Examination of nature's favorite molecules reveals a striking preference for making carbon-heteroatom bonds over carbon-carbon bonds-surely no surprise given that carbon dioxide is nature's starting material and that most reactions are performed in water. Nucleic acids, proteins, and polysaccharides are condensation polymers of small subunits stitched together by carbon-heteroatom bonds. Even the 35 or so building blocks from which these crucial molecules are made each contain, at most, six contiguous C-C bonds, except for the three aromatic amino acids. Taking our cue from nature's approach, we address here the development of a set of powerful, highly reliable, and selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries through heteroatom links (C-X-C), an approach we call "click chemistry". Click chemistry is at once defined, enabled, and constrained by a handful of nearly perfect "spring-loaded" reactions. The stringent criteria for a process to earn click chemistry status are described along with examples of the molecular frameworks that are easily made using this spartan, but powerful, synthetic strategy.

Beyond the Paradigm of Carbonyl ChemistryLife on Earth requires the construction of carbon ± carbon bonds in an aqueous environment. Carbonyl (aldol) chemistry is natures primary engine of CÀC bond formation. Not only do the requisite carbon electrophiles (carbonyls) and nucleophiles coexist in water, but water provides the perfect environment for proton shuttling among reactants, which is required for reversible carbonyl chemistry.With CO 2 as the carbon source and a few good carbonyl chemistry based reaction themes, nature achieves astonishing structural and functional diversity. Carbonyl chemistry is used to make a modest collection of approximately 35 simple building blocks, which are then assembled into biopolymers. The enzymatic polymers serve, in concert with increments of energy provided by adenosine triphosphate, as selective catalysts which prevent natures carbonyl chemistry based syntheses from collapsing into chaos. Since many biosynthetic pathways require a unique enzyme for each step, the enzymecontrol strategy required a heavy investment of time and resources for catalyst development. With a few billion years and a planet at her disposal, nature has had both time and resources to spare, but we, as chemists on a human timescale, do not.Nevertheless, carbonyl-based reactions have always been profoundly appealing to students and practitioners of organic chemistry. It is our contention that organic synthesis conducted, as it has been, in imitation of natures carbonyl chemistry is ill-suited for the rapid discovery of new molecules with desired properties.Many transformations that form ªnewº carbon ± carbon bonds are endowed with only a modest thermodynamic driving force. In particular, equilibrium ªaldolº reactions are often energetically favorable by less than 3 kcal mol À1 . [1] For these processes to reach completion in the laboratory, an additional ªpushº must be provided, often by application of Le Chateliers principle (for example, azeotropic removal of water), by coupling the desired process to an exothermic coreaction (for example, a strong ªbaseº a strong ªacidº), or by virtue of favorable entropic considerations (such as intramolecular ring closure) without enthalpic penalties (such as formation of strained rings). Thus, due in effect to the loss of one ªequivalentº of ester, resonance stabilization, the first

Aryl sulfonyl chlorides (e.g. Ts-Cl) are beloved of organic chemists as the most commonly used S(VI) electrophiles, and the parent sulfuryl chloride, O2 S(VI) Cl2 , has also been relied on to create sulfates and sulfamides. However, the desired halide substitution event is often defeated by destruction of the sulfur electrophile because the S(VI) Cl bond is exceedingly sensitive to reductive collapse yielding S(IV) species and Cl(-) . Fortunately, the use of sulfur(VI) fluorides (e.g., R-SO2 -F and SO2 F2 ) leaves only the substitution pathway open. As with most of click chemistry, many essential features of sulfur(VI) fluoride reactivity were discovered long ago in Germany.6a Surprisingly, this extraordinary work faded from view rather abruptly in the mid-20th century. Here we seek to revive it, along with John Hyatt's unnoticed 1979 full paper exposition on CH2 CH-SO2 -F, the most perfect Michael acceptor ever found.98 To this history we add several new observations, including that the otherwise very stable gas SO2 F2 has excellent reactivity under the right circumstances. We also show that proton or silicon centers can activate the exchange of SF bonds for SO bonds to make functional products, and that the sulfate connector is surprisingly stable toward hydrolysis. Applications of this controllable ligation chemistry to small molecules, polymers, and biomolecules are discussed.

The copper-catalyzed cycloaddition reaction between azides and alkynes functions efficiently in aqueous solution in the presence of a tris(triazolyl)amine ligand. The process has been employed to make rapid and reliable covalent connections to micromolar concentrations of protein decorated with either of the reactive moieties. The chelating ligand plays a crucial role in stabilizing the Cu(I) oxidation state and protecting the protein from Cu(triazole)-induced denaturation. Because the azide and alkyne groups themselves are unreactive with protein residues or other biomolecules, their ligation is of potential utility as a general bioconjugation method.

Water, the medium of choice: Many reactions, such as Claisen rearrangements (see scheme), are dramatically accelerated when performed in aqueous suspension (“on water”) relative to organic solvents or even neat conditions. Low miscibility of organic compounds with water is not detrimental: in fact, it facilitates the isolation of products.