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ReporterCheng-Yu ChungDate:2013/12/27

AdvisorProf.Wen-Chang Chen

Click ChemistryOutlineIntroduction

Experimantal

Copper-catalyzed alkyne-azide cycloaddition Cu-free alkyne-azide cycloaddition DielsAlder reaction Thiolene reaction

Applications

Conclusions

Introduction

3.Such processes proceed rapidly to completion and also tend to behighly selective for a single product 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

2.The reaction must be modular, wide in scope, give very high yields, generate only inoffensive byproducts that can be removed by nonchromatographic methods, and be stereospecific. 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.Angew. Chem. Int. Ed. 2001, 40, 2004 - 2021What is Click chemistry

(The Nobel Prize in Chemistry 2001 ) Objective:K. Barry. Sharpless OutlineIntroduction

Experimantal

Copper-catalyzed alkyne-azide cycloaddition Cu-free alkyne-azide cycloaddition DielsAlder reaction Thiolene reaction

Applications

Conclusions

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

Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition of alkynes and azidesstrain-promoted cycloaddition of alkynes and azidesDielsAlder reactionthiolene reaction.G.K. Such et al. / Progress in Polymer Science 37 (2012) 9851003Copper-catalyzed alkyne-azide cycloaddition

Proposed outline of species involved CuAACTraditional products of thermal 1,3-cycloadditionEur. J. Org. Chem. 2006, 5168 Advantage:

1.CuAAC proceeds efciently at room temperature2. CuAAC proceeds in many protic and a protic solvents,including water3.unaffected by most inorganic and organic functional groups.4.good exo-endo selectivity

Disadvantage:

CuAAC is the need for Cu(I) and the associated potential toxicity.

Mechanism of Cu(I)-Catalyzed AlkyneAzide CouplingCu-free alkyne-azide cycloaddition

Bioorthogonal reaction of cyclooctyne probes with azide-labeledbiomolecules 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) Cyclooctynes designed 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

Scheme 1. Retrosynthesis of BARAC (1)

Scheme 2. Synthesis of BARAC (15)Cu-free alkyne-azide cycloaddition

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 MAc4ManNAz for 3 days. The cells were labeled with 1 M 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 quantied by ow cytometry. The level of uorescenceis reported in mean uorescence intensity (MFI, arbitrary unit). Error bars represent the standard deviation of three replicate experiments. (B) Comparisonof the efciencies of labeling of different cyclooctyne reagents after 1 h. (C) Time-dependent labeling of cyclooctyne-biotin probes. MFI reported as differencebetween signal of cells Az and signal of cells Az.Cu-free alkyne-azide cycloadditionImaging of azide-labeled glycans on live cells using BARAC-Fluor

J. AM. CHEM. SOC. 2010, 132, 36883690Cu-free alkyne-azide cycloadditionDielsAlder reaction

Maleimide functional group: An ideal click substrate.DielsAlder/retro DielsAlder reaction sequence.Advantage:1.DA cycloaddition offer a reagent -free click reaction2.design of thermoreversible materials3.highly sensitive to the temperature4.good exo-endo selectivity

Disadvantage:Temperature too high lead to lower yields (the competing retro DielsAlder reaction)Macromol. Chem. Phys. 2010, 211, 14171425MoleculardesignDielsAlder reaction

Dendron graft polymers via the rDA/DA sequencethermoresponsive segment-block dendrimersthermoreversible symmetrical dendrimers

self healing crosslinked materialsThiolene reaction

==> a single thiol reacts with a single ene to yield the product.

General thiolene coupling : (Michael addition) a) alkyl thiols (b) multifunctional thiolsthiolene polymerization processesTypical multifunctional enesAngew. Chem. Int. Ed. 2010, 49, 1540 1573Advantage: highly efficient, simple to execute with no side products and proceeding rapidly to high yield.Applications:high performance protective polymer networks to processes that are important in the optical, biomedical, sensing, and bioorganic modification fields.Thiolene reaction-Synthetic method

etc.

Thiolene photoinitiated free-radical reaction of a 48-functional ene dendrimer with selective monofunctional thiolsSynthetic method for 48-functional polyol dendrimer using sequential thiolene radical and esterification reactions.Polymeric carrier systems involving Click Chemistry

G.K. Such et al. / Progress in Polymer Science 37 (2012) 9851003OutlineIntroduction

Experimantal

Copper-catalyzed alkyne-azide cycloaddition Cu-free alkyne-azide cycloaddition DielsAlder reaction Thiolene reaction

Applications

Conclusions

Drug delivery

ACS Nano,2010,4(7), pp 42114219OutlineIntroduction

Experimantal

Copper-catalyzed alkyne-azide cycloaddition Cu-free alkyne-azide cycloaddition DielsAlder reaction Thiolene reaction

Applications

Conclusions

ConclusionsThere is now a well- studied set of reactions which satisfy most click criteria and thus the choice of the appropriate reaction for a specic 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 eld of biomedicine where knowledge on the interactions between synthetic delivery systems both in vitro and in vivo is rapidly expanding.

Diversity
Complexity
Devices
Amino Acid
Monomer
Homopolymer
Block Copolymer
Bulk Assembly
Solution Assembly
Cells
Proteins
Polypeptides
Biopolymers
Synthetic Polymers
Roadmap of Diversity vs. Complexity in Natural and Synthetic Polymers