CJLi

Title goes here 1

Exploration of New Chemical Reactivities for Future Chemical Sustainability

Exploration of New Chemical Reactivities for Future Chemical Sustainability

C.-J. LiDepartment of Chemistry and FQRNT Center for Green

Chemistry and Catalysis, McGill University

IGCW2017-SymposiumMumbai, October 06, 2017

C.-J. LiDepartment of Chemistry and FQRNT Center for Green

Chemistry and Catalysis, McGill University

IGCW2017-SymposiumMumbai, October 06, 2017

Sustainability has a deep root in ancient IndiaSustainability has a deep root in ancient India

“in the Indian schools of thought viz. the Vedas, Upanishads (Vedanta), Bhagavad Gita etc”

A. Bhattacharjee, SMS, Vol. IV, No.1, March-August 2011, P14.

• of the resources removed from the Earth, only 10% are retained in the product and 90% are waste

• >97% of all manufactured products involve one or more chemical processes

The Grand Challenge of Sustainability

3

The Challenge of Future Chemical Syntheses

HydrocarbonsCO2, COH2ON2, NH3

Biomass (carbohydrates, lignins, amino acids)O2

Various Chemical products

Cat.

Clean media

4

1. Over-functionalized;2. Many functionals not-comparable with

Standard chemistry.

The Challenge of Future Chemical Syntheses

HydrocarbonsCO2, COH2ON2, NH3

Biomass (carbohydrates, lignins, amino acids)O2

Various Chemical products

Cat.

Clean media

We need to explore new fundamental tools in chemical science.

6

CJLi

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A simple question?

R2C

R1

R3

HR5

C

R4

R6

HR2

C

R1

R3R5

C

R4

R6

Fully functionalizedFully functionalized Fully functionalized

7

The Basis of Modern Organic Syntheses

1) Protection – deprotection, protection-deprotection… (70-80%)

2) Halogenation-dehalogenation, halogenation-dehalogenation… (Grignard, substitution, radical reaction, carbene reactions..)

3) Functionalization-defunctionalization, ….

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“C-” Chemistry for Forming C-C Bonds

-Grignard reactions-Wittig reactions-Wurtz coupling-Ullmann coupling-Aldol condensations-Reformatsky reactions-Gilman-type reaction-Boron Chemistry-Silicon Chemistry-Tin chemistry----

acid, water, ROH, aminesterminal alkynescarbonylsRXalkynealkenealkane

C- Reactivity “C-” Reactivity

carbonylsRXacid, water, ROHaminesterminal alkynesalkynealkenealkane

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1. Grignard-type Reactions in Watera. Allylationb. Allenylation/propargylationc. Reformatsky-type reactiond. Arylation/vinylatione. Alkynylationf. Alkylation

2. Synthetic applications of aqueous “Grignard-type” reactionsa. Sialic acidsb. Styryl lactonesc. Medium ringsd. Amino acids and other applications

1. To eliminate protection-deprotectionsOrganometallic Reactions in Water

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SIALIC ACIDS SYNTHESIS: An ExampleSIALIC ACIDS SYNTHESIS: An Example

HOH

OH OH

OH OH

O

+ BrCO2Me

OOH

HOHO OH

OH

mannose

In/H2OHO

OH OH

OH OH

OH CO2Me+ HO

OH OH

OH OH

OH CO2Me

6 : 1

ozonolysis

HOOH OH

OH OH

OH

O

CO2Me KOHO

HO

CO2HHO

OHHO

HO

OH

(+) KDN

Chan, T. H.; Li, C.-J. J. Chem. Soc., Chem. Commun. 1992, 747.

RH

RX

X2

RMgX

MmOn

ROH(Tf)2O/Et3N

ROTf

NaX

RX

RMgX

Mg

Mg

R' R"

O

R' R"

OH

R

R'X + RX2 +RX3 ...

solvent+drying agents

Mg(OH)X+solvent

MmOn-1+ isomers

NEt3HOTf+solvent

NaOTf + solvent

solvent+drying agents

Mg(OH)X+solvent

RH

R' R"

O

R' R"

OH

R

2. Eliminate More Reactions:Minimizing halogenation-dehalogenation via C-H functionalization

Possibly in water

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CJLi

Title goes here 3

Grignard Reactions via C-H Activation in Water

Shi, X.-Y.; Li, C.-J. Adv. Synth. Catal., 2012, 354, 2933.

Summary: catalytic addition of terminal alkyne to various nucleophiles in water(Li, C.-J. Acc. Chem. Res. 2010, 43, 581-590)

HR

R'

OH

R

N

R' H

"R CORN

R'

"R COR

R

H

N

R' H

"R R(H)N

R'

"R R(H)

RO

R' Cl

R'

O

R

R'

O

R'

O

R

R'

O

R

R'

O

cat. M

R'-H/[O]

R'R

H

H

N

R' H

"R

NH

R'

"R

R

N

R'

H Ts

RN

R' H

Ts

H2O

NR

Ph

Ph

PhR1 N

CH2

CH2

R2

R2

O

R'''N O

R'R''

O

R

R'

H

R1

O

OH

R3

R2

R'

OH

RF3C

O

R' CF3

RCHO

RNH2RCHOCO2

OR'

O

R H

OR'

O

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Adv. Syn. Catal., 2008, 350, 1503Synlett, 2008, 1897Sciences of Synthesis, 2008, 40a, 579Adv. Syn. Catal., 2008, 350, 370Org. Lett. 2007, 9, 627Org. Biomol. Chem., 2007, 5, 435Adv. Cata. Synth. 2006, 348, 1528Org. Lett. 2005, 7, 2675Lett. Org. Chem. 2005, 2, 410QSAR Comb. Sci. 2004, 23, 891Proc. Natl. Acad. Sci. (USA), 2004, 101, 5749Tetrahedron Lett. 2004, 45, 2443Synlett 2004, 1472J. Am. Chem. Soc. 2003, 125, 9584Org. Lett, 2003, 5, 4473J. Am. Chem. Soc. 2002, 124, 5638Chem. Commun. 2002, 268

R CHO R1R2NH R3

R

NR2R1

R3H2O

+ +cat.

cat= [Cu], [Au][, [Ag], [Ru], [Fe], [Co]

Three-Component Coupling of Aldehyde, Alkyne and Amine (A3-Coupling) in Water

Multi-Component Reactions, 2013Can. J. Chem. 2012, 90, 92Org. Lett. 2012, 14, 3000-3003

Aldrichimica Acta, 2011, 44, 43Chem. Sci., 2011, 2, 1241Aldrichemica Acta, 2011, 44, 43Org. Lett. 2011, 13, 442Adv. Synth. Cat. 2010, 352, 0000Green Chemistry, 2010, 12, 570Synlett, 2010, 475Chem. Eur. J. 2010, 16, 126Tetrahedron Lett. 2009, 50, 6791Chem. Eur. J. 2009, 15, 11668Tetrahedron Lett. 2009, 50, 2895Tetrahedron Lett. 2009, 50, 6791Synlett, 2009, 937 15

Three-Component Couping of Aldehyde, Alkyne and Amine (A3-Coupling) in Water

Che et al. Org. Biomol. Chem. 2012

2. Eliminate More Reactions:Minimizing halogenation-dehalogenation via reaction of C-OH

2. Eliminate More Reactions:Minimizing halogenation-dehalogenation via reaction of C-OH

The 2nd Challenge of the ACS-GCI Pharmaceutical Roundtable:

----OH activation for nucleophilic substitution

An Example: The Importance of Aromatics

An Example: The Importance of Aromatics

Pigments, dyes, coatings, textiles, plastics, electronic materials, pharmaceuticals, agrochemicals, …….

CJLi

Title goes here 4

Most have aromatic ring;

>30 % have aromatic amines motif

Synthesis of Anilines

Will be the most abundant renewable aromatic feedstock

ca 30% of biomass in nature

Nu

R

Nu-

?

Direct Coupling of Phenols with Amines

23

Chen, Z.; Zeng, H.; Girard S. A.; Wang, F.; Chen, N.; Li, C.-J. Angew. Chem. Int. Ed. 2015, 54, 14487. (highlighted by Chem. Eng. News, November 16, 2015) (Provisional Patent filed by McGill)

3. Eliminate More Reactions:Minimizing functionalization-defunctionalization

A Simple Dream

Cross-Dehydrogenative-Coupling (CDC) Reaction

Ideally:

CJLi

Title goes here 5

3, Chemistry Beyond Functional Group Transformations

C-H + C-H C-C

Cross-Dehydrogenative-Coupling (CDC)Angew. Chem. Int. Ed., 2014, 53, 74Tetrahedron, 2013, 69, 4436Green Chemistry, 2012, 14, 1577Org. Lett. 2012, 14, 902,Science China: Chemistry, 2011, 54, 1815Org. Lett. 2011, 13, 4977Angew. Chem. Int. Ed. 2011, 50, 8936Org. Lett. 2011, 13, 4581Org. Lett. 2011, 13, 1614,Progress in Chemistry, 2010, 22, 1437J. Am. Chem. Soc. 2010, 132, 1221Top. Curr. Chem. 2010, 292, 281Chem. Commun. 2010, 4184Synlett, 2010, 2002Heterocycles 2010, 82, 555Chem. Eur. J. 2010, 16, 8162Adv. Syn. Cat. 2010, 352, 1446Adv. Syn. Cat. 2010, 352, 1145Tetrahedron Lett. 2010, 51, 1172Acc. Chem. Res., 2009, 42, 335-344.Angew. Chem. Int. Ed. Engl. 2008, 47, 7075Proc. Natl. Acad. Sci. (USA), 2009, 106, 4106

Angew. Chem. Int. Ed. Engl. 2009, 48, 792Adv. Syn. Catal. 2009, 351, 353Org. Lett. 2009, 11, 1171.Synlett, 2009, 138Chem. Eur. J., 2009, 15, 333Angew. Chem. Int. Ed. Engl. 2008, 47, 62780Angew. Chem. Int. Ed. Engl. 2007, 46, 6505Eur. J. Org. Chem. 2007, 4654Green Chemistry 2007, 9, 1047Proc. Natl. Acad. Sci. (USA), 2006, 103, 8928J. Am. Chem. Soc. 2006, 128, 4242Pure & Appl. Chem. 2006, 78, 935Tetrahedron: Asymmetry, 2006, 17, 590Angew. Chem. Int. Ed. Engl. 2006, 45, 1949J. Am. Chem. Soc. 2006, 128, 56Adv. Cat. Syn. 2006, 348, 229Eur. J. Org. Chem. 2006, 869J. Am. Chem. Soc. 2005, 127, 6968J. Am. Chem. Soc. 2005, 127, 3672Eur. J. Org. Chem. 2005, 3173Org. Lett. 2004, 6, 4997J. Am. Chem. Soc. 2004, 126, 11810

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N R1+

Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968.

CDC: sp3 C-H with sp2 C-H

5 mol% CuBr TBHP N R1

NH

RFG

NHFG

R

C&EN News, May 23, 2005

Examples of Groups on CDC ReactionsExamples of Groups on CDC Reactions

Fujiwara, You, Sanford, Glorius, Klaussmann, Murahashi, Kakuchi, Deboef, Fagnou, Shi, Li, Kundig, Dixneuf, Miura, Stephenson, Itami, Vogtle, Dong, Loh, Deng, Tu, Patel, Jiao, Bao, Ji, Che, Prabhu, Rueping, Li, Hu, Nakamura, Pan, Xiao, Wu, Huang, Milstein, Bao, Tung, Moores, Chandrasekharan, Su, Sun, Cheng, Ong, Mancheno, Studer, Wan, Louie, Huang, Zhang, Konig, Lei, Jiang, Liu, Fu, Fujiwara, Todd, Stahl, Lipshutz, Collins, Wang, Kwong, Wong, Zhu, Sames, Gaunt, Daugulis, Chatani, White, Cheng, Yamamoto, Huo, Lu, You, Wu, Bolm, Diederich, Scheuermann, Pappo, Doyle, Gong, Nakamura, Ge, Huang, Kumar, Bordwell, Prabhu, Hashimi, Itoh, Guo, Sodeoka, Liang, McMillian, Toste, Cozzi, Xu, Kappe, Tong, Xie, Alagiri, Qiu, Huang, Kita, Chan, Liang, Curran, Nakai, Studer, Chi, Chai, 27

Cross-Dehydrogenative-Coupling (CDC) for the Formation of C-C Bonds

C Hsp3

C Hsp3C Hsp C Hsp2

Csp3 Csp3

Csp3 Csp

Csp3 Csp2

C Hsp

C Hsp2

Csp Csp3

Csp Csp

Csp Csp2Csp2 Csp

Csp2 Csp

Csp2 Csp2

All are possible!

Summary

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Some Examples of Sustainability related to Energy

CJLi

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“On the arid lands there will spring up industrial colonies without smoke and without smokestacks; forests of glass tubes will extend over the plains and glass buildings will rise everywhere; inside of these will take place the photochemical processes that hitherto have been the guarded secret of the plants, but that will have been mastered by human industry which will know how to make them bear even more abundant fruit than nature, for nature is not in a hurry and mankind is. And if in a distant future the supply of coal becomes completely exhausted, civilization will not be checked by that, for life and civilization will continue as long as the sun shines.” (Sciences, 1912)

-Giacomo Luigi Ciamician

Mc

Gill

165,000 TWof sunlighthit the earthevery day

(Courtesy of Joan Brennecke)

Mc

Gill

Solar Energy Harvesting

Photovotaics Photolysis of water to give H2

H2 storage and transportation

Mc

Gill

C-H Activation and Energy

Li, L.; Mu, X.; Liu, W.; Mi, Z.; Li, C.-J. J. Am. Chem. Soc. 2015, 137, 7575.

A Simple and Efficient System for Combined Solar-Energy Harvesting and Reversible Hydrogen Storage

2H2O (g) → 2H2 (g) + O2 (g), ΔH(298 K) = 484 kJ/mol

C6H12 (g) → C6H6 (g) + 3H2 (g), ΔH(298 K) = 206 kJ/mol

(McGill Patent Application Filed)

solar lightr.t.

>99%

50 oCdark>97%

Recycled > 90 times

Mc

Gill

Science, 2010, 328, 1624.

Shale Gas

Natural Gas: An Alternative to Petroleum?

“These reactions could revolutionize the chemical industry”

Nature, 2007, 446, 391.

Mc

Gill

The Ultimate CDC ReactionNon-oxidative conversion of methane to benzene

(McGill Patent Applied, 2013) Li, L.; Fan, S.; Mu, X.; Mi, Z.; Li, C.-J. J. Am. Chem. Soc. 2014, 136, 7793 (highlighted in Chem. & Eng. News, June 9, 2014)

Angew. Chem. Int. Ed. 2014

CJLi

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Mc

Gill

F in Drugs and Agrochemicals

20% of all drugs35% of all crop agents

Mc

Gill Introduction

Trifluoromethylated building blocks in pharmaceuticals and agrochemicals 38

Metabolic Stability

Transport Rate

Lipophilicity

Pharmacokinetics

Mc

Gill

Simple and Clean Photoinduced Aromatic Trifluoromethylation Reaction

39

J. Am. Chem. Soc. 2016, 138, 5809−5812

Mc

Gill

40

Substrate Scope (UV Light) 

Mc

Gill

41

Proposed Mechanism

“We shall escape the absurdity of growing a whole chicken

in order to eat the breast or wing

[within the next 50 years]

by growing these parts separately

under a suitable medium.”

---- Winston Churchill Fifty Years Hence (1930)

artisticportraits.com/ churchill.jpg

© 1996-2005 Scientific American

Copyright© Buffalowings.com

Maybe we can apply the same statement to Chemical Synthesis?

CJLi

Title goes here 8

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“Faith keep the world going”~ Indian proverb

“Faith keep the world going”~ Indian proverb

Both to develop the economy and protect the environment through Green Chemistry

Acknowledgments

45

www.rsc.org/greenchem

ISI Impact Factor -- 9.1

Green Chemistry –Cutting-edge research for a greener sustainable future