Transitioning Organic Synthesis from Organic Solvents to

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“Transitioning Organic Synthesis from Organic Solvents to Water”

Dr. Joseph Fortunak Dr. Bruce Lipshutz

Professor of Chemistry, Howard University

Professor of Chemistry, Univ. of California, Santa Barbara


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“Transitioning Organic Synthesis From Organic Solvents to Water”

Bruce H. Lipshutz Department of Chemistry & Biochemistry University of California Santa Barbara, CA 93106 USA

Co-produced with the 14

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Soap (as in textbooks) [spherical micelles]

Vollhardt & Schore

Smith

Jones

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soaps, detergents, emulsifying agents, surfactants, etc.

Vollhardt & Schore

Smith

Jones

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soaps, detergents, emulsifying agents, surfactants, etc.

Where from?

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Benign by design “designer” surfactants available from Aldrich

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Comparisons: PTS, TPGS, and TPGS-750-M NRC (2000)

Kodak (1954)

Lipshutz (2011)

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Cryo-Transmission Electron Microscopy: PTS vs. TPGS-750-M vs. TPGS

PTS

TPGS-750-M

TPGS-1000

10 nm spheres & variable sized worms

60 nm spheres

13 nm spheres

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Chemistry in nanoreactors…in water @ room temperature CH3 CH3

CH3

O CH3

H 3C

O O

CH3

O

CH3

O

Me

O 16

O

CH3

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? • 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 28

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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 typically 5-100 for pharma and fine chemicals

E Factor =

kg of waste kg of desired product

(does not include water)

pharma Suzuki-Miyaura Coupling

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

(80%)

aq. Na2CO3/acetone, ∆, 12 h B(OH)2 I + Br

Br PdCl2(dtbpf) (1 mol %), Et3N Org. Proc. Res. Dev. 2003, 7, 362

2 wt % TPGS-750-M/H2O (1 M) 12 h, rt

(93%)

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

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E Factors: What’s Possible with this Technology typically 5-100 for pharma and fine chemicals

E Factor =

kg of waste

(does not include water)

kg of desired product

pharma Suzuki-Miyaura Coupling

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

(80%)

aq. Na2CO3/acetone, ∆, 12 h B(OH)2 I + Br

Br PdCl2(dtbpf) (1 mol %), Et3N 2 wt % TPGS-750-M/H2O (1 M) 12 h, rt

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

(93%)

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E Factors: What’s possible with Recycling

Suzuki-Miyaura Coupling

pharma (41%)

Pd(PPh3)4, aq. Na2CO3 CH3CN, 80 °C

CF3

Cl +

(HO)2B

Cl N

CF3 Cl

N

N

N

Pd(dtbpf)Cl2 (2 mol %) 2 wt % TPGS-750-M/H2O (1 M) (68%) Et3N (3 equiv), rt

J. Med. Chem. 2007, 50, 3497

(45%) (recycled)

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E Factors as a measure of greenness used in this discussion may not tell the whole story. Why not? • 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 35

E Factors: What’s possible with Recycling

pharma

Heck Coupling

(81%)

Pd/C (0.5 mol %) NaOAc (1.2 equiv), DMA, 140 °C

H2 N

+

H2 N

CN

I

CN Pd(t-Bu3P)2 (7.5 mol %) 5 wt % PTS/H2O (1 M) Et3N (3 equiv), 60 °C, 3 M NaCl

(76%) (69%) (recycled)

Org. Proc. Res. and Dev. 2008, 12, 530

E Factors pharma

this work

with recycle

total organic solvent

16.7

2.5

2.8

aqueous workup included

31.1

10.2

2.8

based on:

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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.

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Aminations: Couplings with carbamates in water @ RT

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

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Couplings in water @ RT to 50 °C

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

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C-O Bond construction: Asymmetric lactonizations

O O O 97%, 96% ee

O

O Cl

Cl 95%, 90% ee

O

O

88%, 91% ee

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

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C-C Bond-forming reactions in water @ RT Trifluoromethylations

NaSO2CF3 = Langlois reagent

Fennewald, J. C.; Lipshutz, B. H. Green Chem. 2014, 16, 1097. Baran, P. S. et al. PNAS 2011, 108, 14411.

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C-C Bond-forming reactions in water @ RT olefin metathesis 2 wt % surfactant/H2O, rt, 12 h

+ O

OTBS

Grubbs-2 (2 mol %)

(3 equiv)

N

OTBS

O

N

Cl Ru Cl

Ph P

Surfactant 2.0 wt % TPGS-750-M 2.0 wt % Nok 0.02 M KHSO 4 /2.0 wt % TPGS-750-M 0.02 M KHSO 4 /2.0 wt % Nok a

Time (h)

Conversion (%)a

12 12 4 4

77 76 86 84

by 1H NMR

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

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Olefin metathesis reactions in water @ RT reaction appearance

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What is the key reaction parameter associated with micellar catalysis not usually of consequence in traditional reactions in organic solvents? • • • • •

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

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C-C bond-forming reactions in water @ RT Negishi-like couplings

Zn 46

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C-C bond-forming reactions in water @ RT Negishi couplings

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

Zn

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

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

Lower E Factors = sustainability + $ “The best solvent is no solvent and if a solvent (diluent) is needed then water is preferred." Potential bonuses:

modified impurity profile throughput

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Acknowledgements

NIH, NSF Johnson Matthey (Tom Colacot) Takasago (Hideo Shimizu), Sigma-Aldrich (Chris Thomas, Subir Ghorai)

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Transitioning Organic Synthesis from Organic Solvents to

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