Frequently Asked Questions: Micellar Reactions using "Designer" Surfactants

Micellar catalysis has made many of the most synthetically useful transformations possible under aqueous conditions, vastly reducing the impact of organic solvent on reaction waste streams. This technology is enabled by the aggregation of amphiphiles into nanomicelles, which can surround organic matter and provide a facile environment for transformation to take place.  The Lipshutz group has shown this concept to be highly effective with previous amphiphiles such as polyoxyethanyl-a-tocopheryl sebacate (PTS, 698717), DL-a-tocopherol methoxypolyethylene glycol succinate (TPGS-750-M, 763896), and b-sitosterol methoxyethyleneglycol succinate (SPGS-550-M, 776033) otherwise known as Nok.

General Information


What makes TPGS-750-M so special with regard to other available surfactants?

This surfactant was engineered to provide several features that, in the composite, make it unique relative to other commercially available amphiphiles. These factors include:

  • It is nonionic
  • The stabile ester residues make it relatively inert
  • It was created to be “benign by design”
  • It was designed to produce optimal sized nanomicelles.
  • It was engineered to be water-soluble such that it cannot be extracted with most organic solvents (anything except chlorinated solvents).
  • It is non-frothing

Ester Stability:

Why don’t the esters present in the surfactants undergo saponification in reactions that involve basic conditions, e.g., Suzuki-Miyaura couplings, especially if heating to any extent is needed?

The ester of vitamin E is protected by the 2,6-dimethyl groups, while the PEG-ester is shielded by the highly-coiled PEG chain. Hence, they are unavailable to the highly polar hydroxide that is unlikely to penetrate the micellar environment.


How do you prove the reaction occurs in the micelle, particularly when there is an excess of greasy reagent?

This can easily be tested by running the reaction in the absence of the surfactant; i.e., “on water”, and noting the difference. It is possible that the reaction can be taking place to some degree on water in the background, but usually there are significant differences between these.


Is TPGS-750-M cost effective compared to the other common
solvents I would normally use for my reaction?

This surfactant can be made in >95% yield on any scale. It derives from non-natural vitamin E, succinic anhydride, and MPEG-750. The latter two ingredients are extremely inexpensive, and the cost of racemic vitamin E while variable, is certainly not prohibitive. Thus, the two step preparation can lead to hundreds of grams that are likely to last for quite some time given that it is used typically as a 2 weight percent solution in water (e.g., 20 mg dissolved in 1 mL of water).  Most noteworthy is the fact that many reactions run in this surfactant allow for the aqueous phase to be recycled, since the surfactant will remain in the water upon extraction of the product with EtOAc, an ether, or any hydrocarbon.  So yes, use of this aqueous technology can be highly cost effective, and certainly more environmentally appealing.

Is it cost effective compared to other surfactants?

From strictly catalog pricing, most other surfactants are far less costly, as they are products of various industries (e.g., paint, petroleum, textile, etc.) that use them to mix oil and water. They are 2-component surfactants derived from very cheap materials. However, since they were not designed to maximize a reaction’s outcome (i.e., lead to best levels of conversion and highest yields, and at faster rates that maximize catalyst survival), one should expect poorer results. Given that so little of these designer surfactants is actually present in any reaction, it is far more prudent to opt for the best reaction outcome than to select a surfactant based on catalog pricing.



What are the common impurities present in the surfactant?

Any surfactant based on PEG or MPEG has a broad range of molecular weights associated with these ethylene oxide polymers. Hence, they are “impure” by definition. The other common impurities include small amounts of diesters of vitamin E, and MPEG esters of succinic anhydride, all resulting from the synthesis of the surfactant. These “impurities” are actually crucial for micellar catalysis to take place.

Are there any trace metals?

Only as brought in through the reagents and solvents used in the synthesis of the surfactant; the surfactant synthesis itself is metal-free.

What impurities are typically produced when running reactions in TPGS-750-M?

Since the surfactant remains intact, there should be none, aside from minor impurities produced normally in any reaction. Since these reactions are typically run at RT, the impurity profile compared to reactions run in traditional organic solvents, especially if any heating is involved, is likely to be very different. Most reactions run under micellar catalysis are very clean, making product isolation and purification more facile than with reactions run in organic solvent.

What purity levels of surfactant are necessary for the reaction to work?

This is one reaction parameter that requires no attention whatsoever. As the surfactant normally contains a distribution of PEG chain lengths, and small amounts of related impurities, further purification is not necessary (and in fact, can be disadvantageous).

Setting Up A Reaction Under Micellar Catalysis Conditions


On what scale can I run these reactions?

Micellar catalysis has been used by many industries on huge scales; there is no known limit.


Is there any particular glassware needed to run a reaction in these surfactants?

Academic scale reactions are best run in microwave or 1-10 dram vials; vigorous stirring is the key to success, which is why these vertically oriented reaction vessels are preferred. As the scale increases, traditional round bottom flasks can be used so long as excellent stirring is maintained.


What concentrations of the surfactant are commonly used?

Although 2 weight % has been found to be useful for most reactions studied to date, a range of 1 to 5 weight % in water can be screened to optimize this parameter.

What are the limits to the concentration of surfactant?

The upper limit used to date is 15 weight %.

What are typical reaction concentrations?

Reactions are typically run between 0.3-1.5 M. The concentration is oftentimes determined by the amounts of solid additives in the medium, which can impact the rate of stirring, requiring that more water be present.

Catalyst Complexation:

My reaction requires a ligand to be complexed with a metal. Can I complex these in aqueous solutions containing a surfactant?

Yes; however, complexation times may vary. One option is to pre-complex the metal in a minimum amount of an organic solvent, and then evaporate the solvent prior to the addition of the aqueous medium and reactants. Alternatively, solid surfactant can be mixed with the metal salt and ligand neat, to which a minimum of water is added and the mixture stirred well. Once the complex is formed, it can be diluted to the desired concentration.

Running A Reaction in an Aqueous Surfactant

Aqueous Medium:

What grade of water is necessary?

Degassed HPLC-grade water is recommended. However, these reactions will take place will equal facility in unpurified ocean water.

How do salts affect the reaction results?

Salts, in a number of “name” reactions (e.g., Heck couplings), have been found to improve reaction rates and yields. This is ascribed to the fact that they cause an increase in the size of the nanoparticles, thereby increasing the amount of organic “solvent” per particle and hence, providing a greater opportunity for the substrate(s) and catalyst to remain within the lipophilic core where the reaction takes place.

What do salts do to the micellar solution?

Certain salts, such as NaCl, induce a “salting out” effect, that causes water associated with the PEG portion of a micelle to get released into the aqueous phase where it is needed to solvate the anion (chloride in this case). This causes the coiled PEG chain to unravel and extend further into the water, thereby increasing particle size. This then draws additional surfactant molecules into the micellar array and increases the lipophilic content in which the reactions take place.


What range of temperatures can be accommodated?

Reactions can be run between 4 and 60 oC. Above 70 oC, however, particle shapes become unpredictable; e.g., reorganization from spherical particles to bilayer arrays may occur, and so the quality of reactions run in these modified particles is not predictable.

Above what temperature will the micelles deaggregate.

The micelles will begin to change size and shape above ca. 70 oC.

Reaction Monitoring:

How can reactions be monitored?

Reactions can be spotted directly onto a TLC plate, or an aliquot of a few mLs can be withdrawn to which a few drops of an organic solvent can be added in a vial, after which the mixture can be spotted on a TLC plate or analyzed by GC or HPLC.

pH Effect:

Can reactions be run under acidic and basic pH’s ?

Yes, PTS, TPGS-750-M, and Nok can be used within the range of pH = 2-12.

Water Sensitive Reagents:

My reagents are water-sensitive, can I still use this micellar chemistry?

The logical answer is no, however, the “rules” change when chemistry is performed within nanoparticles where the concentrations of reactants and catalysts are far higher than in typical solutions. Textbooks teach that Negishi couplings with extremely water-sensitive organozinc reagents cannot be exposed to water, but today, these can be run entirely in water.  The same is true for organocopper chemistry, with 1,4-additions now available for use in water only. Cyclodehydrations can be effected in water, and so can esterifications between acids and alcohols.  Perhaps the best answer, then, is “maybe.”


Can solid substrates be utilized under micellar conditions?

Yes. With good mixing, this is usually not a problem, as the solids are broken up and eventually gain exposure to the lipophilic interior where they are “dissolved.”

What should I do if my organic compound won’t dissolve in the surfactant solution?

In such circumstances, there are several options that can be used to aid with solubilization.  These include:

  • Solids should be “ground-up” with a mortar and pestle as much as possible prior to addition to the reaction mixture.
  • Application of minimal heat may help; e.g., a 10 °C increase in temperature may be all that is needed.
  • Addition of a single drop (for small scale reactions) of a water-miscible solvent (e.g., DMSO, DMF, etc.) onto the solid substrate prior to addition of the reaction medium serves to soften the crystal lattice and can have a dramatic positive impact on reaction rates. The organic solvent added is lost in the water, which is recycled.
  • The order of addition may affect substrate solubility. Thus, adding the solid to neat surfactant, followed by addition of a small amount of the total water to be used (with good stirring), can help gain solubility prior to addition of the remaining volume of water.

Surfactant Analysis and Storage

Is there a proper way to store my “neat” surfactant or surfactant solution?

The “neat” surfactant, while stable to air and moisture, is best kept on the bench protected from light, and capped and sealed under an inert atmosphere. Solutions are also bench stable for at least 6 months, although they are best degassed periodically to avoid decomposition of PTS and TPGS-750-M due to oxidation of their ester E component.

How do I know if my surfactant, either solid or solution, is still good?  Is there a test available to determine quality?

Aside from a TLC analysis looking for baseline material associated with vitamin E oxidation, an NMR spectral analysis may reveal extraneous peaks due to decomposition (such as hydrolysis or oxidation). Alternatively, a small scale test reaction, such as an olefin metathesis between allylbenzene and MVK would indicate if the surfactant has remained intact.

Reaction Processing

Reaction Workup:

How do I work up aqueous reactions containing surfactants?

There is no formal workup:  they are already in water, so no additional water need be added to the mixture. The reactions are not removed from the reaction vessel; i.e., they involve an “in-flask” “workup.” Simply adding a minimum amount of a single organic solvent allows for extraction of the desired product, and this process can be repeated three times. Alternatively, the reaction mixture can be poured directly onto a small pad of silica, at the top of which can be placed a small section of the inside material of a baby’s diaper (really!). The highly absorbing material removes the water, while the silica removes the polar surfactant.

Are emulsions a problem with workup, considering micellar catalysis, by definition, works by forming emulsions?

Emulsions are rarely observed, and if encountered can be clarified by dilution with additional water. These surfactants are not “soaps” in the traditional sense; they do not froth or foam with normal handling.

How do I dispose of the surfactant?

The surfactant remains as a component of any waste-water, and hence, should be disposed of properly. Nonetheless, it will be eventually broken down into its three components, each of which is environmentally harmless.

Under what conditions will the surfactant leach into my extraction solvent?

Use of any organic solvent other than DCM or chloroform will cause the surfactant to remain entirely in the aqueous phase.

How do I prevent small amounts of an extraction solvent from staying behind in my aqueous solution, where it can potentially slow down the next reaction to be run in this same medium?

By simply applying a vacuum to the stirred aqueous medium, residual solvents will be quickly removed. Alternatively, for smaller scale reactions, purging with an inert gas can achieve the same end.

My product is a very polar solid; how do I get it out without extracting surfactant?

Diluting the crude mixture with water usually precipitates the product. Alternatively, the use of “warm” organic solvent in the extraction can make a huge difference.


My reaction produces water-soluble by-products; will these affect subsequent runs?

Usually not, as these remain in the aqueous phase and are unlikely to penetrate into the micellar nanoreactors. Hence, they are typically “lost” in, and diluted by, the water.

Can I recover the surfactant after the reaction?

It’s unclear why this would be desirable, as the water in which it is dissolved can be recycled, along with the surfactant. Moreover, given its low concentration (e.g., at 2 weight %, this is 0.02 M, and even lower in its aggregated form), the effort to reclaim it would be far greater than its cost.


Can I recover the catalyst after a reaction?

For reactions that involve organic solvent-soluble catalysts, the in-flask extraction procedure used will, likewise, remove the catalyst, as would any traditional extractive workup. On the other hand, if the catalyst is water soluble, or made water soluble by the addition of solubilizing ligands, then it can be recycled along with the reaction medium.

For a complete listing of the Designer Surfactants available, please click here.