A “Designer” Surfactant for Cross Couplings of Hydrophobic Reagents in Room Temperature Water

“TPGS-750-M: A Second-Generation Amphiphile for Metal-Catalyzed Cross-Couplings in Water at Room Temperature” Lipshutz, B. H.; Ghorai, S.; Abela, A. R.; Moser, R.; Nishikata, T.; Duplais, C.; Krasovskiy, A.; Gaston, R. D.; Gadwood, R. J. Org. Chem. 201176, 4379-4391. DOI: 10.1021/jo101974u

I occasionally run reactions in water, and it is awesome. I LOVE not worrying as much about cancer. Unfortunately many interesting chemicals are simply too hydrophobic to allow reactions to be run in aqueous solution. As anyone who has ever scrubbed a greasy pan will know, one way to get around the solubility problem is with soap. Also called emulsifiers, surfactants, amphiphiles, a soap by any name is pretty much the same thing in my mind (though others will disagree I’m sure). Molecules with hydrophilic and hydrophobic ends can form micelles in water, creating variously-shaped and sized particles with hydrophobic cores. Using those hydrophobic cores as reaction media is a concept known as micellar catalysis. The Lipshutz group was not the first player in this arena, but they have been at it for some time. They recently teamed up with the medicinal chemistry company Kalexsyn and came out with a new amphiphile that caught my eye, dubbed TPGS-750-M. 

I came across this paper while perusing the most recent issue of “Green Chemistry Articles of Interest to the Pharmaceutical Industry” in Organic Process Research & Development, which I highly recommend checking out.

TPGS-750-M is a next generation version of a class of amphiphiles initially synthesized to solubilize the hydrophobic dietary supplement coenzyme Q10. The history of this amphiphile class can be found here, but for now I will simply focus on TPGS-750-M. This amphiphile is cool for three main reasons. First, it seems unlikely to be toxic–it’s hydrophilic portion is comprised of poly(ethylene glycol), which is used commonly in medicine, and its hydrophobic portion is comprised of α-tocopherol, an E vitamin. Awesome. Second, its synthesis is straightforward and high-yielding. Awesomer. Third, its use allows for numerous reactions to be carried out in water at room temperature. Awesomest.

I won’t dwell on the synthesis because it is so straightforward, but check it out:

We’ve already touched on why amphiphiles like TPGS-750-M enable organic reactions to be carried out in water by providing hydrophobic pockets within which those reactions can take place, but we haven’t discussed why they can enable those reactions to occur under lower temperatures than when they are carried out in traditional organic solvents. This part is super neat. The thinking goes that the hydrophobic reactants preferentially partition into the hydrophobic micelle, where the local concentration of reactants can be HUGE, greatly increasing the reaction rates. Thus the term micellar catalysis. This effect is not unique to TPGS-750-M, but as far as I can tell it is the most impressive micellar catalyst out there, as you will soon see.

Check out all these Pd-catalyzed couplings!

All reactions were carried out in H2O with 2-5 wt % TPGS-750-M at room temperature. All reactions were complete in 4-25 h. Pd sources and ligands varied.

In addition to facilitating these Pd-catalyzed reactions, the amphiphile enables Ru-catalyzed olefin metathesis reactions to be carried out in water using Grubbs 2nd generation catalyst.

Definitely the awesomest thing this amphiphile can do is enable these Negishi-like couplings to occur in water.

This is cool because these reactions proceed via highly water-sensitive organozinc reagents formed in situ from alkyl or vinyl halides and metallic zinc. I’m going to quote the article authors here, because this sentence is awesome:

Crucial to success are the relative rates of organozinc halide formation, transmetalation to palladium, and aqueous protonation of RZnX, all controlled such that RZnX is not formed in situ too rapidly so as to avoid quenching by eventual exposure to the nanoparticle-surrounding water.

The paper goes on to use this amphiphile to facilitate a number of other reactions that you can go check out yourself.

The authors also compare  TPGS-750-M to other similar amphiphiles that possess different hydrophobic and hydrophilic portions and different linkers, and  TPGS-750-M generally matches or outperforms all these amphiphiles.

Why the different performance from such similar-looking amphiphiles? The answer to that question is not at all clear.

The authors performed some cryo-TEM experiments to try to figure out if differing performance is caused by differing micelle sizes or shapes, and they conclude that TPGS-750-M outperforms the other amphiphiles due to the larger (50+ nm) micelles of the former. I’ll throw these images up because pictures are awesome, but I concur with the authors that this is an area ripe for mechanistic study.

Cryo-TEM image of (A) aqueous PTS, (B) TPGS-750-M, and (C) TPGS-1000

In addition to micelle size, it’s not clear to me (or anyone else I think??) how the structure of the hydrophobic moiety can affect the reaction outcome. After all, it essentially provides the reaction solvent, so should have a significant influence. I hope to see lots more work in this area to satisfy my mechanistically-oriented brain.

In terms of scale-up and greenness one huge concern with running reactions in water is purification and recycling/disposal of the water. The authors address this issue by isolating the reaction products and catalysts via an aqueous/organic extraction. TPGS-750-M is preferentially soluble in water, so remains in the aqueous phase after this extraction. This allows the water from the previous reaction to be reused up to 8 times with little to no effect on the reaction outcome.


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2 Responses

  1. Bruce Lipshutz replied via e-mail to clarify some issues for us :-) Here is the relevant portion of his e-mail:

    Please let me address the one item you felt was unclear in the paper: why reactions go better in the newly engineered surfactant TPGS-750-M. We have learned from many studies that shape and particle size matter in this chemistry. Thus, we designed this amphiphile to be larger than both TPGS-1000 and PTS, as shown in the paper. The reason it enables better chemistry is that it offers greater surface area (i.e., more grease) within the nanoparticle, and with more grease (the vitamin E), the more time the substrates spend there and the faster the catalysis. This is made more apparent when one considers that the system is totally dynamic, meaning that all components (substrates, catalysts, and the individual molecules of TPGS-750-M) are exchanging between micelles. For this to happen, they must find each other in a dilute solution in water. This takes time, but with larger particles, there are more molecules of the surfactant per micelle, and hence, more grease in the area leading to increased binding constants for the reactants and catalysts. Hence, faster chemistry.

    Thanks again. Yes, we have lots more cool chemistry in water @ RT coming.

    Bruce Lipshutz

  2. Excellent post. Keep posting such kind of information on your blog. Im really impressed by it.

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