Topochemical Azide–Alkyne Cycloaddition Reaction

Abstract

Conspectus Topochemical reactions are solid-state reactions that transpire under the strict control of molecular packing in the crystal lattice. Due to this lattice control, these reactions generate products in a regio-/stereospecific manner and in very high yields. In a broader sense, topochemical reactions mimic nature’s way of carrying out reactions in a confined environment of enzymes giving specific products. Apart from their remarkable specificity, topochemical reactions have many other interesting features that make these reactions more attractive than solution-phase reactions. Solution-phase reactions necessitate the use of reactants, reagents, catalysts, and solvents and often give products along with varying amounts of byproducts, necessitating complex workup and chromatographic purification using various chemicals. These inevitable chemical wastes from solution-state reactions could be avoided by topochemical reactions, as they are solvent-free and catalyst-free and often do not require any chromatographic purification in view of their specificity and high yielding nature. Also the confinement offered by the crystal lattice gives products that are not possible by solution-phase reactions. Another interesting feature of topochemical reactions is the possibility of formation of products in an ordered (crystalline) form, which imparts interesting properties. Thus, topochemical reactions have control not only at the molecular level (regio-/stereospecificity) but also at the supramolecular level (packing). Many topochemical reactions happen in single-crystal-to-single-crystal (SCSC) fashion, and crystal structure analysis of such reactions often gives mechanistic insights and knowledge about the geometrical criteria required for the reaction. Despite all these attractive features, reactions that can be done topochemically are limited. There is tremendous interest in the development of new categories of topochemical reactions and strategies to achieve reactivity in crystals. In this Account, we will summarize our attempts to develop topochemical azide–alkyne cycloaddition (TAAC) reactions. We have used hydrogen-bonding as the main noncovalent interaction for aligning azide-and-alkyne-substituted derivatives of various biomolecules in orientations suitable for their proximity-driven cycloaddition reaction in crystals. Overall, three major classes of biomolecules; carbohydrates, nucleosides, and peptides were successfully exploited for their TAAC reactions using conventional O–H···O, N–H···O, and N–H···N hydrogen bonds as supramolecular glues for controlling their assembly in crystals. The crystals of these monomers underwent TAAC reaction either spontaneously at room temperature or under heating yielding triazole-linked biopolymer mimics. The ordered packing of product molecules imparted special properties to the products formed. The legendary “cream of the crop” azide–alkyne click reaction has diverse applications in the areas of bioconjugation, material science, polymer synthesis, and so forth. Belonging to...

Quantification of Noncovalent Interactions in Azide–Pnictogen, –Chalcogen, and –Halogen Contacts

“…Overall, considering the complexity of further decomposing single contributions to the interaction energy into specific parts of the molecular systems, the unbiased azide–X interaction is estimated to be 1.5 to 3.0 kcal mol −1 . We are convinced that these stabilizing interactions are of importance, not only for the arrangement of azide moieties in supramolecular assemblies and crystal engineering (e.g., click chemistry in the solid state), [81–85] but are also the basis for conformational bias in azido‐functionalized nucleic acids, peptides, proteins, and carbohydrates. Future investigations will reveal whether azido‐based interactions have a similar potential to facilitate catalysis, as has been extensively and successfully explored for halogen and chalcogen bonding.…”

Azide⋅⋅⋅Oxygen Interaction: A Crystal Engineering Tool for Conformational Locking

“…We have developed topochemical azide alkyne cycloaddition (TAAC) reaction wherein proximally placed azide and alkyne in the crystal lattice undergo 1,3-dipolar cycloaddition to yield 1,2,3triazoles in high yield and regiospecificity.W eh ave successfully employed this strategy for the synthesis of several biopolymer mimics. [14,15] As both reacting groups are not identical, head-to-tail arrangement of molecules in the crystal lattice is an important criterion for the TAAC reaction and to al arge extent, such designs are possible by judicious crystal engineering.L ike other topochemical reactions,f or proper orbital interaction, the reacting groups (azide and alkyne) need to be in parallel orientation (and short distance) for attaining at ransition state and thus to undergo the transformation.…”

Exfoliation of 2D Materials for Energy and Environmental Applications

“…Azide–alkyne 1,3‐dipolar cycloadditions have been applied to exfoliate graphene sheets from layered bulk graphite and then functionalize the basal plane of the nanosheets. The basal plane is typically inert, which has hindered its use in many practical applications.…”