Mitsunobu Reaction: Fluorous vs. MPEG

Anyone which has conducted some organic synthesis has probably conducted Mitsunobu reactions for the formation of ethers, esters, or sulfonamides.  It’s really a great reaction which is conducted under mild conditions.  Usually the two substrates are an alcohol as the electrophile and a phenol, carboxylic acid, or sulfonamide as the nucleophile.  The reagents are a phosphine and an diazodicarboxylate such as DIAD.

The reaction is superb, the separation tedious.

There’s generally lots of by-products to remove and it usually requires a chromatography.  In the case of higher pKa nucleophiles, such as electron rich phenols, it can get really dicey as these reactions are not always high yielding leaving a whole slough of by-products which have to be removed.  Because of these issues there have been a number of different phosphine and DIAD variants which have been made all in an effort to simplify the purification of the reaction.  Polymer-supported, acid degradable, aqueous extractable, polymerizable, precipitatable, etc.  You name it and it’s probably been tried.  That’s how big of a problem the purification of a Mitsunobu reaction can be.  It’s also a testament to how useful the reaction can be that so much effort has been put into trying to solve the problem.

Of all the various methods, only one until recently was able to remove all the reaction by-products in a single operation without the need of conducting any further chemistry after the Mitsunobu reaction; fluorous.  By using a fluorous phosphine and a fluorous diazodicarboxylate, all the by-products can be removed using either a fluorous solid phase extraction (FSPE) or a fluorous liquid-liquid extraction (FLLE).  Here are links to the peer-reviewed literature on FSPE Mitsunobu reaction and FLLE Mitsunobu reaction.  And here is a link to our Fluorous Mitsunobu Application Note.

Two recently published papers from Hartley et al at the University of Glasgow, however, report another method similar in concept which accomplishes the same thing.  The first was in Chem. Comm. and the second in ACS Combinatorial Science.  Instead of using fluorous modified phosphine and DIAD, they tag the two reagents with “light” methyl polyethylene glycol oligomers (MPEG) .  The authors started with commercially available MPEG-OH with an average MW = 550 and attached it to a phosphine and a diazodicarboxylate to form the Mitsunobu reagents shown below.  These reagents successfully mediated a Mitsunobu reaction between an alcohol and a carboxylic acid.  The MPEG-tagged by-products could then be easily separated by SPE on normal silica gel which retained the MPEG materials and allowed the product to pass through and be collected in excellent purity.  The authors went on to produce a small 4 x 4 array of compounds using this method.

So here we now have another method which, like fluorous, separates the by-products in a single operation without other chemistry being involved.  In addition, the authors note that compared to fluorous reagents and fluorous silica gel that MPEG and normal silica gel are much cheaper, thereby overcoming the chief drawback of the fluorous Mitsunobu, namely cost.  Just as good and cheaper = better.  A no-brainer, right?

Not so fast, my friend.  Let’s take a closer look.  Here are five reasons why the fluorous vs. MPEG question is not so clear-cut.  In fact, by the end, you might like the fluorous approach better.

1) Nucleophile reactivity – In looking at the substrates reported for both methods there was a clear drop-off in yield for higher pKa nucleophiles, particularly phenols.  In both MPEG and fluorous the purification method resulted in clean product, however.  The big difference here is that even with electron-rich phenols such a 4-OMe phenol and 3-Me phenol, the fluorous method maintained yields in the 55-60% range, about 10-15% lower than using traditional PPh3 and DIAD.  There were no reports using these same substrates with the MPEG reagents, but even 4-Fl-phenol had seen a dropoff to the 45-60% yield range.  More electron-rich phenols are sure to be problematic with MPEG vs. fluorous.

2) Overall reaction mass – One criticism of the fluorous Mitsunobu is that the fluorous chains add a lot of mass to the reagents resulting in a large amount of reagents and by-products relative to the product.  Unfortunately, the MPEG tags don’t change that. Since the MPEG is a mixture of oligomeric species, the authors determined effective molecular weights by microanalysis.  This analysis showed that the mmol/gram of material was actually 15% lower for the MPEG reagents compared to fluorous reagents.  Since the stoichiometries for the reaction were essentially the same, one would use more material for the MPEG reaction than in the fluorous reaction.

3) Adaptability – As noted earlier, the fluorous Mitsunobu can be purified using either FSPE or FLLE, although different fluorous phosphines are required.  Both procedures have been published and found to be effective.  If one were to scale-up the process, a liquid-liquid extraction would be preferable to a SPE.  To date the MPEG procedure only uses the silica gel SPE.  To be fair, given the water solubility of oligoethylene glycols, a liquid-liquid extraction procedure can probably be developed but that procedure hasn’t been published yet.

4) Cost – So this is the big selling point to the MPEG vs. fluorous according to the authors.  They note that commercially available MPEG is quite cheap and that regular silica gel is about 15x less expensive than fluorous silica gel.  All of that is true. Two details, however, really tighten up the cost difference.  First is that both the MPEG-phosphine and the MPEG-DIAD made from commercially available light MPEG-OH failed in the normal silica gel SPE.  The oligomeric distribution of the MPEG caused some of the smaller MPEG by-products to not be retained well enough on the silica gel upon SPE.  The authors had to make the reagents then chromatographically separate some of the lower oligomers in order to obtain a narrower range of MW’s for the reagents.  This resulted in about 30-50% of the material being discarded.  This adds significantly to the cost just on labor alone.  Second, as we often note fluorous silica gel is very easy to recycle and reuse.  We routinely reuse our cartridges 10 times or more.  We know of some customers who use them 20 times over.  That brings the cost down in the same range as normal silica gel.  Combine these two elements and I’m not sure which is less expensive.

5) Commercial availability – As of now MPEG reagents are not commercially available.  Fluorous materials are.  Yes, you can readily make your own MPEG reagents and conduct the chromatography to narrow the MW range, but who wants to do that.  You want to spend your time making compounds, not reagents.

So at the end of the day the comparison between the two methods may not be what it seems at first glance.  While the MPEG is not as fully developed or explored as the fluorous method for now we’d have to say fluorous has a demonstrated better range of reactivity, lower overall mass consumption, more separation choices, comparable cost, and is commercially available.

Might be a no-brainer after all.

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One Response to Mitsunobu Reaction: Fluorous vs. MPEG

  1. milkshake says:

    Another problem with PEG- modified reagents is with their hygroscopicity and poor crystallinity. (No need for extra water in your Mitsunobu). Silica column will bind strongly all basic and highly polar products so this limits the scope of useful substrates (for example you cannot use aminoalcohols as Mitsunobu partners in this case). Also, any cost comparison between a commercial and non-commercial alternative is problematic, to make a good argument they would need to reproduce the synthesis of the commercial fluorous reagents in their lab to see if they could make it significantly cheaper