Click chemistry is a philosophy of natural product synthesis devised by Nobel laureate Prof. K Barry Sharpless of the Scripps Research Institute. Sharpless is critical of the over-reliance of synthetic chemists in imitating the carbonyl chemistry controlled by enzymes in biological systems, suggesting the formation of C-C bonds through aldol reactions, or otherwise, is best left to nature.1 Overall he describes the modern methods of synthesis as not being suited towards the quick and efficient manufacture of molecules with desirable properties. Secondary metabolites produced in nature often have extensive and complex carbon-carbon scaffolds 2 and biological activities that make them valuable lead compounds in the process of drug discovery. Coupled with the recent developments in high-throughput screening and combinatorial computational chemistry, this has allowed the formation of a large library of compounds in search new highly active, targeted drugs. However, existing synthetic strategies relied heavily on individual reactions to synthesise the carbon-carbon frameworks, causing the process of synthesizing and modifying lead compounds to be difficult, time consuming and unecconomical.2 Sharpless's 2001 review paper on the topic of 'click' chemistry,3 outlines a 'modular' approach to generate novel compounds using highly reliable chemical reactions to generate functionality through carbon-heteroatom bonds from olefinic starting materials. Since the introduction of 'click' chemistry, it has found uses in areas of research as diverse as polymer design4 and bioconjugation (the covalent attachment of synthetic 'tags' to a biomolecular framework).5-6
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utilize readily available starting materials
give high chemical yields
generate no harmful byproducts
have simple conditions
use readily available materials
be easily performed, with products that can be removed by non-chromatographic methods (i.e. filtration or distillation)
be conducted neat or in a benign solvent, preferably water
be stereo- and regio- specific
These triazole and tetrazole forming reactions are perhaps the most studied click reactions to date. Although the properties,reactions and syntheses of 1,2,3-triazoles were researched in the 1900s by Dimroth,7 the potential of the cycloaddition reaction between acetylenes and azides was only recognised in the 1960s by Rolf Huisgen.8 Sharpless improved upon both the reaction conditions and catalysts to generate a regiospecific 3+2 cycloaddition creating 1,4- or 1,5- substituted 1,2,3-triazoles.9 The starting materials are easily accessible, azides being easily obtainable through nucleophilic substitution of R-X species (X=Cl, Br, I), and a vast array of alkynes from the cracking of petroleum.
By introducing a Cu(I) based catalyst, Sharpless was able to run the reaction at room temperature, and introduced 1,4- regioselectivity to the product.
CuAAC is chemoselective - compatible with esters, alcohols, acids, alkenes and amines (virtually eliminating the need for protecting groups) - results in a product that can easily be obtained by filtration and generally has yields of >95 %.10 The reduction in situ of copper(II) salts such as copper sulphate with sodium ascorbate in alcoholic aqueous solution allows the formation of 1,4-triazoles at room temperature with less than 2 mol % catalyst loading. Constantly striving for improvement, Sharpless refined the reaction by introducing a Cu(I)-stabilizing polytriazolic-amide catalyst.11 This protected the Cu(I) from disproportionation and oxidation, while improving its catalytic ability.
Fulfilling all of the reaction criteria, CuAAC has become known as 'the' click reaction.
Several variants of the Huisgen cycloaddition exist. One, employing a Ruthenium catalyst was first demonstrated by Sharpless et al in 2005, allowing efficient regioselection for 1,5-substitution for the first time, however limited by the necessity of an aryl azide.12 This was further improved by his Scripps Institute colleagues Fokin et al in 2007.13 Fokin's synthesis employed microwave irradiation to reduce reaction time and improve yield. Despite the refinement, yields varied from 25-90 %, demonstrating more work must be done before this becomes a viable click reaction.
Furthermore, Sharpless discovered tetrazoles can easily be synthesised by modification of the starting alkyne to an acyl cyanide14 or sulfonyl cyanide.15 This yields an acyl or sulfonyl tetrazole, respectively.
Nucleophilic ring opening
The opening of three-membered rings by nucleophiles is facilitated by the release of strain energy.16 Sharpless has termed these functional groups 'spring-loaded electrophiles.'3
These rings can easily be formed from their parent olefins. If asymmetry in the starting epoxide is required, reactions such as the Sharpless asymmetric epoxidation can be used.17 The rings can be further activated by protonation, to give oxiranium, aziridinium and episulphonium cations respectively in regards to Figure 1.
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The regioselective ring opening of these groups usually proceeds by an SN2 mechanism, and the process is reliable, stereospecific and nearly quantitative in yield. With a huge library of nucleophiles, ring opening can impart a huge diversity of functionalities to a molecule. For epoxides the ring opening is generally solvent controlled, while for aziridines it is mainly dependent on the substrate structure,18 and the composition of the N- attached group .3
Overall, nucleophilic ring opening reactions of epoxides (and more specifically oxiranes) and aziridines can be high yielding, regioselective, and stereospecific, fulfilling the requirements of click reactions.
Other Click Reactions
Reactions not discussed, but allowed by Sharpless in the scope of click chemistry include:3
Non-aldol carbonyl chemistry - including acetal, imine, oxime, and cyanohydrin formation and Michael addition reactions.
The Sharpless asymmetric aminohydroxylation19 and asymmetric dihydroxylation of alkenes.20
Impact of click chemistry
Bioconjugation and Medicinal Chemistry
Although azides and alkynes display high reactivity mutually, in organic synthesis and towards biological molecules they are amongst the least active functional groups. This has led them to be termed 'bioorthogonal.'21
The use of CuAAC in various fields has increased year on year, with Sharpless's team at the Scripps institution leading the way in discovering the applications afforded by triazole formation. In 2003 Sharpless demonstrated the effectiveness of CuAAC in bioconjugation, labelling a simple virus 'decorated' with azide functionalities positioned on cysteine and lysine residues with a alkyne functionalised dye .22 In addition, using a similar technique, CuAAC has been used in activity-based protein profiling to selectively label active protein sites. Once an enzyme target has been tagged with an azide in vivo, it can be extracted and allowed to undergo cycloaddition with a alkyne reaction partner, then isolated and purified. Using this method, a team of researchers isolated several enzymes instigated in breast cancer cell lines that had not been identified using in vitro techniques.23
Click chemistry has been utilised in target-guided synthesis (the use of modified enzymes/kinases to build their own inhibitors). Molecular fragments that interact with the target site of the enzyme/kinase will react to form an inhibiting compound.24 Utilizing azide and alkyne functionalities within the fragments allowed cycloaddition to occur in order to support this process. Sharpless used this method to develop a potent inhibitor for acetylcholinesterase, an enzyme that catalyzes the hydrolyses of the neurotransmitter acetylcholine.25
Materials and Polymer Chemistry
CuAAC has caught the attention of many polymer scientists, and is now widely used in the synthesis of linear, branched, dendritic and co-polymers.26 Previously the synthesis of dendrimers had been complicated by difficult purification, requiring time consuming separations using chromatography to separate impure products. This partially belied their unique properties due to the regular repeating structure until Sharpless and colleagues developed a method to synthesize triazole based dendrimers with near quantitative yield.27
'Click Chemistry' was introduced by Sharpless as stringent criteria for a set of reliable chemical reactions to help develop novel pharmaceutical agents quickly and efficiently. Currently CuAAC is synonymous with 'click chemistry' as the reaction most befitting the criteria, and most research has been conducted with regards to this reaction. While there is no doubt that click chemistry was a refreshing philosophy that has resulted in some breakthrough in synthetic and materials chemistry, the impact has perhaps been less than initially expected.
Given that the main aim of 'click chemistry' was aimed at eliminating the need to create C-C bonds, it is perhaps ironic that it is the creation of C-C bonds that has reached even greater prominence in recent years through paladium catalysed cross-linking reactions.28-30 Efficient C-C bond formation is now a key weapon in every synthetic chemists arsenal and, although there is much to be gained from the philsophy of click chemistry, it's strive towards perfection is perhaps in fact its greatest weakness. The limited scope of reactions restricts creation of complex frameworks and thus its use in fine chemical synthesis. It is perhaps for this reason that most attention has been focused around the click reaction (CuAAC) and it's uses, as opposed to the overall philosophy.
Even if the potential of click chemistry has not been fully realised by the scientific community, it does not take away from Sharpless's exemplary research record. Each day thousands of chemists perform the asymmetric epoxidation, dihydroxylation and hydroxyamination reactions that won him a share of the Nobel Prize for Chemistry in 2001.
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