g Rohprodukt (69% d.Th.). Farblose Nadeln aus Benzen vom Schmp. 93-94°C; C6,H15,O5,PS (230,23).

Google translation of the Wegener and Couralt paper with my additions in brackets.
Methylsulfonylmethane-phosphonic acid diethyl ester (2): To a Solution of 30 g (0.15 mol) of 1 in 100 ml of abs. Ether is at a Reaction temperature of 20 ° C in abs. Ether dissolved about 13% Peracetic acid is added dropwise until wetted potassium iodide [starch] paper is blue. You leave the mixture for two days and stand then concentrated in vacuo to dryness. Yield: 24 g of crude product (69% of theory). Colorless needles from Benzen [gasoline?] from [melting point]. 93-94 ° C; C₆H₁₅O₅PS (230.23).

The recrystallization solvent is a little unclear to me.  If they had written "Benzin," then I would assume that they used gasoline.  I am a bit puzzled by their use of potassium iodide starch paper.  It sounds as if they did not measure out a set amount of the peracetic acid.  However, if I can use recrystallization conditions from one of these papers, it might help.

[Babcock_Hall]

Here is the Google translation of the relevant paragraph from Eberlein et al., 1984 Chem. Ber. 107 1275-1284.  My additions or corrections are in brackets, as above. 
(Methylsulfonylmethyl) phosphonic acid diathyl ester (30): To the solution of 10 g (50.5 mmol) (methylthiomethyl) phosphonate diethylester¹⁷) in 100 ml of CH₂Cl₂ at 0° C with stirring slowly 20 g (101 mmol) of m-chloroperbenzoic acid in 350 ml CH₂Cl₂ dropped. Thereafter, stirring is continued for about 10 minutes until the m-chlorobenzoic acid has precipitated as a crystalline precipitate. It is filtered off with suction and the filtrate is washed successively with 5 percent strength. NaHCO₃ solution and with sat. NaCl solution. After drying over Na₂SO₄, [in vacuo] concentrated to dryness. From ethyl acetate 3.2 g (28%), mp 90-93 ° C. IR (KBr): 1150, 1325 cm-1 (SO₂). - NMR (CDCl₃): 6 = 3.21 ppm (s, CH₃SO₂),? 3.7 (d, CH₂P, JP, H = 17 Hz).

[wildfyr]

I think the starch paper indicates you are just into excess of peracetic acid. You sure Benzen isnt benzene (not trying to be obnoxious)? Heptane seems like it might do in a pinch if they do mean gasoline!

[Babcock_Hall]

What is odd is if the reaction happens quickly (and consumes all of the peracetic acid), then why stir for two days?  I have one of my two German-English dictionaries with me right now, but I do not have the other one.  It gives "benzol" as the German equivalent of "benzene."

With respect to the 1974 paper, I am tempted to speculate that the yield might have been low owing to the recrystallization solvent or to incomplete partitioning of the crude product into dichloromethane in the extraction.

[rolnor]

The produvt will be very polar and losses can be in the water-phase.

[wildfyr]

Consumption of per acetic acid is fast but some other step is rate limiting?

[Babcock_Hall]

Yesterday I removed the DCM from the extraction and put the product under a vacuum.  I checked the H-1 and P-31 NMR signals in chloroform against the literature.  Based on related compounds (RS Edmundson CRC Handbook of Phosphorus-31 Nuclear Magnetic Resonance Data, Ed. by J.C. Tebby, CRC Press, Boca Raton, (1991), Chap. 11, pp. 584.), one would predict an upfield shift of about 11 ppm from sulfide to sulfone, and we observed a difference of 12.8 ppm.  One discrepancy I found was that I observed a lower chemical shift for the bridging methylene hydrogens than one group (Drabowicz et al.) had reported, by almost one ppm.  This signal is a doublet from a two-bond coupling to phosphorus, with J about 16-17 Hz.   One other group reported a value that was close to mine, and one group who had made a related molecule also reported a value similar to mine.  I saw no impurities by P-31.  I did see a small peak next to the water peak in chloroform, but that was the only hint of an impurity there.

I did not obtain an emulsion in the extraction, possibly owing to the high salt concentration in the aqueous phase.  I started a scaled-up synthesis yesterday and completed it today, except for the vacuum step.  I am inclined not to attempt to purify this material further, but I would listen to all points of view.