Bringing New and Green Chemistryinto Undergraduate Laboratories

David A. Vosburg(and many student coworkers)

Department of ChemistryHarvey Mudd College

Why Go Green?

• minimize toxicity, hazards, and/or waste

• reduce dependence on fume hoods

• modernize with new and exciting chemistry

• innovate, merge with research goals

• contribute to chemical education

• create life-long student advocates

Why Go Green?

researchinnovations

teachinginnovations

Green Ketone Reduction with Carrots

Ravía, S.; Gamenara, D.; Schapiro, V.; Bellomo, A.; Adum, J.; Seoane, G.; Gonzalez, D. J. Chem. Educ. 2006, 83, 1049.

harmless reagent and solvent, no heating

monitor by thin-layer chromatography (TLC)

extraction, Pasteur pipet column

1H NMR, optical rotation

O O carrot bits

H2O, rt

O OH

Green, Solventless Diels-Alder Reaction

McKenzie, L.C.; Huffman, L.M.; Hutchison, J.E.; Rogers, C.E.; Goodwin, T.E. J. Chem. Educ. 2009, 86, 488.

O

O

O

neat, rt+

OH

?

Green, Solventless Diels-Alder Reaction

McKenzie, L.C.; Huffman, L.M.; Hutchison, J.E.; Rogers, C.E.; Goodwin, T.E. J. Chem. Educ. 2009, 86, 488.

fast, no solvent, no heating, no purification

compare to 110 °C in toluene

melting point, IR spectroscopy

1H and 1H-1H COSY NMR

O

O

O

neat, rt+

OHO

CO2H

O

Green, Organocatalytic Synthesis of Warfarin

Kim, H.; Yen, C.; Preston, P.; Chin, J. Org. Lett. 2006, 8, 5239.Wong, T.C.; Sultana, C.M.; Vosburg, D.A. J. Chem. Educ. 2010, 87, 194.

Terence WongCamille Sultana

+

no heating, no stirring

water/acetone recrystallization

high stereoselectivity

melting point, 1H NMR, optical rotation

O

O

O

OH

O O

OH O

warfarin(anticoagulant)

NH2H2N

AcOH, THFrt, 1 week

(5 mol%)

Green, Enzymatic Synthesis of Divanillin

Rachel NishimuraChiara Giammanco

Russell, W.R.; Scobbie, L.; Chesson, A. Bioorg. Med. Chem. 2005, 13, 2537.Nishimura, R.T.; Giammanco, C.H.; Vosburg, D.A. J. Chem. Educ. 2010, 87, 526.

horseradishperoxidase

dilute vinegardilute H2O2

clean, easy reaction

simple purification

no toxic waste

solubility, melting point, NMR

divanillin(flavor enhancer)

H3CO

HO

H

O

vanillin

H3CO

HO

H

O

OH

OCH3

H

O

+ H2O

Flavor Properties of Divanillin

Gatfield, I.; Reiss, I.; Krammer, G.; Schmidt, C.O.; Kindel, G.; Bertram, H.-J. Perfum. Flavor. 2006, 31, 18.

Divanillin and Diapocynin

divanillin(flavor enhancer)

H3CO

HO

H

O

vanillin

H3CO

HO

H

O

OH

OCH3H

O

diapocynin(antioxidant)

H3CO

HO

O

apocynin

H3CO

HO

O

OH

OCH3

O

Green Synthesis of Citronellal

Anna Cunningham, Haley Ham

practicalenantioselective

catalyst?

expensive,

tedious,

or not stereoselective

citral(lemongrass oil)

O

H

citronellal(citronella oil)

O

H

Green Syntheses of Natural Perfumes

Cunningham, A.D.; Ham, E.Y.; Vosburg, D.A. J. Chem. Educ. 2011, 88, 322. Anna Cunningham, Haley Ham

reducealkene

simple, green,

biomimetic,

and chemoselective

citral(lemongrass oil)

O

H

citronellal(citronella oil)

O

H

geraniol(geranium oil)

OH

epoxycitral(mite pheromone)

O

H

O

reducealdehyde

oxidizealkene

Green Syntheses of Natural Perfumes

Cunningham, A.D.; Ham, E.Y.; Vosburg, D.A. J. Chem. Educ. 2011, 88, 322. Anna Cunningham, Haley Ham

smells wonderful (citrus, rose)

purify by simple extraction

detect by smell, TLC, GC/GC-MS, NMR, IR

citral(lemongrass oil)

O

H

natural perfumes

green, chemoselective,biomimetic reagents

Liquid CO2 Extraction of Limonene from Oranges

McKenzie, L.C.; Thompson, J.E.; Sullivan, R.; Hutchison, J.E. Green Chem. 2004, 6, 355. GCEW 2010

visually impressive, nice smell

no hazardous waste, no purification

optical rotation, GC/GC-MS

liquid CO2extraction

(+)-limonene

Liquid CO2 Extraction of Limonene from Oranges

McKenzie, L.C.; Thompson, J.E.; Sullivan, R.; Hutchison, J.E. Green Chem. 2004, 6, 355. GCEW 2010

Green Bromination of Stilbene

Doxsee, K.M.; Hutchison, J.E. Green Organic Chemistry: Strategies, Tools, and Laboratory Experiments, Brooks/Cole, 2004, 125. GCEW 2010

brief reflux, color change

avoids use of Br2 and CH2Cl2

melting point, GC/GC-MS

trans-stilbene

HBr, H2O2

ethanol

Br

Br

Green Chemistry Spreads to the Research Lab

researchinnovations

teachinginnovations

Davanone

• natural product from Indian sageArtemisia pallens

• antifungal and antispasmodic

• davana oil is used in perfume, as askin ointment, and in folk medicine

Artemisia pallens

OOH

davanone

Components of Davana Oil

Misra, L.N.; Chandra, A.; Thakur, R.S. Phytochemistry 1991, 30, 549.

OO

H

davanone

OO

H

artemone

OO

H

isodavanone

OO

H

nordavanone

O

OH

OH

davana acid

OO

H

trans-davanone

OO

H

cis-hydroxydavanone

OH

O

OEt

OH

davana acid ethyl ester

OO

H

trans-hydroxydavanone

OH

38% of davana oil by mass 5% 3%

3% 2% 1.5%

1.5% 2.5% 0.7%

Biological Activity of Davanone

Antispasmodic: Perfumi, M.; Paparelli, F.; Cingolani, M.L. J. Essent. Oil Res. 1995, 7, 387.Antifungal: Vajs, V.; et al. J. Serb. Chem. Soc. 2004, 69, 969.

• Antispasmodic0.2 µM in guinea pig small intestines

• Antifungal100 µM vs. ten fungi

OO

H

cis-hydroxydavanone

OH

N

N

bifonazole

25 µM 32 µM

Synthetic Economy

Newhouse, T.; Baran, P.S.; Hoffmann, R.W. Chem. Soc. Rev. 2009, 38, 310.

Our Green, Seven-step Synthesis

Morrison, K.C.; Litz, J.P.; Scherpelz, K.P.; Dossa, P.D.; Vosburg, D.A. Org. Lett. 2009, 11, 2217.

OAc OAc

OH

OAc

OHO

SAE

83%

OAc

OO

H

OH O

OEt

OAc N

S

Ph

Cl

EtOHi-Pr2NEt

5:1 anti/syn 83%

O

OEt

OH

SO3•pyrDMSO

O

NO

OH

OO

H

(+)-davanone

ClMg

HNO

i-PrMgCl

96%

2.5:1 cis/trans

Pd2dba3

87%

C3-(S)-TunePhos

90% 62%

SeO2

72%

(31% pure anti,cisfrom aldehyde)

Green, 4-Step Route to (+)-Artemone

Eric NacsaJonathan Litz

Jeep SrisuknimitMary Van Vleet

OO

H

(–)-linalool

artemone

OH

H

OOHSeO2

t-BuOOH

BrIn

OHO

H

OO

H

H

75% anti,cis

microwave120 °C, 20 min

NH OTMS

PhPh

O

I

O

OAcOAc

AcO

25 °C

25 °C

25 °C

Natural Compounds Synthesized

OO

H

davanone

OO

H

artemone

OO

H

isodavanone

OO

H

nordavanone

O

OH

OH

davana acid

OO

H

trans-davanone

OO

H

cis-hydroxydavanone

OH

O

OEt

OH

davana acid ethyl ester

OO

H

trans-hydroxydavanone

OH

Kanny WanEric Nacsa

Jonathan LitzKaren Morrison

Jeep SrisuknimitMary Van Vleet

Outcomes

• reduced toxicity, hazards, waste, and dependence on fume hoods

• students get excited about green chemistry

• colleague support and adoption

• inspires innovation in research projects

• several student-authored posters and publications

• adopting labs in US, Europe, Asia, South America

Recommended Green Resources

• ACS Green Chemistry Institute (ACS GCI)

• Green Chemistry Education Network (GCEdNet)

• Green Chemistry in Education Workshop (GCEW)

• Greener Education Materials for Chemists (GEMs)

• greenchem.uoregon.edu

Acknowledgements

FundingHarvey Mudd Chemistry DepartmentCamille & Henry Dreyfus Foundation

Beckman Scholars FoundationHoward Hughes Medical Institute

American Chemical Society Petroleum Research FundResearch Corporation for Science Advancement

National Science Foundation Research Experiences for UndergraduatesMerck-AAAS Summer Undergraduate Research Program

Pfizer Summer Undergraduate Research Fellowships (SURF)Division of Organic Chemistry SURF

Rose Hills FoundationChristian Scholars Foundation

Pomona Chemistry Department

Green PedagogyRachel Nishimura ’09Terence Wong 09Andrew Chung ’10Helen Fitzmaurice ’10Chiara Giammanco ’10Camille Sultana ’10Athena Anderson ’11Anna Cunningham ’11Haley Ham ’12Jeep Srisuknimit ’12Cory Evans-Klock ’13Bryan Visser ’13Katherine Maloney

DavanonePaul Dossa ’06Kathryn Poindexter ’07Karen Brown ’08Jonathan Litz ’09Ryan Pakula ’09Eric Nacsa ’10Kanny Wan ’11Jeep Srisuknimit ’12Mary Van Vleet ’12Katherine Maloney

12 Principles of Green Chemistry

1. Prevent waste2. Atom economy3. Less hazardous syntheses4. Design safer chemicals5. Safer solvents and auxiliaries6. Energy efficiency7. Renewable feedstocks8. Reduce derivatives9. Catalysis10.Design for degradation11.Real-time analysis for pollution prevention12.Prevent accidents

Anastas, P.T.; Warner, J.C. Green Chemistry: Theory and Practice, New York: Oxford University Press, 1998.

Potential biosynthetic paths to davanone

OO

H

(+)-davanone

OPP

farnesyl diphosphate

oxidation,hydration

OPP

OH O

OOH

hydrolysis,oxidation

conjugateaddition

allylicalkylation

Eric Nacsa, Jonathan Litz

Green Organocatalysis with Proline

Helen FitzmauriceBrown, S.P.; Brochu, M.P.; Sinz, C.J.; MacMillan, D.W.C.J. Am. Chem. Soc. 2003, 125, 10808.

HN

proline

"the simplest enzyme"

H

O

R

H

O

R

ON

+ ONH

fast reaction

nice color change (green to yellow)

unstable product

difficult purification

OH

O