Gas Phase Calculations of Ether Synthesis from

Peroxy-AlkylsTristan Truttmann, Ruth Pardini, and Rebecca Meier

● Introduction○ Ethers in industry, nature○ Traditional synthesis○ A new synthesis

● Computational procedure○ Recalculations and struggles

● Results○ Quantitative and Qualitative

● Conclusions

Overview

Industrial Ethers

● Common chemical feedstock● Used in starting fluid

Ethers in the Natural World

Maito

Maitotoxin

● A toxin produced by dinoflagellates found in the maito fish

● 0.14µg lethal in mice

Ethers in the Natural WorldBrevetoxins

● Series of toxins produced from a dinoflagellate in the Gulf of Mexico

● Responsible for the toxicity of the Florida Red Tide

Tetrodotoxin● Present in puffer fish● Responsible for the intoxicating effects and

danger of the Japanese cuisine “fugu”

Ethers in the Natural World

Traditional Ether Preparation

● All common variations of ether synthesis use nucleophilic oxygen, electrophilic carbon.

● The Williamson Ether synthesis epitomizes this

A New Route for Ether Synthesis

Willand-Charnley synthesis● Electrophilic oxygen via peroxide● Nucleophilic carbon via organometallic

Willand-Charnley et al., “Oxacycle Synthesis via Intramolecular Reaction of Carbanions and Peroxides,” 2014

Our Project

Goal: Provide a limited computational analysis of this of Willand-Charnley’s synthesis method

Our Project: Original Calculations

Additional Calculations Increasing Bulk

Metal R1 R2 R3Li Tert-butyl Tert-butyl Methyl

Na Tert-butyl Tert-butyl Methyl

K Tert-butyl Tert-butyl Methyl

Li THP Tert-butyl Methyl

Na THP Tert-butyl Methyl

K THP Tert-butyl Methyl

Li Tert-butyl Methyl Tert-butyl

Na Tert-butyl Methyl Tert-butyl

K Tert-butyl Methyl Tert-butyl

Computation● Level of Theory: B3YLP● Basis Set: 6-31+G(d,p)● Calculation types

o Opt + Vib Freqo Saddle Calculationo Transition State Optimizationo Forward and Reverse IRC

Locating structures

Checking structures

Stage I: Structures

Stage II: Structures

Stage II: Difficulties

Original Conformer“Axial”

Located using Opt + Vib Freq

Lower Energy Conformer“Equatorial”

Located using IRC calculations

Stage III- Transition State

● R3 partially binds to Oxygeno R-M-O angle decreases

● O-O bond lengthens by ~0.5 Å

Stage IV: Structures

Stage V: Structures

Discussion- Trends

Discussion-Trends

Discussions-Trends

Discussion-Trends

Conclusion● Gas phase versus solvent calculations

o Quantitative results by themselves will not be very applicable to the laboratory.

● However, trends will likely hold trueo We expect all the trends discussed on this slideshow

to hold true on analogous solvent calculations and thus in the laboratory.

Future Work● Expand on bulk calculations● Solvent calculations● Cyclic ethers● Highly Electrophilic Peroxides to overcome

ring strain

Acknowledgements● Keith Kuwata for providing us with the

intellectual tools to tackle this project● Midwestern Undergraduate

Computational Chemistry Consortiumfor providing computational resources

● Patrick Dussault for discovering this chemistry in the lab and working with us on this project

References:● Nakata, T. “SnI2-induced reductive cyclization for the synthesis of cyclic ethers and applications

in natural product synthesis.” Chemical Society Reviews 2010, 39, 1955-1972.● Willand-Charnley, R.; Puffer, P. W.; Dussault, P. H. “Oxacycle Synthesis via Intramolecular

Reaction of Carbanions and Peroxides.” Journal of the American Chemical Society 2014, 136, 5821-5823.

● Karas, L.; Piel W. J. “Ethers.” In Kirk-Othmer Encyclopedia of Chemical Technology, 4; Kroschwitz, J. I., Howe-Grant, M.; John Wiley & Sons: New York, 1998.

● Rao, A. S.. “Addition Reactions with Formation of Carbon-Oxygen Bonds: (i) General Methods of Epoxidation.” In Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Volume 7; Ley S. V.; Pergamon Press: New York, 1991; 3.1.2.

● Politzer, P. “Bond Energy” In Macmillan Encyclopedia of Chemistry, Volume 1; Lagowski, J. J.; Macmillan Refference USA: New York, 1997.

● Robert J. Ouellette, J. David Rawn. Organic Chemistry Study Guide: Key Concepts, Problems, and Solutions, 1st ed.; Elsevier Inc: Amsterdam, 2014; Chapter 3.

● WebMO, Schmidt, J.R.; Polik, W.F. WebMO Enterprise, version 13.0; WebMO LLC: Holland, MI, USA, 2013; http://www.webmo.net (accessed Nov- Dec, 2014)

References:● Gaussian09, Revision C.01,M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci,G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian,A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada,M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima,Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr.,J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers,K. N. Kudin, V. N. Staroverov, T. Keith, R. Kobayashi, J. Normand,K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi,M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross,V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann,O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski,R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. V oth,P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels,O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, and D. J. Fox, Gaussian, Inc., Wallingford CT, 2010.

References: sources of images● http://en.wikipedia.org/wiki/Fugu● http://en.wikipedia.org/wiki/Tetrodotoxin● http://en.wikipedia.org/wiki/Brevetoxin● http://en.wikipedia.org/wiki/Maitotoxin● http://en.wikipedia.org/wiki/Tetraodontidae● http://en.wikipedia.org/wiki/Diethyl_ether● http://en.wikipedia.org/wiki/Striated_surgeonfish● http://www.zoro.com/i/G4579443/?utm_source=google_shopping&utm_medium=cpc&utm_camp

aign=Google_Shopping_Feed&gclid=CjwKEAiAk8qkBRDOqYediILQ5BMSJAB40A5UAJoN-cIFkvYdIOsL3JdHCkmXjjn4w0gWZMwW0ApitxoCypjw_wcB