1 DIRECT SYNTHESIS OF TETRAZINE-BASED COVALENT ORGANIC

NETWORKS

• Songyang HanBiological and Chemical Sciences• Illinois Institute of Technology

• April 14th 2015

1

Outlines

Motivation and ObjectivesBackground InformationDesign: polymerization via Inverse Electron-Demand Diels-Alder ReactionsDesign: polymerization via Coupling ReactionsDesign: polymerization via Modified Pinner Reaction/ Ni(OTf)2 Catalyzed ReactionFuture Directions

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Hock et al., ACS Catal. 2013, 3, 826−830

Motivation and ObjectivesMetal catalysts suffer stability and recycling issues

Immobilize metals onto heterogeneous supports

Hydrosilylation of ketones and aldehydes

Low catalyst loading

Mild and fast

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• Porous• Support metal• Catalytic active

Ultimate Goal

PSM

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How?Why not directly synthesize what we want? Not possible!

http://www.ezorchards.com/farm-market/pears/http://www.tech-food.com/kndata/1045/0090482.htmhttp://www.foodnewsie.com/articles/pearapple-cross-breed-or-mutant

A pear with apple shape?

Monomer1 Monomer2 Polymers

A

B

E

C

D A D

A B

E

A

A

1 Smarter StrategyWe plant apple tree, graft pear branches

A X A X

B

C

D

E

A

A

A

A

Polymerization PSM

Monomer1 Monomer X PolymersPolymer X

Result: pear looks like apple and share apple scent

Introduce functionalities by post-synthetic modification

Happy End achieved by changing strategy

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Introduction Inorganic materials: activated carbon and zeolites Inorganic-organic hybrid polymers: metal-organic

frameworks, coordination polymers Organic polymers

Porous Materials

http://www.moftechnologies.com/

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Sodium aluminium silicate minerals

oxygen, silicon and aluminum atoms forming tetrahedral single units(Al is negative charged)

Microporous(<2nm) with regular pore sizes

Functionalized by doping certain counter-ions instead of Sodium

Robust, dirt cheap

Porous MaterialsZeolites

OSiAl

OO

O O OO

AlO

OO

OS

iA

lO

OOO

OO

Al O

OO

http://en.wikipedia.org/wiki/Zeolite#/media/File:Zeolite-ZSM-5-3D-vdW.png

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Metal-organic frameworks

Metal containing cores, ligands and organic bridges reversible linkage

Micro- and mesoporous (2 nm - 50 nm) uniform pore sizes, large surface areas

Post-synthetic modification however, limited

Air/moisture-sensitive

Porous MaterialsMOFs

Xamena et al., Journal of Catalysis 250 (2007) 294–298

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Porous Organic Polymers(POP), conjugated microporous polymers(CMP), porous aromatic frameworks(PAF))

Highly cross-linked, amorphous, high internal surface area, not uniform pore sizes

Stable than MOF

More Choices for post-synthetic modification

Porous MaterialsCovalent Organic Networks

https://communities.acs.org/docs/DOC-3866

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Porosity of Covalent Organic Networks

Ultra high Porosity

Left: Ben et al., Angew. Chem. Int. Ed. 2009, 48, 9457 –9460.Right: Yaghi et al., Science 2007, 316, 268 – 272.

BET surface are:5600 m2/g BET surface are:4210 m2/gActivated Carbon: 500 m2/g

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Han et al., ACS Appl. Mater. Interfaces 2013, 5, 4166−4172.

Synthesize of Covalent Organic Networks

Click Chemistry

Condensation (ketal formation)

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J.-X. Jiang, et al Chem. Commun., pp. 486-488, 2008.P. M. Budd, et alChemical Communications, pp. 230-231, 2004 .

Cyclization

(trimerization)

Coupling

Synthesize of Covalent Organic Networks

Click Chemistry (Continue)

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What are attractive features of such materials?Several Routes towards the same goal

Feature of Covalent Organic Networks

Nguyen et al., ACS Catal. 2011, 1, 819–835.

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• Present condition of Covalent Organic Networks

• Employ synthetic strategies that will result in new functionality in polymers that can then be post-synthetic modified

• Broaden the classes of ligands that can be generated

Why We Care about Covalent Organic Networks

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Synthesis of Covalent Organic Network Catalysts

Nguyen et al., ACS Catal. 2011, 1, 819–835.

Centers Linkers

Covalent Organic Network

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Implementation of 1,2,4,5-Tetrazines as Key FunctionalityNN N

N

R2

R1

1

24

5High nitrogen containing aromatic compounds, electron deficient

N

N NN

N

NN

NNN

N

NNN 862KJ/mol

Early studies on explosives

Recent studies on Inverse Electron Demand Diels-Alder Reaction

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1,2,4,5-Tetrazines Applied in Polymer Science

Anseth et al., Biomacromolecules, 2013, 14 (4), pp 949–953

Inverse electron-demand Diels-Alder reaction

1

• Initial Strategy: Double Diels-Alder Reaction• Formation of Triazene from Tetrazine

N

N N

N

R

R

R'

NH

X

dioxane/DMF

R.T

N

NNH

N

N

R

R

R'X

-N2 NN N

R

R

R'X

H

-HX NN N

R

R

R'

• Triazene could undergo Second D-A Reaction to Pyridazine

• Requirement: Reactivity of tetrazines must be guaranteed Clean reaction without side-reactions

NN N

R

R

R'

R'

NH

X

dioxane/DMF N

N

N

N

R

R

R'

R'

HX -N2

-HX

NN

R

RR'

R'

X: SMe, NH2, OEt

Design: Polymerization via Inverse Electron Demand Diels-Alder Reaction

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Reactivity on Tetrazines and DienophilesInverse electron-demand Diels-Alder reaction

D. L. Boger et al Journal of the American Chemical Society, vol. 107, pp. 5745-5754, 1985.

Electron-deficient dienes

Electron-rich dienophiles

D. L. Boger et al The Journal of organic chemistry, vol. 68, pp. 3593-3598, 2003.

N

N N

N

NHAc

SMe

> > > >>N

N N

N

NHBoc

SMe

N

N N

N

SMe

SMe

N

N N

N

SMe

OMe

N

N N

N

OMe

OMe

N

N N

N

NHBoc

SO2Me

>N

N N

N

CO2Me

CO2Me

N

N N

N

CO2Me

CO2Me

> >>>N

N N

N

CF3

CF3

N

N N

N

N

N

N

N N

N

R2N EtO OEt OEt OAc> > >

NR2 OEt Ph CO2Me

> > >

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Reactivity Test of Tetrazines and Dienophiles

N

N N

N

COOMe

COOMe

O

R.T. dioxane

N2 bubbling, color faded,

product isolated

Tetrazines Reaction with weak dienophile

N

N N

N

N

NN

N

O

R.T dioxane

overnight

No reaction

Reflux dioxane sealed

overnight

Red color disappeared

Product isolated

NN N

N

N

N

O

R.T. DMF/Phenol

3h

No Reaction

70-100°C

DMF/Phenol(note 1)

30minutes

Color faded

Product isolated

N

N N

N

O

70-100°C

overnight

Almost No reaction

80% Starting Tetrazine

Recovered

N

N N

N

C6H13

C6H13

O

R.T. dioxane No Reaction

70°C overnight

No Reaction, Starting

Tetrazine Quantatively

Recovered

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Reactivity Test of Tetrazines and Dienophiles

Tetrazines Reaction with strong dienophile

N

N N

N

COOMe

COOMe

NH

NH2

R.T. dioxane

N2 bubbling, color faded

Multiple spots on TLC

N

N N

N

N

NN

N

NH

NH2

R.T in DMF 1h

Red precipitate formed

HN

N

detected

N

N N

N

NH2

NN

NH

NH2

R.T in ACN 3h

No Reaction

70°C overnight

Starting Tetrazine

Quantitively Recovered

N

N N

N

HN

NN

NH2

NH

NH2

R.T. dioxane 3h

No Reaction

70°C overnight

No Reaction Starting

Tetrazine Recovered

N

N N

N

O

NN

NH

NH2

R.T. dioxane

Simutaneously precipitaton

HN

N

detected

NN N

N

N

N

NH

NH2

70°C overnight

Color faded

Several Spot on TLC

Electron rich substituted pyrazole tetrazine is not reactive

SnAr Reaction happened on dipyrazole tetrazine

N

N N

N

O

H

Proline+DBU

60°C

30minutes

N2 generated

Color faded

Product isolated

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Multiple Reactions of amidine with tetrazines and triazene rearrangement

The bad solubility of amidine as well as hard to make

Failed to push second Diels-Alder reaction through desired pathway

Issues in Double Diels-Alder Reaction

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Solubility is the eternal problemNH

NH2

NHH2N

HN

H2N

HN NH2

NHH2N

NHH2N

O

NHH2N

NHH2N

O

O

HN

NH2

NH2

NH

R Nn

LHMDS

Refulx

HCl/EtOHR

n NH

NH2HCl

LDA

DMFR

n NH

NH2

S

NH

NN N

N

Ar

Ar

nn N

NN

Ar

Ar

n

NR

R

n

N

Ar

Ar

n

The special requirement for amidine synthesis

Tetrazine and amidine reactions are hard to control, methylthioimidate can be alternative, however make procedure even complicate

Conclusions

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Design: Polymerization via Coupling Reactions Tetrazine containing polymers

Ding et al., J. Am. Chem. Soc. 2010, 132, 13160–13161

Used for solar cells Good thermal stability

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• Build up a polymer that contains tetrazine• More post synthetic modifications can be

done on the tetrazine

Things to concern

• Can other coupling reaction be used• Higher reactivity, the better?

>B

OH

OH>ZnX

>MgX

KumadaCoupling

NegishiCoupling

SuzukiCoupling

Stille Coupling

Why polymerization via coupling

Benefit

• Which monomer is easier to synthesize and can improve the overall reactivity

Br

Br

Br

Br

N

N N

N

Br

Br

Or

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• Benefit sometimes have drawbacks

A. Kotschy et al. Tetrahedron, vol. 60, pp. 1991-1996, 2004.

Screening the Coupling Method

• Coupling Reaction limited to Suzuki Reaction and Stille Reaction

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• Can we make boronic acid containing tetrazines?

Entry Tetrazine Condition Result

1 NN

N NBrBr

-78°C, n-BuLi

Then B(OEt)3

Purple color faded fast. No

desired product was detected

2 NN

N NBrBr

-78°C, t-BuLi

Then B(OEt)3

Color faded during lithium

halogen exchange period,

although slower

3 NN

N NBrBr

-78°C, B(Oi-Pr)3

Then n-BuLi

No desired product detected

4 NN

N N

N NBrBr

-78°C, B(Oi-Pr)3

Then n-BuLi

No bronic acid product

Study of Suzuki Coupling

• Why we want to make boronic acid containing tetrazines

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• The only choice left is to make boronic acid on tetraphenyl methane

Entry Tetrazine Result

1 NN

N NBrBr

Around 10% pink precipitate

Not starting material

2 NN

N NN NBrBr

All brownish mud

No sign of product

3 NN

N N

HN

NH Br

Br

Around 10% dark red product

Not starting material

Test of Suzuki Reaction with Benzene Boronic Acid

HN

N N

NNHN

OH-

HN

N N

NNHNHO

H OH

HN

N N

NNHNHO H

-N2HN NN

HN

OH

HN NHN

HN

O

Study of Suzuki Coupling

• Tetrazines found destroyed during test reaction in DMF with Na2CO3

Pd0

R2 X

oxidative addition

Pd2R2 X

NaOH

NaX

Pd2R2 OH

Pd2R2 R1

R1 R2

R1 B OH

OH

OH

Reductive elimination

Transmetalation

NaOH

Na+R1 B

OH

OH

HO B OH

OH

OH

Tetrazine Destruction

1

• Successfully made the trimethyltin on tetrazine this time, 30% yield, X

Br

CN

X= C, N

Sn Sn

Pd(PPh3)2Cl2dioxane3h reflux

X

CN

Sn

S, NH2NH2

EtOH reflux

X

Me3Sn

NN

NH

HN

X

SnMe3

AcOH, NaNO2

X

Me3Sn

NN

NN

X

SnMe3

X

SnMe3

NN NH

NH

X

SnMe3 AcOH, NaNO2

X

Me3Sn

NN N

N

X

SnMe3

Br

1 equiv

4equiv

Pd(dba)2dioxane

No Reaction

Recovered

X=C, N

DMF/Toluene

90°C 24h

90°C 24h

Add CsF

Another 24h

X

NN NH

NH

X

No coupling Product

AcOH, NaNO2

X

NN N

N

X

BrBr

Br Br

0.5 equiv

Pd(PPh3)4

Study of Stille Reaction

• No reaction due to dihydrotetrazine chelation

1

Successful coupling reaction through Stille Coupling(in collaboration with Lili Kang)

NN N

N

Br

Br

+ Pd(PPh3)4, Toluene, DMF

100 oC, 48 h56%

Sn

SnSn

Sn

NN

NN

NN

N N

NN

NN

NN N

N

NN

NN

N N

NN

NNN

N

1

ATR-IR

1400 cm-1 C=N stretches in tetrazines

Disappearance of saturated C-H stretches at 2900-3000 cm-1

Peak at 2365 cm-1 might be CO2

Characterizations

Sn

SnSn

Sn

NN N

N

Br

Br

NN

NN

1

Characterizations

Energy dispersive X-ray analysis (EDX)

Spot analysis

1

BET analysis

1

Post-Synthetic Modification

In situ generation of enamine

NN

NN

NN

O

H

L-proline, DBU, chloroform60 oC, overnight

86%

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• What is modified pinner Synthesis?

H2N NH2

SH2N

HN SH

Ar NAr

NH

N NH2

HS

ArN

N N

HNNH

Ar Ar

HHS

-H2S

N N

HNNH

Ar Ar

N N

NHHNAr Ar

[O]

N N

NNAr Ar

-H+

+H+ -H+

+H+

B-

• How it is applied in tetrazine-based polymer synthesis?

X.-H. Bu et al., RSC Advances, vol. 2, pp. 408-410, 2012.

NC

NC CN

CN

S, N2H2

90°C overnightSolvent

NN

NN

nCH3COOH, NaNO2

RT 30min yield 70-80%after two stepsN

N

NH

NH

n

Solvent: none Ethylene Glycol, THF etc.

• What is the benefit? • No metal• Only one monomer is needed

for each polymer

Polymerization via Modified Pinner synthesis

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• Reference comparison: Can we make the polymer with the same SSA?

• Will solvent polarity affect the surface area? POP Hydrazine/ml Sulphur/g Reaction

Time Temperature Solvent

Tz-1 16 0.6 3 days 90°C None

Tz-2 18 0.6 overnight 90°C Ethylene Glycol

Tz-3 18 0.6 overnight 90°C Benzyl Alcohol

Tz-4 18 0.6 overnight 90°C Glycerol

• Tz-1 and Tz-2 analysis is still going• Tz-3 BET analysis showed only around 170m2g-1

• Swelling in solvent guaranteed its application as catalyst

Experimental Section

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• Prospective 1-amino-1,3,4-triazole formation during chronic heating

NN

NH

HN

HeatN

N

N

HN H

NN

N

HN

H

+H+

-H-

N N

NNH

H

+H+

-H-N N

N

NH2

• Same issue on another reaction• Color unchanged after oxidization

CN

NN

NN

4

4

n

Issues During Modified Pinner Synthesis

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• Solid State C13 NMRN

N

NNR

R

160ppm

N N

NR

R

NH2150ppm

Carbon Shift is different

How to prove existence of 1-amino-1,3,4-triazole?

How to solve the problem?

Reduce reaction time

Prevent high temperature Any other problems?

Formation of dihydrotetrazine but can not be oxidized

Reaction does not complete properly

Problem Shooting

1

• Benefit of Lewis Acid Catalyzed Tetrazine Formation R1

CN

R2

CN

1) 5mol %catalystN2H2 60°C, 24h

2) NaNO2 1M HCl

N

N N

N

R2

R1

J. Yang et al., Angewandte Chemie, vol. 124, pp. 5312-5315, 2012.

• Oil-like compound after formation. Formed plastic-like material after heating

CNNC Ni(OTf)2

NH2NH2

Polymer[O]

Ni(OTf)2 Catalyzed Polymer Formation

R N M2+NH

H2N

N M2+NH

H2NR

N M2+

NHHN

Mechanism

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• Optimize Modified Pinner Tetrazine Formation

• make polymer reactive or with chelation site

N

N

N N

CN

CNNC

NC

N

N

N

N

CN

CN

NC

NC

• Infinite possibilities using Ni(OTf)2 catalyzed methodHN

NC HN

CN

NH

NC NH

CN

Polymer

NCCN

O

O

CN

NC

CN

NCO

CNNCNC

CN

O

O

O

CN

NC

NO O

O

NC CN

CN

Future Direction

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Acknowledgement

• Thank Dr. Unni for his guidance during research

• Thank Dr. Rogachev attending the defence

• Special thank for Lili Kang, Ph.D. student in collaboration

• Thank undergraduate student Nicholas Politis, Dan Yi for their help

• Thank my parents, friends and all those who care about me