Optimizing Product Conversion with Metathesis Reactions in Micelles through Flow Chemistry

Michael Jones and David BrownhollandCarthage College

2001 Alford Park Drive, Kenosha, WI 53140Department of Chemistry

AbstractWater is in many ways the ideal “green” solvent – it is

non-toxic, abundant, and renewable. Unfortunately, the water insolubility of organic compounds limits its ability to facilitate organic reactions. Recent work on using aqueous micellar solutions have helped remove the insolubility challenge. Non-polar organic compounds are entropically driven into the interior of the micelle and react. Flow chemistry has generated increased interest for organic synthesis, especially in the pharmaceutical industry. Compared to traditional batch chemistry, reactions conducted in flow occur faster, have greater temperature homogeneity, enable rapid changes to conditions for rapid condition screening, and allow for safe high-pressure conditions. We report the results of micelle-catalyzed metathesis reactions, in-flow. We successfully completed a ring-closing metathesis reaction under these conditions of diethyl diallyl malonate in yields compatible to those obtained in batch conditions of either dichloromethane or through micelle-catalyzed reactions. The progress of micelle-catalyzed cross-metathesis reactions, in-flow, is also reported.

Homo Metathesis

Ring Closing Metathesis

BackgroundFlow chemistry is an essential method used for many

different reaction schemes with little limitations. Pharmaceutical companies such as DSM use flow chemistry to efficiently produce drugs at a small scale with a faster reaction time. Another use of flow chemistry involves space reactions. With zero gravity conditions, batch reactions would be hard to replicated, and the data would be inconsistent. However, space reactions are possible with flow chemistry because the tubing confines the liquid to a small amount of area. This makes flow chemistry the only available and reliable method of performing chemical reactions in space.

In flow chemistry, there is one limitation of precipitation reactions. Any solid that forms in the tubing could cause clogging, and could prevent continuous flow for the rest of the reaction. Aside from precipitation reactions, all other reaction types can be performed through flow chemistry. These reactions can also be performed in any condition through flow. An advantage of flow chemistry is the rapid optimization of reactions. The environment of the tubing can be changed, then the reaction mixture can be analyzed for each different environment in one continuous flow. Also, since the reactions are ran at small scales, the amount of organic solvent needed can be minimized.

The solvent used in the metathesis reactions is called Nok. It is an aqueous solution with long chains consisting of a hydrophilic head and a hydrophobic tail. When this compound is put into water, it created a micelle where the organic reaction can occur. Once the reaction has occurred, a little organic solvent can extract the product from the micelles, and the micelles can be used again. These micelles will help to minimize the use of organic solvent for reactions.

We aim to analyze these metathesis reactions in different conditions to find the optimal environment in flow. Also, while trying to minimize organic solvent, a surfactant called Nok will be used in water as the solvent for these reactions.

• Grubbs 1st generation is a Ruthenium based catalyst used to catalyze the self metathesis reaction

• The reagent, undec-10-en-1-ol, has the necessary terminal alkene for the self metathesis to occur

• Grubbs 2nd generation is a Ruthenium based catalyst used to catalyze the ring closing metathesis reaction

• The reagent, diethyl diallyl malonate, has two terminal alkenes in the same structure for the ring closing metathesis to occur

Results

• The homo metathesis reaction only had a 20% product conversion, while using a weaker catalyst than in the ring closing metathesis.

• The ring closing metathesis reaction had successful product conversion percentages that matched the batch chemistry.

• Nok surfactant in H2O was successful as a solvent to these reactions in flow.

Acknowledgements• Carthage College Department of Chemistry• SURE Program

Future Direction• Optimize the homo metathesis reaction in different

conditions• Perform cross metathesis reaction involving two

structurally different compounds

References

1. Klumphu, P.; Lipshutz, B. H. The Journal of Organic Chemistry 2014, 79, 888-900.

2. Greco, G. E. The Journal of Chemical Education 2007, 84, 1995-1997

3. Lipshutz, B. H.; Boskovic, Z.; Crowe, C. S.; Davis, V. K.; Whittemore, H. C.; Vosburg, D. A.; Wenzel, A.G. Journal of Chemical Education2013, 90 (11), 1514-1517

4. Lipshutz, B. H.; Ghorai, Subir; Abela, A. R.; Moser, Ralph; The Journal of Organic Chemistry 2011 76 (11), 4379-4391

Conclusion

H1NMR of Ring Closing Metathesis

Cross Metathesis Reaction

Performing a Chemical Reaction Inside a Micelle

Reaction Type Solvent Temp. CatalystEquiv.

Product Conversion

Residence Time

Batch Dichloromethane 23oC 3% N/A 20 hours

Flow 2%(w/v) Nok in H2O 45oC 5% 100% 13 minutes

20 seconds

Flow 2%(w/v) Nok in H2O 23OC 5% 99% 17minutes

36 seconds

Flow 2%(w/v) Nok in H2O 23oC 2% 60% 14 minutes

7 seconds

Flow 2%(w/v) Nok in H2O 45oC 2% 100% 12 minutes

8 seconds

Reaction Type Solvent Temp. CatalystEquiv.

Product Conversion

Residence Time

Batch Dichloromethane 23oC 3% N/A 20 hours

Flow 2%(w/v) Nok in H2O 23oC 5% 0% 20 minutes

2 seconds

Flow 2%(w/v) Nok in H2O 45OC 5% 20% 20 minutes

17 seconds

Syringe pumps with coiled tubing

1. BA

B

AC

2.

C

C

3.

+

1. The aqueous micellar solution is formed from amphiphilicsurfactants, generating a protected, non-polar interior. The non-polarreactants and reagents (A and B) enter the micelle through anentropically driven process.

2. The interior of the micelle is a medium in which the organic reactantscan react to generate the product, C. Because the reactants areconcentrated in the micelle, they often react faster and at lowertemperatures, often room temperature.

3. Once the product has formed, the product can be removed from themicelle via extraction with a small amount of organic solvent.

• This reaction has been shown successful in flow analyzed by Thin Layer Chromatography

• Future analysis includes 1H and 13C NMR to find integration between products and reactants in the final mixture.