Contributed by Bruce H. Lipshutz, Ph.D., University of California, Santa Barbara, Dept. of Chemistry & Biochemistry

 

In 2011, the Presidential Green Chemistry Challenge Award was given to the Lipshutz Research Group at the University of California, Santa Barbara on the promise that our second generation designer surfactant, TPGS-750-M, would lead to new technologies that avoid the use of organic solvents as the reaction medium – that following nature’s lead, very limited amounts of water could be used instead. Indeed, in return for the EPA’s vote of confidence, there are now many commonly used reactions in organic synthesis that no longer need to be run in organic solvents (Figure 1), thereby dramatically dropping the levels of what is, by far, the major component of organic waste created by the chemical enterprise worldwide.1

 

nok-fig1.png

nok-fig2.png

Notwithstanding these successes, it seemed obvious that alternatives to TPGS-750-M would be needed, as it would be naïve to assume that this single surfactant should work in every situation. Moreover, we were still learning the new rules for organic synthesis that prevail under these very different conditions. In a medium of 98 percent water, homogeneous catalysis is happening inside a nanomicelle’s hydrophobic core, where concentrations are approximately 10 times those typically used in reactions, and everything in the pot is undergoing micelle-to-micelle exchange through the aqueous mixture. The fact that this surfactant is composed of vitamin E, a commodity chemical, also meant that it could be subject to shortages, and is by far the most costly component of the three involved in its two-step synthesis. These considerations prompted us to look for a third generation surfactant that would not only function akin to TPGS-750-M,2 but would also be a less expensive alternative. For this, we looked at phytosterols, with many of these natural products being both available and even healthy, that might also be derivatized to form similar micellar arrays in water. Enter Nok.

 

This assignment went to first-year graduate student Piyatida Klumphu, from Thailand, who asked to be called by her nickname: Nok. In time, Nok found that using b-sitosterol, the major component of a mix of double bond isomers (and therefore, inexpensive), can be combined with succinic anhydride and MPEG-550 to form… Nok (Figure 2).3

 

Although Nok that is dissolved in water above its critical micelle concentration (ca. 10-4 M) leads to nanomicelles that are about the same size as those formed from TPGS-750-M (ca. 45-60 nm), the surprise came from its cryo-TEM analysis. Rather than forming spherical particles, Nok forms rods and worm-shaped nanomicelles. This unexpected observation may account for the differences seen occasionally in its chemistry versus its predecessor.

 

The initial disclosure of this new surfactant was in 2014, when it was shown to behave like TPGS-750-M in many types of reactions. It has since become readily available as an item of commerce (Aldrich catalog number 776033). In general, we view it as the first option for running reactions in water. As a mix of phytosterols (mainly b-sitosterol), it is far less expensive than racemic vitamin E, though with each being used at the 2 weight percent level, it is unlikely to make either a driver in any process used at scale.

 

Among the reports that use Nok as the surfactant of choice, the recent (2016) disclosure of the monophosphine ligand HandaPhos that forms 1:1 complexes with Pd is included.4 This new catalyst is active at the ppm level (≤1000 ppm, or ≤0.1 mol percent) in Suzuki-Miyaura cross-couplings in water at ambient temperatures (Figure 3, A). A study in 2015 appeared involving the reduction of aryl bromides in nanomicelles composed of Nok, a reaction determined to be generally far less efficient when using other surfactants, such as cremophore, PTS and TPGS-750-M (Figure 3, B).5 Another study that will soon be submitted favors Nok as the surfactant, enabling several gold-catalyzed processes to be carried out not only in water at ambient temperatures, but also at the ppm level of this precious metal, with recycling of everything in the pot (i.e., the water, surfactant, and the chelated gold catalyst).6 What’s the secret to this new technology? HandaPhos (Figure 3, C).

 

A: ppm Pd-catalyzed Suzuki-Miyaura reactions using (HandaPhos)Pd

 

figure-a.png

 

B: Reductions of aryl bromides in water at rt, enabled by Nok

 

figure-b.png

 

C: Representative ppm Au-catalyzed reactions in Nok/H2O using HandaPhos technology (“L” in LAuCl = HandaPhos)

 

nok-fig3.png

Although Nok is still rather new to the micellar catalysis scene, it seems to have a bright future in that it provides a cost-effective alternative to TPGS-750-M in general, and can also be the surfactant of choice. To date, it has been purchased by almost 100 different institutions, suggesting that it is certainly being tested. Understanding why one designer surfactant might function in a superior fashion to another, however, remains for future investigations.

 

As for Nok – the first-year graduate student who was assigned this project in the first place? She successfully defended her thesis on Nov. 28, 2016, and soon thereafter assumed a faculty position at Maejo University in Chiang Mai, Thailand.

 

References

 

  1. For reviews on the use of designer surfactants in water, see:  (a) Lipshutz, B. H. ; Ghorai, S. Aldrichimica Acta.2008, 41, 59.; (b) Lipshutz, B. H. ; Ghorai, S. Aldrichimica Acta.2012, 45, 3.; (c) Lipshutz, B. H. ; Ghorai, S. Green Chem.2014, 16, 3660. See also: La Sorella, G.; Strukul, G.; Scarso, A. Green Chem. 2015, 17, 644. and references therein.
  2. Lipshutz, B. H.; Ghorai, S.; Abela, A. R.; Moser, R.; Nishikata, T.; Duplais, C.; Krasovskiy, A.; Gaston, R. D.; Gadwood, R. C. J. Org. Chem. 2011,76, 4379.
  3. Klumphu, P.; Lipshutz, B. H. J. Org. Chem. 2014,76, 888.
  4. Handa, S.; Andersson, M. P.; Gallou, F.; Reilly, J.; Lipshutz, B. H. Angew. Chem., Int. Ed. 2016,55 (16), 4914.
  5. Fennewald, J. C.; Landstrom, E. B.; Lipshutz, B. H. Tetrahedron Lett.2015, 56, 3608.
  6. Klumphu, P.; Handa, S.; Desfeux, C.; Lipshutz, B. H. manuscript in preparation.

 

 

“The Nexus Blog” is a sister publication of “The Nexus” newsletter. To sign up for the newsletter, please email gci@acs.org, or if you have an ACS ID, login to your email preferences and select “The Nexus” to subscribe.

 

To read other posts, go to Green Chemistry: The Nexus Blog home.