Strain-promoted azide-alkyne cycloaddition (SPAAC)
As a prevalent click reaction, strain-promoted alkyne-azide cycloaddition (SPAAC) operates without the need for metal catalysts, reducing agents, or enduring ligands. Instead, it harnesses the enthalpy liberated from the inherent ring strain of cyclooctyne to facilitate the formation of stable triazoles.
Introduction
The Bertozzi research team expanded upon one of Huisgen's copper-free click reactions to address the cytotoxicity associated with the CuAAC reaction.[1] In lieu of employing Cu(I) for alkyne activation, they opted for a strained difluorooctyne (DIFO), where the electron-withdrawing gem-fluorines, located at the propargylic position, collaboratively with the ring strain, effectively destabilize the alkyne.[2] This heightened destabilization enhances the driving force of the reaction, intensifying the cycloalkyne's inclination to alleviate its inherent ring strain.
Fig 1.Scheme of the Strain-promoted Azide-Alkyne Cycloaddition
This reaction follows a concerted [3+2] cycloaddition to the triple bond within a cyclooctyne, employing a mechanism akin to the Huisgen 1,3-dipolar cycloaddition. The incorporation of substituents on the cyclooctyne, such as benzene rings, is also permissible.
SPAAC demonstrates efficient execution for several reasons. Firstly, the azide and alkyne substrates possess a notably high chemical potential energy, rendering them well-suited for the cycloaddition process. The generation of stable triazole during the reaction releases more than 188 kJ/mol of heat, fulfilling the prerequisite for reactants with high energy demands. Additionally, azides and alkynes exhibit reluctance to react with biomolecules under standard reaction conditions, remaining inert to most other reaction reagents and solvents. Furthermore, the small molecular weights and weak polarities of alkynyl and azide groups minimally influence the chemical properties of connected structures. This characteristic aligns with the selectivity requirements in various applications, such as biology and materials. Consequently, SPAAC capitalizes on the inherent high ring tension of cyclic alkynes, enabling a copper-catalyst-free click reaction with chemical regioselectivity.[3]
SPAAC emerges as a remarkably efficient bioorthogonal reaction suitable for application in biological systems. It exhibits robust activity and selectivity under biologically relevant conditions while maintaining inertness to acidic, oxidative environments, and active amino acid molecules. Nevertheless, it is noteworthy that this reaction necessitates a precise monomer structure, posing a challenge in terms of synthesis and preparation.
Application
Due to its benefits of gentle reaction conditions, simplicity, high efficiency, and biological orthogonality, SPAAC has gained widespread application in diverse fields, including biomedicine and chemical materials. This underscores its strong potential for future applications.
Pharmaceutical Field
SPAAC exhibits excellent regioselectivity. Notably, the directional binding process ensures the absence of impurities. The incorporation of low molecular weight azides and cycloalkynes into macromolecules does not compromise the effective energy expression of the macromolecules post-binding. Moreover, SPAAC offers the unique advantage of spontaneous occurrence under physiological conditions. Consequently, SPAAC serves as a guiding mechanism for specific binding in the medical field, establishing itself as a crucial tool. Beyond its pivotal role in the synthesis of targeted anticancer drugs and its use as a tracer in pathological research, SPAAC extends its applicability to the synthesis and delivery of conventional drugs. Furthermore, it plays a key role in the preparation of highly active radiopharmaceuticals.
Life Science
SPAAC demonstrates excellent bioorthogonality in the context of biomolecules. By eliminating the need for a copper catalyst, the introduction of azides and cycloalkynes alone does not introduce biological toxicity or compromise the efficiency of biomolecules. This capability facilitates the accomplishment of numerous syntheses and specific bindings that were challenging to achieve previously. Its remarkable biological orthogonal reactivity allows it to operate within living cells or tissues without disrupting essential biological processes. For instance, SPAAC enables the precise construction of a range of hydrogels with controllable viscoelasticity, stiffness, and degradation properties.
Material Science
The high efficiency and selectivity exhibited by SPAAC hold promising applications in the field of materials science. This remarkable feature finds utility in the fabrication of films, coatings, adhesives, functional polymers, and dendrimers, as well as in the surface modification and alteration of materials. As an illustration, the application of SPAAC in the interaction between azide-functionalized gold nanoclusters and cyclooctyne has introduced an innovative platform for modifying the surface of nanoclusters post-functional assembly.
Reference
1. Huisgen, R. Angew. Chem. Int. Ed. Engl. 1963, 2, 565
2. Agard, N. J.; Baskin, J. M.; Prescher, J. A.; Lo, A.; Bertozzi, C. R. (2006). "A Comparative Study of Bioorthogonal Reactions with Azides". ACS Chem. Biol. 1 (10): 644–648. https://doi.org/10.1021/cb6003228
3. Yiming Liao; et al. Strain-Promoted Azide-Alkyne Cycloaddition [J]. Progress in Chemistry. 2022, 1-16.