Click chemistry: function follows form

In chemistry, as in many architectural endeavors, function and form are intimately connected. It is the function of molecules that matters most, and the creation of new function is the goal of all chemical research from the discovery of pharmaceuticals to the invention of polymers. Within the vast potential pool of molecular structures, there must be many answers to any chemical question—that is, many different molecules that have a desired function. The problem, of course, is to find them, a goal which depends first upon their construction and then upon their evaluation. To a unique extent among the sciences, therefore, chemistry requires synthesis.

In the more than 150-year history of modern chemistry, a great many techniques for joining molecular pieces to each other have been developed. Many of these are quite sophisticated, requiring the delicate handling of highly reactive reagents under tightly controlled conditions. In 2001, a group of chemists led by K. Barry Sharpless at The Scripps Research Institute gave the name of “click chemistry” to the very best chemical reactions. They are easy to perform, give rise to their intended products in very high yields with little or no byproducts, work well under many conditions, and are unaffected by the nature of the groups being connected to each other. The “click” moniker is meant to signify that with the use of these methods, joining molecular pieces is as easy as “clicking” together the two pieces of a buckle. The buckle works no matter what is attached to it, as long as its two pieces can reach each other. And the components of the buckle can make a connection only with each other.

The central question posed by Sharpless and colleagues is whether or not desired functions can be obtained from molecules made using only the very best (click) chemical reactions, or using them as much as possible. In this deliberate eschewing of more subtle synthetic techniques is an implicit challenge to organic chemists that make complex structures by complex methods (can complex structures be made by simple methods?), and an explicit tip of the hat to the synthesis of functional polymers, which cannot occur without reactions that meet the click chemistry standard. As usual, Nature provides inspiration by example, since many natural molecules of the most sophisticated function, such as proteins and nucleic acids, are made by the seemingly simple repetition of reliable bond-forming operations.

Click reactions share the following attributes:

(1) Many click components are derived from alkenes and alkynes, and thus ultimately from the cracking of petroleum. Carbon–carbon multiple bonds provide both energy and mechanistic pathways to be elaborated into reactive structures for click connections.

(2) Most click reactions involve the formation of carbon–heteroatom (mostly N, O, and S) bonds. This stands in contrast to the march of modern synthetic organic chemistry, which has emphasized the formation of carbon–carbon bonds.

(3) Click reactions are strongly exothermic, either by virtue of highly energetic reactants or strongly stabilized products.

(4) Click reactions are usually fusion processes (leaving no byproducts) or condensation processes (producing water as a byproduct).

(5) Many click reactions are highly tolerant of—and often accelerated by—the presence of water.

Only a handful of transformations possess most or all of these properties. Among them, the azide–alkyne cycloaddition (AAC) reactions, producing 1,2,3-triazoles, occupy a special place, for reasons that will become clear to the reader of many of the articles in this themed issue. AAC processes are uniquely useful because of the properties of the reactive substituents. Both azides and alkynes are high in chemical potential energy, and their fusion to make triazoles is exothermic by more than 45 kcal mol⁻¹. However, the rate of this reaction is quite slow, normally requiring prolonged heating for unactivated alkynes.

Azide and alkyne groups are stable in the presence of the nucleophiles, electrophiles, and solvents common to standard reaction conditions, the azide being a rare example of a 1,3-dipolar reagent to have this quality. Each functionality is almost completely unreactive toward biological molecules. They are small, incapable of significant hydrogen bonding, and relatively nonpolar, and thus are unlikely to significantly change the properties of structures to which they are attached. Lastly, both can be easily introduced into organic compounds. The AAC process has been accelerated by making the alkyne electron-deficient or strained, and by catalysis with copper(I) or ruthenium(II) complexes. Because of its high rate and use of the small and easily synthesized azide and terminal alkyne groups, the copper-catalyzed (CuAAC) version has been the most widely used, but other variants are highly significant. This issue of Chemical Society Reviews includes the following contributions that, taken together, comprise an excellent, while necessarily incomplete, snapshot of the current state of understanding of click reactions and their applications to problems in widely diverse fields.

Jewett and Bertozzi (DOI: 10.1039/b901970g) illustrate the power of the click concept in their discussion of the uses of azides in metal-free click reactions with biological molecules, highlighting the importance of bioorthogonality to applications in vitro and in vivo. This is further illustrated by the use of uncatalyzed azide–alkyne ligations to identify molecules that bind tightly to macromolecular targets, as discussed in articles by Hu and Manetsch (DOI: 10.1039/b904092g), and Mamidyala and Finn (DOI: 10.1039/b901969n).

The basics of the CuAAC reaction and what is known and suspected of its mechanism are discussed by one of the reaction’s discoverers, Valery Fokin (DOI: 10.1039/b904091a). One can categorize the applications of the CuAAC process in terms of the size of the molecules created or modified. On the small-molecule side, fluorogenic CuAAC reactions have proven to be highly useful in revealing the occurrence and the physical location of click reaction events: the infiltration of new terrain with unobtrusive agents is of little use unless those agents can illuminate the landscape when desired. Le Droumaguet, Wang, and Wang (DOI: 10.1039/b901975h) discuss fluorogenic variations on the CuAAC reaction theme, and applications of those reactions to problems of visualization on the molecular or cellular scale. Somewhat larger are the esthetically pleasing, functionally rich, synthetically challenging architectures of supramolecular chemistry. Hänni and Leigh (DOI: 10.1039/b901974j) show how the synthesis of catenanes and rotaxanes has been significantly enabled by the CuAAC reaction, while Hua and Flood (DOI: 10.1039/b818033b) report on the ability of triazoles to function as hydrogen bond donors in the formation of selective anion-binding agents. Lastly, Holub and Kirshenbaum (DOI: 10.1039/b901977b) describe the modification of peptidomimetic oligomers by the copper click reaction, illustrating, among other things, the similarities in structure and properties between amide bonds and 1,2,3-triazole linkages.

The CuAAC reaction also finds natural application in the synthesis and derivatization of macromolecules such as polymeric materials and surfaces. Golas and Matyjaszewski (DOI: 10.1039/b901978m) highlight examples of many such applications to synthetic macromolecules that form nanoscale objects. Similar efficiencies of ligation, but under vastly different conditions, are observed in the CuAAC modification of polynucleotides, described by El-Sagheer and Brown (DOI: 10.1039/b901971p). The use of CuAAC methods for the preparation of electroactive surfaces, useful for the modeling of redox enzymes, is reported by Decréau, Collman, and Hosseini (DOI: 10.1039/b901972n).

In addition to their utility in joining diverse molecular building blocks, click reactions can be performed in many different environments. Kappe and Van der Eycken (DOI: 10.1039/b901973c) survey some unusual methods in which click reactions have been carried out or pushed when necessary. Lastly, the development and use of the powerful thiol-ene reaction—a click process in every sense of the term—is described by Hoyle, Lowe, and Bowman (DOI: 10.1039/b901979k). It is with great sadness that we note Professor Hoyle’s untimely death in late 2009. The fields and practitioners of polymer chemistry, materials science, and click chemistry are much the poorer for the loss of this matchless researcher, teacher, and mentor.

The rationale of click chemistry is simple: the more tolerant the connection reaction between molecular building blocks, the more diverse the blocks that can be brought to bear on any problem, and the more likely it will be that solutions to the problem can be found and produced in quantity. If indeed it is useful function that is the goal, then keeping chemistry simple is a useful rule to remember.

Footnote

† Part of a themed issue reviewing the latest applications of click chemistry.

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