certain characteristics: modularity insensitivity to solvent parameters high chemical yields insensitivity towards oxygen and water regiospecificity and stereospecificity a large thermodynamic driving force (>20 kcal/mol) to favor a reaction with a single reaction product. A distinct exothermic reaction makes a reactant "spring-loaded". The process would preferably: have simple reaction conditions use readily available starting materials and reagents use no solvent or use a solvent that is benign or easily removed (preferably water) provide simple product isolation by non-chromatographic methods (crystallisation or distillation) have high atom economy. Many of the click chemistry criteria are subjective, and even if measurable and objective criteria could be agreed upon, it is unlikely that any reaction will be perfect for every situation and application. However, several reactions have been identified that fit the concept better than others: [3+2] cycloadditions, such as the Huisgen 1,3-dipolar cycloaddition, in particular the Cu(I)-catalyzed stepwise variant, are often referred to simply as Click reactions Thiol-ene reaction Diels-Alder reaction and inverse electron demand Diels-Alder reaction [4+1] cycloadditions between isonitriles (isocyanides) and tetrazines nucleophilic substitution especially to small strained rings like epoxy and aziridines carbonyl-chemistry-like formation of ureas but not reactions of the aldol type due to low thermodynamic driving force. addition reactions to carbon-carbon double bonds like dihydroxylation or the alkynes in the thiol-yne reaction. Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) The classic click reaction is the copper-catalyzed reaction of an azide with an alkyne to form a 5-membered heteroatom ring: a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The first triazole synthesis, from diethyl acetylenedicarboxylate and phenyl azide, was reported by Arthur Michael in 1893. Later, in the middle of the 20th century, this family of 1,3-dipolar cycloadditions took on Rolf Huisgen's name after his studies of their reaction kinetics and conditions. The copper(I)-catalysis of the Huisgen 1,3-dipolar cycloaddition was discovered concurrently and independently by the groups of Valery V. Fokin and K. Barry Sharpless at the Scripps Research Institute in California and Morten Meldal in the Carlsberg Laboratory, Denmark. The copper-catalyzed version of this reaction gives only the 1,4-isomer, whereas Huisgen's non-catalyzed 1,3-dipolar cycloaddition gives both the 1,4- and 1,5-isomers, is slow, and requires a temperature of 100 degrees Celsius. Moreover, this copper-catalyzed "click" does not require ligands on the metal, although accelerating ligands such as tris(triazolyl)methyl amine ligands with various substituents have been reported and used with success in aqueous solution. Other ligands such as PPh3 and TBIA can also be used, even