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Click Chemistry. Reporter : Cheng-Yu Chung Date:2013/12/27 Advisor : Prof.Wen -Chang Chen. Outline. Introduction Experimantal C opper-catalyzed alkyne- azide cycloaddition Cu-free alkyne- azide cycloaddition Diels–Alder reaction Thiol – ene reaction Applications Conclusion s.

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Click chemistry

ClickChemistry

Reporter:Cheng-Yu Chung

Date:2013/12/27

Advisor:Prof.Wen-Chang Chen


Outline

Outline

  • Introduction

  • Experimantal

    Copper-catalyzed alkyne-azidecycloaddition

    Cu-free alkyne-azidecycloaddition

    Diels–Alder reaction

    Thiol–enereaction

  • Applications

  • Conclusions


Introduction

Introduction


What is click chemistry

(The Nobel Prize in Chemistry 2001 )

What is “Click” chemistry?

Defination:

We endeavor to generate substances by joining small units together with heteroatom links (C-X-C). The goal is to develop an expanding set of powerful, selective, and modular“blocks” that work reliably in both small- and large-scale applications. It is important to recognize that click reactions achieve their required characteristics by having a high thermodynamic driving force, usually greater than 20 kcal/mol

Objective:

K. Barry. Sharpless

1.We present here synthetic methods for drug discovery that adhere to one rule: all searches must be restricted to molecules that are easy to make.

2.The reaction must be modular, wide in scope, give very high yields, generate only inoffensive byproducts that can be removed by nonchromatographicmethods, and be stereospecific.

3.Such processes proceed rapidly to completion and also tend to be

highly selective for a single product

Angew. Chem. Int. Ed. 2001, 40, 2004 - 2021


Outline1

Outline

  • Introduction

  • Experimantal

    Copper-catalyzed alkyne-azidecycloaddition

    Cu-free alkyne-azidecycloaddition

    Diels–Alder reaction

    Thiol–enereaction

  • Applications

  • Conclusions


Selection of reactions that best meet the criteria for a click reaction

Selection of reactions that best meet the criteria for a “click” reaction

Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition of alkynes and azides

strain-promoted cycloaddition of

alkynes and azides

Diels–Alder reaction

thiol–ene reaction.

G.K. Such et al. / Progress in Polymer Science 37 (2012) 985–1003


Copper catalyzed alkyne azide cycloaddition

Copper-catalyzed alkyne-azidecycloaddition

Mechanism of Cu(I)-Catalyzed Alkyne–Azide Coupling

Advantage:

1.CuAAC proceeds efficiently at room

temperature

2. CuAAC proceeds in many protic and a

proticsolvents,including water

3.unaffected by most inorganic and organic

functional groups.

4.good exo-endo selectivity

Traditional products of thermal 1,3-cycloaddition

Disadvantage:

CuAAC is the need for Cu(I) and the associated

potential toxicity.

Proposed outline of species involved CuAAC

Eur. J. Org. Chem. 2006, 51–68


Cu free alkyne azide cycloaddition

Cu-free alkyne-azidecycloaddition

Bioorthogonal reaction of cyclooctyne probes with azide-labeled

biomolecules allows their interrogation in cell-based systems.

Cells are treated with azide-functionalized metabolic substrates. The azides are then detected with a cyclooctyne-functionalized probe.

(B) Cyclooctynesdesigned for fast Cu-free click chemistry (1-3) and reactivity studies (4).

The R-group denotes the location for linkage to a probe moiety.


Synthesis strategies

Cu-free alkyne-azidecycloaddition

Synthesis strategies 

Scheme 1. Retrosynthesis of BARAC (1)

Scheme 2. Synthesis of BARAC (15)


Click chemistry

Cu-free alkyne-azidecycloaddition

Figure 2. BARAC-probe conjugates label live cells with superior sensitivity compared to DIFO and DIBO reagents. (A) Structures of BARAC-biotin (16)

and BARAC-Fluor (17). (B C) Flow cytometry plots of live cell labeling with BARAC-biotin. Jurkat cells were incubated with ( Az) or without ( Az)

25 µMAc4ManNAz for 3 days. The cells were labeled with 1 µM cyclooctyne-biotin for various times and then treated with FITC-avidin. Cyclooctyne-

biotin probes used were DIBO-biotin, BARAC-biotin, or DIFO-biotin. The degree of labeling was quantified by flow cytometry. The level of fluorescence

is reported in mean fluorescence intensity (MFI, arbitrary unit). Error bars represent the standard deviation of three replicate experiments. (B) Comparison

of the efficiencies of labeling of different cyclooctyne reagents after 1 h. (C) Time-dependent labeling of cyclooctyne-biotin probes. MFI reported as difference

between signal of cells Az and signal of cells Az.


Imaging of azide labeled glycans on live cells using barac fluor

Cu-free alkyne-azidecycloaddition

Imaging of azide-labeled glycans on live cells using BARAC-Fluor

J. AM. CHEM. SOC. 2010, 132, 3688–3690


Diels alder reaction

Diels–Alder reaction

Advantage:

1.DA cycloaddition offer a reagent

-free ‘click’ reaction

2.design of thermoreversiblematerials

3.highly sensitive to the temperature

4.good exo-endo selectivity

Maleimide functional group: An ideal ‘click’ substrate.

Disadvantage:

Temperature too high lead to lower yields

(the competing retro Diels–Alder reaction)

Diels–Alder/retro Diels–Alder reaction sequence.

Macromol. Chem. Phys. 2010, 211, 1417–1425


Diels alder reaction1

Diels–Alder reaction

Molecular

design

self healing crosslinked materials

thermoreversible symmetrical dendrimers

thermoresponsive segment-block dendrimers

Dendron graft polymers via the rDA/DA sequence


Thiol ene reaction

Thiol–ene reaction

General thiol–ene coupling :

(Michael addition)

==>a single thiolreacts with a single ene to yield the product.

thiol–ene polymerization processes

a) alkyl thiols(b) multifunctional thiols

Typical multifunctional enes

Advantage: highly efficient, simple to execute with no side products and proceeding rapidly to high yield.

Applications:highperformance protective polymer networks to processes that are important in the optical,

biomedical, sensing, and bioorganic modification fields.

Angew. Chem. Int. Ed. 2010, 49, 1540 – 1573


Thiol ene reaction synthetic method

Thiol–enereaction-Syntheticmethod

Synthetic method for 48-functional polyoldendrimerusingsequential thiol–ene radical and esterification reactions.

etc.

Thiol–enephotoinitiated free-radical reaction of a 48-functional enedendrimerwithselective monofunctionalthiols


Polymeric carrier systems involving click chemistry

Polymeric carrier systems involving “Click Chemistry”

G.K. Such et al. / Progress in Polymer Science 37 (2012) 985–1003


Outline2

Outline

  • Introduction

  • Experimantal

    Copper-catalyzed alkyne-azidecycloaddition

    Cu-free alkyne-azidecycloaddition

    Diels–Alder reaction

    Thiol–enereaction

  • Applications

  • Conclusions


Drug delivery

Drug delivery

ACS Nano, 2010, 4 (7), pp 4211–4219


Outline3

Outline

  • Introduction

  • Experimantal

    Copper-catalyzed alkyne-azidecycloaddition

    Cu-free alkyne-azidecycloaddition

    Diels–Alder reaction

    Thiol–enereaction

  • Applications

  • Conclusions


Conclusions

Conclusions

  • There is now a well- studied set of reactions which satisfy most click criteria and thus the choice of the appropriate reaction for a specific set of conditions is straightforward.

  • Click chemistry offers a powerful toolbox for material scientists to design the next generation of materials with targeted response to the environment.

  • This is particularly true in the field of biomedicine where knowledge on the interactions between synthetic delivery systems both in vitro and in vivo is rapidly expanding.


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