The structural complexity of molecules isolated from biological sources has always served as an inspiration for organic chemists. Since the first synthesis of a natural product, urea, chemists have been challenged to prepare exact copies of natural structures in the laboratory. As a result, a broad repertoire of synthetic transformations has been developed over the years. It is now feasible to synthesize organic molecules of enormous complexity, and also molecules with less structural complexity but prodigious societal impact, such as nylon, TNT, polystyrene, statins, estradiol, XTC, and many more. Unfortunately, only a few chemical transformations are so mild and precise that they can be used to selectively modify biochemical structures, such as proteins or nucleic acids; these are the so-called bioconjugation strategies. Even more challenging is to apply a chemical reaction on or in living cells or whole organisms; these are the so-called bioorthogonal reactions. These fields of research are of particular importance because they not only pose a worthy challenge for chemists but also offer unprecedented possibilities for studying biological systems, especially in areas in which traditional biochemistry and molecular biology tools fall short. Recent years have seen tremendous growth in the chemical biology toolbox. In particular, a rapidly increasing number of bioorthogonal reactions has been developed based on chemistry involving strained alkenes or strained alkynes. Such strained unsaturated systems have the unique ability to undergo (3 + 2) and (4 + 2) cycloadditions with a diverse set of complementary reaction partners. Accordingly, chemistry centered around strain-promoted cycloadditions has been exploited to precisely modify biopolymers, ranging from nucleic acids to proteins to glycans. In this Account, we describe progress in bioconjugation centered around cycloadditions of these strained unsaturated systems. Being among the first to recognize the utility of strain-promoted cycloadditions between alkenes and dipoles, we highlight our report in 2007 of the reaction of oxanobornadienes with azides, which occurs through a sequential cycloaddition and retro Diels-Alder reaction. We further consider the subsequent refinement of this reaction as a valuable tool in chemical biology. We also examine the development of the reaction of cyclooctyne, the smallest isolable cyclic alkyne, with a range of substrates. Owing to severe deformation of the triple bond from ideal linear geometry, the cyclooctynes show high reactivity toward dienes, 1,3-dipoles, and other molecular systems. In the search for bioorthogonal reactions, cycloadditions of cyclic alkenes and alkynes have now established themselves as powerful tools in reagent-free bioconjugations.

Biohybrid amphiphiles have been prepared from terminal azide functionalised polystyrene and an alkyne functionalised peptide or protein via a Cu(I) catalysed Huisgen [3 + 2] dipolar cycloaddition reaction.

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Biohybrid amphiphiles composed of a protein head group and a hydrophobic polymer tail self‐assemble in water in a similar way as low molecular weight surfactants. Owing to the presence of the protein, biohybrid amphiphiles, and their assemblies, however, hold the additional feature of a built‐in (bio)functionality. These compounds therefore are promising building blocks for the synthesis of functional nanometer‐sized materials. We discuss recent advances in the relatively young field of protein–polymer hybrid amphiphiles, which so far mainly involved exploratory and fundamental studies providing a conceptual basis for the development of more complex systems with interesting applications in the future.

Block copolymers consisting of a poly(ethylene glycol) chain and a thymine‐ or adenine‐functional polymethacrylate block have been prepared with atom transfer radical polymerization, and their aggregation behavior in an aqueous medium has been studied. Upon the mixing of the two block copolymers, the critical aggregation concentration increases in comparison with the critical aggregation concentration of the individual block copolymers. It has therefore been demonstrated that the amphiphilic behavior of this class of block copolymers is affected by the interaction between the complementary nucleobases, which leads to an unexpected increase in the hydrophilicity of the block copolymer ensemble.