transitioning organic synthesis from organic solvents … · 12/3/2014 7 13 “transitioning...

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What’s Your Green Chemistry? #mygreenchem

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“Chemistry & the Economy: 2014 Year-

End Review”

Paul Hodges, Chairman, International eChem

Dr. Mark Jones, Executive External Strategy and Communications

Fellow, Dow Chemical Corporation

Thursday, January 15, 2015

“Rookie Lab Mistakes and Other Facts Not

Found in Textbooks”

Dr. Alison Frontier, Professor of Chemistry, University of Rochester

Bill Courtney, Chemist and Chef, Cheese-Ology

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“Transitioning Organic Synthesis from Organic Solvents to Water”


Co-produced with the ACS Green Chemistry Institute


Dr. Joseph Fortunak Professor of Chemistry,

Howard University Dr. Bruce Lipshutz Professor of Chemistry,

Univ. of California, Santa Barbara

Bruce H. Lipshutz

Department of Chemistry & Biochemistry

University of California

Santa Barbara, CA 93106 USA

“Transitioning Organic Synthesis

From Organic Solvents to Water”

Co-produced with the

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Smith Jones

Vollhardt & Schore

Soap (as in textbooks)

[spherical micelles]

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Smith Jones

Vollhardt & Schore

soaps, detergents,

emulsifying agents,

surfactants, etc.

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soaps, detergents, emulsifying agents,

surfactants, etc.

Where from?

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Benign by design “designer” surfactants available from Aldrich 22

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Comparisons: PTS, TPGS, and TPGS-750-M

NRC (2000)

Kodak (1954)

Lipshutz (2011)

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PTS

10 nm spheres

&

variable sized worms

TPGS-750-M 60 nm spheres

TPGS-1000 13 nm spheres

Cryo-Transmission Electron Microscopy:

PTS vs. TPGS-750-M vs. TPGS

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Chemistry in nanoreactors…in water @ room temperature

O

CH3

CH3

CH3

OO

OO

Me

H3C

CH3 CH3CH3

O

CH3

O

16

reactions take

place here

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TPGS-750-M vs. related surfactants

Ring-Closing Metathesis

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Recycling PTS & TPGS-750-M

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How might PEG in a nonionic surfactant control

the particle size of nanomicelles?

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• by its release from the surfactant into the

surrounding water

• by its length and, therefore, extent of coiling

• by interactions with other PEGs in nearby micelles

• by forming crown ether-like arrays around trace

metals found in water

• it doesn't have anything to do with determining

particle size

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Designer surfactant technologies; in water @ RT

Can the impact be quantified?

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E Factors: What’s Possible with this Technology

E Factor =kg of waste

kg of desired product

typically 5-100 for pharma and fine chemicals

(does not include water)

I

Br

B(OH)2

Br

Org. Proc. Res. Dev. 2003, 7, 362

2 wt % TPGS-750-M/H2O (1 M)

12 h, rt

PdCl2(dtbpf) (1 mol %), Et3N

aq. Na2CO3/acetone, ∆, 12 h

Pd(OAc)2 (5 mol %)Ph3P (10 mol %) (80%)

(93%)

+

Suzuki-Miyaura Coupling

pharma

[ Lipshutz, Isley, Fennewald, Slack, Angew. Chem., Int. Ed. 2013, 52, 10911 ] 32

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E Factor =kg of waste

kg of desired product

typically 5-100 for pharma and fine chemicals

(does not include water)

I

Br

B(OH)2

Br

Org. Proc. Res. Dev. 2003, 7, 362

2 wt % TPGS-750-M/H2O (1 M)

12 h, rt

PdCl2(dtbpf) (1 mol %), Et3N

aq. Na2CO3/acetone, ∆, 12 h

Pd(OAc)2 (5 mol %)Ph3P (10 mol %) (80%)

(93%)

+


pharma

E Factors: What’s Possible with this Technology

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E Factors: What’s possible with Recycling


N N

ClCl

Pd(PPh3)4, aq. Na2CO3

N N

Cl

CF3

(41%)

2 wt % TPGS-750-M/H2O (1 M)

Et3N (3 equiv), rt

(68%)

(45%)J. Med. Chem. 2007, 50, 3497

+

Pd(dtbpf)Cl2 (2 mol %)

CH3CN, 80 °C

(recycled)

CF3

(HO)2B

pharma

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E Factors as a measure of greenness used in this

discussion may not tell the whole story. Why not?

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• they misrepresent the true nature of organic waste

• they do not consider the origins of materials being

used in reactions

• they do not include salts present, or formed, in a

reaction

• they involve too many mathematical assumptions and

unknowns

• they originated in Europe

Heck Coupling

H2N

I

CN

Pd/C (0.5 mol %) (81%)

5 wt % PTS/H2O (1 M)

Et3N (3 equiv), 60 °C, 3 M NaCl

(76%)

(69%)

+

Pd(t-Bu3P)2 (7.5 mol %)

NaOAc (1.2 equiv), DMA, 140 °C

H2N

CN

(recycled)Org. Proc. Res. and Dev. 2008, 12, 530

pharma

pharma this work

16.7

31.1

2.5

10.2

based on:

total organic solvent

aqueous workup included 2.8

with recycle

2.8

E Factors

E Factors: What’s possible with Recycling

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Designer surfactant technologies; in water @ RT

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Aminations in PTS or TPGS-750-M, in Water @ RT

Lipshutz, B.H.; Chung, D.; Rich, B. Adv. Synth. Catal. 2009, 351, 1717. 38

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Aminations: Couplings with carbamates

in water @ RT

Isley, Dobarco, Lipshutz, Green Chem. 2014, 16, 1480. 39

Couplings in water @ RT to 50 °C

Salome, C.; Schmitt, M. et al. Green Chem. 2014, 16, 4170. alkyl amines

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C-O Bond construction:

Handa, S.; Lippincott, D. J.; Aue, D. H.; Lipshutz, B. H. Angew. Chem., Int. Ed. 2014, 53, 10658.

Asymmetric lactonizations

O

O

O

97%, 96% ee

OO

Cl

Cl

95%, 90% ee

O

88%, 91% ee

O

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Trifluoromethylations

NaSO2CF3 = Langlois reagent

Baran, P. S. et al. PNAS 2011, 108, 14411.

Fennewald, J. C.; Lipshutz, B. H. Green Chem. 2014, 16, 1097.

C-C Bond-forming reactions in water @ RT

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olefin metathesis

Klumphu, P.; Lipshutz, B. H. J. Org. Chem. 2014, 79, 888.

C-C Bond-forming reactions in water @ RT

OTBS

+

O

(3 equiv)

Grubbs-2 (2 mol %)

2 wt % surfactant/H2O, rt, 12 h

OTBSO

N N

Ru

Ph

P

Cl

Cl

Surfactant Time (h)

2.0 wt % TPGS-750-M

2.0 wt % Nok

0.02 M KHSO4 /2.0 wt % TPGS-750-M

0.02 M KHSO4 /2.0 wt % Nok

Conversion (%)a

12

12

4

4

76

86

84

a by 1H NMR

77

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reaction appearance

Olefin metathesis reactions in water @ RT

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What is the key reaction parameter associated with

micellar catalysis not usually of consequence in

traditional reactions in organic solvents?

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• greater solubility of organic substrates in water

• pH of the water

• use of a rigorously dried Ar atmosphere

• lipophilicity of the reaction components

• use of room temperature as defined in Southern California

Negishi-like couplings

C-C bond-forming reactions in water @ RT

Zn 46

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Negishi couplings

Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. J. Am. Chem. Soc. 2009, 131, 15592.

C-C bond-forming reactions in water @ RT

Duplais, C.; Krasovskiy, A.; Lipshutz, B. H. Organomet. 2011, 30, 6090. Zn

47

Summary

Potential bonuses:

modified impurity profile

throughput

“The best solvent is no solvent

and if a solvent (diluent) is needed

then water is preferred."

Lower E Factors = sustainability + $

Still running reactions in organic solvents? What’s your E Factor?

48

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Acknowledgements

NIH, NSF

Takasago (Hideo Shimizu), Sigma-Aldrich (Chris Thomas, Subir Ghorai)

Johnson Matthey (Tom Colacot)

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What’s Your Green Chemistry? #mygreenchem

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Share your Green Chem…Blog it. Film it. Picture it.

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End Review”









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“ACS Webinars are entertaining and

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Neurocrine Biosciences

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Benefits of ACS Membership

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Chemical & Engineering News (C&EN) The preeminent weekly news source.

NEW! Free Access to ACS Presentations on Demand® ACS Member only access to over 1,000 presentation recordings from recent ACS meetings and select events.

NEW! ACS Career Navigator Your source for leadership development, professional education, career services, and much more.

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ACS Webinars does not endorse any products or

services. The views expressed in this

presentation are those of the presenter and do

not necessarily reflect the views or policies of the

American Chemical Society.

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End Review”









transitioning organic synthesis from organic solvents … · 12/3/2014 7 13 “transitioning...

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